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Sample records for therapeutic drug monitoring

  1. Therapeutic drug monitoring: antiarrhythmic drugs

    OpenAIRE

    Campbell, T. J.; Williams, K. M.(Virginia Polytechnic Institute and State University, 24061, Blacksburg, VA, USA)

    1998-01-01

    Antiarrhythmic agents are traditionally classified according to Vaughan Williams into four classes of action. Class I antiarrhythmic agents include most of the drugs traditionally thought of as antiarrhythmics, and have as a common action, blockade of the fast-inward sodium channel on myocardium. These agents have a very significant toxicity, and while they are being used less, therapeutic drug monitoring (TDM) does significantly increase the safety with which they can be administered. Class ...

  2. Therapeutic drug monitoring: antiarrhythmic drugs

    Science.gov (United States)

    Campbell, T J; Williams, K M

    1998-01-01

    Antiarrhythmic agents are traditionally classified according to Vaughan Williams into four classes of action. Class I antiarrhythmic agents include most of the drugs traditionally thought of as antiarrhythmics, and have as a common action, blockade of the fast-inward sodium channel on myocardium. These agents have a very significant toxicity, and while they are being used less, therapeutic drug monitoring (TDM) does significantly increase the safety with which they can be administered. Class II agents are antisympathetic drugs, particularly the β-adrenoceptor blockers. These are generally safe agents which do not normally require TDM. Class III antiarrhythmic agents include sotalol and amiodarone. TDM can be useful in the case of amiodarone to monitor compliance and toxicity but is generally of little value for sotalol. Class IV antiarrhythmic drugs are the calcium channel blockers verapamil and diltiazem. These are normally monitored by haemodynamic effects, rather than using TDM. Other agents which do not fall neatly into the Vaughan Williams classification include digoxin and perhexiline. TDM is very useful for monitoring the administration (and particularly the safety) of both of these agents. PMID:9803978

  3. [Therapeutic drug monitoring of antimicrobials

    NARCIS (Netherlands)

    Mouton, J.W.; Aarnoutse, R.E.

    2014-01-01

    The importance of dose adjustments of antimicrobials based on measured concentrations in an individual ('therapeutic drug monitoring', TDM) is increasingly recognized. There are several reasons for this. First, there is a better understanding of the relationships between doses administered,

  4. Therapeutic drug monitoring, a practical application

    NARCIS (Netherlands)

    Kees Neef, C.; Touw, D.J.

    Therapeutic Drug Monitoring (TDM) is an indispensable tool in therapeutic handling and medication safety. A definition of TDM is: Therapeutic drug monitoring is a system of quality assurance of a drug management system, aiming that the right drug is given tot the right patient in the right dose in

  5. Therapeutic drug monitoring of aminoglycosides in neonates

    NARCIS (Netherlands)

    Touw, Daniël J; Westerman, Elsbeth M; Sprij, Arwen J

    2009-01-01

    The efficacy and toxicity of aminoglycosides show a strong direct positive relationship with blood drug concentrations, therefore, therapy with aminoglycosides in adults is usually guided by therapeutic drug monitoring. Dosing regimens in adults have evolved from multiple daily dosing to

  6. Therapeutic Drug Monitoring of Lithium

    DEFF Research Database (Denmark)

    Mose, Tina; Damkier, Per; Petersen, Magnus

    2015-01-01

    BACKGROUND: Serum lithium is monitored to ensure levels within the narrow therapeutic window. This study examines the interlaboratory variation and inaccuracy of lithium monitoring in Denmark. METHODS: In 16 samples consisting of (1) control materials (n = 4), (2) pooled patient serum (n = 5......), and (3) serum from individual patients (n = 7), lithium was measured in 19 laboratories using 20 different instruments. The lithium concentrations were targeted by a reference laboratory. Ion-selective electrode (n = 5), reflective spectrophotometric (RSM, n = 5), and spectrophotometric (n = 10) methods...... of >12%. Seven of these instruments had a systematic positive or negative bias and more so at lower lithium concentrations. Three poorly calibrated instruments were found in the ion-selective electrode group, 3 in the spectrophotometric group, and 2 in the RSM group. The instruments using reflectance...

  7. Antiretroviral therapeutic drug monitoring | Maartens | Southern ...

    African Journals Online (AJOL)

    Antiretroviral therapeutic drug monitoring (TDM) is an additional monitoring tool to assist in the management of HIV-infected patients. Antiretroviral TDM is frequently undertaken in Europe, but less often in the USA. This overview will assess the principles, current evidence for, and limitations of TDM. Lastly, the potential role ...

  8. Voriconazole therapeutic drug monitoring practices in the intensive care

    NARCIS (Netherlands)

    van Wanrooy, Marjolijn J. P.; Rodgers, Michael G. G.; Span, Lambert F. R.; Zijlstra, Jan G.; Uges, Donald R. A.; Kosterink, Jos G. W.; van der Werf, Tjip S.; Alffenaar, Jan-Willem C.

    BACKGROUND: Routine therapeutic drug monitoring of voriconazole appears to be beneficial. This study investigated the therapeutic drug monitoring practices in intensive care to derive possible recommendations for improvement. METHODS: A retrospective chart review was performed for patients aged ≥ 18

  9. Biosensing Technologies for Therapeutic Drug Monitoring.

    Science.gov (United States)

    Meneghello, Anna; Tartaggia, Stefano; Alvau, Maria Domenica; Polo, Federico; Toffoli, Giuseppe

    2017-07-20

    Therapeutic drug monitoring (TDM) is the clinical practice of measuring pharmaceutical drug concentrations in patients' biofluids at designated intervals to allow a close and timely control of their dosage. This practice allows for rapid medical intervention in case of toxicity-related issues and/or adjustment of dosage to better fit the therapeutic demand. Currently, TDM is performed in centralized laboratories employing instruments, such as immunoassay analyzers and mass spectrometers that can be run only by trained personnel. However the time required for the preparation, samples analysis, and data processing, together with the related financial cost, severely affects the application of TDM in medical practices. Therefore, a new generation of analytical tools is necessary to respond to the timely need of drug administration or reduction aiming at effectively treating oncologic patients. Technological advances in the field of nanosciences and biosensors offer the unique opportunity to address such issues. The interest for the so-called nanobiosensors is considerably increasing, particularly in drug discovery and clinical chemistry, even though there are only few examples reporting their use for TDM. The techniques employing nanobiosensors are mainly based on electrochemical, optical, and mass detection systems. In this review we described the most promising methodologies that, in our opinion, will bring TDM towards the next stage of clinical practice in the future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  10. [Therapeutic drug monitoring of primidone and phenobarbital].

    Science.gov (United States)

    Bentué-Ferrer, Danièle; Verdier, Marie-Clémence; Tribut, Olivier

    2012-01-01

    Primidone is a minor first-generation antiepileptic drug, little currently prescribed for this indication, but except marketing authorization, remains a first-line treatment of essential tremor. Although it is metabolized in phenyl-ethyl-malondamide and phenobarbital, active metabolites that contribute also to its action, primidone is not a prodrug and is active by itself. The rate of conversion of primidone to phenobarbital is highly variable according to the subject. Generally accepted therapeutic range for primidone is between 5 and 10 mg/L (23-46 mmol/L). The therapeutic drug monitoring (TDM) of primidone must be accompanied by the determination of phenobarbital concentrations. The level of proof of the interest of the TDM primidone was estimated to be "probably useless". Phenobarbital, a very ancient anticonvulsant, is much less used today, for the benefit of other more recent compounds. It remains prescribed in neonatology and is one of the compounds used in status epilepticus. It is a molecule with a long half-life, metabolized in p-hydroxy-phenobarbital. It is a potent inducer of CYP3A4. Several side effects, especially drowsiness, are concentration-dependent. Generally accepted therapeutic range for phenobarbital is between 10 and 40 mg/L (43 - 172 mmol/L), without considering the type of crise. The level of proof of the interest of TDM of phenobarbital was evaluated as "recommended". © 2012 Société Française de Pharmacologie et de Thérapeutique.

  11. Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

    Directory of Open Access Journals (Sweden)

    Matthew D. Krasowski

    2010-06-01

    Full Text Available In the past twenty years, 14 new antiepileptic drugs have been approved for use in the United States and/or Europe. These drugs are eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. In general, the clinical utility of therapeutic drug monitoring has not been established in clinical trials for these new anticonvulsants, and clear guidelines for drug monitoring have yet to be defined. The antiepileptic drugs with the strongest justifications for drug monitoring are lamotrigine, oxcarbazepine, stiripentol, and zonisamide. Stiripentol and tiagabine are strongly protein bound and are candidates for free drug monitoring. Therapeutic drug monitoring has lower utility for gabapentin, pregabalin, and vigabatrin. Measurement of salivary drug concentrations has potential utility for therapeutic drug monitoring of lamotrigine, levetiracetam, and topiramate. Therapeutic drug monitoring of the new antiepileptic drugs will be discussed in managing patients with epilepsy.

  12. Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications

    Science.gov (United States)

    Krasowski, Matthew D.

    2010-01-01

    In the past twenty years, 14 new antiepileptic drugs have been approved for use in the United States and/or Europe. These drugs are eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin and zonisamide. In general, the clinical utility of therapeutic drug monitoring has not been established in clinical trials for these new anticonvulsants, and clear guidelines for drug monitoring have yet to be defined. The antiepileptic drugs with the strongest justifications for drug monitoring are lamotrigine, oxcarbazepine, stiripentol, and zonisamide. Stiripentol and tiagabine are strongly protein bound and are candidates for free drug monitoring. Therapeutic drug monitoring has lower utility for gabapentin, pregabalin, and vigabatrin. Measurement of salivary drug concentrations has potential utility for therapeutic drug monitoring of lamotrigine, levetiracetam, and topiramate. Therapeutic drug monitoring of the new antiepileptic drugs will be discussed in managing patients with epilepsy. PMID:20640233

  13. Evaluation of theophylline therapeutic drug monitoring service

    Directory of Open Access Journals (Sweden)

    Neža Rugelj

    2015-05-01

    Full Text Available BackgroundTherapeutic monitoring of theophylline serum levels is required due to its narrow therapeutic range and marked interindividual pharmacokinetic variability. We evaluated therapeutic drug monitoring service for theophylline in Slovenian clinical setting, which currently includes no pharmacokinetic evaluation of measured theophylline serum concentrations. MethodsWe  retrospectively evaluated 127 randomly selected theophylline serum level determinations performed in 2010 in a tertiary clinical setting in Slovenia. Demographic data, information on theophylline dosing and blood sampling was collected from patients’ data files. Authors evaluated the appropriateness of the following procedures: indications for theophylline serum concentration measurement, timing of blood sampling and dosage adjustments made after theophylline levels had been reported. On the basis of collected data, population pharmacokinetic model for theophylline was built and further used for the evaluation of dosage adjustments. ResultsOut of 127 cases, 107 (84.3% had clinically justified indication for theophylline serum level measurement. Near half of measurements (44.9% were performed before the steady state of theophylline concentrations was established. 65% of measured concentrations were subtherapeutic and the average measured concentration was below therapeutic range (53.1 μmol/L. Despite subtherapeutic concentrations the dose of theophylline was mainly not increased. Pharmacokinetic model enabled the calculation of average optimal daily dose which was significantly higher than the average actual daily dose used (876 mg vs. 572 mg, p < 0.001. ConclusionsTheophylline TDM service should be optimized and pharmacokinetic interpretation of theophylline serum levels should be integrated into clinical practice.

  14. Therapeutic drug monitoring of lopinavir/ritonavir in pregnancy.

    LENUS (Irish Health Repository)

    Lambert, J S

    2011-03-01

    The aim of the study was to determine total and unbound lopinavir (LPV) plasma concentrations in HIV-infected pregnant women receiving lopinavir\\/ritonavir (LPV\\/r tablet) undergoing therapeutic drug monitoring (TDM) during pregnancy and postpartum.

  15. Zin en onzin van bloedspiegelbepalingen : Therapeutic drug monitoring bij ouderen

    NARCIS (Netherlands)

    Touw, D.J.; Edelbroek, P.M.; De Vries, O.J.

    2000-01-01

    The goal of therapeutic drug monitoring (TDM) is to maximise the effect of drug therapy and to minimise toxicity. TDM is meaningful if on the one hand there is a relationship between the serum concentration of the drug and its effect and on the other hand there is no obvious relationship between

  16. Therapeutic drug monitoring and drug-drug interactions involving antiretroviral drugs.

    NARCIS (Netherlands)

    Boffito, M.; Acosta, E.; Burger, D.M.; Fletcher, C.V.; Flexner, C.; Garaffo, R.; Gatti, G.; Kurowski, M.; Perno, C.F.; Peytavin, G.; Regazzi, M.; Back, D.

    2005-01-01

    The consensus of current international guidelines for the treatment of HIV infection is that data on therapeutic drug monitoring (TDM) of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pls) provide a framework for the implementation of TDM in certain defined

  17. Nanosensors for early cancer detection and for therapeutic drug monitoring.

    Science.gov (United States)

    Salvati, Elisa; Stellacci, Francesco; Krol, Silke

    2015-01-01

    The use of nanotechnology for drug delivery in cancer therapy has raised high expectations. Additionally, the use of nanomaterials in sensors to extract and detect tumor specific biomarkers, circulating tumor cells, or extracellular vesicles shed by the tumor holds the promise to detect cancer much earlier and hence improve long-term survival of the patients. Moreover, the monitoring of the anticancer drug concentration, which has a narrow therapeutic window, will allow for a personalized dosing of the drug and will lead to improved therapeutic outcome and life quality of the patient. This review will provide an overview on the use of nanosensors for the early diagnosis of cancer and for the therapeutic drug monitoring, giving some examples. We envision nanosensors to make significant improvements in the cancer management as easy-to-use point-of-care devices for a broad population of users.

  18. Therapeutic drug monitoring in clinical research

    NARCIS (Netherlands)

    Neef, Cees; Touw, Daniel J.; Stolk, Leo M.

    2008-01-01

    The development of a new drug is characterized by distinct developmental stages, usually described as phases I to IV. Dose tolerance and dose response exploration studies are undertaken in phase II or III. Pharmacokinetic studies are often involved in these phases, but frequently only as an

  19. Optimal experimental design and therapeutic drug monitoring.

    Science.gov (United States)

    Kulcsár, C; Pronzato, L; Walter, E

    1994-06-01

    A simple example of intravenous theophylline therapy is used to present and compare various drug administration policies based on stochastic control theory. The simplest approach (Heuristic-Certainty-Equivalence (HCE) control) assumes that the model parameters are known. Prior uncertainty on these parameters can be taken into account by using average optimal (AO) control. The available knowledge about the system can be improved by measuring the drug concentration some time after the beginning of the treatment. This corresponds to the notion of feedback and leads to the HCE feedback (HCEF) and AO feedback (AOF) policies. A further step towards optimality consists in choosing the optimal measurement time given that the final purpose is the control of the system and not the estimation of its parameters. Finally, closed-loop optimal (CLO) control optimally chooses both the dosage regimen and measurement time.

  20. Therapeutic drug monitoring of atazanavir/ritonavir in pregnancy.

    LENUS (Irish Health Repository)

    Else, L J

    2014-11-01

    Pregnant women experience physiological changes during pregnancy that can have a significant impact on antiretroviral pharmacokinetics. Ensuring optimal plasma concentrations of antiretrovirals is essential for maternal health and to minimize the risk of vertical transmission. Here we describe atazanavir\\/ritonavir (ATV\\/r) plasma concentrations in a cohort of pregnant women undergoing routine therapeutic drug monitoring (TDM).

  1. Therapeutic Drug Monitoring of Venlafaxine in an Everyday Clinical Setting

    DEFF Research Database (Denmark)

    Hansen, Morten Rix; Kuhlmann, Ida Berglund; Pottegård, Anton

    2017-01-01

    Venlafaxine is a commonly used antidepressant agent. We aimed to provide detailed information on the associations between venlafaxine dose and concentrations of venlafaxine, by patient age and sex. From a therapeutic drug monitoring (TDM) database located at Odense University Hospital, Denmark, we...

  2. Is there a role for therapeutic drug monitoring with codeine?

    Science.gov (United States)

    Kelly, Lauren E; Madadi, Parvaz

    2012-06-01

    Codeine is an old and commonly used analgesic agent for mild to moderate pain. It is the prototypical "prodrug" in that its analgesic effect is almost wholly dependent on its biotransformation to morphine, a process that is mediated by the polymorphic cytochrome P450 2D6 enzyme. As such, interindividual variability in codeine metabolism and response is a clinical reality, and there has been much progress in characterizing the genetic causes of this variability in diverse populations. Yet despite the potential for both life-threatening adverse reactions and lack of therapeutic effect, codeine is not commonly indicated for therapeutic drug monitoring. This review will discuss the relative role of pharmacogenetics and therapeutic drug monitoring in predicting and/or maintaining adequate and safe analgesia with codeine. The review will end on a discussion of how the marriage of these 2 fields may provide new insights into the mechanisms of codeine-induced toxicity and analgesia.

  3. Voriconazole Therapeutic Drug Monitoring Practices in Intensive Care.

    Science.gov (United States)

    van Wanrooy, Marjolijn J P; Rodgers, Michael G G; Span, Lambert F R; Zijlstra, Jan G; Uges, Donald R A; Kosterink, Jos G W; van der Werf, Tjip S; Alffenaar, Jan-Willem C

    2016-06-01

    Routine therapeutic drug monitoring of voriconazole seems to be beneficial. This study investigated the therapeutic drug monitoring practices in intensive care to derive possible recommendations for improvement. A retrospective chart review was performed for patients aged ≥18 years who started treatment with voriconazole, which lasted for at least 3 days while being admitted to an intensive care unit to assess possible differences between the patients with and without voriconazole trough concentrations measured. In 64 (76%) of the 84 patients, voriconazole trough concentrations were measured. The groups differed significantly with respect to the duration of voriconazole treatment and intensive care unit admission. Time of sampling was very early and therefore inappropriate for 49% of the first measured voriconazole trough concentrations and in 48% of the subsequent measured concentrations. Of the 349 trough concentrations measured, 129 (37%) were outside the therapeutic window. In 11% of these cases, no recommendation was provided without identifiable reason. In addition, 27% of recommended dose adjustments were not implemented, probably because the advice was not suited for the specific clinical situation. The performance of voriconazole therapeutic drug monitoring can still be improved although voriconazole concentrations were monitored in most patients. A multidisciplinary approach-for instance by means of antifungal stewardship-will probably be able to overcome problems encountered such as timing of sampling, incompleteness of data in clinical context, and lack of implementation of recommendations.

  4. Therapeutic drug monitoring and methods of quantitation for carbamazepine

    Directory of Open Access Journals (Sweden)

    Cristian Tuchila

    2017-10-01

    Full Text Available Carbamazepine is an early anticonvulsant still used today in the treatment of several forms of epilepsy. An active metabolite in the human body contributes to its pharmacological effect. Carbamazepine metabolism has high inter-individual variability, such that it is relatively difficult to establish a direct link between dose and concentration, or between concentration and pharmacological effect. Carbamazepine is thus a good candidate for therapeutic drug monitoring (TDM. Good UV specific absorbance and high plasmatic concentrations allow for the use of UV detection, which is often more accessible than other methods of detection. This paper presents several methods used for the detection of carbamazepine in plasma, methods that are capable of detecting drug and metabolites at adequate levels/ acceptance criteria. These methods have possible application not only in pharmacokinetic, bioequivalence, and permeability studies, but also in the therapeutic drug monitoring of carbamazepine.

  5. [Therapeutic drug monitoring of three antiepileptic drugs - Back on twenty years of experience].

    Science.gov (United States)

    Serragui, Samira; Zalagh, Fatima; Tanani, Driss Soussi; Ouammi, Lahcen; Moussa, Latifa Ait; Badrane, Narjis; Bencheikh, Rachida Soulaymani

    2016-01-01

    The therapeutic drug monitoring (TDM) of antiepileptic drugs is a tool widely used in the management of epilepsy. In Morocco, this monitoring is carried out by the Centre Anti Poison et Pharmacovigilance (CAPM) since April 1995. This is a retrospective study spanning 20 years. It concerns the therapeutic drug monitoring of Phenobarbital (PB) of carbamazepine (CBZ) and valproic acid (VPA). Therapeutic drug monitoring of the 3 antiepileptic drugs represent 58.85% of all applications received by the CAPM. The dosage of PB was ranked first followed by that of CBZ and finally by the VPA. Weak demand for therapeutic drug monitoring in Morocco could be explained by the low number of neurologists in addition to social factors. With its affordable price by patients, PB is the most prescribed antiepileptic drug in our country, which explains the high demand for its dosage. As for the therapeutic drug monitoring of the antiepileptic drug, they were mainly related to age, the occurrence of adverse effects, the association antiepileptic drugs or in the case of verification of patient compliance. Efforts are required for promoting the interests of therapeutic drug monitoring of antiepileptic drug in the management of epilepsy in Morocco.

  6. Therapeutic drug monitoring in voriconazole-associated hyponatremia

    OpenAIRE

    Xu, Ren-ai; Zheng, Shuang-li; Xiao, Li-li; Cai, Xue-ding; Lai, Xi-xi; Lin, Guan-yang; Hu, Lu-feng; Zhang, Chun-hong; Xu, Zhi-sheng; Zhang, Xiu-hua

    2013-01-01

    Voriconazole is a second generation triazole antifungal agent and the first choice therapy for invasive aspergillosis (IA). Although voriconazole may be associated with many adverse events, hyponatremia has been rarely reported which potentially could result in death. Therapeutic drug monitoring (TDM) and individualization of therapy by measuring voriconazole plasma concentrations improved the efficacy and safety in patients. We report the effect of TDM to adjust voriconazole dosage in a vori...

  7. Therapeutic drug monitoring for imatinib: Current status and Indian experience.

    Science.gov (United States)

    Arora, Brijesh; Gota, Vikram; Menon, Hari; Sengar, Manju; Nair, Reena; Patial, Pankaj; Banavali, S D

    2013-07-01

    Imatinib is the current gold standard for treatment of chronic myeloid leukemia (CML). Recent pharmacokinetic studies have shown considerable variability in trough concentrations of imatinib due to variations in its metabolism, poor compliance, or drug-drug interactions and highlighted its impact on clinical response. A trough level close to 1000 ng/mL, appears to be correlated with better cytogenetic and molecular responses. Therapeutic Drug Monitoring (TDM) for imatinib may provide useful added information on efficacy, safety and compliance than clinical assessment alone and help in clinical decision making. It may be particularly helpful in patients with suboptimal response to treatment or treatment failure, severe or rare adverse events, possible drug interactions, or suspected nonadherence. Further prospective studies are needed to confirm relationship between imatinib plasma concentrations with response, and to define effective plasma concentrations in different patient populations.

  8. Methods of theophylline assay and therapeutic monitoring of this drug.

    Science.gov (United States)

    Mounié, J; Richard, L; Ribon, B; Hersant, J; Sarmini, H; Houin, G; Mouine, J

    1990-01-01

    The purpose of this article is to review various analytical methods of monitoring plasma theophylline. This article was investigated by the "Drug Commission" of SFBC (Société Française de Biologie Clinique). The primary objective is to provide the "know-how", particular for this analysis, which allows the choice between various analytical methods available: immunochemical or physiochemical ones. The techniques described are not necessarily the best, they are approved and tested methods which are the most frequently used in routine practice. The proposed immunochemical methods are: absorption spectroscopy methods: Enzyme ImmunoAssay (EIA), Enzyme Multiplied ImmunoAssay Technique (EMIT); Reflectance spectroscopy method: Apoenzyme Reactivation Immunoassay System (ARIS); Fluorometry spectroscopy method: Substrate Labeled FluoroImmunoAssay (SLFIA); Fluorometry spectroscopy on solid base; Polarization fluorescence spectroscopy ImmunoAssay (FPIA); Turbidimetric measurements: Particle Enhanced Turbidimetric Inhibition ImmunoAssay (PETINIA); Nephelometric measurement: Nephelometric Inhibition ImmunoAssay (NIIA). And the proposed physicochemical methods are: High Performance Liquid Chromatography (HPLC), Gas Chromatography (GC). The second objective is a review of pharmacological properties of theophylline, necessary for a good understanding of therapeutic drug monitoring: intestinal resorption, distribution, metabolism and elimination, drug interactions, dose/response relationship, physiopathological variations and proposed "predictive" "theophylline test". The authors conclude that because of the multiplicity of methodologies used in theophylline therapeutic monitoring the choice of one of them is not easy. The best way to compare different techniques available would be the use of a "reference material" for theophylline monitoring and a quality control network between different clinical pharmacological laboratories.

  9. Multicenter Study of Voriconazole Pharmacokinetics and Therapeutic Drug Monitoring

    Science.gov (United States)

    Dolton, Michael J.; Ray, John E.; Chen, Sharon C.-A.; Ng, Kingsley; Pont, Lisa G.

    2012-01-01

    Voriconazole is a first-line agent in the treatment of many invasive fungal infections and is known to display highly variable pharmacokinetics. Previous studies of voriconazole therapeutic drug monitoring (TDM) have suggested concentration monitoring to be clinically useful but have been limited by small patient samples at a single institution. This multicenter retrospective study aimed to investigate relationships between voriconazole concentration and clinical outcomes and adverse events and to assess clinical factors and drug interactions that may affect voriconazole concentration. Medical records were reviewed for patients who received voriconazole and had at least 1 concentration measured at seven hospitals in Australia. The study included 201 patients with 783 voriconazole trough concentrations. Voriconazole concentrations of voriconazole concentrations of >5 mg/liter (10/31 patients [32%]) than at concentrations of ≤5 mg/liter (2/170 patients [1.2%]) (P voriconazole concentration identified associations between increasing patient weight, oral administration of voriconazole, and coadministration of phenytoin or rifampin and significantly reduced concentrations, and associations between increasing patient age and coadministration of proton pump inhibitors and increased concentrations. Coadministration of glucocorticoids was found to significantly reduce voriconazole concentrations, inferring a previously unreported drug interaction between glucocorticoids and voriconazole. PMID:22751544

  10. Utility of voriconazole therapeutic drug monitoring: a meta-analysis.

    Science.gov (United States)

    Luong, Me-Linh; Al-Dabbagh, Mona; Groll, Andreas H; Racil, Zdenek; Nannya, Yasuhito; Mitsani, Dimitra; Husain, Shahid

    2016-07-01

    Voriconazole therapeutic drug monitoring (TDM) is increasingly used in clinical practice. However, the utility of voriconazole TDM to guide therapy remains uncertain and controversial. We conducted a meta-analysis of studies assessing the relationship between voriconazole serum concentration and clinical outcomes of success and toxicity. We searched bibliographic databases for studies on voriconazole serum concentrations and clinical outcomes. We compared success outcomes between patients with therapeutic and subtherapeutic voriconazole serum concentrations, and toxicity outcomes between patients with and without supratherapeutic serum concentrations. Twenty-four studies were analysed. Pooled analysis for efficacy endpoint demonstrated that patients with therapeutic voriconazole serum concentrations (1.0-2.2 mg/L) were more likely to have successful outcomes compared with those with subtherapeutic voriconazole serum concentrations (OR 2.30; 95% CI 1.39-3.81). A therapeutic threshold of 1.0 mg/L was most predictive of successful outcome (OR 1.94; 95% CI 1.04-3.62). Patients with therapeutic concentrations did not have better survival rates. Pooled analysis for toxicity endpoint demonstrated that patients with supratherapeutic voriconazole serum concentrations (4.0-6.0 mg/L) were at increased risk of toxicity (OR 4.17; 95% CI 2.08-8.36). A supratherapeutic threshold of 6.0 mg/L was most predictive of toxicity (OR 4.60; 95% CI 1.49-14.16). Patients with therapeutic voriconazole serum concentrations were twice as likely to achieve successful outcomes. The likelihood of toxicity associated with supratherapeutic voriconazole serum concentrations was 4-fold that of therapeutic concentrations. Our findings suggest that the use of voriconazole TDM to aim for serum concentrations between 1.0 and 6.0 mg/L during therapy may be warranted to optimize clinical success and minimize toxicity. © The Author 2016. Published by Oxford University Press on behalf of the British Society

  11. Therapeutic drug monitoring of antiretroviral drugs in HIV-infected patients

    NARCIS (Netherlands)

    Punyawudho, B.; Singkham, N.; Thammajaruk, N.; Dalodom, T.; Kerr, S.J.; Burger, D.M.; Ruxrungtham, K.

    2016-01-01

    INTRODUCTION: Therapeutic drug monitoring (TDM) may be beneficial when applied to antiretroviral (ARV). Even though TDM can be a valuable strategy in HIV management, its role remains controversial. Areas covered: This review provides a comprehensive update on important issues relating to TDM of ARV

  12. Therapeutic drug monitoring of lopinavir/ritonavir in pregnancy.

    LENUS (Irish Health Repository)

    Lambert, J S

    2012-02-01

    OBJECTIVES: The aim of the study was to determine total and unbound lopinavir (LPV) plasma concentrations in HIV-infected pregnant women receiving lopinavir\\/ritonavir (LPV\\/r tablet) undergoing therapeutic drug monitoring (TDM) during pregnancy and postpartum. METHODS: Women were enrolled in the study who were receiving the LPV\\/r tablet as part of their routine prenatal care. Demographic and clinical data were collected and LPV plasma (total) and ultrafiltrate (unbound) concentrations were determined in the first, second and third trimesters using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS\\/MS). Postpartum sampling was performed where applicable. Antepartum and postpartum trough concentrations (C(trough) ) were compared independently [using analysis of variance (anova)] and on a longitudinal basis (using a paired t-test). RESULTS: Forty-six women were enrolled in the study (38 Black African). Forty women initiated LPV\\/r treatment in pregnancy. Median (range) gestation at initiation was 25 (15-36) weeks and median (range) baseline CD4 count and viral load were 346 (14-836) cells\\/muL and 8724 (<50-267408) HIV-1 RNA copies\\/mL, respectively. Forty women (87%) had LPV concentrations above the accepted minimum effective concentration for wild-type virus (MEC; 1000 ng\\/mL). Geometric mean (95% confidence interval [CI]) total LPV concentrations in the first\\/second [3525 (2823-4227) ng\\/mL; n=16] and third [3346 (2813-3880) ng\\/mL; n=43] trimesters were significantly lower relative to postpartum [5136 (3693-6579) ng\\/mL; n=12] (P=0.006). In a paired analysis (n=12), LPV concentrations were reduced in the third trimester [3657 (2851-4463) ng\\/mL] vs. postpartum (P=0.021). No significant differences were observed in the LPV fraction unbound (fu%). Conclusions The above target concentrations achieved in the majority of women and similarities in the fu% suggest standard dosing of the LPV\\/r tablet is appropriate during pregnancy

  13. Therapeutic drug monitoring: how to improve drug dosage and patient safety in tuberculosis treatment

    Directory of Open Access Journals (Sweden)

    Giovanni Sotgiu

    2015-03-01

    Full Text Available In this article we describe the key role of tuberculosis (TB treatment, the challenges (mainly the emergence of drug resistance, and the opportunities represented by the correct approach to drug dosage, based on the existing control and elimination strategies. In this context, the role and contribution of therapeutic drug monitoring (TDM is discussed in detail. Treatment success in multidrug-resistant (MDR TB cases is low (62%, with 7% failing or relapsing and 9% dying and in extensively drug-resistant (XDR TB cases is even lower (40%, with 22% failing or relapsing and 15% dying. The treatment of drug-resistant TB is also more expensive (exceeding €50 000 for MDR-TB and €160 000 for XDR-TB and more toxic if compared to that prescribed for drug-susceptible TB. Appropriate dosing of first- and second-line anti-TB drugs can improve the patient's prognosis and lower treatment costs. TDM is based on the measurement of drug concentrations in blood samples collected at appropriate times and subsequent dose adjustment according to the target concentration. The ‘dried blood spot’ technique offers additional advantages, providing the rationale for discussions regarding a possible future network of selected, quality-controlled reference laboratories for the processing of dried blood spots of difficult-to-treat patients from reference TB clinics around the world.

  14. Impact of Laboratory Practices on Interlaboratory Variability in Therapeutic Drug Monitoring of Immunosuppressive Drugs.

    Science.gov (United States)

    Christians, Uwe; Vinks, Alexander A; Langman, Loralie J; Clarke, William; Wallemacq, Pierre; van Gelder, Teun; Renjen, Varun; Marquet, Pierre; Meyer, Eric J

    2015-12-01

    The immunosuppressants cyclosporine, tacrolimus, sirolimus, everolimus, and probably also mycophenolic acid require therapeutic drug monitoring (TDM)-guided dosing to ensure that blood concentrations are kept within the target range in transplant patients. Reliable, accurate, and precise test methods are therefore essential to effectively monitor levels and to make proper dose adjustments. Data from proficiency testing programs have shown substantial interlaboratory variability. Only few attempts have been made to study the underlying causes. The aim of this study was to systematically document current practices used for immunosuppressant drug TDM in clinical laboratories and identify methodological and practice differences, which may cause the variability observed among laboratories. Data collection was primarily conducted by a structured Web-based survey. Invitations to participate in the survey were distributed to clinical laboratories providing immunosuppressant drug TDM. Surveys were completed by 76 laboratories in 14 countries. The results of our survey suggest that there are 3 main reasons for interlaboratory variability: (1) lack of standardization of laboratory procedures and workflows starting with sample collection and handling, (2) lack of use of appropriate reference materials (eg, isotope-labeled internal standards for liquid chromatography-tandem mass spectroscopy), and (3) poor compliance with internationally accepted good laboratory practice guidelines (eg, related to quality control, quality assurance, validation, training of personnel). The results of the survey also suggest that interlaboratory variability is a multifactorial problem. Technical-level consensus on laboratory operational procedures, quality systems, and personnel training will be of great importance to improve quality and interlaboratory comparability.

  15. Variability in the pharmacokinetics of mycophenolic acid: Implications for therapeutic drug monitoring

    NARCIS (Netherlands)

    B.C.M. de Winter (Brenda)

    2010-01-01

    textabstractMycophenolate mofetil (MMF) is an immunosuppressive drug used to prevent rejection following solid organ transplantation. MMF was introduced in 1995 with a recommended fixed-dose regimen of 1 g twice daily. Nowadays, dose individualization using therapeutic drug monitoring (TDM) of the

  16. Therapeutic drug monitoring (TDM of atazanavir in pregnancy

    Directory of Open Access Journals (Sweden)

    S Khoo

    2012-11-01

    Full Text Available Purpose of the study: Pregnant women experience physiological changes during pregnancy resulting in clinically significant alterations in antiretroviral pharmacokinetics (PK. Therefore, achieving and maintaining optimal plasma concentrations of antiretroviral drugs is essential for maternal health and minimising the risk of mother-to-child transmission of HIV. The aim of this study is to describe atazanavir/ritonavir (ATV/r PK during pregnancy. Methods: Pregnant HIV-positive women received ATV/r as part of their routine pre-natal care. Demographic and clinical data were collected, and ATV plasma concentrations [ATV] were determined in the first (T1, second (T2 and third (T3 trimester using HPLC-MS/MS (LLQ=0.05 µg/mL. Postpartum (PP sampling was performed where applicable. Antepartum (AP and PP PK parameters were compared using a one-way ANOVA. Summary of results: From January 2007, 44 women (37 black African were enrolled in the study. All received ATV/r at a standard dose of 1 tablet once daily (300/100 mg od. 24 women were receiving ART prior to pregnancy, and 20 women initiated ATV/r during pregnancy. Median (range gestation at treatment initiation in these patients was 23.5 weeks (7–35. At the time nearest to delivery 31 patients had an undetectable plasma viral load (pVL, 6 patients had detectable pVL and 2 were unavailable. [ATV] were determined in 11/44 (T1; 25/44 (T2; 35/44 (T3 and 28/44 (PP patients. Time of TDM sampling, gestation time and [ATV] (geometric mean; 95% CI are given in the Table. 6 patients were either below or approaching the ATV MEC (0.15 µg/mL during pregnancy; of these, 4/6 achieved undetectable pVL at the time of delivery (1=pVL of 291 copies/mL; 1 unavailable. [ATV] were significantly lower at T2/T3 relative to T1/PP. Equally, in a paired analysis of 28 patients (T2/T3 vs. PP, [ATV] were significantly reduced at T2/T3 (P=0.003. Conclusions: This study represents one of the larger cohorts of women undergoing TDM

  17. On the slow diffusion of Point of Care systems in Therapeutic Drug Monitoring

    Directory of Open Access Journals (Sweden)

    Barbara eSanavio

    2015-02-01

    Full Text Available Recent advancements in point-of-care technologies show great transformative promises for personalized preventative and predictive medicine. However, fields like therapeutic drug monitoring, that first allowed for personalized treatment of patient’ disease, still lag behind in the widespread application of point-of-care devices for monitoring of patients. Surprisingly, very few applications in commonly monitored drugs, such as anti-epileptics, are paving the way for a point of care (PoC approach to patient’ therapy monitoring, compared to other fields –like intensive care cardiac markers monitoring, glycemic controls in diabetes, or bench-top hematological parameters analysis at the local drug store. Such delay in the development of portable fast clinically effective drug monitoring devices is in our opinion due more to an inertial drag on the pervasiveness of these new devices into the clinical field than a lack of technical capability. At the same time, some very promising technologies failed in the clinical practice for inadequate understanding of the outcome parameters necessary for a relevant technological breakthrough that has superior clinical performance. We hope, by overviewing both therapeutic drug monitoring practice and its yet unmet needs and latest advancement in micro and nanotechnology applications to PoC clinical devices, to help bridging the two communities, the one exploiting analytical technologies and the one mastering the most advanced techniques, into translating existing and forthcoming technologies in effective devices.

  18. The significance of sampling time in therapeutic drug monitoring of clozapine

    DEFF Research Database (Denmark)

    Jakobsen, M I; Larsen, J R; Svensson, C K

    2017-01-01

    OBJECTIVE: Therapeutic drug monitoring (TDM) of clozapine is standardized to 12-h postdose samplings. In clinical settings, sampling time often deviates from this time point, although the importance of the deviation is unknown. To this end, serum concentrations (s-) of clozapine and its metabolite...

  19. The AGNP-TDM expert group consensus guidelines: therapeutic drug monitoring in psychiatry.

    Science.gov (United States)

    Baumann, P; Hiemke, C; Ulrich, S; Eckermann, G; Gaertner, I; Gerlach, M; Kuss, H-J; Laux, G; Müller-Oerlinghausen, B; Rao, M L; Riederer, P; Zernig, G

    2004-11-01

    Therapeutic Drug Monitoring (TDM) is a valid tool to optimise pharmacotherapy. It enables the clinician to adjust the dosage of drugs according to the characteristics of the individual patient. In psychiatry, TDM is an established procedure for lithium, some antidepressants and antipsychotics. In spite of its obvious advantages, however, the use of TDM in everyday clinical practice is far from optimal. The interdisciplinary TDM group of the Arbeitsgemeinschaft fur Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has therefore worked out consensus guidelines to assist psychiatrists and laboratories involved in psychotropic drug analysis to optimise the use of TDM of psychotropic drugs. Five research-based levels of recommendation were defined with regard to routine monitoring of plasma concentrations for dose titration of 65 psychoactive drugs: (1) strongly recommended, (2) recommended, (3) useful, (4) probably useful and (5) not recommended. A second approach defined indications to use TDM, e. g. control of compliance, lack of clinical response or adverse effects at recommended doses, drug interactions, pharmacovigilance programs, presence of a genetic particularity concerning the drug metabolism, children, adolescents and elderly patients. Indications for TDM are relevant for all drugs either with or without validated therapeutic ranges. When studies on therapeutic ranges are lacking, target ranges should be plasma concentrations that are normally observed at therapeutic doses of the drug. Therapeutic ranges of plasma concentrations that are considered to be optimal for treatment are proposed for those drugs, for which the evaluation of the literature demonstrated strong evidence. Moreover, situations are defined when pharmacogenetic (phenotyping or genotyping) tests are informative in addition to TDM. Finally, practical instructions are given how to use TDM. They consider preparation of TDM, analytical procedures, reporting and interpretation of results

  20. Amiodarone Rifampicin Drug-Drug Interaction Management with Therapeutic Drug Monitoring.

    Science.gov (United States)

    Oude Munnink, Thijs H; Demmer, Anna; Slenter, Roel H J; Movig, Kris L L

    2018-02-20

    The authors present a case of a 69-year-old man with arrhythmogenic right ventricular cardiomyopathy controlled with amiodarone and an infected orthopedic prosthesis requiring treatment with rifampicin. This combination involves a pharmacokinetic drug-drug interaction leading to subtherapeutic drug concentrations of amiodarone and its active metabolite. The long half-life of amiodarone and its active metabolite in combination with the late onset and offset of cytochrome P4503A (CYP3A4) induction by rifampicin makes this a challenging drug-drug interaction to cope with in clinical practice. Before, during, and after rifampicin treatment, the serum concentrations of amiodarone and its active metabolite were measured and the amiodarone dose was adjusted accordingly. The amiodarone dose required to maintain effective concentrations was 450% of the initial dose. The drug-drug interaction between amiodarone and rifampicin is relevant, both clinically and pharmacokinetically, and can be managed by dose adjustments of amiodarone based on serum concentrations.

  1. Update zum Therapeutic Drug Monitoring und zu pharmakogenetischen Untersuchungen zur Optimierung der Therapie mit Psychopharmaka

    OpenAIRE

    Rentsch, Katharina M.

    2017-01-01

    Das Therapeutic Drug Monitoring von Psychopharmaka wird in zahlreichen Laboratorien immer häufiger durchgeführt, ebenso wie pharmakogenetische Untersuchungen. In diesem Übersichtsartikel wurde die dazugehörige Literatur aus den Jahren 2011 und 2012 zusammengefasst. Die Guidelines der AGNP enthalten alle wichtigen Informationen, die notwendig sind, um Konzentrationen von Psychopharmaka richtig zu interpretieren. Die Bestimmung von Serotonin im Urin könnte ein Marker zur Beurteilung des Therapi...

  2. Antiretroviral Drug Interactions: Overview of Interactions Involving New and Investigational Agents and the Role of Therapeutic Drug Monitoring for Management

    Directory of Open Access Journals (Sweden)

    R. Chris Rathbun

    2011-10-01

    Full Text Available Antiretrovirals are prone to drug-drug and drug-food interactions that can result in subtherapeutic or supratherapeutic concentrations. Interactions between antiretrovirals and medications for other diseases are common due to shared metabolism through cytochrome P450 (CYP450 and uridine diphosphate glucuronosyltransferase (UGT enzymes and transport by membrane proteins (e.g., p-glycoprotein, organic anion-transporting polypeptide. The clinical significance of antiretroviral drug interactions is reviewed, with a focus on new and investigational agents. An overview of the mechanistic basis for drug interactions and the effect of individual antiretrovirals on CYP450 and UGT isoforms are provided. Interactions between antiretrovirals and medications for other co-morbidities are summarized. The role of therapeutic drug monitoring in the detection and management of antiretroviral drug interactions is also briefly discussed.

  3. Quantitative Analysis of Therapeutic Drugs in Dried Blood Spot Samples by Paper Spray Mass Spectrometry: An Avenue to Therapeutic Drug Monitoring

    Science.gov (United States)

    Manicke, Nicholas Edward; Abu-Rabie, Paul; Spooner, Neil; Ouyang, Zheng; Cooks, R. Graham

    2011-09-01

    A method is presented for the direct quantitative analysis of therapeutic drugs from dried blood spot samples by mass spectrometry. The method, paper spray mass spectrometry, generates gas phase ions directly from the blood card paper used to store dried blood samples without the need for complex sample preparation and separation; the entire time for preparation and analysis of blood samples is around 30 s. Limits of detection were investigated for a chemically diverse set of some 15 therapeutic drugs; hydrophobic and weakly basic drugs, such as sunitinib, citalopram, and verapamil, were found to be routinely detectable at approximately 1 ng/mL. Samples were prepared by addition of the drug to whole blood. Drug concentrations were measured quantitatively over several orders of magnitude, with accuracies within 10% of the expected value and relative standard deviation (RSD) of around 10% by prespotting an internal standard solution onto the paper prior to application of the blood sample. We have demonstrated that paper spray mass spectrometry can be used to quantitatively measure drug concentrations over the entire therapeutic range for a wide variety of drugs. The high quality analytical data obtained indicate that the technique may be a viable option for therapeutic drug monitoring.

  4. Practical recommendations for the use of therapeutic drug monitoring of biopharmaceuticals in inflammatory diseases

    Directory of Open Access Journals (Sweden)

    Dreesen E

    2017-10-01

    Full Text Available Erwin Dreesen,1 Peter Bossuyt,2,3 Denis Mulleman,4 Ann Gils,1 Dora Pascual-Salcedo5 1Laboratory for Therapeutic and Diagnostic Antibodies, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, 2Imelda GI Clinical Research Centre, Imelda Ziekenhuis, Bonheiden, 3Translational Research in GastroIntestinal Disorders (TARGID, Department of Clinical and Experimental Medicine, KU Leuven, Leuven, Belgium; 4Department of Rheumatology, Université François-Rabelais de Tours, CNRS, UMR 7292, Tours, France; 5Institute for Research IdiPAZ, University Hospital La Paz, Madrid, Spain Abstract: Biopharmaceuticals directed against tumor necrosis factor-alpha, integrins, interleukins, interferons and their receptors have become key agents for the management of inflammatory diseases in the fields of gastroenterology, rheumatology, dermatology and neurology. However, response to these treatments is far from optimal. Therapeutic failure has been attributed in part to inadequate serum concentrations of the drug and the formation of antidrug antibodies (ADA. Therapeutic drug monitoring (TDM based on drug concentrations and ADA represents a pharmacologically sound tool for guiding dosage adjustments to optimize exposure. Although becoming standard practice in tertiary care centers, the widespread accessibility and recognition of TDM is hindered by several hurdles, including a lack of education of health care providers on TDM. In this paper, the Monitoring of monoclonal Antibodies Group in Europe (MAGE provides an introduction on the fundamental principles of the concept of TDM, aiming to educate clinicians and assist them in the process of implementing TDM of anti-inflammatory biopharmaceuticals. Keywords: therapeutic drug monitoring, biopharmaceuticals, trough concentration, immunogenicity, antidrug antibodies, inflammatory diseases 

  5. Recommendations for Optimizing Tuberculosis Treatment: Therapeutic Drug Monitoring, Pharmacogenetics, and Nutritional Status Considerations.

    Science.gov (United States)

    Choi, Rihwa; Jeong, Byeong Ho; Koh, Won Jung; Lee, Soo Youn

    2017-03-01

    Although tuberculosis is largely a curable disease, it remains a major cause of morbidity and mortality worldwide. Although the standard 6-month treatment regimen is highly effective for drug-susceptible tuberculosis, the use of multiple drugs over long periods of time can cause frequent adverse drug reactions. In addition, some patients with drug-susceptible tuberculosis do not respond adequately to treatment and develop treatment failure and drug resistance. Response to tuberculosis treatment could be affected by multiple factors associated with the host-pathogen interaction including genetic factors and the nutritional status of the host. These factors should be considered for effective tuberculosis control. Therefore, therapeutic drug monitoring (TDM), which is individualized drug dosing guided by serum drug concentrations during treatment, and pharmacogenetics-based personalized dosing guidelines of anti-tuberculosis drugs could reduce the incidence of adverse drug reactions and increase the likelihood of successful treatment outcomes. Moreover, assessment and management of comorbid conditions including nutritional status could improve anti-tuberculosis treatment response.

  6. Insufficient fluconazole exposure in pediatric cancer patients and the need for therapeutic drug monitoring in critically ill children

    NARCIS (Netherlands)

    van der Elst, Kim CM; Pereboom, Marieke; van den Heuvel, Edwin R; Kosterink, Jos G W; Scholvinck, Elisabeth H.; Alffenaar, Jan-Willem C

    2014-01-01

    Background. Fluconazole is recommended as first-line treatment in invasive candidiasis in children and infants. Although timely achievement of adequate exposure of fluconazole improves outcome, therapeutic drug monitoring is currently not recommended. Methods. We conducted a retrospective study of

  7. Therapeutic drug monitoring for patients with Alzheimer dementia to improve treatment with donepezil.

    Science.gov (United States)

    Hefner, Gudrun; Brueckner, Anne; Hiemke, Christoph; Fellgiebel, Andreas

    2015-06-01

    Aiming to verify that therapeutic drug monitoring has the potential to optimize treatment with acetylcholine esterase inhibitors of patients with Alzheimer dementia, this study investigated whether serum concentrations of donepezil are associated with clinical improvement. Clinical improvement was measured using the clinical global impression (CGI) scale, and donepezil concentrations were measured in serum by a high-performance liquid chromatographic method with spectrophotometric detection. In total, 206 serum samples from 106 patients (49.5% female) were retrospectively available for analysis. Patients included were treated under everyday conditions. Their mean ± SD age was 72 ± 9 years, daily doses of donepezil were 5 and 10 mg, and their mean ± SD serum concentrations were 23 ± 9 and 47 ± 18 ng/mL, respectively. Serum concentrations correlated significantly (P donepezil serum concentrations of at least 50 ng/mL may be recommended for maximal clinical benefit. Because donepezil serum concentrations were highly variable between individual patients and the majority of patients exhibited concentrations that were below 50 ng/mL at therapeutic doses of 5 and 10 mg/d, it can be concluded that therapeutic drug monitoring may be used to enhance the effectiveness of donepezil treatment.

  8. Integrated hollow microneedle-optofluidic biosensor for therapeutic drug monitoring in sub-nanoliter volumes

    Science.gov (United States)

    Ranamukhaarachchi, Sahan A.; Padeste, Celestino; Dübner, Matthias; Häfeli, Urs O.; Stoeber, Boris; Cadarso, Victor J.

    2016-07-01

    Therapeutic drug monitoring (TDM) typically requires painful blood drawn from patients. We propose a painless and minimally-invasive alternative for TDM using hollow microneedles suitable to extract extremely small volumes (drug candidates during extraction, without requirements of sample transfer. An optofluidic device is integrated with this microneedle to rapidly quantify drug analytes with high sensitivity using a straightforward absorbance scheme. Vancomycin is currently detected by using volumes ranging between 50-100 μL with a limit of detection (LoD) of 1.35 μM. The proposed microneedle-optofluidic biosensor can detect vancomycin with a sample volume of 0.6 nL and a LoD of <100 nM, validating this painless point of care system with significant potential to reduce healthcare costs and patients suffering.

  9. Therapeutic drug monitoring as a measure of proactive pharmacovigilance in child and adolescent psychiatry.

    Science.gov (United States)

    Gerlach, Manfred; Egberts, Karin; Dang, Su-Yin; Plener, Paul; Taurines, Regina; Mehler-Wex, Claudia; Romanos, Marcel

    2016-11-01

    Off-label or unlicensed use of psychotropic drugs is common rather than the exception in child and adolescent psychiatry. This use exposes patients to an unknown additional risk of ineffective or even harmful treatment. In addition, treatment with psychotropic drugs during a period of life when the patient undergoes marked developmental hormonal and neurobiological changes often requires different dosing regimes in later life and may result in adverse drug reactions, which are either not seen in adults at all or not in the same frequency. Areas covered: Given these critical safety issues, efficient pharmacovigilance methods as part of routine practice are essential for the improvement of patient care. The purpose of this article is to introduce methods to increase the safety of psychotropic drug use in youngsters. In particular, therapeutic drug monitoring (TDM) as a routine measure of proactive pharmacovigilance is discussed. Expert opinion: Given the special features of psychopharmacological therapy in children and adolescents in day-to-day clinical practise, proactive surveillance by using a close standardized 'patient monitoring' and long-term follow-up with TDM is very important. This approach could minimize the risk of exposing paediatric patients to ineffective treatments of uncertain or unknown risks.

  10. Novel fluorescence-based POCT platform for therapeutic drug monitoring in transplanted patients (Conference Presentation)

    Science.gov (United States)

    Baldini, Francesco; Berrettoni, Chiara; Giannetti, Ambra; Tombelli, Sara; Trono, Cosimo; Porro, Giampiero; Bernini, Romeo; Grimaldi, Immacolata Angelica; Testa, Genni; Persichetti, Gianluca; Gärtner, Claudia; Becker, Holger; Berner, Marcel; Schubert, Markus B.; O'Connell, Mark T.; Carney, Daniel; Orellana, Guillermo; Descalzo, Ana B.; Salis, Francesca; Freitas, Paulo P.; Luppa, Peter B.; Bittersohl, Heike; Gauglitz, Günter; Hilbig, Urs; Freudenberger, Kathrin

    2017-02-01

    A novel therapeutic drug monitoring point of care testing (POCT) optical device for the detection of immunosuppressants in transplanted patients was designed and tested, with the body interface constituted by an intravascular microdialysis catheter (MicroEye®) which provides the dialysate as clinical sample. An optical biochip with 10 microchannels, based on total internal reflection fluorescence (TIRF), enables the frequent measurement of immunosuppressants. Heterogeneous competitive immunoassays for the detection of mycophenolic acid, tacrolimus and cyclosporine A are implemented on the different microchannels, with the derivative of the immunosuppressants immobilised on the bottom part of the micro-channels.

  11. Sub-therapeutic nevirapine concentration during antiretroviral treatment initiation among children living with HIV: Implications for therapeutic drug monitoring.

    Directory of Open Access Journals (Sweden)

    Bindu Parachalil Gopalan

    Full Text Available Nevirapine, a component of antiretroviral therapy (ART in resource-limited settings, known for auto-induction of metabolism, is initiated at half therapeutic dose until day 14 ('lead-in period', and subsequently escalated to full dose. However, studies have shown that this dosing strategy based on adult studies may not be appropriate in children, given that younger children have higher drug clearance rates. In this prospective cohort study, we studied trough plasma nevirapine levels by high performance liquid chromatography (HPLC at days 7, 14 (lead-in period and 28 (full dose period after ART initiation amongst HIV-1 infected children initiating nevirapine-based ART in southern India. Among the 20 children (50% male, median age 9 years included in the study, sub-therapeutic trough plasma nevirapine concentration (<4μg/ml was seen in 65% (13/20 of children during the lead-in period within two weeks of ART initiation and among 10% of children at 4 weeks during full-dose nevirapine. Adherence was documented as ≥95% in all children by both caregiver self-report and pill count. Median nevirapine concentrations achieved at week 1 was 4.8 μg/ml, significantly lower than 8 μg/ml, the concentration achieved at week 4 (p = 0.034. Virological failure at one year of ART was observed in six children, and was not associated with median nevirapine concentration achieved during week 1, 2 or 4. We conclude that the dose escalation strategy currently practiced among young children living with HIV-1 resulted in significant subtherapeutic nevirapine concentration (≤4μg/ml during the lead-in period. We call for a closer look at pediatric-focused dosing strategies for nevirapine initiation in young children. Further studies to establish age-appropriate threshold nevirapine concentration are warranted in young children to corroborate the role of therapeutic drug monitoring in predicting virological outcome.

  12. Therapeutic drug monitoring in the past 40 years of the Journal of Antimicrobial Chemotherapy.

    Science.gov (United States)

    Reeves, David; Lovering, Andrew; Thomson, Alison

    2016-12-01

    Since the Journal of Antimicrobial Chemotherapy was first published in 1975, papers addressing therapeutic drug monitoring (TDM) have been a regular feature. Initially they focused on laboratory aspects of drug concentration measurement then they changed more to the application of TDM in a clinical setting. Over its history, the Journal has provided its readership with the latest technological and scientific advances in TDM and has helped to drive changes in TDM that have directly impacted on patient care. These have varied from improvement in the quality of antimicrobial measurements through better identification of dosage regimens and TDM targets that help predict outcome and adverse events. Despite these advances in our understanding of the science and practice of TDM, there remain many areas of uncertainty. As we move into the next 40 years, it is clear that the Journal will continue to provide the readership with the latest science and opinion in this important area. © Crown copyright 2016.

  13. Comments on the Eslicarbazepine Acetate Section of the Article ‘Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications’

    OpenAIRE

    Patricio Soares-da-Silva; Öztiryaki, Ahmet H.

    2010-01-01

    The recent review of Matthew D. Krasowski on ‘Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications’ is a useful foundation of comparative interpretations on our current knowledge about therapeutic drug monitoring. Within the review, the statement that therapeutic drug monitoring has a minimal role in the therapeutic use of eslicarbazepine acetate due to its relatively predictable pharmacokinetics reflects the existing body of evidence although some information such as eslicarbaz...

  14. A Case Report of Clonazepam Dependence: Utilization of Therapeutic Drug Monitoring During Withdrawal Period.

    Science.gov (United States)

    Kacirova, Ivana; Grundmann, Milan; Silhan, Petr; Brozmanova, Hana

    2016-03-01

    Clonazepam is long-acting benzodiazepine agonist used in short-acting benzodiazepine withdrawal; however, recent observations suggest the existence of its abuse. We demonstrate a 40-year-old man with a 20-year history of psychiatric care with recently benzodiazepine dependence (daily intake of ∼60 mg of clonazepam and 10 mg of alprazolam). High serum levels of both drugs were analyzed 3 weeks before admission to hospitalization (clonazepam 543.9 ng/mL, alprazolam 110 ng/mL) and at the time of admission (clonazepam 286.2 ng/mL, alprazolam 140 ng/mL) without any signs of benzodiazepine intoxication. Gradual withdrawal of clonazepam with monitoring of its serum levels and increase of gabapentin dose were used to minimize physical signs and symptoms of clonazepam withdrawal. Alprazolam was discontinued promptly. Clinical consequences of the treatment were controllable tension, intermittent headache, and rarely insomia. It is the first case report showing utilization of therapeutic drug monitoring during withdrawal period in the patient with extreme toleration to severe benzodiazepine dependence.

  15. Therapeutic drug monitoring of digoxin in cardiac heart failure outpatients: comparisons of two analytical methods

    Directory of Open Access Journals (Sweden)

    Isabel Cristina Medeiros Barros

    2014-01-01

    Full Text Available Objective: To compare two analytical techniques used in the determination of plasma digoxin (LC-MS/MS and immunoassay and to verify which one better answer the need of the clinical monitoring routine of patients with cardiac heart failure. Method: The clinical findings in 15 cardiac heart failure (CHF outpatients of the Cardiac Heart Service of the Goias Federal University Clinical Hospital were investigated. Blood samples of the patients were collected and analysed by Immunoassay and by Liquid Chromatography coupled to Mass Spectrometry (LC-MS/MS. Results: The results of the statistic test (Student p = 0,05 showed a significant difference between the analytical methods: immunoassay concentrations were higher than the concentrations determined by LCMS/ MS. The explanation may be because immunoassay method measures digoxin plus other metabolites and endogenous substances, while the LC-MS/MS method measures only the digoxin molecule. None of the patients, showed relevant clinical data suggestive of digitalis intoxication, even several drugs with potential interaction were associated with treatment. Conclusion: It was concluded, therefore, that LC-MS/MS me thod is safer, more selective and specific than immunoassay, being an option for therapeutic drug monitoring of digoxin, since the reference values would be obtain for digoxinemia by LC-MS/MS.

  16. Comparison of Morisky Medication Adherence Scale with therapeutic drug monitoring in apparent treatment-resistant hypertension.

    Science.gov (United States)

    Pandey, Ambarish; Raza, Fayez; Velasco, Alejandro; Brinker, Stephanie; Ayers, Colby; Das, Sandeep R; Morisky, Donald E; Halm, Ethan A; Vongpatanasin, Wanpen

    2015-06-01

    The Morisky Medication Adherence Scale (MMAS-8) is a questionnaire developed for screening of non-adherence in patients with several chronic conditions, including uncomplicated hypertension. However, its accuracy in predicting non-adherence in patients with apparent treatment-resistant hypertension (a-TRH) is not known. Accordingly, we performed a retrospective study in 47 patients with a-TRH who had completed the eight-item MMAS during the initial clinic visit. Non-adherence was defined as presence of undetected serum levels of at least one prescribed antihypertensive drug by therapeutic drug monitoring. We found that 26% of patients were considered to have low adherence score (monitoring. Sensitivity of the MMAS-8 was 26% (95% confidence interval, 10.3%-48.4%) with specificity of 75% (95% confidence interval, 53.3%-90.2%). By multivariate analysis, the MMAS-8 score was not an independent predictor of non-adherence, while certain clinical parameters such as heart rate were found to be independent predictors of non-adherence. Our study suggested limited accuracy of the MMAS-8 in detecting medication non-adherence in a-TRH. Copyright © 2015 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  17. [The therapeutic drug monitoring network server of tacrolimus for Chinese renal transplant patients].

    Science.gov (United States)

    Deng, Chen-Hui; Zhang, Guan-Min; Bi, Shan-Shan; Zhou, Tian-Yan; Lu, Wei

    2011-07-01

    This study is to develop a therapeutic drug monitoring (TDM) network server of tacrolimus for Chinese renal transplant patients, which can facilitate doctor to manage patients' information and provide three levels of predictions. Database management system MySQL was employed to build and manage the database of patients and doctors' information, and hypertext mark-up language (HTML) and Java server pages (JSP) technology were employed to construct network server for database management. Based on the population pharmacokinetic model of tacrolimus for Chinese renal transplant patients, above program languages were used to construct the population prediction and subpopulation prediction modules. Based on Bayesian principle and maximization of the posterior probability function, an objective function was established, and minimized by an optimization algorithm to estimate patient's individual pharmacokinetic parameters. It is proved that the network server has the basic functions for database management and three levels of prediction to aid doctor to optimize the regimen of tacrolimus for Chinese renal transplant patients.

  18. Combined approach with therapeutic drug monitoring and pharmacogenomics in renal transplant recipients

    Directory of Open Access Journals (Sweden)

    S Manvizhi

    2013-01-01

    Full Text Available In patients undergoing renal transplantation, dose individualization for tacrolimus is routinely achieved with therapeutic drug monitoring (TDM. The patient started on 5.5 mg/day of tacrolimus had a significantly elevated tacrolimus trough concentration. The tacrolimus dose was regularly reduced following TDM at many time periods in the post transplant period but the tacrolimus concentration was consistently elevated. Genomic analysis done after four years revealed mutations in the genes encoding for CYP3A5 and MDR1 (2677G > T. Pharmacogenomics alongside TDM, will soon emerge as the backbone of dose individualization. But for genomics to be beneficial, it should be advocated in the pre-transplant or early post transplant period.

  19. Voriconazole dosing and therapeutic drug monitoring in children: experience from a paediatric tertiary care centre.

    Science.gov (United States)

    Boast, Alison; Curtis, Nigel; Cranswick, Noel; Gwee, Amanda

    2016-07-01

    Therapeutic drug monitoring (TDM) of voriconazole is recommended to achieve trough concentrations of 1-5 mg/L. In children, this is challenging due to age-related variability in voriconazole pharmacokinetics. This study describes our experience with voriconazole, focusing on dosing regimens, dose adjustment and TDM. We reviewed the medical records of immunocompromised children who received voriconazole from July 2009 to January 2015 and had TDM. Demographic, clinical and voriconazole dosing and monitoring data were collected. Fifty-five children received 62 courses of voriconazole and had TDM, with a total of 256 samples taken. Only 71.0% of courses (44/62) had TDM at the correct time, and at least one therapeutic level was achieved in only 52.3% (23/44) of these. Twenty-six courses had at least one sub-therapeutic level and in only 61.5% was the dose adjusted. Patients aged 12 years required median intravenous doses of 8.8, 7.5 and 4.0 mg/kg twice daily, respectively (P 12 years required median doses of 4.7 and 4.3 mg/kg twice daily, respectively (P = 0.307). Levels within the target range were observed to fall below 1 mg/L in 36.4% of unchanged dosing regimens. Photosensitive skin reactions (20.0%) and hepatotoxicity (12.7%) were the most frequent adverse events and occurred in children with voriconazole levels voriconazole concentrations in children, particularly in children <6 years of age. This warrants repeated TDM throughout treatment. Standardized guidelines for TDM and dose adjustment are required in children. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  20. A photoacoustic tool for therapeutic drug monitoring of heparin (Conference Presentation)

    Science.gov (United States)

    Wang, Junxin; Hartanto, James; Jokerst, Jesse V.

    2017-03-01

    Heparin is used broadly in cardiac, pulmonary, surgical, and vascular medicine to treat thrombotic disorders with over 500 million doses per year globally. Despite this widespread use, it has a narrow therapeutic window and is one of the top three medication errors. The active partial thromboplastin time (PTT) monitors heparin, but this blood test suffers from long turnaround times, a variable reference range, and limited utility with low molecular weight heparin. Here, we describe an imaging technique that can monitor heparin concentration and activity in real time using photoacoustic spectroscopy via methylene blue as a simple and Federal Drug Agency-approved contrast agent. We found a strong correlation between heparin concentration and photoacoustic signal measured in phosphate buffered saline (PBS) and blood (R2>0.90). Clinically relevant concentrations were detected in blood with a heparin detection limit of 0.28 U/mL and a low molecular weight heparin (enoxaparin) detection limit of 72 μg/mL. We validated this imaging approach by correlation to the PTT (Pearson's r = 0.86; p<0.05) as well as with protamine sulfate treatment. To the best of our knowledge, this is the first report to use imaging data to monitor anticoagulation.

  1. Therapeutic drug monitoring : how to improve drug dosage and patient safety in tuberculosis treatment

    NARCIS (Netherlands)

    Sotgiu, Giovanni; Alffenaar, Jan-Willem C.; Centis, Rosella; D'Ambrosio, Lia; Spanevello, Antonio; Piana, Andrea; Migliori, Giovanni Battista

    In this article we describe the key role of tuberculosis (TB) treatment, the challenges (mainly the emergence of drug resistance), and the opportunities represented by the correct approach to drug dosage, based on the existing control and elimination strategies. In this context, the role and

  2. Revolutionizing Therapeutic Drug Monitoring with the Use of Interstitial Fluid and Microneedles Technology

    Directory of Open Access Journals (Sweden)

    Tony K.L. Kiang

    2017-10-01

    Full Text Available While therapeutic drug monitoring (TDM that uses blood as the biological matrix is the traditional gold standard, this practice may be impossible, impractical, or unethical for some patient populations (e.g., elderly, pediatric, anemic and those with fragile veins. In the context of finding an alternative biological matrix for TDM, this manuscript will provide a qualitative review on: (1 the principles of TDM; (2 alternative matrices for TDM; (3 current evidence supporting the use of interstitial fluid (ISF for TDM in clinical models; (4 the use of microneedle technologies, which is potentially minimally invasive and pain-free, for the collection of ISF; and (5 future directions. The current state of knowledge on the use of ISF for TDM in humans is still limited. A thorough literature review indicates that only a few drug classes have been investigated (i.e., anti-infectives, anticonvulsants, and miscellaneous other agents. Studies have successfully demonstrated techniques for ISF extraction from the skin but have failed to demonstrate commercial feasibility of ISF extraction followed by analysis of its content outside the ISF-collecting microneedle device. In contrast, microneedle-integrated biosensors built to extract ISF and perform the biomolecule analysis on-device, with a key feature of not needing to transfer ISF to a separate instrument, have yielded promising results that need to be validated in pre-clinical and clinical studies. The most promising applications for microneedle-integrated biosensors is continuous monitoring of biomolecules from the skin’s ISF. Conducting TDM using ISF is at the stage where its clinical utility should be investigated. Based on the advancements described in the current review, the immediate future direction for this area of research is to establish the suitability of using ISF for TDM in human models for drugs that have been found suitable in pre-clinical experiments.

  3. Therapeutic drug monitoring of infliximab: performance evaluation of three commercial ELISA kits.

    Science.gov (United States)

    Schmitz, Ellen M H; van de Kerkhof, Daan; Hamann, Dörte; van Dongen, Joost L J; Kuijper, Philip H M; Brunsveld, Luc; Scharnhorst, Volkher; Broeren, Maarten A C

    2016-07-01

    Therapeutic drug monitoring (TDM) of infliximab (IFX, Remicade®) can aid to optimize therapy efficacy. Many assays are available for this purpose. However, a reference standard is lacking. Therefore, we evaluated the analytical performance, agreement and clinically relevant differences of three commercially available IFX ELISA kits on an automated processing system. The kits of Theradiag (Lisa Tracker Infliximab), Progenika (Promonitor IFX) and apDia (Infliximab ELISA) were implemented on an automated processing system. Imprecision was determined by triplicate measurements of patient samples on five days. Agreement was evaluated by analysis of 30 patient samples and four spiked samples by the selected ELISA kits and the in-house IFX ELISA of Sanquin Diagnostics (Amsterdam, The Netherlands). Therapeutic consequences were evaluated by dividing patients into four treatment groups using cut-off levels of 1, 3 and 7 μg/mL and determining assay concordance. Within-run and between-run imprecision were acceptable (≤12% and ≤17%, respectively) within the quantification range of the selected ELISA kits. The apDia assay had the best precision and agreement to target values. Statistically significant differences were found between all assays except between Sanquin Diagnostics and the Lisa Tracker assay. The Promonitor assay measured the lowest IFX concentrations, the apDia assay the highest. When patients were classified in four treatment categories, 70% concordance was achieved. Although all assays are suitable for TDM, significant differences were observed in both imprecision and agreement. Therapeutic consequences were acceptable when patients were divided in treatment categories, but this could be improved by assay standardization.

  4. Therapeutic drug monitoring of caffeine in preterm infants: Could saliva be an alternative to serum?

    Science.gov (United States)

    Chaabane, Amel; Chioukh, Fatma Z; Chadli, Zohra; Ben Fredj, Nadia; Ben Ameur, Karim; Ben Hmida, Hayet; Boughattas, Naceur A; Monastiri, Kamel; Aouam, Karim

    2017-12-01

    Evaluate whether saliva could be a useful alternative to serum for routine therapeutic drug monitoring of caffeine in preterm infants using the enzyme multiplied immunoassay technique (EMIT) assay. We conducted a prospective study including preterm infants (less than 34 weeks' amenorrhea) admitted to the intensive care and neonatal medicine department. All infants received 5, 10, 15, 20 and 25mg/kg/day of citrate caffeine intravenously from the first to the fifth day of birth, respectively. For each patient, two concomitant blood and saliva samples corresponding to the trough concentrations were collected 24hours after each caffeine dose. The caffeine concentrations were determined using the EMIT ® 2000 caffeine assay. Thirteen preterm infants were included. The saliva and the serum caffeine concentration increased proportionally to the administered dose. Saliva and serum kinetics were comparable and the saliva caffeine concentrations were correlated to the serum ones (r 2 =0.76). Saliva caffeine monitoring by EMIT is a valid, useful and safe alternative to serum in preterm infants. Copyright © 2017 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  5. Electrochemical microfluidic chip based on molecular imprinting technique applied for therapeutic drug monitoring.

    Science.gov (United States)

    Liu, Jiang; Zhang, Yu; Jiang, Min; Tian, Liping; Sun, Shiguo; Zhao, Na; Zhao, Feilang; Li, Yingchun

    2017-05-15

    In this work, a novel electrochemical detection platform was established by integrating molecularly imprinting technique with microfluidic chip and applied for trace measurement of three therapeutic drugs. The chip foundation is acrylic panel with designed grooves. In the detection cell of the chip, a Pt wire is used as the counter electrode and reference electrode, and a Au-Ag alloy microwire (NPAMW) with 3D nanoporous surface modified with electro-polymerized molecularly imprinted polymer (MIP) film as the working electrode. Detailed characterization of the chip and the working electrode was performed, and the properties were explored by cyclic voltammetry and electrochemical impedance spectroscopy. Two methods, respectively based on electrochemical catalysis and MIP/gate effect were employed for detecting warfarin sodium by using the prepared chip. The linearity of electrochemical catalysis method was in the range of 5×10(-6)-4×10(-4)M, which fails to meet clinical testing demand. By contrast, the linearity of gate effect was 2×10(-11)-4×10(-9)M with remarkably low detection limit of 8×10(-12)M (S/N=3), which is able to satisfy clinical assay. Then the system was applied for 24-h monitoring of drug concentration in plasma after administration of warfarin sodium in rabbit, and the corresponding pharmacokinetic parameters were obtained. In addition, the microfluidic chip was successfully adopted to analyze cyclophosphamide and carbamazepine, implying its good versatile ability. It is expected that this novel electrochemical microfluidic chip can act as a promising format for point-of-care testing via monitoring different analytes sensitively and conveniently. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Use of saliva in therapeutic drug monitoring of caffeine in preterm infants

    NARCIS (Netherlands)

    de Wildt, SN; Kerkvliet, KTM; Wezenberg, MGA; Ottink, S; Hop, WCJ; Vulto, AG; van den Anker, JN

    Caffeine is frequently used to treat apnea of prematurity in preterm infants. Because caffeine has a narrow therapeutic window, plasma concentrations are generally monitored weekly. It would be advantageous to monitor this therapy without blood sampling; saliva might offer this possibility. Paired

  7. Drug persistence and need for dose intensification to adalimumab therapy; the importance of therapeutic drug monitoring in inflammatory bowel diseases.

    Science.gov (United States)

    Gonczi, Lorant; Kurti, Zsuzsanna; Rutka, Mariann; Vegh, Zsuzsanna; Farkas, Klaudia; Lovasz, Barbara D; Golovics, Petra A; Gecse, Krisztina B; Szalay, Balazs; Molnar, Tamas; Lakatos, Peter L

    2017-08-08

    Therapeutic drug monitoring (TDM) aid therapeutic decision making in patients with inflammatory bowel disease (IBD) who lose response to anti-TNF therapy. Our aim was to evaluate the frequency and predictive factors of loss of response (LOR) to adalimumab using TDM in IBD patients. One hundred twelve IBD patients (with 214 TDM measurements, CD/UC 84/28, male/female 50/62, mean age CD/UC: 36/35 years) were enrolled in this consecutive cohort from two referral centres in Hungary. Demographic data were comprehensively collected and harmonized monitoring strategy was applied. Previous and current therapy, laboratory data and clinical activity were recorded at the time of TDM. Patients were evaluated either at the time of suspected LOR or during follow-up. TDM measurements were determined by commercial ELISA (LISA TRACKER, Theradiag, France). Among 112 IBD patients, LOR/drug persistence was 25.9%/74.1%. The cumulative ADA positivity (>10 ng/mL) and low TL (<5.0 μg/mL) was 12.1% and 17.8% after 1 year and 17.3% and 29.5% after 2 years of adalimumab therapy. Dose intensification was needed in 29.5% of the patients. Female gender and ADA positivity were associated with LOR (female gender: p < 0.001, OR:7.8 CI 95%: 2.5-24.3, ADA positivity: p = 0.007 OR:3.6 CI 95%: 1.4-9.5). ADA development, low TL and need for dose intensification were frequent during adalimumab therapy and support the selective use of TDM in IBD patients treated with adalimumab. ADA positivity and gender were predictors of LOR.

  8. Therapeutic Drug Monitoring of Voriconazole in the Management of Invasive Fungal Infections: A Critical Review.

    Science.gov (United States)

    Elewa, Hazem; El-Mekaty, Eman; El-Bardissy, Ahmed; Ensom, Mary H H; Wilby, Kyle John

    2015-12-01

    The broad-spectrum triazole antifungal agent voriconazole is highly efficacious against invasive fungal infections (IFIs) caused by Aspergillus spp. and Candida spp. IFIs are associated with high rates of mortality and morbidity, especially in vulnerable populations such as patients with hematopoietic stem cell transplant as well as other immunocompromised patients. Efficacy of voriconazole in these patients is critical to ensure positive outcomes and reduce mortality. However, a major limitation of voriconazole is the risk of adverse events such as hepatotoxicity and neurotoxicity. As such, therapeutic drug monitoring (TDM) has been suggested as a mechanism to optimize both efficacy and safety. The aim of this review was to summarize and evaluate evidence from the primary literature that assessed TDM outcomes for voriconazole as well as evaluate the association between CYP2C19 polymorphism and the clinical outcomes of voriconazole. Findings showed associations for both efficacy and safety outcomes with measurement of drug concentrations, yet exact targets or thresholds remain unclear. As such, TDM should be reserved for those patients not responding to therapy with voriconazole or those experiencing adverse drug reactions. Future studies should attempt to further define these populations within controlled settings. Studies that evaluated the effect of CYP2C19 genetic polymorphism on clinical outcomes found no significant relationship between CYP2C19 genotype and hepatotoxicity. These negative findings may be due to lack of power, use of phenotypes not well-defined, and the presence of other interacting factors that may impact voriconazole pharmacokinetics. Future well-designed studies are warranted to confirm these findings.

  9. Voriconazole therapeutic drug monitoring: results of a prematurely discontinued randomized multicenter trial.

    Science.gov (United States)

    Neofytos, D; Ostrander, D; Shoham, S; Laverdiere, M; Hiemenz, J; Nguyen, H; Clarke, W; Brass, L; Lu, N; Marr, K A

    2015-12-01

    Voriconazole (VOR) levels are highly variable, with potential implications to both efficacy and safety. We hypothesized that VOR therapeutic drug monitoring (TDM) will decrease the incidence of treatment failures and adverse events (AEs). We initiated a prospective, randomized, non-blinded multicenter study to compare clinical outcomes in adult patients randomized to standard dosing (clinician-driven) vs. TDM (doses adjusted based on levels). VOR trough levels were obtained on day 5, 14, 28, and 42 (or at completion of drug; ± 3 days). Real-time dose adjustments were made to maintain a range between 1-5 μg/mL on the TDM-arm, while levels were assessed retrospectively in the standard-arm. Patient questionnaires were administered to assess subjective AEs. The study was discontinued prematurely, after 29 patients were enrolled. Seventeen (58.6%) patients experienced 38 AEs: visual changes (22/38, 57.9%), neurological symptoms (13/38, 34.2%), and liver abnormalities (3/38, 7.9%). VOR was discontinued in 7 (25%) patients because of an AE (4 standard-arm, 3 TDM-arm). VOR levels were frequently out of range in the standard-arm (8 tests >5 μg/mL; 9 tests <1 μg/mL). Three dose changes occurred in the TDM-arm for VOR levels <1 μg/mL. Levels decreased over time in the standard-arm, with mean VOR levels lower at end of therapy compared to TDM (1.3 vs. 4.6 μg/mL, P = 0.008). VOR TDM has become widespread clinical practice, based on known variability in drug levels, which impaired accrual in this study. Although comparative conclusions are limited, observations of variability and waning levels over time support TDM. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Validation of a Commercial Assay and Decision Support Tool for Routine Paclitaxel Therapeutic Drug Monitoring (TDM).

    Science.gov (United States)

    Joerger, Markus; Kraff, Stefanie; Jaehde, Ulrich; Hilger, Ralf A; Courtney, Jodi B; Cline, Daniel J; Jog, Sonali; Baburina, Irina; Miller, M Craig; Salamone, Salvatore J

    2017-12-01

    The value of therapeutic drug monitoring (TDM) for paclitaxel (PTX) was recently demonstrated in the largest TDM trial ever conducted in oncology. The trial demonstrated significant reduction in neuropathy when using TDM. Dose adjustment for PTX was based on time above a threshold concentration (Tc>0.05). Tc>0.05 must be calculated with a pharmacokinetic model and complex nonlinear mixed-effects software. The use of the software and chromatographic methods to measure PTX requires specialized expertise. User-friendly methods to quantitate PTX and calculate Tc>0.05 could simplify the introduction of TDM into routine clinical practice. The immunoassay (MyPaclitaxel) was used to quantitate PTX in samples from the clinical trial; the results were used to calculate Tc>0.05 using a stand-alone computer program with a simple, friendly graphical user interface for nonlinear mixed-effects pharmacokinetic calculations (MyCare Drug Exposure Calculator). The resulting dose recommendations from the calculated Tc>0.05 were compared with those using liquid chromatography-ultraviolet detection and NONMEM to examine the efficacy of the simpler tools for TDM. There was a good agreement between the immunoassay and liquid chromatography-ultraviolet detection: Passing-Bablok regression slope was 1.045 and intercept was -6.00, R was 0.9757, and mean bias was -1.77 ng/mL (-2.07 nmol/L). Dosing recommendations were identical for 70% of the cycles and within 10% for 89% of the samples. All Tc>0.05 values were at the same or adjacent medical decision points. MyPaclitaxel assay and MyCare Drug Exposure Calculator are convenient, user-friendly tools that may be suitable for routine TDM of PTX in clinical care.

  11. Therapeutic Drug Monitoring in Neonatal HSV Infection on Continuous Renal Replacement Therapy.

    Science.gov (United States)

    Funaki, Takanori; Miyata, Ippei; Shoji, Kensuke; Enomoto, Yuki; Sakamoto, Seisuke; Kasahara, Mureo; Miyairi, Isao

    2015-07-01

    Optimal acyclovir dosing under continuous renal replacement therapy (CRRT) in neonates is unknown. We monitored serum acyclovir levels and herpes simplex virus 1 (HSV-1) DNA levels in a neonate with disseminated HSV-1 infection and renal failure undergoing CRRT. A full-term, 5-day-old female presented with a 2-day history of lethargy and fever. She developed fulminant hepatitis and was diagnosed with HSV-1 infection by real-time polymerase chain reaction. Acyclovir was initiated at 60 mg/kg/day, which was lowered to 20 mg/kg/day because of development of renal failure. She was placed on continuous hemodialysis. Acyclovir dosing was adjusted according to serum acyclovir levels, and HSV-1 viral load was sequentially monitored. Semiquantification of serum HSV-1 levels was performed by real-time polymerase chain reaction. Acyclovir levels were measured by using liquid chromatography-tandem mass spectrometry. Acyclovir was administered at 20 mg/kg intravenously over 1 hour; peak concentration was 18.9 μg/mL. The half-life of acyclovir was estimated to be 2 to 3 h. Viral load remained high during dosing every 24 hours, with a decline of 0.17 log copies/24 hours. Acyclovir dosing was changed to 20 mg/kg/dose every 8 hours, with an average viral load decline of 0.44 log copies/24 hours. Despite the guideline recommendation of 24-hour redosing, acyclovir was dialyzed at a rate that resulted in suboptimal treatment. Individual therapeutic drug monitoring for acyclovir and dosing adjustment may be required to optimize therapy for patients undergoing CRRT. Copyright © 2015 by the American Academy of Pediatrics.

  12. Optical Drug Monitoring: Photoacoustic Imaging of Nanosensors to Monitor Therapeutic Lithium In Vivo

    Science.gov (United States)

    Cash, Kevin J.; Li, Chiye; Xia, Jun; Wang, Lihong V.; Clark, Heather A.

    2015-01-01

    Personalized medicine could revolutionize how primary care physicians treat chronic disease and how researchers study fundamental biological questions. To realize this goal we need to develop more robust, modular tools and imaging approaches for in vivo monitoring of analytes. In this report, we demonstrate that synthetic nanosensors can measure physiologic parameters with photoacoustic contrast, and we apply that platform to continuously track lithium levels in vivo. Photoacoustic imaging achieves imaging depths that are unattainable with fluorescence or multiphoton microscopy. We validated the photoacoustic results that illustrate the superior imaging depth and quality of photoacoustic imaging with optical measurements. This powerful combination of techniques will unlock the ability to measure analyte changes in deep tissue and will open up photoacoustic imaging as a diagnostic tool for continuous physiological tracking of a wide range of analytes. PMID:25588028

  13. Reduced chance of hearing loss associated with Therapeutic Drug Monitoring of Aminoglycosides in the treatment of Multidrug Resistant Tuberculosis

    NARCIS (Netherlands)

    van Altena, R; Dijkstra, J.A.; van der Meer, M E; Borjas Howard, J F; Kosterink, J G W; van Soolingen, D; van der Werf, T S; Alffenaar, J W C

    Hearing loss and nephrotoxicity are associated with prolonged treatment duration and higher dosage of amikacin and kanamycin. In our Tuberculosis Center, we have employed therapeutic drug monitoring (TDM) targeting pre-set pharmacokinetic/pharmacodynamic (PK/PD) surrogate endpoints in an attempt to

  14. A systematic review and combined analysis of therapeutic drug monitoring studies for long-acting risperidone.

    Science.gov (United States)

    Schoretsanitis, Georgios; Spina, Edoardo; Hiemke, Christoph; de Leon, Jose

    2017-09-01

    This systematic review of therapeutic drug monitoring (TDM) identifies three long-acting injectable (LAI) risperidone formulations. Areas covered: Limited data is available on two formulations (RBP-7000 and in Situ Microparticle), but 20 TDM articles on the microsphere formulation were found. Risperidone TDM includes the serum concentrations of risperidone and its active metabolite, 9-hydroxyrisperidone, used for calculating: 1) the risperidone/9-hydroxyrisperidone (R/9-OH-R) ratio (a measure of CYP2D6; values >1 are indicative of a CYP2D6 poor metabolizer) and 2) the total risperidone concentration-to-dose (C/D) ratio (a measure of risperidone clearance with a normal value around 7 in oral risperidone). The weighted mean R/9-OH-R ratio was 0.48 (approximately twice that of oral risperidone TDM) in a combined analysis from 329 patients in 6 risperidone LAI studies without major confounders. The total C/D ratios from 297 patients in 6 risperidone LAI studies ranged from 7.4 to 9.7 ng/ml/mg/day with a weighted mean of 8.8 ng/ml/mg/day. Expert commentary: Clinicians using TDM for risperidone LAI microsphere formulation need to: 1) consider steady state to be reached ≥ 6 weeks after the first injection, 2) pay attention to a) co-medications with inducers/inhibitors, b) severe inflammations/infections, and c) hepatic/renal impairment, and 3) use Castberg's recommendation to calculate risperidone dosing.

  15. Characterisation of zuclopenthixol metabolism by in vitro and therapeutic drug monitoring studies.

    Science.gov (United States)

    Davies, S J C; Westin, A A; Castberg, I; Lewis, G; Lennard, M S; Taylor, S; Spigset, O

    2010-12-01

    Zuclopenthixol pharmacokinetics is incompletely characterised. We investigated potential interactions mediated through cytochrome P450 enzymes. In vitro, we examined the impact of CYP2D6 and CYP3A4 inhibitors on zuclopenthixol metabolism in microsomes from six human livers. Subsequently, we compared dose-corrected serum zuclopenthixol concentrations in 923 samples from a therapeutic drug monitoring database from patients prescribed oral (n = 490) or injected (n = 423) zuclopenthixol alone or with fluoxetine, paroxetine, levomepromazine or carbamazepine. In vitro fluoxetine, paroxetine, ketoconazole and quinidine all significantly inhibited zuclopenthixol metabolism. Ketoconazole and quinidine together abolished zuclopenthixol disappearance. Clinically, dose-corrected oral zuclopenthixol serum concentrations increased significantly, after adjustment, by 93%, 78% and 46% during co-treatment with fluoxetine, paroxetine and levomepromazine and decreased 67% with carbamazepine. Carbamazepine caused dose-dependent reductions in the oral zuclopenthixol concentration-dose ratio (P Results for injected zuclopenthixol were similar but not all reached statistical significance. The In vitro study suggests zuclopenthixol is metabolised primarily by CYP2D6 and CYP3A4. The clinical study supports this, demonstrating the impact of co-prescribed inhibitors or inducers. Guidelines should incorporate these interactions noting the potential for zuclopenthixol-related toxicity or treatment failure. © 2010 John Wiley & Sons A/S.

  16. Therapeutic drug monitoring of flucytosine in serum using a SERS-active membrane system

    Science.gov (United States)

    Berger, Adam G.; White, Ian M.

    2017-02-01

    A need exists for near real-time therapeutic drug monitoring (TDM), in particular for antibiotics and antifungals in patient samples at the point-of-care. To truly fit the point-of-care need, techniques must be rapid and easy to use. Here we report a membrane system utilizing inkjet-fabricated surface enhanced Raman spectroscopy (SERS) sensors that allows sensitive and specific analysis despite the elimination of sophisticated chromatography equipment, expensive analytical instruments, and other systems relegated to the central lab. We utilize inkjet-fabricated paper SERS sensors as substrates for 5FC detection; the use of paper-based SERS substrates leverages the natural wicking ability and filtering properties of microporous membranes. We investigate the use of microporous membranes in the vertical flow assay to allow separation of the flucytosine from whole blood. The passive vertical flow assay serves as a valuable method for physical separation of target analytes from complex biological matrices. This work further establishes a platform for easy, sensitive, and specific TDM of 5FC from whole blood.

  17. Therapeutic Drug Monitoring of Continuous Infusion Doripenem in a Pediatric Patient on Continuous Renal Replacement Therapy.

    Science.gov (United States)

    Cies, Jeffrey J; Moore, Wayne S; Conley, Susan B; Shea, Paul; Enache, Adela; Chopra, Arun

    2017-01-01

    An 11-year-old African American male with severe combined immunodeficiency variant, non-cystic fibrosis bronchiectasis, pancreatic insufficiency, chronic mycobacterium avium-intracellulare infection, chronic sinusitis, and malnutrition presented with a 1-week history of fevers. He subsequently developed respiratory decompensation and cefepime was discontinued and doripenem was initiated. Doripenem was the carbapenem used due to a national shortage of meropenem. By day 7 the patient (24.7 kg) had a positive fluid balance of 6925 mL (28% FO), and on days 7 into 8 developed acute kidney injury evidenced by an elevated serum creatinine of 0.68 mg/dL, an increase from the baseline of 0.28 mg/dL. On day 9, the patient was initiated on continuous renal replacement therapy (CRRT) and the doripenem dosing was changed to a continuous infusion of 2.5 mg/kg/hr (60 mg/kg/day). Approximately 12.5 hours after the start of the doripenem a serum concentration was obtained, which was 4.01 mg/L corresponding to a clearance of 10.5 mL/min/kg. The pediatric dosing and pharmacokinetic data available for doripenem suggest a clearance estimate of 4.4 to 4.8 mL/min/kg, and the adult clearance estimate is 2.4 to 3.78 mL/min/kg. The calculated clearance in our patient of 10.5 mL/min/kg is over double the highest clearance estimate in the pediatric literature. This case demonstrates that doripenem clearance is significantly increased with CRRT in comparison with the published pediatric and adult data. An appropriate pharmacodynamic outcome (time that free drug concentration > minimum inhibitory concentration) can be achieved by continuous infusion doripenem with concurrent therapeutic drug monitoring.

  18. Therapeutic Drug Monitoring of Posaconazole: a Monocentric Study with 54 Adults▿

    Science.gov (United States)

    Lebeaux, David; Lanternier, Fanny; Elie, Caroline; Suarez, Felipe; Buzyn, Agnès; Viard, Jean-Paul; Bougnoux, Marie-Elisabeth; Lecuit, Marc; Jullien, Vincent; Lortholary, Olivier

    2009-01-01

    Posaconazole is a potent broad-spectrum triazole antifungal. Little is known about the prevalence and risk factors for low plasma posaconazole concentrations (PPCs). We retrospectively reviewed all adult patients whose PPCs were measured after at least 5 days of treatment between April 2006 and July 2008 at the Hôpital Necker Enfants Malades. A low PPC was defined as a concentration lower than 500 ng/ml. Fifty-four patients were included: 36 receiving prophylactic (200 mg three times a day) and 18 receiving curative (400 mg twice a day) posaconazole therapy. The prevalence of low PPCs was 44% (16/36) in the prophylaxis group and 22% (4/18) in the curative-treatment group. In the prophylaxis group, low PPCs tended to be more frequent in cases of digestive disease (62.5% versus 30%; P = 0.051) and were significantly more frequent among patients with diarrhea (71.4% versus 27%; P = 0.009) or mucositis (100% versus 33%; P = 0.004). In the curative-treatment group, low PPCs were significantly more frequent in cases of diarrhea (75% versus 7%; P = 0.018). In the prophylaxis group, the only two patients who subsequently developed invasive fungal infections exhibited low PPCs. The only adverse event was hepatotoxicity for 2/54 patients (3.7%), which was not related to high plasma drug concentrations. In conclusion, low PPC is common, significantly more frequent in cases of diarrhea or mucositis, and potentially associated with subsequent invasive fungal infection. Therapeutic drug monitoring of posaconazole is therefore mandatory for immunosuppressed adults, at least for those with gastrointestinal disorders. PMID:19752284

  19. Performance evaluation of enzyme immunoassay for voriconazole therapeutic drug monitoring with automated clinical chemistry analyzers.

    Science.gov (United States)

    Jeon, Yongbum; Han, Minje; Han, Eun Young; Lee, Kyunghoon; Song, Junghan; Song, Sang Hoon

    2017-08-01

    Voriconazole is a triazole antifungal developed for the treatment of fungal infectious disease, and the clinical utility of its therapeutic drug monitoring has been evaluated. Recently, a new assay for analyzing the serum voriconazole concentration with an automated clinical chemistry analyzer was developed. We evaluated the performance of the new assay based on standardized protocols. The analytical performance of the assay was evaluated according to its precision, trueness by recovery, limit of quantitation, linearity, and correlation with results from liquid chromatography-tandem mass spectrometry (LC-MS/MS). The evaluation was performed with the same protocol on two different routine chemistry analyzers. All evaluations were performed according to CLSI Guidelines EP15, EP17, EP6, and EP9 [1-4]. Coefficients of variation for within-run and between-day imprecision were 3.2-5.1% and 1.5-3.0%, respectively, on the two different analyzers for pooled serum samples. The recovery rates were in the range of 95.4-102.2%. The limit of blank was 0.0049 μg/mL, and the limit of detection of the samples was 0.0266-0.0376 μg/mL. The percent recovery at three LoQ levels were 67.9-74.6% for 0.50 μg/mL, 75.5-80.2% for 0.60 μg/mL, and 89.9-96.6% for 0.70 μg/mL. A linear relationship was demonstrated between 0.5 μg/mL and 16.0 μg/mL (R2 =0.9995-0.9998). The assay correlated well with LC-MS/MS results (R2 =0.9739-0.9828). The assay showed acceptable precision, trueness, linearity, and limit of quantification, and correlated well with LC-MS/MS. Therefore, its analytical performance is satisfactory for monitoring the drug concentration of voriconazole.

  20. The significance of sampling time in therapeutic drug monitoring of clozapine.

    Science.gov (United States)

    Jakobsen, M I; Larsen, J R; Svensson, C K; Johansen, S S; Linnet, K; Nielsen, J; Fink-Jensen, A

    2017-02-01

    Therapeutic drug monitoring (TDM) of clozapine is standardized to 12-h postdose samplings. In clinical settings, sampling time often deviates from this time point, although the importance of the deviation is unknown. To this end, serum concentrations (s-) of clozapine and its metabolite N-desmethyl-clozapine (norclozapine) were measured at 12 ± 1 and 2 h postdose. Forty-six patients with a diagnosis of schizophrenia, and on stable clozapine treatment, were enrolled for hourly, venous blood sampling at 10-14 h postdose. Minor changes in median percentage values were observed for both s-clozapine (-8.4%) and s-norclozapine (+1.2%) across the 4-h time span. Maximum individual differences were 42.8% for s-clozapine and 38.4% for s-norclozapine. Compared to 12-h values, maximum median differences were 8.4% for s-clozapine and 7.3% for s-norclozapine at deviations of ±2 h. Maximum individual differences were 52.6% for s-clozapine and 105.0% for s-norclozapine. The magnitude of s-clozapine differences was significantly associated with age, body mass index and the presence of chronic basophilia or monocytosis. The impact of deviations in clozapine TDM sampling time, within the time span of 10-14 h postdose, seems of minor importance when looking at median percentage differences. However, substantial individual differences were observed, which implies a need to adhere to a fixed sampling time. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Enantioselective assay for therapeutic drug monitoring of eslicarbazepine acetate: no interference with carbamazepine and its metabolites.

    Science.gov (United States)

    Alves, Gilberto; Fortuna, Ana; Sousa, Joana; Direito, Rosa; Almeida, Anabela; Rocha, Marília; Falcão, Amílcar; Soares-da-Silva, Patrício

    2010-08-01

    As add-on therapy, phase III clinical trials of eslicarbazepine acetate (ESL) conducted in patients with refractory partial-onset seizures have shown good efficacy, safety, and tolerability, even in patients taking carbamazepine (CBZ) at baseline (approximately 60% of the enrolled patients). Thus, considering the pharmacological disadvantages of CBZ and the similar efficacy spectrum of CBZ and ESL, switching to ESL may be successful in many patients. As ESL is a prodrug almost instantaneously converted to S-licarbazepine (S-Lic; approximately 95%), an interest in therapeutic drug monitoring (TDM) of S-Lic is likely to develop in the future. This study investigated the plasma concentrations of S-Lic and R-licarbazepine (R-Lic) enantiomers in patients under CBZ long-term treatment to assess the potential interference of CBZ or its metabolites in the enantioselective TDM of ESL (using S-Lic concentrations). A chiral high-performance liquid chromatography assay with ultraviolet detection (HPLC-UV) previously developed and validated by our research group was used. Twenty-four patients admitted to the Coimbra University Hospital and supposedly receiving CBZ long-term treatment were identified. Blood samples were collected from patients and serum CBZ concentrations were measured by the usual TDM protocol. Aliquots of plasma from such patients were also submitted to a chiral HPLC-UV analysis. The bioanalytical data indicated that S-Lic and R-Lic were not present at detectable concentrations in plasma samples of the CBZ-treated patients. The chromatograms generated by the analysis of patient plasma samples, when compared with those obtained from blank plasma samples spiked with S-Lic and R-Lic, clearly showed the absence of interferences at the retention times of both Lic enantiomers. These data support the usefulness of the chiral HPLC-UV method used for the enantioselective TDM of ESL (using S-Lic) for programs in which switching from CBZ to ESL is implemented.

  2. A simple dried blood spot method for therapeutic drug monitoring of the tricyclic antidepressants amitriptyline, nortriptyline, imipramine, clomipramine, and their active metabolites using LC-MS/MS

    NARCIS (Netherlands)

    Berm, E. J. J.; Paardekooper, J.; Brummel-Mulder, E.; Hak, E.; Wilffert, B.; Maring, J. G.

    2015-01-01

    Therapeutic drug monitoring (TOM) of tricyclic antidepressants (TCAs) is considered useful in patients with major depressive disorder, since these drugs display large individual differences in clearance, and the therapeutic windows of these drugs are relatively small. We developed an assay for

  3. Urine Colorimetry for Therapeutic Drug Monitoring of Pyrazinamide during Tuberculosis Treatment.

    Science.gov (United States)

    Zentner, Isaac; Modongo, Chawangwa; Zetola, Nicola M; Pasipanodya, Jotam G; Srivastava, Shashikant; Heysell, Scott K; Mpagama, Stellah; Schlect, Hans P; Gumbo, Tawanda; Bisson, Gregory P; Vinnard, Christopher

    2017-12-15

    Pyrazinamide is a key drug in the first-line tuberculosis treatment regimen, with a potent sterilizing effect. Although low pyrazinamide peak serum concentrations (Cmax) are associated with poor treatment outcomes, many resource-constrained settings do not have sufficient laboratory capacity to support therapeutic drug monitoring. Our objective was to determine whether a colorimetric test of urine can identify tuberculosis patients with adequate pyrazinamide exposures, as defined by the serum Cmax above a target threshold. In the derivation study of healthy volunteers, we evaluated 3 dose sizes of pyrazinamide and performed intensive pharmacokinetic blood sampling over an 8-hour interval, with a timed urine void at 4hours post-dosing. We performed an isolation of pyrazinamide in urine by spin column centrifugation with an exchange resin followed by colorimetric analysis, and measured the absorbance peak at 495nm. The urine assay was then evaluated in a study of 39 HIV/tuberculosis patients in Botswana enrolled in an intensive pharmacokinetic study. Receiver-operating-characteristic (ROC) curves were used to measure diagnostic accuracy. We evaluated the guideline-recommended pyrazinamide serum Cmax target of 35mg/L in the primary analysis, and in a secondary analysis evaluated the higher serum Cmax target of 58mg/L, which was predictive of favorable outcomes in a clinical study. At the optimal cut-off identified in the derivation sample, the urine colorimetric assay was 97% sensitive and 50% specific to identify 35 of 39 HIV/tuberculosis patients with pharmacokinetic target attainment, with an area under the ROC curve of 0.81 (95% confidence interval 0.60, 0.97). Diagnostic accuracy was lower at the 58mg/L serum Cmax target, with an area under the ROC curve of 0.68 (95% confidence interval 0.48 to 0.84). Men were less likely than women to attain either serum pharmacokinetic target. The urine colorimetric assay was sensitive but not specific for the detection of

  4. Comparative study of both versions of an immunoassay commercialized for therapeutic drug monitoring of adalimumab in rheumatoid arthritis.

    Science.gov (United States)

    Llinares-Tello, Francisca; Rosas, José; de la Torre, Inmaculada; Valor, Lara; Barber, Xavier; Senabre, José Miguel

    2014-01-01

    To describe the results of the comparative study between both versions of an immunoassay commercialized for therapeutic drug monitoring of adalimumab (ADA) in rheumatoid arthritis (AR). 140 samples of patients with RA treated with ADA 40mg every 14 days were analyzed by both versions of the test (V1 or previous and V2 or updated). A good correlation was obtained by both versions. In general V2 provides higher results of ADA's concentration than V1 and presents greater precision in the range of concentrations for clinical decisions, adjusting for the real concentration of the drug in blood. In addition, V2 allows for complete automation, which simplifies the analysis and reduces significantly the variability. ADA's monitoring with the updated version demonstrated to have technical significant advantages, constituting a more practical tool for therapeutic decisions in patients with RA. Copyright © 2013 Elsevier España, S.L. All rights reserved.

  5. Adherence with perindopril therapy: a pilot study using therapeutic drug monitoring of perindoprilat and an evaluation of the clearance estimation.

    Science.gov (United States)

    Šíma, Martin; Vodička, Martin; Marešová, Věra; Šálek, Tomáš; Čabala, Radomír; Slanař, Ondřej

    2017-10-01

    Background Although measurement of drug serum levels is an objective direct method for testing compliance, it can be distorted by "white-coat compliance" or by variations in drug elimination. Objective The aim of this prospective study was to evaluate the prevalence of noncompliance with perindopril therapy in adult out-patients using pharmacokinetic simulations. The additional aim was to compare the predictive performance of two glomerular filtration rate markers-creatinine and cystatin C. Setting Department of Cardiology, Tomas Bata Regional Hospital in Zlín, Czech Republic. Method Perindoprilat pharmacokinetic models individualized according to patient characteristics were compared with measured perindoprilat serum concentrations to document compliance. Linear regression was used to evaluate the relations between perindoprilat clearance and glomerular filtration rate estimated using creatinine and cystatin C. Main outcome measure Assessment of non-compliance with medication using drug concentration measurements reinforced with therapeutic drug monitoring. Results Non-detectable perindoprilat levels were observed in 26.1% of patients. Another 21.7% were classified as non-compliant based on therapeutic drug monitoring pharmacokinetic simulations. Volume of distribution, clearance and half-life median value (interquarti°range) for perindoprilat were 408.3 (360.4-456.8) L, 10.1 (4.9-17.0) L h-1 and 24.7 (19.4-62.7) h, respectively. Linear regression models showed tight relationship between cystatin C and perindoprilat clearance. Conclusions Assessment of adherence with medication reinforced with therapeutic drug monitoring and pharmacokinetic simulations is proposed as an optimal method reducing disadvantages of simple drug concentration measurements. Cystatin C proves to be better surrogate marker for perindoprilat elimination than creatinine.

  6. Pharmacotherapy for mood disorders in pregnancy: a review of pharmacokinetic changes and clinical recommendations for therapeutic drug monitoring.

    Science.gov (United States)

    Deligiannidis, Kristina M; Byatt, Nancy; Freeman, Marlene P

    2014-04-01

    Pharmacotherapy for mood disorders during pregnancy is often complicated by pregnancy-related pharmacokinetic changes and the need for dose adjustments. The objectives of this review are to summarize the evidence for change in perinatal pharmacokinetics of commonly used pharmacotherapies for mood disorders, discuss the implications for clinical and therapeutic drug monitoring (TDM), and make clinical recommendations. The English-language literature indexed on MEDLINE/PubMed was searched for original observational studies (controlled and uncontrolled, prospective and retrospective), case reports, and case series that evaluated or described pharmacokinetic changes or TDM during pregnancy or the postpartum period. Pregnancy-associated changes in absorption, distribution, metabolism, and elimination may result in lowered psychotropic drug levels and possible treatment effects, particularly in late pregnancy. Mechanisms include changes in both phase 1 hepatic cytochrome P450 and phase 2 uridine diphosphate glucuronosyltransferase enzyme activities, changes in hepatic and renal blood flow, and glomerular filtration rate. Therapeutic drug monitoring, in combination with clinical monitoring, is indicated for tricyclic antidepressants and mood stabilizers during the perinatal period. Substantial pharmacokinetic changes can occur during pregnancy in a number of commonly used antidepressants and mood stabilizers. Dose increases may be indicated for antidepressants including citalopram, clomipramine, imipramine, fluoxetine, fluvoxamine, nortriptyline, paroxetine, and sertraline, especially late in pregnancy. Antenatal dose increases may also be needed for lithium, lamotrigine, and valproic acid because of perinatal changes in metabolism. Close clinical monitoring of perinatal mood disorders and TDM of tricyclic antidepressants and mood stabilizers are recommended.

  7. Comments on the Eslicarbazepine Acetate Section of the Article ‘Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications’

    Directory of Open Access Journals (Sweden)

    Patricio Soares-da-Silva

    2010-12-01

    Full Text Available The recent review of Matthew D. Krasowski on ‘Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications’ is a useful foundation of comparative interpretations on our current knowledge about therapeutic drug monitoring. Within the review, the statement that therapeutic drug monitoring has a minimal role in the therapeutic use of eslicarbazepine acetate due to its relatively predictable pharmacokinetics reflects the existing body of evidence although some information such as eslicarbazepine acetate’s chemical structure, proportions of its metabolites, their pharmacokinetics and chiral method of plasma level measurement need to be revised. These critical characteristics differentiate the novel compound from former dibenzazepines such as carbamazepine and oxcarbazepine in its clinical effects and needs for therapeutic drug monitoring.

  8. Comments on the Eslicarbazepine Acetate Section of the Article ‘Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications’

    Science.gov (United States)

    Öztiryaki, Ahmet H.; Soares-da-Silva, Patricio

    2010-01-01

    The recent review of Matthew D. Krasowski on ‘Therapeutic Drug Monitoring of the Newer Anti-Epilepsy Medications’ is a useful foundation of comparative interpretations on our current knowledge about therapeutic drug monitoring. Within the review, the statement that therapeutic drug monitoring has a minimal role in the therapeutic use of eslicarbazepine acetate due to its relatively predictable pharmacokinetics reflects the existing body of evidence although some information such as eslicarbazepine acetate’s chemical structure, proportions of its metabolites, their pharmacokinetics and chiral method of plasma level measurement need to be revised. These critical characteristics differentiate the novel compound from former dibenzazepines such as carbamazepine and oxcarbazepine in its clinical effects and needs for therapeutic drug monitoring.

  9. Using Six Sigma to improve once daily gentamicin dosing and therapeutic drug monitoring performance.

    LENUS (Irish Health Repository)

    Egan, Sean

    2012-08-07

    BACKGROUND: Safe, effective therapy with the antimicrobial gentamicin requires good practice in dose selection and monitoring of serum levels. Suboptimal therapy occurs with breakdown in the process of drug dosing, serum blood sampling, laboratory processing and level interpretation. Unintentional underdosing may result. This improvement effort aimed to optimise this process in an academic teaching hospital using Six Sigma process improvement methodology. METHODS: A multidisciplinary project team was formed. Process measures considered critical to quality were defined, and baseline practice was examined through process mapping and audit. Root cause analysis informed improvement measures. These included a new dosing and monitoring schedule, and standardised assay sampling and drug administration timing which maximised local capabilities. Three iterations of the improvement cycle were conducted over a 24-month period. RESULTS: The attainment of serum level sampling in the required time window improved by 85% (p≤0.0001). A 66% improvement in accuracy of dosing was observed (p≤0.0001). Unnecessary dose omission while awaiting level results and inadvertent disruption to therapy due to dosing and monitoring process breakdown were eliminated. Average daily dose administered increased from 3.39 mg\\/kg to 4.78 mg\\/kg\\/day. CONCLUSIONS: Using Six Sigma methodology enhanced gentamicin usage process performance. Local process related factors may adversely affect adherence to practice guidelines for gentamicin, a drug which is complex to use. It is vital to adapt dosing guidance and monitoring requirements so that they are capable of being implemented in the clinical environment as a matter of routine. Improvement may be achieved through a structured localised approach with multidisciplinary stakeholder involvement.

  10. Renal sympathetic denervation after Symplicity HTN-3 and therapeutic drug monitoring in severe hypertension

    Directory of Open Access Journals (Sweden)

    Sverre Erik Kjeldsen

    2015-02-01

    Full Text Available Renal sympathetic denervation (RDN has been and is still proposed as a new treatment modality in patients with apparently treatment resistant hypertension (TRH, a condition defined as persistent blood pressure elevation despite prescription of at least 3 antihypertensive drugs including a diuretic. However, the large fall in blood pressure after RDN reported in the first randomized study, Symplicity HTN-2 and multiple observational studies has not been confirmed in five subsequent prospective randomized studies and may be largely explained by non-specific effects such as improvement of drug adherence in initially poorly adherent patients (the Hawthorne effect, placebo effect and regression to the mean. The overall blood-pressure lowering effect of RDN seems rather limited and the characteristics of true responders are largely unknown. Accordingly, RDN is not ready for clinical practice. In most patients with apparently TRH, drug monitoring and improvement of drug adherence may prove more effective and cost-beneficial to achieve blood pressure control. In the meantime, research should aim at identifying characteristics of those patients with truly TRH who may respond to RDN.

  11. Insufficient fluconazole exposure in pediatric cancer patients and the need for therapeutic drug monitoring in critically ill children.

    Science.gov (United States)

    van der Elst, Kim C M; Pereboom, Marieke; van den Heuvel, Edwin R; Kosterink, Jos G W; Schölvinck, Elisabeth H; Alffenaar, Jan-Willem C

    2014-12-01

    Fluconazole is recommended as first-line treatment in invasive candidiasis in children and infants. Although timely achievement of adequate exposure of fluconazole improves outcome, therapeutic drug monitoring is currently not recommended. We conducted a retrospective study of critically ill children treated with fluconazole from January 2007 to October 2013 and for whom fluconazole concentrations were available. We collected demographic, clinical, and treatment data through review of the medical records and determined the correlation of clinical variables with the fluconazole concentration. Additionally, we assessed the relation between the fluconazole concentration and the time to culture conversion in patients with proven invasive candidiasis. In total, 99 pediatric patients met the inclusion criteria. The fluconazole concentration was considered subtherapeutic in 40% of the patients. Multiple linear regression analysis showed a significant, independent, and positive association of the fluconazole trough concentration with the fluconazole dose (P fluconazole concentration was associated with a shorter time to culture conversion (hazard ratio = 1.076 [95% confidence interval, 1.017-1.138]; P = .011). The fluconazole concentration is not sufficient in pediatric cancer patients with the currently recommended dose regimen, and a higher fluconazole dose is required to achieve adequate drug exposure. Therapeutic drug monitoring of fluconazole can be a valuable tool to detect possible underexposure in critically ill children. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  12. Therapeutic drug monitoring of piperacillin-tazobactam using spent dialysate effluent in patients receiving continuous venovenous hemodialysis.

    Science.gov (United States)

    Connor, Michael J; Salem, Charbel; Bauer, Seth R; Hofmann, Christina L; Groszek, Joseph; Butler, Robert; Rehm, Susan J; Fissell, William H

    2011-02-01

    Sepsis and multisystem organ failure are common diagnoses affecting nearly three-quarters of a million Americans annually. Infection is the leading cause of death in acute kidney injury, and the majority of critically ill patients who receive continuous dialysis also receive antibiotics. Dialysis equipment and prescriptions have gradually changed over time, raising concern that current drug dosing recommendations in the literature may result in underdosing of antibiotics. Our research group directed its attention toward antibiotic dosing strategies in patients with acute renal failure (ARF), and we sought data confirming that patients receiving continuous dialysis and antibiotics actually were achieving therapeutic plasma drug levels during treatment. In the course of those investigations, we explored "fast-track" strategies to estimate plasma drug concentrations. As most antimicrobial antibiotics are small molecules and should pass freely through modern high-flux hemodialyzer filters, we hypothesized that continuous renal replacement therapy (CRRT) effluent could be used as the medium for drug concentration measurement by reverse-phase high-pressure liquid chromatography (HPLC). Here we present the first data demonstrating this approach for piperacillin-tazobactam. Paired blood and dialysate trough-peak-trough samples were drawn from 19 patients receiving piperacillin-tazobactam and continuous venovenous hemodialysis (CVVHD). Total, free, and dialysate drug concentrations were measured by HPLC. Dialysate drug levels predicted plasma free drug levels well (r(2) = 0.91 and 0.92 for piperacillin and tazobactam, respectively) in all patients. These data suggest a strategy for therapeutic drug monitoring that minimizes blood loss from phlebotomy and simplifies analytic procedures.

  13. Computerized clinical decision support systems for therapeutic drug monitoring and dosing: A decision-maker-researcher partnership systematic review

    Directory of Open Access Journals (Sweden)

    Weise-Kelly Lorraine

    2011-08-01

    Full Text Available Abstract Background Some drugs have a narrow therapeutic range and require monitoring and dose adjustments to optimize their efficacy and safety. Computerized clinical decision support systems (CCDSSs may improve the net benefit of these drugs. The objective of this review was to determine if CCDSSs improve processes of care or patient outcomes for therapeutic drug monitoring and dosing. Methods We conducted a decision-maker-researcher partnership systematic review. Studies from our previous review were included, and new studies were sought until January 2010 in MEDLINE, EMBASE, Evidence-Based Medicine Reviews, and Inspec databases. Randomized controlled trials assessing the effect of a CCDSS on process of care or patient outcomes were selected by pairs of independent reviewers. A study was considered to have a positive effect (i.e., CCDSS showed improvement if at least 50% of the relevant study outcomes were statistically significantly positive. Results Thirty-three randomized controlled trials were identified, assessing the effect of a CCDSS on management of vitamin K antagonists (14, insulin (6, theophylline/aminophylline (4, aminoglycosides (3, digoxin (2, lidocaine (1, or as part of a multifaceted approach (3. Cluster randomization was rarely used (18% and CCDSSs were usually stand-alone systems (76% primarily used by physicians (85%. Overall, 18 of 30 studies (60% showed an improvement in the process of care and 4 of 19 (21% an improvement in patient outcomes. All evaluable studies assessing insulin dosing for glycaemic control showed an improvement. In meta-analysis, CCDSSs for vitamin K antagonist dosing significantly improved time in therapeutic range. Conclusions CCDSSs have potential for improving process of care for therapeutic drug monitoring and dosing, specifically insulin and vitamin K antagonist dosing. However, studies were small and generally of modest quality, and effects on patient outcomes were uncertain, with no convincing

  14. Development and validation of a liquid chromatography-tandem mass spectrometry analytical method for the therapeutic drug monitoring of eight novel anticancer drugs.

    Science.gov (United States)

    Herbrink, M; de Vries, N; Rosing, H; Huitema, A D R; Nuijen, B; Schellens, J H M; Beijnen, J H

    2017-11-22

    To support therapeutic drug monitoring of patients with cancer, a fast and accurate method for simultaneous quantification of the registered anticancer drugs afatinib, axitinib, ceritinib, crizotinib, dabrafenib, enzalutamide, regorafenib and trametinib in human plasma using liquid chromatography tandem mass spectrometry was developed and validated. Human plasma samples were collected from treated patients and stored at -20°C. Analytes and internal standards (stable isotopically labeled analytes) were extracted with acetonitrile. An equal amount of 10 mm NH4 CO3 was added to the supernatant to yield the final extract. A 2 μL aliquot of this extract was injected onto a C18 -column, gradient elution was applied and triple-quadrupole mass spectrometry in positive-ion mode was used for detection. All results were within the acceptance criteria of the latest US Food and Drug Administration guidance and European Medicines Agency guidelines on method validation, except for the carry-over of ceritinib and crizotinib. These were corrected for by the injection order of samples. Additional stability tests were carried out for axitinib and dabrafenib in relation to their reported photostability. In conclusion, the described method to simultaneously quantify the eight selected anticancer drugs in human plasma was successfully validated and applied for therapeutic drug monitoring in cancer patients treated with these drugs. Copyright © 2017 John Wiley & Sons, Ltd.

  15. The use of liquid chromatography-tandem mass spectrometry for therapeutic drug monitoring of antibiotics in cancer patients.

    Science.gov (United States)

    El-Najjar, Nahed; Jantsch, Jonathan; Gessner, André

    2017-08-28

    Cancer remains a leading cause of mortality and morbidity worldwide. In addition to organ failure, the most frequent reasons for admission of cancer patients to intensive care units (ICU) are: infections and sepsis. As critically ill, the complexity of the health situation of cancer patients renders the standard antimicrobial regimen more complex and even inadequate which results in increased mortality rates. This is due to pathophysiological changes in the volume of distribution, increased clearance, as well as to organ dysfunction. While in the former cases a decrease in drug efficacy is observed, the hallmark of the latter one is overdosing leading to increased toxicity at the expense of efficacy. Furthermore, an additional risk factor is the potential drug-drug interaction between antibiotics and antineoplastic agents. Therefore, therapeutic drug monitoring (TDM) is a necessity to improve the clinical outcome of antimicrobial therapy in cancer patients. To be applied in routine analysis the method used for TDM should be cheap, fast and highly accurate/sensitive. Furthermore, as ICU patients are treated with a cocktail of antibiotics the method has to cover the simultaneous analysis of antibiotics used as a first/second line of treatment. The aim of the current review is to briefly survey the pitfalls in the current antimicrobial therapy and the central role of TDM in dose adjustment and drug-drug interaction's evaluation. A major section is dedicated to summarize the currently published analytical methods and to shed light on the difficulties and potential problems that can be encountered during method development.

  16. Utility of therapeutic drug monitoring in the management of HIV-infected pregnant women in receipt of lopinavir.

    LENUS (Irish Health Repository)

    Caswell, R J

    2011-01-01

    The pharmacokinetics of antiretroviral drugs in pregnancy is poorly understood. We reviewed the use of therapeutic drug monitoring (TDM) in clinical settings to document plasma concentrations of lopinavir during pregnancy and investigated how clinicians acted upon TDM results. A retrospective review was carried out of all HIV-infected pregnant women taking boosted lopinavir-based highly active antiretroviral therapy (HAART) at five National Health Service (NHS) centres in the UK between May 2004 and March 2007. Seventy-three women in receipt of lopinavir were identified, of whom 89% had plasma lopinavir concentrations above the suggested minimum recommended for wild-type HIV. Initial TDM results prompted dosage change in 10% and assessment of adherence and\\/or pharmacist review in 11%. TDM was repeated in 29%. TDM can play an important role in the clinical management of HIV-positive pregnant women, allowing informed dose modification and an alternative measure of adherence.

  17. CYP2C19 Polymorphisms and Therapeutic Drug Monitoring of Voriconazole: Are We Ready for Clinical Implementation of Pharmacogenomics?

    Science.gov (United States)

    Obeng, Aniwaa Owusu; Egelund, Eric F.; Alsultan, Abdullah; Peloquin, Charles A.; Johnson, Julie A.

    2014-01-01

    Since its approval by the United States Food and Drug Administration in 2002, voriconazole has become a key component in the successful treatment of many invasive fungal infections, including the most common, aspergillosis and candidiasis. Despite voriconazole’s widespread use, optimizing its treatment in an individual can be challenging due to significant interpatient variability in plasma concentrations of the drug. Variability is due to nonlinear pharmacokinetics and the influence of patient characteristics such as age, sex, weight, liver disease, and genetic polymorphisms in the cytochrome P450 2C19 gene (CYP2C19) encoding for the CYP2C19 enzyme, the primary enzyme responsible for metabolism of voriconazole. CYP2C19 polymorphisms account for the largest portion of variability in voriconazole exposure, posing significant difficulty to clinicians in targeting therapeutic concentrations. In this review, we discuss the role of CYP2C19 polymorphisms and their influence on voriconazole’s pharmacokinetics, adverse effects, and clinical efficacy. Given the association between CYP2C19 genotype and voriconazole concentrations, as well as the association between voriconazole concentrations and clinical outcomes, particularly efficacy, it seems reasonable to suggest a potential role for CYP2C19 genotype to guide initial voriconazole dose selection followed by therapeutic drug monitoring to increase the probability of achieving efficacy while avoiding toxicity. PMID:24510446

  18. Therapeutic drug monitoring of A77 1726, the active metabolite of leflunomide: Serum concentrations predict response to treatment in patients with rheumatoid arthritis

    NARCIS (Netherlands)

    Van Roon, E.N.; Jansen, T.L.T.A.; Van De Laar, M.A.F.J.; JANSSEN, M; Yska, J.P.; Keuper, R.; Houtman, P.M.; Brouwers, J.R.B.J.

    2005-01-01

    Background: Leflunomide is the prodrug of the disease modifying antirheumatic metabolite A77 1726. More than 50% of patients withdraw from leflunomide treatment within one year, mainly because of adverse drug reactions. Therapeutic drug monitoring of A77 1726 may be useful in predicting the efficacy

  19. New-Generation, non-SSRI Antidepressants: Therapeutic Drug Monitoring and Pharmacological Interactions. Part 1: SNRIs, SMSs, SARIs

    Science.gov (United States)

    Mandrioli, Roberto; Protti, Michele; Mercolini, Laura

    2017-07-12

    New-generation antidepressants (NGAs) are the latest additions to the clinician's arsenal in the fight against depression. After the introduction of selective serotonin reuptake inhibitors (SSRIs), a plethora of other groups followed, identified by their main mechanisms of activity: serotonin and norepinephrine reuptake inhibitors (SNRI); serotonin modulators and stimulators (SMS); serotonin antagonists and reuptake inhibitors (SARI); noradrenergic and selective serotonergic antidepressants (NaSSA); norepinephrine reuptake inhibitors (NeRI); serotonin, norepinephrine and dopamine reuptake inhibitors (SNDRI) or triple reuptake inhibitors (TRI); and melatonin and serotonin agonists (MaSA). Although SSRIs are still the most widely used and well known NGAs, the other groups are increasingly being used in the current therapeutic settings obtaining comparable clinical results, and with tolerability and safety profiles that can often provide significant advantages over those of SSRIs. Scopus and PubMed databases were searched for the most significant papers centered on the medicinal chemistry, pharmacodynamics, pharmacokinetics and analysis in human biological fluids of the following antidepressants: venlafaxine, duloxetine, milnacipran, trazodone, vortioxetine, vilazodone. The main characteristics of commercially available non-SSRI NGAs (belonging to the SNRI, SARI and SMS classes) are described, focusing on the role of analytical methods that can be applied to perform therapeutic drug monitoring (TDM), but also including drug pharmacokinetics, metabolism and interactions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  20. Therapeutic drug monitoring, electronic health records, and pharmacokinetic modeling to evaluate sirolimus drug exposure-response relationships in renal transplant patients

    Science.gov (United States)

    Zimmerman, Kanecia O.; Wu, Huali; Greenberg, Rachel; Hill, Kevin; Patel, Uptal D.; Ku, Lawrence; Gonzalez, Daniel; Hornik, Christoph; Jiang, Wenlei; Zheng, Nan; Melloni, Chiara; Cohen-Wolkowiez, Michael

    2016-01-01

    Background Sirolimus, an immunosuppressant agent used in renal transplantation, can prevent allograft rejection. Identification of the therapeutic index (ratio of minimum toxic concentration to minimum therapeutic concentration) for immunosuppresants is necessary to optimize the care of patients and set standards for bioequivalence evaluation of sirolimus products. However, the therapeutic index for sirolimus has been inconsistently defined, potentially due to inconsistencies in sirolimus exposure-response relationships. Methods The authors used retrospective therapeutic drug monitoring data from the electronic health records of patients treated in a tertiary healthcare system from 2008 to 2014, to: 1) develop a population pharmacokinetic model, 2) use the model to simulate sirolimus concentrations, and 3) characterize the exposure-response relationship. Using Wilcoxon rank-sum and Fisher’s exact tests, the authors determined relationships between sirolimus exposure and adverse events (anemia, leukopenia, thrombocytopenia, hyperlipidemia, decline in renal function) and the composite efficacy endpoint of graft loss or rejection. Results The developed 2-compartment population pharmacokinetic model showed appropriate goodness of fit. In a late-phase (>12 months), post-renal transplant population of 27 inpatients, the authors identified statistically significant relationships between 83 simulated peak and trough sirolimus concentrations and outcomes: graft loss or rejection (p=0.018), and decline in renal function (p=0.006), respectively. Conclusions Use of therapeutic drug monitoring results and pharmacokinetic modeling permitted correlation of sirolimus concentrations with graft loss or rejection, and decline in renal function. However, the method was limited in its assessment of other adverse events. To better evaluate sirolimus exposure-response relationships, the method should be applied to a larger sample of newly-transplanted patients with a higher propensity

  1. [Pharmacokinetics of methotrexate and therapeutic drug monitoring in children with osteosarcoma. Computer simulation using a pharmacokinetic model].

    Science.gov (United States)

    Piekarczyk, A; Zimak, J; Taljański, W

    2000-01-01

    The pharmacokinetics of methotrexate (MTX) and the therapeutic drug monitoring (TDM) in children treated-with high-dose of MTX (HD MTX) have been discussed. The pharmacokinetics of MTX was studied in 15 children (54 courses) with osteosarcoma, treated with HD MTX (8, 10 and 12 g/m2; 4 h i.v. infusion). Pharmacokinetic analysis was performed by standard non-compartmental methods and using two-compartment nonlinear model with coexistence of additional, parallel linear route of elimination from the central compartment. This proposed model can be used for computer simulation and prognosis of the serum-level curve course depending on the simulated dosage, enhanced diuresis and simulated kidney or liver insufficiency during the dose individualisation. The usage of the pharmacokinetic model for computer simulations may improve the understanding of MTX kinetics and can optimalise dosage regimens for the next cycles of chemotherapy.

  2. Therapeutic Drug Monitoring of Everolimus: Comparability of Concentrations Determined by 2 Immunoassays and a Liquid Chromatography Tandem Mass Spectrometry Method.

    Science.gov (United States)

    Shipkova, Maria; Rapp, Sonja; Rigo-Bonnin, Raül; Wieland, Eberhard; Peter, Andreas

    2017-04-01

    Therapeutic drug monitoring is recommended to guide therapy with the immunosuppressant everolimus (EVL) in solid organ transplantation to prevent rejections and to limit toxicity. For therapeutic drug monitoring, predose EVL concentrations are measured in whole blood mainly by liquid chromatography tandem mass spectrometry (LC-MS/MS). In addition, 2 immunoassays [Quantitative Microsphere System (QMS) EVL and Elecsys EVL] are commercially available. The aim of this study was to evaluate the comparability of EVL results determined with the 2 immunoassays and a validated LC-MS/MS test using samples from kidney, liver, and heart transplant (KT, LT, and HT, respectively) recipients. Analysis of predose samples from KT (n = 56), LT (n = 60), and HT (n = 59) recipients, obtained at variable time points after transplantation, was performed by LC-MS/MS and with the 2 immunoassays. The QMS EVL assay was applied on Dimension Xpand Plus and the Elecsys EVL assay on cobas e 411 analyzer. Results were compared by the Spearman's rank correlation coefficient, unbiased Passing and Bablok linear regression test, and Bland-Altman plot. Results generated with both immunoassays correlated well with those of LC-MS/MS. An overestimation of EVL concentrations by the Elecsys EVL compared with LC-MS/MS was observed (mean bias: 34.2%). Using the QMS EVL, a small but significant negative deviation (mean bias: -8.0%) was found. Looking at KT, HT, and LT samples separately, the bias to LC-MS/MS seen with the Elecsys EVL was similar. With the QMS EVL, the best agreement was observed with the KT samples followed by LT and HT. Results generated by the 3 methods are not consistent regarding their diagnostic value. Both laboratories and manufacturers should take care to inform their costumers about the between-method differences to avoid misinterpretation of the results in clinical practice.

  3. [Therapeutic drug monitoring of tyrosine-kinase inhibitors in the treatment of chronic myelogenous leukaemia: interests and limits].

    Science.gov (United States)

    Bouchet, Stéphane; Royer, Bernard; Le Guellec, Chantal; Titier, Karine

    2010-01-01

    During the last decade, imatinib was current gold standard treatment of chronic myelogenous leukemia (CML), showing a great effectiveness. Thus, the Therapeutic Drug Monitoring (TDM), rarely applied in clinical oncology practice, did not appear necessary at the moment. However, the absence of response among patients and the metabolic profile of imatinib (involving the CYP3A4) suggested the existence of a great interindividual variability. During the last 4 years, studies about the pharmacokinetic/pharmacodynamic relationship have confirmed this variability and highlighted a relation between the trough concentrations of imatinib and the clinical response. An effectiveness threshold, close to 1000 ng/mL, seems to be correlated with better cytogenetic and molecular responses. Consequently, TDM could assist in investigation of the observance, the absence of response, the drug-drug interactions, but the proof of its utility requires complementary studies. In conclusion, the level of proof of imatinib TDM in LMC varies between levels "recommended" and "potentially useful". © 2010 Société Française de Pharmacologie et de Thérapeutique.

  4. Therapeutic drug monitoring of voriconazole helps to decrease the percentage of patients with off-target trough serum levels.

    Science.gov (United States)

    Guinea, Jesús; Escribano, Pilar; Marcos-Zambrano, Laura Judith; Peláez, Teresa; Kestler, Marta; Muñoz, Patricia; Vena, Antonio; López-Fabal, Fátima; Bouza, Emilio

    2016-05-01

    We monitored trough voriconazole serum concentrations from 107 patients (n = 258 samples) at 6 hospitals in Madrid. Most of the patients were male (67%) and had the following underlying conditions: hematological cancer (42%), solid organ transplantation (15%), chronic obstructive pulmonary disease (14%), human immunodeficiency virus infection (8.4%), solid cancer (5.6%), and other (29%). The indication for voriconazole administration was aspergillosis treatment (74.6%) and prophylaxis (14%). The main reasons for voriconazole trough drug monitoring were initiation of treatment/prophylaxis (33%), patient monitoring (47%), and suspected toxicity (3.5%). Levels (μg/ml) were subtherapeutic (5.5; 10.5%). The samples percentage with on-target levels was significantly lower for the first sample than for subsequent samples (62.6% vs. 77.5%). "Subsequent samples," "admission in nonpediatric wards," "voriconazole used for treatment of invasive aspergillosis," and "use of proton pump inhibitors" were predictors of voriconazole therapeutic levels (≥1 μg/ml). © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. A Case Report of Clonazepam Dependence: Utilization of Therapeutic Drug Monitoring During Withdrawal Period

    National Research Council Canada - National Science Library

    Kacirova, Ivana; Grundmann, Milan; Silhan, Petr; Brozmanova, Hana

    2016-01-01

    ...) without any signs of benzodiazepine intoxication. Gradual withdrawal of clonazepam with monitoring of its serum levels and increase of gabapentin dose were used to minimize physical signs and symptoms of clonazepam withdrawal...

  6. Therapeutic drug monitoring of amlodipine and the Z-FHL/HHL ratio ...

    African Journals Online (AJOL)

    treatment-resistant' hypertension. Objective. To determine whether monitoring plasma amlodipine concentrations and inhibition of angiotensin-converting enzyme (ACE) can be adjunct adherence tools. Methods. Patients with hypertension who were ...

  7. On the possibility of low cost, adherent therapeutic drug monitoring in oncology

    Science.gov (United States)

    Dalla Marta, Silvia; Fornasaro, Stefano; Jaworska, Aleksandra; Toffoli, Giuseppe; Bonifacio, Alois; Sergo, Valter

    2016-05-01

    A frequent quantification of drugs concentrations in plasma of patients subject to chemotherapy is seldom performed, mostly because the standard methods (Gas or Liquid Chromatography coupled with Mass Spectroscopy) are expensive and time consuming. In this paper we report the approach pursued in one of the research units of the EU project RAMAN4CLINICS to tackle the problem of a low cost, time adherent quantification of drugs used for oncological patients using a Surface Enhanced Raman Scattering (SERS) spectroscopy. More specifically, the issues concerning the repeatability of the nanostructured substrates will be presented and some promising results to increase the selectivity of the measures toward specific drugs will be discussed, with examples concerning one cytotoxic agent, Irinotecan and one kinase inhibitor, Sunitinib.

  8. Individualized treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring

    NARCIS (Netherlands)

    Bolhuis, Mathieu S; Akkerman, Onno W; Sturkenboom, Marieke G G; de Lange, Wiel C M; van der Werf, Tjip S; Alffenaar, Jan-Willem C

    2016-01-01

    OBJECTIVE/BACKGROUND: Globally, approximately 50% of patients with multidrug-resistant tuberculosis (MDR-TB) experience treatment failure. MDR-TB treatment is hindered by adverse events, toxicity of the second-line anti-TB drugs, logistics and costs, especially in low-income countries, and problems

  9. MW PHARM, AN INTEGRATED SOFTWARE PACKAGE FOR DRUG-DOSAGE REGIMEN CALCULATION AND THERAPEUTIC DRUG-MONITORING

    NARCIS (Netherlands)

    PROOST, JH; MEIJER, DKF

    The pharmacokinetic software package MW/Pharm offers an interactive, user-friendly program which gives rapid answers in clinical practice. It comprises a database with pharmacokinetic parameters of 180 drugs, a medication history database, and procedures for an individual drug dosage regimen

  10. Dosing and therapeutic drug monitoring of voriconazole in bottlenose dolphins (Tursiops truncatus).

    Science.gov (United States)

    Ferrier, Krm; van Elk, C E; Bunskoek, P E; van den Broek, Mph

    2017-02-01

    Bottlenose dolphins (Tursiops truncatus) can suffer from fungal infections, which can be treated with voriconazole. In common practice, the voriconazole doses are extrapolated from human doses by adjusting for body weight only, because no dose regimen is available yet. Therefore, the aim of this study was to define a dose regimen for voriconazole in bottlenose dolphins. Dolphins treated with voriconazole between November 2005 and September 2015 at the Dolfinarium Harderwijk, the Netherlands, and TDM was performed were included. Voriconazole plasma concentrations were analyzed with a HPLC-UV method. A population pharmacokinetic model was developed using Mw/Pharm in which the elimination rate constant (k e ) and apparent total distribution volume (Vd) was calculated. The loading dose was calculated using the central Vd (Vd c ). The maintenance dose was simulated in Mw/Pharm using k e and total Vd.Eleven dolphins were included. K e was estimated to be 0.0026 ± 0.0007 hour -1 (mean ± SD), Vd 5.3 ± 3.2 l/kg (mean ± SD), and Vd c ranged between 1.8 and 2.8 l/kg (mean 2.2 l/kg). In order to obtain a median top plasma concentration of 5 mg/l, the loading dose was calculated to be 10 mg/kg (range 9.0-14.2 mg/kg) divided in three administrations (3.3 mg/kg every 24 hours). The maintenance dose was calculated to be 4 mg/kg once a week (range 1.7-6.0 mg/kg); 17% of the dolphins did not reach the therapeutic window of 1-5 mg/l without TDM. A TDM-guided dosing algorithm was developed in order to obtain therapeutic plasma concentrations in this population. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. An LC-MS Assay with Isocratic Separation and On-Line Solid Phase Extraction to Improve the Routine Therapeutic Drug Monitoring of Busulfan in Plasma

    Directory of Open Access Journals (Sweden)

    Ialongo Cristiano

    2017-04-01

    Full Text Available Background: Busulfan (Bu requires therapeutic drug monitoring (TDM in subjects undergoing a conditioning regimen for hematopoietic stem cell transplantation (HSCT. To speed up the procedure and increase reproducibility, we improved our routine LC-MS/MS assay using the on-line solid-phase extraction (SPE of samples.

  12. Comparison of indinavir + ritonavir 600 + 100 mg vs. 400 + 100 mg BID combinations in HIV1-infected patients guided by therapeutic drug monitoring.

    NARCIS (Netherlands)

    Wasmuth, J.C.; Rodermann, E.; Voigt, E.; Vogel, M.; Lauenroth-Mai, E.; Jessen, A.; Burger, D.M.; Rockstroh, J.K.

    2007-01-01

    OBJECTIVE: To compare two reduced dose indinavir (IDV) + ritonavir (RTV) combinations guided by therapeutic drug monitoring (TDM) in treatment-naive HIV1-infected patients. METHODS: HIV1-infected treatment naive patients were prospectively randomized to treatment with IDV 600 mg or 400 mg BID each

  13. Therapeutic drug monitoring and use of an adjusted body weight strategy for high-dose voriconazole therapy.

    Science.gov (United States)

    Richards, Patrick G; Dang, Kimberlyn M; Kauffman, Carol A; Stalker, Kay Lyn; Sudekum, David; Kerr, Lisa; Brinker-Bodley, Michelle; Cheriyan, Beena; West, Nina; Collins, Curtis D; Polega, Shikha; Malani, Anurag N

    2017-04-01

    A high-dose 12 mg/kg/day (6 mg/kg twice daily) voriconazole regimen was recommended by the CDC to treat patients injected with contaminated methylprednisolone acetate that caused a multi-state fungal outbreak in 2012-13. Therapeutic drug monitoring results of this unique regimen are unknown, as is the most appropriate dosing weight for obese patients. We evaluated voriconazole trough measurements for this dosing scheme, as well as the use of adjusted body weight dosing for obese patients. Voriconazole trough levels were analysed in obese (BMI ≥35 kg/m 2 ) and non-obese (BMI voriconazole troughs were supratherapeutic (>5 mg/L) in 65 (47%) patients, therapeutic (2-5 mg/L) in 57 (41%) patients and subtherapeutic (Voriconazole doses >11 and >8 mg/kg/day produced mainly first steady-state supratherapeutic troughs in 44 obese and 94 non-obese patients, respectively. An initial 12 mg/kg/day was progressively lowered to a median maintenance dose of 8.5 mg/kg/day in the obese and 8.6 mg/kg/day in the non-obese. A high-dose voriconazole regimen produced initial supratherapeutic troughs that required dose adjustment downward by nearly 30%. Adjusted body weight dosing in obese patients resulted in a similar maintenance dose to total body weight dosing in the non-obese, and appears to be a sensible dosing strategy for these patients.

  14. Therapeutic drug monitoring of ganciclovir for postnatal cytomegalovirus infection in an extremely low birth weight infant: a case report.

    Science.gov (United States)

    Sunada, Mariko; Kinoshita, Daisuke; Furukawa, Naoko; Kihara, Minako; Nishimura, Akira; Moriuchi, Masako; Moriuchi, Hiroyuki

    2016-08-22

    Ganciclovir is a therapeutic choice for extremely premature infants with severe postnatal cytomegalovirus disease, but little is known about its optimal dose size and dosing interval for them. We treated an extremely premature female infant with postnatal cytomegalovirus infection with intravenous administration of ganciclovir since 49 days of life (postmenstrual age of 31 weeks). After ganciclovir treatment was initiated at a dose of 5 mg/kg every 12 h, cytomegalovirus loads in the peripheral blood were markedly decreased. However, since plasma ganciclovir trough level was too high, the interval was extended to every 24 h. Subsequently, the trough level and the estimated 12-h area under the concentration-time curve (AUC0-12) were decreased from 3.5 mg/L to 0.3 mg/L and 53.9 mg · h/L to 19.2 mg · h/L, respectively, resulting in an exacerbation of viremia and clinical condition. Adjustment of dosing interval from 24 h to 12 h led to a peak level of 4.2 mg/L, trough level of 1.1 mg/L, and AUC0-12 of 31.8 mg · h/L, resulting in a marked suppression of viral load. Monitoring the therapeutic drug levels and cytomegalovirus loads is useful in obtaining a proper treatment effect and preventing overdosage during ganciclovir therapy in premature infants with postnatal cytomegalovirus infection.

  15. Variation in prescribing patterns and therapeutic drug monitoring of intravenous busulfan in pediatric hematopoietic cell transplant recipients.

    Science.gov (United States)

    McCune, Jeannine S; Baker, K Scott; Blough, David K; Gamis, Alan; Bemer, Meagan J; Kelton-Rehkopf, Megan C; Winter, Laura; Barrett, Jeffrey S

    2013-03-01

    Personalizing intravenous (IV) busulfan doses in children using therapeutic drug monitoring (TDM) is an integral component of hematopoietic cell transplant. The authors sought to characterize initial dosing and TDM of IV busulfan, along with factors associated with busulfan clearance, in 729 children who underwent busulfan TDM from December 2005 to December 2008. The initial IV busulfan dose in children weighing ≤12 kg ranged 4.8-fold, with only 19% prescribed the package insert dose of 1.1 mg/kg. In those children weighing >12 kg, the initial dose ranged 5.4-fold, and 79% were prescribed the package insert dose. The initial busulfan dose achieved the target exposure in only 24.3% of children. A wide range of busulfan exposures were targeted for children with the same disease (eg, 39 target busulfan exposures for the 264 children diagnosed with acute myeloid leukemia). Considerable heterogeneity exists regarding when TDM is conducted and the number of pharmacokinetic samples obtained. Busulfan clearance varied by age and dosing frequency but not by underlying disease. The authors- group is currently evaluating how using population pharmacokinetics to optimize initial busulfan dose and TDM (eg, limited sampling schedule in conjunction with maximum a posteriori Bayesian estimation) may affect clinical outcomes in children. © The Author(s) 2013.

  16. Dose individualization of sunitinib in metastatic renal cell cancer: toxicity-adjusted dose or therapeutic drug monitoring.

    Science.gov (United States)

    Sabanathan, Dhanusha; Zhang, Alison; Fox, Peter; Coulter, Sally; Gebski, Val; Balakrishnar, Bavanthi; Chan, Mathew; Liddle, Christopher; Gurney, Howard

    2017-08-01

    Dose individualization of sunitinib has been proposed using therapeutic drug monitoring (TDM) or toxicity-adjusted dose (TAD). We prospectively studied aspects of TDM and TAD to inform future trials, namely (1) intrapatient variability (CV) of sunitinib and (2) feasibility of a TAD protocol. Sunitinib dose was adjusted to ensure grade 1 or 2 toxicity on 10-20 days of each 42-day cycle. Total trough levels (TTL) C min of sunitinib and its active metabolite were measured every 6 weeks. In 45 patients with mRCC, 283 TTL samples were assayed over a median 30 weeks (6-108 weeks). Fifteen patients (33%) had an intrapatient CV of >25% in TTL. Ninety-one percent achieved target toxicity with a final sunitinib dose of 25 mg (18%), 37.5 mg (27%), 50 mg (50%), and 62.5 or 75 mg (7%). TTL C min was 100 ng/mL in 7 (15%), 31 (69%), and 7 patients (15.5%), respectively. The median overall survival was 32 months. Sunitinib level has minimal variability in the majority of patients on stable dose. A subset of patients had a significant intrapatient variation, so we recommend two samples 4 to 6 months apart. TAD is feasible for dosing sunitinib and showed a favourable outcome.

  17. Therapeutic Drug Monitoring

    Science.gov (United States)

    ... carbamazepine , ethosuximide, sometimes gabapentin, lamotrigine, levetiracetam , topiramate, zonisamide, eslicarbazepine acetate, felbamate, lacosamide, oxcarbazepine, pregabalin, rufinamide, stiripentol, tiagabine, vigabatrin ...

  18. Therapeutic Drug Monitoring

    Science.gov (United States)

    ... LDL Particle Testing (LDL-P) Lead Legionella Testing Leptin Levetiracetam Lipase Lipid Profile Lipoprotein (a) Lithium Liver ... Bronchodilators Theophylline , caffeine Asthma , chronic obstructive pulmonary disorder (COPD) , neonatal apnea ... tacrolimus , sirolimus , mycophenolate mofetil , ...

  19. Antiretroviral therapeutic drug monitoring

    African Journals Online (AJOL)

    Winnie

    NRTIs are therefore not suitable for TDM. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) display highly variable pharmacokinetics. The key cytochrome. P450 isoenzyme responsible for metabolising efavirenz,. CYP2B6, has a polymorphism that results in slower metabolism. This polymorphism occurs much more ...

  20. Educational and organizational interventions to improve the usefulness of clinical pharmacological advice for personalized drug dosing based on therapeutic drug monitoring.

    Science.gov (United States)

    Pea, Federico; Dose, Lucia; Cojutti, Piergiorgio; Baraldo, Massimo; Fontana, Fabrizio; Favaretti, Carlo; Furlanut, Mario

    2014-11-01

    This study was aimed at increasing the clinical usefulness of clinical pharmacological advice (CPA) for personalized drug dosing based on therapeutic drug monitoring (TDM). Educational and organizational interventions focused on improving the knowledge of clinical pharmacology among hospital healthcare workers and reducing the incidence of errors throughout the process were planned. After a pre-interventional period of risk assessment, different list forms of the types of error occurring in the various phases of the process (Phase 1, request for CPA and blood sampling for TDM; Phase 2, sample delivery to and check in at the CPU; Phase 3, TDM execution and CPA production) were created. In the interventional period, the errors were collected daily and educational programmes were carried out. The pre-intervention error rate was 19.5%, and resulted significantly higher for the requests coming from the medical wards compared with those from the surgical wards or the ICUs (26.0% versus 10.5% versus 13.7%, p < 0.001). The educational programme trained 303 nurses and 145 physicians. Afterwards, the error percentage progressively dropped (15.5% in the 2nd trimester; 12.3% in the 3rd one; 10.5% in the 4th one). The adopted strategy resulted in significant improvements which may be useful both to improve quality of patient care and to reduce waste in healthcare costs. © 2014 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  1. Ethambutol Is Cleared by a Contemporary High-Flux Hemodialyzer, and Drug Monitoring Ensures Safety and Therapeutic Effect.

    Science.gov (United States)

    Chew, Rusheng; Jongbloed, Sarah; Jegatheesan, Dev; Healy, Helen; Ta, Kim; Ungerer, Jacobus; McWhinney, Brett; Donovan, Peter; Woods, Marion L

    2017-06-01

    It is uncertain, given the lack of recent data and the inconclusive nature of previous data, whether ethambutol is cleared by hemodialysis using contemporary dialyzers. We measured serum ethambutol concentrations before, during, and 1 h after hemodialysis in a 75-year-old Caucasian man receiving ethambutol for disseminated Bacille Calmette-Guérin infection. There was a mean 41% decrease in serum ethambutol concentration during dialysis, confirming the hemodialyzability of ethambutol and the utility of drug monitoring in ensuring safety. Copyright © 2017 American Society for Microbiology.

  2. Simultaneous UHPLC-UV analysis of hydroxychloroquine, minocycline and doxycycline from serum samples for the therapeutic drug monitoring of Q fever and Whipple's disease.

    Science.gov (United States)

    Armstrong, Nicholas; Richez, Magali; Raoult, Didier; Chabriere, Eric

    2017-08-15

    A fast UHPLC-UV method was developed for the simultaneous analysis of Hydroxychloroquine, Minocycline and Doxycycline drugs from 100μL of human serum samples. Serum samples were extracted by liquid-liquid extraction and injected into a phenyl hexyl reverse phase column. Compounds were separated using a mobile phase linear gradient and monitored by UV detection at 343nm. Chloroquine and Oxytetracycline were used as internal standards. Lower and upper limits of quantifications, as well as the other levels of calibration, were validated with acceptable accuracy (<15% deviation) and precision (<15% coefficient of variation) according to the European Medicines Agency guidelines. This new method enables cost and time reduction and was considered suitable for the clinical laboratory. It is the first published assay for the therapeutic drug monitoring of patients diagnosed with Q fever or Whipple's disease. Copyright © 2017 Elsevier B.V. All rights reserved.

  3. Quantification of imatinib in human serum: validation of a high-performance liquid chromatography-mass spectrometry method for therapeutic drug monitoring and pharmacokinetic assays

    Directory of Open Access Journals (Sweden)

    Rezende VM

    2013-08-01

    Full Text Available Vinicius Marcondes Rezende,1 Ariane Rivellis,1 Mafalda Megumi Yoshinaga Novaes,1 Dalton de Alencar Fisher Chamone,2 Israel Bendit1,21Laboratory of Tumor Biology, 2Department of Hematology, School of Medicine, University of São Paulo, São Paulo, BrazilBackground: Imatinib mesylate has been a breakthrough treatment for chronic myeloid leukemia. It has become the ideal tyrosine kinase inhibitor and the standard treatment for chronic-phase leukemia. Striking results have recently been reported, but intolerance to imatinib and noncompliance with treatment remain to be solved. Molecular monitoring by quantitative real-time polymerase chain reaction is the gold standard for monitoring patients, and imatinib blood levels have also become an important tool for monitoring.Methods: A fast and cheap method was developed and validated using high-performance liquid chromatography-mass spectrometry for quantification of imatinib in human serum and tamsulosin as the internal standard. Remarkable advantages of the method includes use of serum instead of plasma, less time spent on processing and analysis, simpler procedures, and requiring reduced amounts of biological material, solvents, and reagents. Stability of the analyte was also studied. This research also intended to drive the validation scheme in clinical centers. The method was validated according to the requirements of the US Food and Drug Administration and Brazilian National Health Surveillance Agency within the range of 0.500–10.0 µg/mL with a limit of detection of 0.155 µg/mL. Stability data for the analyte are also presented.Conclusion: Given that the validated method has proved to be linear, accurate, precise, and robust, it is suitable for pharmacokinetic assays, such as bioavailability and bioequivalence, and is being successfully applied in routine therapeutic drug monitoring in the hospital service.Keywords: imatinib, high-performance liquid chromatography-mass spectrometry, therapeutic

  4. Dose optimisation of voriconazole with therapeutic drug monitoring in children: a single-centre experience in China.

    Science.gov (United States)

    Liu, Liang; Zhou, Xing; Wu, Tingting; Jiang, Hongliang; Yang, Sitao; Zhang, Yang

    2017-04-01

    The pharmacokinetic profile of voriconazole is highly variable, rendering inconsistent and/or inadequate dosing, especially in children voriconazole with at least one plasma trough level (C trough ) monitored. Statistical analyses were performed to examine the dose-exposure relationship as well as other factors potentially affecting voriconazole C trough in children of different ages. A total of 107 paediatric patients were included, of whom 75 were voriconazole C trough was highly variable in patients aged voriconazole exposure. Co-administration of omeprazole significantly increased the voriconazole level (P = 0.032), likely through CYP2C19 inhibition. This is the largest series to date describing voriconazole dose-exposure relationships in children aged <2 years. A starting maintenance dose of 5 to <7 mg/kg intravenously twice daily may be required for most children of Asian origin to reach the therapeutic target. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  5. The Utility of Infliximab Therapeutic Drug Monitoring among Patients with Inflammatory Bowel Disease and Concerns for Loss of Response: A Retrospective Analysis of a Real-World Experience

    Science.gov (United States)

    Shuster, Constantin; DeMarco, Mari L.; Rosenfeld, Gregory

    2016-01-01

    Background. Infliximab (IFX) therapeutic drug monitoring (TDM) allows for objective decision making in patients with inflammatory bowel disease (IBD) and loss of response. Questions remain about whether IFX TDM improves outcomes. Methods. Patients with IBD who had IFX TDM due to concerns for loss of response were considered for inclusion. Serum IFX trough concentration and anti-drug antibody (ADA) concentrations were measured. Patients were grouped by TDM results: group 1, low IFX/high ADA; group 2, low IFX/low ADA; group 3, therapeutic IFX. Changes in management were analyzed according to groupings; remission rates were assessed at 6 months. Results. 71 patients were included of whom 37% underwent an appropriate change in therapy. Groups 1 (67%) and 2 (83%) had high adherence compared to only 9% in group 3. At 6 months, 57% had achieved remission. More patients who underwent an appropriate change in therapy achieved remission, though this did not reach statistical significance (69% versus 49%; P = 0.098). Conclusions. A trend towards increased remission rates was associated with appropriate changes in management following TDM results. Many patients with therapeutic IFX concentrations did not undergo an appropriate change in management, potentially reflecting a lack of available out-of-class options at the time of TDM or due to uncertainty of the meaning of the reported therapeutic range. PMID:27957480

  6. The Utility of Infliximab Therapeutic Drug Monitoring among Patients with Inflammatory Bowel Disease and Concerns for Loss of Response: A Retrospective Analysis of a Real-World Experience

    Directory of Open Access Journals (Sweden)

    Robert A. Mitchell

    2016-01-01

    Full Text Available Background. Infliximab (IFX therapeutic drug monitoring (TDM allows for objective decision making in patients with inflammatory bowel disease (IBD and loss of response. Questions remain about whether IFX TDM improves outcomes. Methods. Patients with IBD who had IFX TDM due to concerns for loss of response were considered for inclusion. Serum IFX trough concentration and anti-drug antibody (ADA concentrations were measured. Patients were grouped by TDM results: group 1, low IFX/high ADA; group 2, low IFX/low ADA; group 3, therapeutic IFX. Changes in management were analyzed according to groupings; remission rates were assessed at 6 months. Results. 71 patients were included of whom 37% underwent an appropriate change in therapy. Groups 1 (67% and 2 (83% had high adherence compared to only 9% in group 3. At 6 months, 57% had achieved remission. More patients who underwent an appropriate change in therapy achieved remission, though this did not reach statistical significance (69% versus 49%; P=0.098. Conclusions. A trend towards increased remission rates was associated with appropriate changes in management following TDM results. Many patients with therapeutic IFX concentrations did not undergo an appropriate change in management, potentially reflecting a lack of available out-of-class options at the time of TDM or due to uncertainty of the meaning of the reported therapeutic range.

  7. Tacrolimus concentration/dose ratio as a therapeutic drug monitoring strategy: The influence of gender and comedication

    Directory of Open Access Journals (Sweden)

    Rančić Nemanja

    2015-01-01

    Full Text Available Background/Aim. A combination of tacrolimus and other drugs such as corticosteroids has been commonly used immunosuppresive regimens. On the other hand, there is a growing body of evidence that male and female may differ in their response to the equal drug treatment. The aim of the study was to estimated the use of tacrolimus concentration/dose (C/D ratio for the assessment of the influence of gender differences and comedication on tacrolimus exposure in renal transplant recipients. Methods. This prospective case series study included 54 patients, in which the unit of monitoring was outpatient examination (1,872 of the renal transplant patients. The patients were monitored in the period 2010-2014, starting one month after the transplantation. Tacrolimus trough concentrations (TTC were measured by chemiluminescence microparticles immunoassay. Results. TTC and the tacrolimus C/D ratio were significantly lower in the females comparing with the males. Contrary to the males, in the females a significant increase of the tacrolimus daily dose (TDD per body weight and TTC, along with the corticosteroid dose increase, was not accompanied by any significant changes in the tacrolimus C/D ratio; in different corticosteroid doses faster elimination of tacrolimus was found with the exception of the doses > 0.25 mg/kg. In the patients treated with proton pump inhibitors, mainly with pantoprazole TDD per body weight and TTC were significantly higher, while the tacrolimus C/D ratio was significantly lower compared to the patients without this treatment. In the patients treated with calcium channel blockers, TDD per body weight was significantly lower (particularly with amlodipine while the tacrolimus C/D ratio was higher compared to the patients who were not treated by them. Conclusion. A lower tacrolimus exposure was detected in females in comparison to males. When gender differences were considered in the context of different corticosteroid doses, faster

  8. Liquid chromatography-tandem mass spectrometry assay for therapeutic drug monitoring of the tyrosine kinase inhibitor, midostaurin, in plasma from patients with advanced systemic mastocytosis.

    Science.gov (United States)

    Bourget, Philippe; Amin, Alexandre; Chandesris, Marie-Olivia; Vidal, Fabrice; Merlette, Christophe; Hirsch, Isabelle; Cabaret, Laure; Carvalhosa, Ana; Mogenet, Agnès; Frenzel, Laurent; Damaj, Gandhi; Lortholary, Olivier; Hermine, Olivier

    2014-01-01

    We developed and validated quantitative bioanalytical liquid chromatography-tandem mass spectrometry assay for the protein kinase inhibitor, midostaurin. Plasma samples were pre-treated using a protein precipitation with methanol containing midostaurin-d5 as an internal standard. After centrifugation, 5μL of the supernatant was injected into the chromatographic system. The system consisted of a 3.5μm particle bonded octadecyl silica column, with gradient elution using a mixture of 0.1% (v/v) formic acid in acetonitrile and 10mM ammonium formate in water with 0.1% formic acid. The analyte was quantified using the selected reaction-monitoring mode of a triple quadrupole mass spectrometer equipped with a heated electrospray interface. The assay was validated in a 75-2500ng/mL calibration range. For quality control, within-day and between-day precisions were 1.2-2.8%, and 1.2-6.9%, respectively. The β-expectation tolerance limit (accuracy) met the limits of acceptance ±15% (±20% for the LLQ). The drug was sufficiently stable under all relevant analytical conditions. The assay has successfully been used to assess drug levels for therapeutic drug monitoring in patients presenting advanced systemic mastocytosis and treated with the promising midostaurin. Copyright © 2013 Elsevier B.V. All rights reserved.

  9. Variability in protein binding of teicoplanin and achievement of therapeutic drug monitoring targets in critically ill patients: lessons from the DALI Study.

    Science.gov (United States)

    Roberts, J A; Stove, V; De Waele, J J; Sipinkoski, B; McWhinney, B; Ungerer, J P J; Akova, M; Bassetti, M; Dimopoulos, G; Kaukonen, K-M; Koulenti, D; Martin, C; Montravers, P; Rello, J; Rhodes, A; Starr, T; Wallis, S C; Lipman, J

    2014-05-01

    The aims of this study were to describe the variability in protein binding of teicoplanin in critically ill patients as well as the number of patients achieving therapeutic target concentrations. This report is part of the multinational pharmacokinetic DALI Study. Patients were sampled on a single day, with blood samples taken both at the midpoint and the end of the dosing interval. Total and unbound teicoplanin concentrations were assayed using validated chromatographic methods. The lower therapeutic range of teicoplanin was defined as total trough concentrations from 10 to 20 mg/L and the higher range as 10-30 mg/L. Thirteen critically ill patients were available for analysis. The following are the median (interquartile range) total and free concentrations (mg/L): midpoint, total 13.6 (11.2-26.0) and free 1.5 (0.7-2.5); trough, total 11.9 (10.2-22.7) and free 1.8 (0.6-2.6). The percentage free teicoplanin for the mid-dose and trough time points was 6.9% (4.5-15.6%) and 8.2% (5.5-16.4%), respectively. The correlation between total and free antibiotic concentrations was moderate for both the midpoint (ρ = 0.79, P = 0.0021) and trough (ρ = 0.63, P = 0.027). Only 42% and 58% of patients were in the lower and higher therapeutic ranges, respectively. In conclusion, use of standard dosing for teicoplanin leads to inappropriate concentrations in a high proportion of critically ill patients. Variability in teicoplanin protein binding is very high, placing significant doubt on the validity of total concentrations for therapeutic drug monitoring in critically ill patients. Copyright © 2014 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

  10. Pharmacokinetic variability, efficacy and tolerability of eslicarbazepine acetate-A national approach to the evaluation of therapeutic drug monitoring data and clinical outcome.

    Science.gov (United States)

    Svendsen, Torleiv; Brodtkorb, Eylert; Reimers, Arne; Molden, Espen; Sætre, Erik; Johannessen, Svein I; Johannessen Landmark, Cecilie

    2017-01-01

    Eslicarbazepine acetate (ESL) is a new antiepileptic drug (AED), still insufficiently studied regarding pharmacokinetic variability, efficacy and tolerability. The purpose of this study was to evaluate therapeutic drug monitoring (TDM) data in Norway and relate pharmacokinetic variability to clinical efficacy and tolerability in a long-term clinical setting in patients with refractory epilepsy. This retrospective observational study included TDM-data from the main laboratories and population data from the Norwegian Prescription Database in Norway, in addition to clinical data from medical records of adult patients using ESL for up to three years, whenever possible. TDM-data from 168 patients were utilized for assessment of pharmacokinetic variability, consisting of 71% of the total number of patients in Norway using ESL, 2011-14. Median daily dose of ESL was 800mg (range 400-1600mg), and median serum concentration of ESL was 53μmol/L (range 13-132μmol/L). Inter-patient variability of ESL was extensive, with 25-fold variability in concentration/dose ratios. Additional clinical data were available from 104 adult patients out of the 168, all with drug resistant focal epilepsy. After 1, 2 and 3 years follow-up, the retention rate of ESL was 83%, 72% and 64%, respectively. ESL was generally well tolerated as add-on treatment, but sedation, cognitive impairment and hyponatremia were reported. Hyponatremia (sodium <137mmol/L) was present in 36% of the patients, and lead to discontinuation in three. Pharmacokinetic variability of ESL was extensive and the demonstration of usefulness of TDM requires further studies. In patients with drug resistant focal Epilepsy, the high retention rate indicated good efficacy and tolerability. Hyponatremia was observed in one third of the patients. The present results point to a need for individualization of treatment and TDM may be useful. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Impact of β-lactam antibiotic therapeutic drug monitoring on dose adjustments in critically ill patients undergoing continuous renal replacement therapy.

    Science.gov (United States)

    Economou, Caleb J P; Wong, Gloria; McWhinney, Brett; Ungerer, Jacobus P J; Lipman, Jeffrey; Roberts, Jason A

    2017-05-01

    The objective of this study was to describe the effect of therapeutic drug monitoring (TDM) and dose adjustments of β-lactam antibiotics administered to critically ill patients undergoing continuous renal replacement therapy (CRRT) in a 30-bed tertiary intensive care unit (ICU). β-Lactam TDM data in our tertiary referral ICU were retrospectively reviewed. Clinical, demographic and dosing data were collected for patients administered β-lactam antibiotics while undergoing CRRT. The target trough concentration range was 1-10× the minimum inhibitory concentration (MIC). A total of 111 TDM samples from 76 patients (46 male) with a mean ± standard deviation age of 56.6 ± 15.9 years and weight of 89.1 ± 25.8 kg were identified. The duration of antibiotic therapy was between 2 days and 42 days. TDM identified a need for dose modification of β-lactam antibiotics in 39 (35%) instances; in 27 (24%) samples, TDM values resulted in decreasing the prescribed dose of β-lactam antibiotic whereas an increase in the prescribed dose occurred in 12 (11%) cases. In patients treated for hospital-acquired pneumonia and primary or secondary bacteraemia, the dose was required to be decreased in 10/25 (40%) and 7/46 (15%) cases, respectively, to attain target concentrations. β-Lactam TDM is a useful tool for guiding drug dosing in complex patients such as those receiving CRRT. Although over one-third of patients manifested concentrations outside the therapeutic range, most of these CRRT patients had excessive β-lactam concentrations. Copyright © 2017 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.

  12. A computerised sampling strategy for therapeutic drug monitoring of lithium provides precise estimates and significantly reduces dose-finding time

    DEFF Research Database (Denmark)

    Høgberg, Lotte Christine Groth; Jürgens, Gesche; Zederkof, Vivian Wederking

    2012-01-01

    citrate. Bayesian approach was performed in the intervention groups, and estimation of lithium steady-state trough concentration was obtained from non-steady-state blood sample, collected about 12 hr after the first lithium study dose. The estimate was compared with the actually measured steady......-state concentration. In the control group, lithium monitoring was traditionally performed as steady-state blood sampling. Predicted and measured lithium concentrations were comparable. The desired lithium dose was reached significantly faster in the intervention group compared to control; 2.47 ± 2.22 days versus 9.......96 ± 11.24 days (mean ± S.D.) (p = 0.0003). Bayesian approach was an advantage for the clinicians as a fast and safe aid to obtain the optimal lithium treatment dose....

  13. Serum trough infliximab and anti-infliximab antibodies in a cohort of gastroenterology and rheumatology patients' infliximab therapeutic drug monitoring.

    Science.gov (United States)

    Barlow, Nicola L; Mohammed, Pervaz; Berg, Jonathan D

    2016-07-01

    Infliximab, a monoclonal antibody directed against tumour necrosis factor, is widely used in the treatment of chronic inflammatory conditions including Crohn's disease and rheumatoid arthritis. Its use is limited by development of anti-infliximab antibodies, which can lead to loss of therapeutic efficacy. Serum infliximab and anti-infliximab antibody measurements have recently become routinely available in the UK. The study aimed to assess the clinical utility of antibodies as an adjunct to trough infliximab. Serum trough infliximab was measured in 201 samples from 108 gastroenterology and rheumatology patients on maintenance infliximab therapy. Results were correlated with C-reactive protein concentrations. Total anti-infliximab antibodies were measured in 164 samples. The median (25th-75th percentile) trough infliximab was 3.7 µg/mL (1.2-5.2 µg/mL) and 23% of samples had a concentration ≤1 µg/mL. A notable proportion had positive anti-infliximab antibodies: 84/164 (51%), which subdivided to 85% and 28% with infliximab ≤1 and >1 µg/mL, respectively.Serum C-reactive protein was found to be significantly higher where infliximab was ≤1 compared to >1 µg/mL (10 mg/L [infliximab and C-reactive protein differed depending on antibody status and there was no association between C-reactive protein and the presence or absence of antibodies. Our findings support measurement of anti-infliximab antibodies only in the context of low infliximab concentrations infliximab concentrations. © The Author(s) 2015.

  14. Dose Escalation of Tamoxifen in Patients with Low Endoxifen Level: Evidence for Therapeutic Drug Monitoring-The TADE Study.

    Science.gov (United States)

    Fox, Peter; Balleine, Rosemary L; Lee, Clara; Gao, Bo; Balakrishnar, Bavanthi; Menzies, Alexander M; Yeap, Shang Heng; Ali, Sayed Sahanawaz; Gebski, Val; Provan, Pamela; Coulter, Sally; Liddle, Christopher; Hui, Rina; Kefford, Richard; Lynch, Jodi; Wong, Mark; Wilcken, Nicholas; Gurney, Howard

    2016-07-01

    Endoxifen is the major mediator of tamoxifen effect and endoxifen levels <15 nmol/L may be associated with increased risk of breast cancer recurrence. We increased tamoxifen dose in breast cancer patients with low endoxifen levels and assessed the influence of various parameters on reaching 15 nmol/L and 30 nmol/L endoxifen levels. Tamoxifen dose was increased in those with endoxifen levels below 30 nmol/L. Toxicity, including hot flash score, was measured. CYP2D6 metabolizer status was classified as ultra-rapid (UM), extensive (EM), intermediate (IM), or poor (PM) based genotype of somatic DNA. Dosage was escalated in 68 of 122 participants. On 20 mg tamoxifen, 24% had endoxifen levels below 15 nmol/L and this reduced to 6% following dose escalation. In over 50% of cases, there was no identified cause for low endoxifen. Low baseline endoxifen level, and not CYP2D6 metabolizer status, independently predicted reaching threshold targets for both the 15 nmol/L and 30 nmol/L targets (P = 0.04 and 0.003 respectively). The 15 nmol/L target was reached in all UM/EM and IM patients, 63% of PM patients, and 58% of those with baseline endoxifen of <10 nmol/L. There was no correlation between hot flash score and genotype or any tamoxifen metabolite level including endoxifen (R = 0.07). Low endoxifen on standard dose tamoxifen was the only independent predictor of failure to achieve potentially therapeutic levels. Trials examining tamoxifen dose escalation and breast cancer outcome should be guided by endoxifen levels alone, without reference to CYP2D6 genotype or presence of hot flashes. Clin Cancer Res; 22(13); 3164-71. ©2016 AACRSee related commentary by Hertz and Rae, p. 3121. ©2016 American Association for Cancer Research.

  15. Therapeutic drug monitoring of posaconazole oral suspension in paediatric patients younger than 13 years of age: a retrospective analysis and literature review.

    Science.gov (United States)

    Jancel, T; Shaw, P A; Hallahan, C W; Kim, T; Freeman, A F; Holland, S M; Penzak, S R

    2017-02-01

    Posaconazole is an extended-spectrum triazole antifungal with activity against a variety of clinically significant yeasts and moulds. Posaconazole is not currently approved by the U.S. Food and Drug Administration for use in children younger than 13 years of age. Our primary objective was to describe the dosing and observed trough concentrations with posaconazole oral suspension in paediatric patients at the National Institutes of Health Clinical Center (Bethesda, MD). This retrospective single-centre study reviewed paediatric patients younger than 13 years of age initiated on posaconazole oral suspension. Patients were included if they were initiated on posaconazole for prophylaxis or treatment for fungal infections from September 2006 through March 2013 with at least one trough concentration collected after at least 7 days of therapy. A total of 20 male patients were included, of whom 15 (75%) had chronic granulomatous disease. The median age of patients was 6·5 years (range: 2·8-10·7). A total of 79 posaconazole trough concentrations were measured in patients receiving posaconazole as prophylaxis (n = 8) or treatment (n = 12). Posaconazole dose referenced to total body weight ranged from 10·0 to 49·2 mg/kg/day. Posaconazole trough concentrations ranged from undetectable (suspension remain challenging. Until studies are conducted to determine the appropriate dosing of posaconazole in this patient population, therapeutic drug monitoring should be considered to ensure adequate posaconazole exposure. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

  16. Therapeutic drug monitoring of cyclosporine Neoral in de novo Chinese cardiac transplant recipients treated with an everolimus-cyclosporine immunosuppressive regimen.

    Science.gov (United States)

    Wang, C-H; Chou, N-K; Wu, F-L L; Ko, W-J; Tsao, C-I; Chi, N-H; Hsu, R-B; Wang, S-S

    2006-09-01

    This study determined cyclosporine Neoral (CsA) pharmacokinetics and the accuracy of a limited sampling strategy to predict the 12-hour CsA area-under-the-curve (AUC) to provide a practical method for more accurate therapeutic drug monitor of CsA among de novo Chinese heart transplant recipients treated with an everolimus-CsA immunosuppressive regimen. Blood samples were collected at 0, 0.5, 1, 2, 3, 4, 6, 8, 10, and 12 hours after oral administration of CsA in six de novo heart recipients receiving a CsA, everolimus, and methylprenisolone immunosuppressive regimen after rabbit antithymoglobulin sequential immuno-induction. We analyzed the pharmacokinetics of the first dose (PK-1) and steady state dose (PK-2) at 1 month after transplantation. The accuracy of a single-point sampling method to predict the AUC was generated by linear regression analyses. The t(max) and dose-normalized C(max) of PK-1 and PK-2 were similar. The correlations in single-point blood levels of PK-1 to predict the AUC(0-infinity) were much lower than the corresponding sampling times in PK-2. In PK-2 study, C4 had the best correlation (r(2) = 0.913, P = .003) to predict AUC(0-12). In addition, the trough concentrations, C(0) (r(2) = 0.875, P = .006) and C(12) (r(2) = 0.783, P = .02) also showed good correlations. C2 had insufficient correlation to predict AUC(0-infinity) in PK-1 or AUC(0-12) in the PK-2 study. In conclusion, the absorption of CsA was similar during PK-1 and PK-2. At steady dose, C4 had the best single-point correlation to predict AUC(0-12). Trough blood levels may be more practical in clinical use to monitor CsA.

  17. Therapeutic drug monitoring of continuous-infusion acylovir for disseminated herpes simplex virus infection in a neonate receiving concurrent extracorporeal life support and continuous renal replacement therapy.

    Science.gov (United States)

    Cies, Jeffrey J; Moore, Wayne S; Miller, Kyle; Small, Christine; Carella, Dominick; Conley, Susan; Parker, Jason; Shea, Paul; Chopra, Arun

    2015-02-01

    Disseminated herpes simplex virus (HSV) infection in neonates represents a devastating entity that yields high mortality. Acyclovir is the primary antiviral agent used to treat life-threatening HSV infections in neonates; however, even though the agent has reduced morbidity overall from these infections, mortality with disseminated disease remains high. Currently, to our knowledge, no data exist regarding therapeutic drug monitoring of acyclovir in the setting of extracorporeal life support (ECLS) or continuous renal replacement therapy (CRRT) coupled with ECLS. We describe the case of a 14-day-old female with disseminated HSV-1 infection that progressed to fulminant hepatic and renal failure, necessitating the use of ECLS for hemodynamic support and CRRT as a treatment modality for hepatic and renal failure. The standard dosage of acyclovir 20 mg/kg/dose intravenously every 8 hours had been initiated, but after conversion to ECLS and CRRT, the patient's dosage was increased to 30 mg/kg/dose every 8 hours. After a repeat viral load remained unchanged from the initial viral load at 1 × 10(8)  copies/ml, the patient was transitioned from intermittent dosing to a continuous infusion of acyclovir added to the dialysate solution for CRRT at a concentration of 5.5 mg/L. To provide an optimal outcome, dosing was designed to maintain acyclovir plasma concentrations of at least 3 mg/L in order to maintain an acyclovir concentration of at least 1 mg/L in the cerebrospinal fluid. The patient's acyclovir serum concentrations measured at 24 and 72 hours after starting continuous-infusion acyclovir via the dialysate were 8.8 and 5.3 mg/L, respectively, allowing for a continuous serum concentration above 3 mg/L. Unfortunately, before a repeat viral load could be obtained to assess the efficacy of the continuous infusion acyclovir, the patient experienced an intracerebral hemorrhage as a complication related to ECLS after which technological support was withdrawn

  18. Hydrogel-Forming Microneedle Arrays Allow Detection of Drugs and Glucose In Vivo: Potential for Use in Diagnosis and Therapeutic Drug Monitoring.

    Directory of Open Access Journals (Sweden)

    Ester Caffarel-Salvador

    Full Text Available We describe, for the first time the use of hydrogel-forming microneedle (MN arrays for minimally-invasive extraction and quantification of drug substances and glucose from skin in vitro and in vivo. MN prepared from aqueous blends of hydrolysed poly(methyl-vinylether-co-maleic anhydride (11.1% w/w and poly(ethyleneglycol 10,000 daltons (5.6% w/w and crosslinked by esterification swelled upon skin insertion by uptake of fluid. Post-removal, theophylline and caffeine were extracted from MN and determined using HPLC, with glucose quantified using a proprietary kit. In vitro studies using excised neonatal porcine skin bathed on the underside by physiologically-relevant analyte concentrations showed rapid (5 min analyte uptake. For example, mean concentrations of 0.16 μg/mL and 0.85 μg/mL, respectively, were detected for the lowest (5 μg/mL and highest (35 μg/mL Franz cell concentrations of theophylline after 5 min insertion. A mean concentration of 0.10 μg/mL was obtained by extraction of MN inserted for 5 min into skin bathed with 5 μg/mL caffeine, while the mean concentration obtained by extraction of MN inserted into skin bathed with 15 μg/mL caffeine was 0.33 μg/mL. The mean detected glucose concentration after 5 min insertion into skin bathed with 4 mmol/L was 19.46 nmol/L. The highest theophylline concentration detected following extraction from a hydrogel-forming MN inserted for 1 h into the skin of a rat dosed orally with 10 mg/kg was of 0.363 μg/mL, whilst a maximum concentration of 0.063 μg/mL was detected following extraction from a MN inserted for 1 h into the skin of a rat dosed with 5 mg/kg theophylline. In human volunteers, the highest mean concentration of caffeine detected using MN was 91.31 μg/mL over the period from 1 to 2 h post-consumption of 100 mg Proplus® tablets. The highest mean blood glucose level was 7.89 nmol/L detected 1 h following ingestion of 75 g of glucose, while the highest mean glucose concentration

  19. Emerging therapeutic drugs for AML

    National Research Council Canada - National Science Library

    Stein, Eytan M; Tallman, Martin S

    2016-01-01

    Multiple new drugs are being developed to treat acute myeloid leukemia (AML), including novel formulations of traditional chemotherapy-antibody drug conjugates and agents that target specific mutant enzymes...

  20. Ultrafast and high-throughput mass spectrometric assay for therapeutic drug monitoring of antiretroviral drugs in pediatric HIV-1 infection applying dried blood spots.

    NARCIS (Netherlands)

    Meesters, R.J.; Kampen, J.J. van; Reedijk, M.L.; Scheuer, R.D.; Dekker, L.J.; Burger, D.M.; Hartwig, N.G.; Osterhaus, A.D.; Luider, T.M.; Gruters, R.A.

    2010-01-01

    Kaletra (Abott Laboratories) is a co-formulated medication used in the treatment of HIV-1-infected children, and it contains the two antiretroviral protease inhibitor drugs lopinavir and ritonavir. We validated two new ultrafast and high-throughput mass spectrometric assays to be used for

  1. Ultrafast and high-throughput mass spectrometric assay for therapeutic drug monitoring of antiretroviral drugs in pediatric HIV-1 infection applying dried blood spots

    NARCIS (Netherlands)

    R.J.W. Meesters (Roland); J.J.A. van Kampen (Jeroen); M.L. Reedijk (Mariska); R.D. Scheuer (Rachel); L.J.M. Dekker (Lennard); D.M. Burger (David); N.G. Hartwig (Nico); A.D.M.E. Osterhaus (Albert); T.M. Luider (Theo); R.A. Gruters (Rob)

    2010-01-01

    textabstractKaletra® (Abott Laboratories) is a co-formulated medication used in the treatment of HIV-1-infected children, and it contains the two antiretroviral protease inhibitor drugs lopinavir and ritonavir. We validated two new ultrafast and high-throughput mass spectrometric assays to be used

  2. A Survey Study of Gastroenterologists' Attitudes and Barriers Toward Therapeutic Drug Monitoring of Anti-TNF Therapy in Inflammatory Bowel Disease.

    Science.gov (United States)

    Grossberg, Laurie B; Papamichael, Konstantinos; Feuerstein, Joseph D; Siegel, Corey A; Ullman, Thomas A; Cheifetz, Adam S

    2017-12-19

    Therapeutic drug monitoring (TDM) may improve the efficacy and cost-effectiveness of anti-TNF therapy. A standardized approach of utilizing TDM has not been established. The objective of this study was to determine gastroenterologists' attitudes and barriers toward TDM of anti-TNF therapy in clinical practice. An 18-question survey was distributed to members of the American College of Gastroenterology and Crohn's and Colitis Foundation via email. We collected physician characteristics, practice demographics, and data regarding TDM use and perceived barriers to TDM. Factors associated with the use of TDM were determined by logistic regression analysis. A total of 403 gastroenterologists from 42 US states (76.4% male) met inclusion criteria: 90.1% use TDM, mostly reactively for secondary loss of response (87.1%) and primary nonresponse (66%); 36.6% use TDM proactively. The greatest barriers to TDM implementation were uncertainty about insurance coverage (77.9%), high out-of-pocket patient costs (76.4%), and time lag from serum sample to result (38.5%). Factors independently associated with the use of TDM and proactive TDM were practice in an academic setting (P = 0.019), and more IBD patients seen per month (P = 0.015), and Crohn's and Colitis Foundation membership (P < 0.001), and more IBD patients on anti-TNF therapy per month (P = 0.006), respectively. If all barriers were removed, an additional one-third of physicians would apply proactive TDM. Lack of insurance coverage, high out-of-pocket costs, and the time lag from test to result limit use of TDM in the United States. Validation of low-cost assays, point of care testing, and studies that standardize the use of TDM are needed to make TDM more commonplace.

  3. The ANTIBIOPERF study: a nationwide cross-sectional survey about practices for β-lactam administration and therapeutic drug monitoring among critically ill patients in France.

    Science.gov (United States)

    Charmillon, A; Novy, E; Agrinier, N; Leone, M; Kimmoun, A; Levy, B; Demoré, B; Dellamonica, J; Pulcini, C

    2016-07-01

    Our objective was to assess current practices about the administration (intermittent, extended, or continuous infusions) and therapeutic drug monitoring (TDM) of β-lactam antibiotics and vancomycin in France. We conducted a nationwide cross-sectional survey in May-August 2015, using an online questionnaire, sent as an e-mail link to infectious disease specialists and intensive care specialists through national mailing lists. We used clinical vignettes of critically ill patients to assess physicians' practices about administration and TDM practices for amoxicillin, cloxacillin, piperacillin/tazobactam, cefotaxime, ceftazidime, cefepime, meropenem and vancomycin. In all, 507 physicians participated (507/1200, response rate 42%). TDM was rarely available for β-lactams (from 16.5% (81/490) for cloxacillin to 30% (145/490) for ceftazidime), whereas vancomycin TDM was available in 97% (477/490) of the cases. In the clinical vignettes, ceftazidime and piperacillin/tazobactam were the β-lactams administered most frequently by extended or continuous infusions (76% (336/440) and 57% (252/444), respectively). Gaps in knowledge about the duration of stability of intravenous β-lactams were common (correct answers ranged from 8% (35/432) for cloxacillin to 33% (146/438) for ceftazidime). Most physicians (77%, 339/442) were convinced of the value of extended or continuous infusions for β-lactams in critically ill patients, but 48% (211/442) did not have access to practical guidelines. Our survey found that most infectious disease and intensive care specialists are favourable to optimized administration of β-lactams in critically ill patients. But the lack of guidelines and limited TDM availability for β-lactams in hospitals are potential barriers to its implementation. Copyright © 2016 European Society of Clinical Microbiology and Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

  4. Monitoração terapêutica da azatioprina: uma revisão Therapeutic drug monitoring of azathioprine: a review

    Directory of Open Access Journals (Sweden)

    Maurílio Pacheco Neto

    2008-06-01

    study, we also discuss the therapeutic monitoring of these drugs by means of red blood cell 6-TGN levels, which correlate with immunosuppression and mielotoxicity. 6-MMP is directly connected with hepatotoxicity. These metabolites assays are associated with the use of appropriate doses of this drug, what results in a better control of the disease and a decreased use of corticosteroids.

  5. Prospective, Observational Study of Voriconazole Therapeutic Drug Monitoring among Lung Transplant Recipients Receiving Prophylaxis: Factors Impacting Levels of and Associations between Serum Troughs, Efficacy, and Toxicity

    Science.gov (United States)

    Mitsani, Dimitra; Shields, Ryan K.; Toyoda, Yoshiya; Kwak, Eun J.; Silveira, Fernanda P.; Pilewski, Joseph M.; Crespo, Maria M.; Bermudez, Christian; Bhama, Jay K.; Clancy, Cornelius J.

    2012-01-01

    Voriconazole prophylaxis is common following lung transplantation, but the value of therapeutic drug monitoring is unknown. A prospective, observational study of lung transplant recipients (n = 93) receiving voriconazole prophylaxis was performed. Serum voriconazole troughs (n = 331) were measured by high-pressure liquid chromatography. The median initial and subsequent troughs were 1.91 and 1.46 μg/ml, respectively. The age of the patient directly correlated with initial troughs (P = 0.005). Patients that were ≥60 years old and cystic fibrosis patients were significantly more likely to have higher and lower initial troughs, respectively. In 95% (88/93) of patients, ≥2 troughs were measured. In 28% (25/88) and 32% (28/88) of these patients, all troughs were ≤1.5 μg/ml or >1.5 μg/ml, respectively. Ten percent (10/93) and 27% (25/93) of the patients developed invasive fungal infection (tracheobronchitis) and fungal colonization, respectively. The median troughs at the times of positive and negative fungal cultures were 0.92 and 1.72 μg/ml (P = 0.07). Invasive fungal infections or colonization were more likely with troughs of ≤1.5 μg/ml (P = 0.01) and among patients with no trough of >1.5 μg/ml (P = 0.007). Other cutoff troughs correlated less strongly with microbiologic outcomes. Troughs correlated directly with aspartate transferase levels (P = 0.003), but not with other liver enzymes. Voriconazole was discontinued due to suspected toxicity in 27% (25/93) of the patients. The troughs did not differ at the times of suspected drug-induced hepatotoxicity, central nervous system (CNS) toxicity, or nausea/vomiting and in the absence of toxicity. Voriconazole prophylaxis was most effective at troughs of >1.5 μg/ml. A cutoff for toxicity was not identified, but troughs of >4 μg/ml were rare. The data support a target range of >1.5 to 4 μg/ml. PMID:22330924

  6. Long-term Treatment of Teicoplanin for Methicillin-resistant Staphylococcus aureus Sternal Osteomyelitis with Renal Impairment: A Case of High Teicoplanin Trough Levels Maintained by Therapeutic Drug Monitoring.

    Science.gov (United States)

    Shiohira, Hideo; Nakamatsu, Masashi; Kise, Yuya; Higa, Futoshi; Tateyama, Masao; Hokama, Nobuo; Kuniyoshi, Yukio; Ueda, Shinichiro; Nakamura, Katsunori; Fujita, Jiro

    2016-01-01

    Teicoplanin, a glycopeptide antibiotic for methicillin-resistant Staphylococcus aureus, is recommended for therapeutic drug monitoring during treatment. Maintaining a high trough range of teicoplanin is also recommended for severe infectious disease. However, the optimal dose and interval of treatment for severe renal impairment is unknown. We report a 79-year-old man who received long-term teicoplanin treatment for methicillin-resistant Staphylococcus aureus bacteremia due to postoperative sternal osteomyelitis with renal impairment. Plasma teicoplanin trough levels were maintained at a high range (20-30 μg/mL). Although the patient required long-term teicoplanin treatment, a further decline in renal function was not observed, and blood culture remained negative after the start of treatment. Teicoplanin treatment that is maintained at a high trough level by therapeutic drug monitoring might be beneficial for severe methicillin-resistant Staphylococcus aureus infection accompanied by renal impairment.

  7. Carboplatin therapeutic monitoring in preterm and full-term neonates.

    Science.gov (United States)

    Veal, Gareth J; Errington, Julie; Hayden, James; Hobin, David; Murphy, Dermot; Dommett, Rachel M; Tweddle, Deborah A; Jenkinson, Helen; Picton, Susan

    2015-09-01

    Administration of the most appropriate dose of chemotherapy to neonates is particularly challenging and frequently not standardised based on any scientific rationale. We report the clinical utility of carboplatin therapeutic drug monitoring in preterm and full-term neonates within the first month of life. Carboplatin therapeutic monitoring was performed to achieve target drug exposures area under the plasma concentration-time curve (AUC values) in nine preterm and full-term neonates diagnosed with retinoblastoma or neuroblastoma treated over an 8 year period. Carboplatin was administered over 3 days with therapeutic drug monitoring utilised to target cumulative AUC values of 5.2-7.8 mg/ml min. AUC values achieved were within 15% of target values for the individual courses of treatment in all but one patient (12/13 courses of treatment), with dose modifications of up to 215% required to achieve target AUC values, based on initial mg/kg dosing schedules. Carboplatin clearance determined across three consecutive chemotherapy courses in two patients increased from 3.4 to 7.1 ml/min and from 7.2 to 16.5 ml/min, representing increases of 210-230% over several weeks of treatment. Complete remission was observed in 8/9 patients, with no renal toxicity reported and only one patient experiencing ototoxicity. The study highlights the benefits of utilising therapeutic drug monitoring to achieve target carboplatin AUC values in preterm and full-term neonates treated within the first few weeks of life, particularly in view of marked increases in drug clearance observed over consecutive chemotherapy courses. In the absence of therapeutic drug monitoring, body-weight based dosing is recommended, with dosing guidance provided for both approaches to inform future treatment. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  8. Effectiveness of a reduced dose of efavirenz plus 2 NRTIs as maintenance antiretroviral therapy with the guidance of therapeutic drug monitoring.

    Science.gov (United States)

    Yang, Shang-Ping; Liu, Wen-Chun; Lee, Kuan-Yeh; Wu, Bing-Ru; Su, Yi-Ching; Wu, Pei-Ying; Zhang, Jun-Yu; Luo, Yu-Zhen; Sun, Hsin-Yun; Chang, Sui-Yuan; Lin, Shu-Wen; Hung, Chien-Ching

    2014-01-01

    Wide inter-patient variation of plasma efavirenz (EFV) concentrations has been observed, and a substantial proportion of HIV-positive patients may have unnecessarily higher plasma EFV concentrations than recommended while receiving EFV-containing combination antiretroviral therapy (cART) at the currently recommended daily dose of 600 mg. A lower daily dose (400 mg) of EFV has recently been demonstrated to be as efficacious as the recommended 600 mg when combined with tenofovir/mtricitabine in a multinational clinical trial, with a lower incidence of adverse effects. We aimed to use a therapeutic drug monitoring (TDM)-guided strategy to optimize the EFV dose in HIV-positive Taiwanese patients. The plasma EFV concentrations at 12 hours (C12) after taking the previous dose were determined among HIV-positive adults who had received EFV-containing cART with viral suppression (plasma HIV RNA load (PVL) EFV C12 >2.0 mg/L, EFV (Stocrit, MSD) was reduced to half a tablet daily. Determinations of EFV C12 were repeated 4-12 weeks after switch using high-performance liquid chromatography. CYP2B6 G516T polymorphisms were determined using polymerase-chain-reaction restriction fragment-length polymorphism. Between April 2013 and June 2014, 111 patients (95.5% male; mean age, 39 years; 96.4% with PVL 2.0 mg/L were switched to a reduced dose (1/2# hs) of EFV; 45.5% of them had CYP2B6 G516T or TT genotypes; and 32.4% weighed 60 kg or less. The mean baseline EFV C12 before switch was 3.65 mg/L (interquartile range (IQR), 2.62-4.17) for 111 patients, which decreased to 1.96 mg/L (IQR, 1.53-2.33) for 64 patients who had completed follow-up of C12 EFV 4 weeks after switch, with a reduction of 49.4% (IQR, 38.9-57.0%). As of 10 July, 2014, all of the 38 patients (100%) who had completed at least one follow-up of PVL achieved undetectable PVL (EFV after a mean observation of 13 weeks (IQR, 7-15 weeks). Switch to cART containing a half tablet of EFV (1/2#) in HIV-positive Taiwanese patients

  9. Therapeutic Drug Mornitoring: Perception among Health-care ...

    African Journals Online (AJOL)

    Therapeutic Drug Mornitoring: Perception among Health-care Workers in a Developing Tertiary Institution. ... To assess the perception of TDM among health workers in the University of Benin Teaching Hospital, Benin City, Nigeria. ... Monitoring time interval was suggested by 167(27.60%) respondents on hourly bases.

  10. Cross-validation of a mass spectrometric-based method for the therapeutic drug monitoring of irinotecan: implementation of matrix-assisted laser desorption/ionization mass spectrometry in pharmacokinetic measurements.

    Science.gov (United States)

    Calandra, Eleonora; Posocco, Bianca; Crotti, Sara; Marangon, Elena; Giodini, Luciana; Nitti, Donato; Toffoli, Giuseppe; Traldi, Pietro; Agostini, Marco

    2016-07-01

    Irinotecan is a widely used antineoplastic drug, mostly employed for the treatment of colorectal cancer. This drug is a feasible candidate for therapeutic drug monitoring due to the presence of a wide inter-individual variability in the pharmacokinetic and pharmacodynamic parameters. In order to determine the drug concentration during the administration protocol, we developed a quantitative MALDI-MS method using CHCA as MALDI matrix. Here, we demonstrate that MALDI-TOF can be applied in a routine setting for therapeutic drug monitoring in humans offering quick and accurate results. To reach this aim, we cross validated, according to FDA and EMA guidelines, the MALDI-TOF method in comparison with a standard LC-MS/MS method, applying it for the quantification of 108 patients' plasma samples from a clinical trial. Standard curves for irinotecan were linear (R (2) ≥ 0.9842) over the concentration ranges between 300 and 10,000 ng/mL and showed good back-calculated accuracy and precision. Intra- and inter-day precision and accuracy, determined on three quality control levels were always methods, the percentage differences within 20 % in more than 70 % of the total amount of clinical samples analysed.

  11. Therapeutic drug monitoring of amlodipine and the Z-FHL/HHL ratio: Adherence tools in patients referred for apparent treatment-resistant hypertension

    Directory of Open Access Journals (Sweden)

    E S W Jones

    2017-10-01

    Full Text Available Background. Non-adherence to antihypertensives is a cause of ‘pseudo-treatment-resistant’ hypertension. Objective. To determine whether monitoring plasma amlodipine concentrations and inhibition of angiotensin-converting enzyme (ACE can be adjunct adherence tools. Methods. Patients with hypertension who were prescribed enalapril and amlodipine were enrolled. Blood pressures (BPs were monitored and an adherence questionnaire was completed. Steady-state amlodipine was assayed using liquid chromatography-mass spectrometry and degree of ACE inhibition using the Z-FHL/HHL (z-phenylalanine-histidine-leucine/hippuryl-histidine-leucine ratio. Results. One hundred patients (mean (standard deviation age 50.5 (12 years, 46% male were enrolled. Based on plasma assays, 26/97 patients (26.8% were unsuppressed by enalapril and 20/100 (20% were sub-therapeutic for amlodipine. There were significant BP differences based on plasma levels of the medication: 21/20 mmHg lower in the group with suppressed ACE and 26/20 mmHg in the group with steady-state amlodipine concentrations. Conclusions. Monitoring antihypertensive adherence by assaying plasma medication concentrations is a feasible option for evaluating true v. pseudo-resistant hypertension.

  12. Heterogeneity of publicly accessible online critical values for therapeutic drugs

    Directory of Open Access Journals (Sweden)

    Colt M McClain

    2011-01-01

    Full Text Available Introduction: Critical values are reported to clinicians when laboratory values are life threatening and require immediate attention. To date no definitive critical value limit recommendations have been produced regarding therapeutic drug monitoring. Some laboratories choose to publish critical value lists online. These publicly available values may be accessed and potentially utilized by laboratory staff, patient care providers, and patients. Materials and Methods: A web-based search of laboratories associated with the Accreditation Council for Graduate Medical Education pathology residency programs was initiated to determine which therapeutic drugs had critical values and to examine the degree of variation in published critical values for these institutions. Results: Of the 107 institutions with university-based pathology training programs, 36 had published critical values online for review. Thirteen therapeutic drugs were investigated and the number of institutions reporting critical value limits for the drug, as well as the median, range, standard deviation, and the coefficient of variation of critical value concentration limits for each drug were determined. A number of the online critical value limits were deemed to be erroneous, most likely due to incorrectly listed units of measurement. Conclusions: There was a large degree of heterogeneity with regard to the chosen critical value limits for therapeutic drugs. This wide variance in critical values appears to be greater than that observed in interassay proficiency testing. Institutions should reexamine the rationale for their current critical value parameters and ensure that critical value limits and associated units are accurately published online.

  13. [Anticancer drugs: Which prices for therapeutic innovations?].

    Science.gov (United States)

    Gonçalves, Anthony; Maraninchi, Dominique; Marino, Patricia

    2016-04-01

    The expanding knowledge of the biological mechanisms underlying tumor development made it possible the recent emergence of new therapeutic approaches that are considered as undoubtedly innovative. Yet, to define and to evaluate the magnitude of a drug innovation require an examination of its intrinsic drug properties, medical utility as well as its mode of emergence. Recently, international academic societies, such as ESMO and ASCO, have proposed practical tools that may help quantifying the medical value of a given innovation. Currently, the sustained flux of therapeutic innovations in oncology is associated with an unprecedented growth of costs, the actual determinants of which remain under debate, but raising the critical issue of drugs pricing, and their potential individual or societal "financial toxicity". Copyright © 2016. Published by Elsevier Masson SAS.

  14. A simple and rapid LC-MS/MS method for therapeutic drug monitoring of cetuximab: a GPCO-UNICANCER proof of concept study in head-and-neck cancer patients.

    Science.gov (United States)

    Becher, François; Ciccolini, Joseph; Imbs, Diane-Charlotte; Marin, Clémence; Fournel, Claire; Dupuis, Charlotte; Fakhry, Nicolas; Pourroy, Bertrand; Ghettas, Aurélie; Pruvost, Alain; Junot, Christophe; Duffaud, Florence; Lacarelle, Bruno; Salas, Sebastien

    2017-06-02

    Administration of first-in-class anti-EGFR monoclonal antibody cetuximab is contingent upon extensive pharmacogenomic testing. However in addition to tumor genomics, drug exposure levels could play a critical, yet largely underestimated role, because several reports have demonstrated that cetuximab pharmacokinetic parameters, in particular clearance values, were associated with survival in patients. Here, we have developed an original bioanalytical method based upon the use of LC-MS/MS technology and a simplified sample preparation procedure to assay cetuximab in plasma samples from patients, thus meeting the requirements of standard Therapeutic Drug Monitoring in routine clinical practice. When tested prospectively in a pilot study in 25 head-and-neck cancer patients, this method showed that patients with clinical benefit had cetixumab residual concentrations higher than non-responding patients (i.e., 49 ± 16.3 µg/ml VS. 25.8 ± 17 µg/ml, p < 0.01 t test). Further ROC analysis showed that 33.8 µg/ml was the Cmin threshold predictive of response with an acceptable sensitivity (87%) and specificity (78%). Mass spectrometry-based therapeutic drug monitoring of cetuximab in head-and-neck cancer patients could therefore help to rapidly predict cetuximab efficacy and to adapt dosing if required.

  15. Nationale Drug Monitor : Jaarbericht 2006

    NARCIS (Netherlands)

    Laar, M.W. van; Cruts, A.A.N.; Verdurmen, J.E.E.; Ooyen-Houben, M.M.J. van; Meijer, R.F.

    2007-01-01

    De Nationale Drug Monitor (NDM) die sinds 1999 wordt samengesteld door het Trimbos-instituut in samenwerking met het WODC is een beschrijvend rapport dat een overkoepelend beeld geeft van het middelengebruik (drugs, alcohol en tabak) en – sinds 2002 – ook van de geregistreerde drugscriminaliteit en

  16. Nationale Drug Monitor : Jaarbericht 2007

    NARCIS (Netherlands)

    Laar, M.W. van; Cruts, A.A.N.; Verdurmen, J.E.E.; Ooyen-Houben, M.M.J. van; Meijer, R.F.

    2008-01-01

    De Nationale Drug Monitor (NDM) die sinds 1999 wordt samengesteld door het Trimbos-instituut in samenwerking met het WODC is een beschrijvend rapport dat een overkoepelend beeld geeft van het middelengebruik (drugs, alcohol en tabak) en – sinds 2002 – ook van de geregistreerde drugscriminaliteit en

  17. Do drug advertisements provide therapeutic information?

    Science.gov (United States)

    Stimson, G V

    1977-01-01

    In this study of advertisements appearing in medical periodicals and by direct mail advertising to general practitioners, Dr. Stimson, a sociologist, concludes that from what is intended to provide therapeutic information hardly any therapeutic information is provided. He reminds the reader of the safeguards which surround all drug advertising by law and by the code of practice of the Association of the British Pharmaceutical Industry but these safeguards do not appear to control real or potential sins of omission. Frequently in these advertisements the literature relating to the drug is quoted but Dr. Stimson found that it was difficult to trace all the papers quoted in different types of medical library. (Some references quoted were to unpublished papers but surely the blame should be shared in this situation?) Dr. Stimson also gives a vivid and fascinating glimpse of what he calls the 'images and stereotypes' of the patients who, it is claimed, would benefit from the drug being advertised. Certainly most general practitioners must be aware that when they prescribe that image is displaced by an individual but the portrait gallery is indeed depressing. However, to balance these advertisements drug companies issue data sheets which must be more informative than advertisements and conform to regulations in their format. Unfortunately data sheets are only issued every 15 months whereas the 'average general practitioner is potentially exposed to 1,300 advertisements every month'. In other words, the data sheet and not the advertisement should be the guideline but it arrives too infrequently to offset the lack of therapeutic information contained in advertisements. PMID:870694

  18. Therapeutic potential of cannabis-related drugs.

    Science.gov (United States)

    Alexander, Stephen P H

    2016-01-04

    In this review, I will consider the dual nature of Cannabis and cannabinoids. The duality arises from the potential and actuality of cannabinoids in the laboratory and clinic and the 'abuse' of Cannabis outside the clinic. The therapeutic areas currently best associated with exploitation of Cannabis-related medicines include pain, epilepsy, feeding disorders, multiple sclerosis and glaucoma. As with every other medicinal drug of course, the 'trick' will be to maximise the benefit and minimise the cost. After millennia of proximity and exploitation of the Cannabis plant, we are still playing catch up with an understanding of its potential influence for medicinal benefit. Copyright © 2015 Elsevier Inc. All rights reserved.

  19. Nationale drug monitor : Jaarbericht 2004

    NARCIS (Netherlands)

    Laar, M.W. van; Cruts, A.A.N.; Verdurmen, J.E.E.; Ooyen, M.M.J. van; Ketelaars, A.P.M.; Gelder, P. van

    2004-01-01

    De Nationale Drug Monitor (NDM) die sinds 1999 wordt samengesteld door het Trimbos-instituut in samenwerking met het WODC is een beschrijvend rapport dat een overkoepelend beeld geeft van het middelengebruik en – sinds 2002 – ook van de geregistreerde drugscriminaliteit en de strafrechtelijke

  20. Therapeutic performances of some selected aqua drugs

    Directory of Open Access Journals (Sweden)

    Rasheduzzaman Khan Dipu

    2014-08-01

    Full Text Available This study was carried out at the Disease Laboratory of the Faculty of Fisheries, Bangladesh Agricultural University, Mymensingh, Bangladesh to verify the therapeutic performances of six commercial aqua drugs; three doses were selected as less than recommended, recommended and more than recommended to assess their performances. Before starting therapeutic experimental nine climbing perch (Anabas testudineus and six stinging catfish (Heteropneustes fossilis were confirmed as diseased ones by their clinical signs. The backswimmers (Notonecta glauca were collected from faculty of fisheries pond and fish louses (Argulus sp. were collected from tilapia fishes. Effective doses and their performances were determined on the basis of desired water quality change and clinical signs. It was found that all the drugs performed better at more than recommended doses as follows Aqua Ox performed better at the rate of 0.2 mg/l, GR Plus, 0.0005 ml/l, ID Plus (5%, 0.00026 ml/l; Active Blue, 0.0002 ml/l; Hashpoka Killer, 0.0001 ml/l; and Para Control, 0.001 ml/l. So these doses were suggested as recommended doses.

  1. Novel bioequivalence approach for narrow therapeutic index drugs.

    Science.gov (United States)

    Yu, L X; Jiang, W; Zhang, X; Lionberger, R; Makhlouf, F; Schuirmann, D J; Muldowney, L; Chen, M-L; Davit, B; Conner, D; Woodcock, J

    2015-03-01

    Narrow therapeutic index drugs are defined as those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. The US Food and Drug Administration proposes that the bioequivalence of narrow therapeutic index drugs be determined using a scaling approach with a four-way, fully replicated, crossover design study in healthy subjects that permits the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The proposed bioequivalence limits for narrow therapeutic index drugs of 90.00%-111.11% would be scaled based on the within-subject variability of the reference product. The proposed study design and data analysis should provide greater assurance of therapeutic equivalence of narrow therapeutic index drug products. © 2014 American Society for Clinical Pharmacology and Therapeutics.

  2. Psyllium as therapeutic and drug delivery agent.

    Science.gov (United States)

    Singh, Baljit

    2007-04-04

    There is no doubt that fibers, in particular viscous dietary fibers, have positive effects on human health, both in the prevention and in treatment of chronic diseases. Dietary fibers from psyllium have been used extensively both as pharmacological supplements, food ingredients, in processed food to aid weight control, to regulation of glucose control for diabetic patients and reducing serum lipid levels in hyperlipidemics. Keeping in view, the pharmacological importance of psyllium polysaccharide and its gel-forming nature, this article discusses the therapeutic value of psyllium for the treatment of constipation, diarrhea, irritable bowel syndrome, inflammatory bowel disease-ulcerative colitis, colon cancer, diabetes and hypercholesterolemia and exploitation of psyllium for developing drug delivery systems.

  3. Evidence Based Digoxin Therapeutic Monitoring - A Lower and Narrower Therapeutic Range

    Directory of Open Access Journals (Sweden)

    Amine BENLMOUDEN

    2016-06-01

    Full Text Available Cardiac glycosides have been used for congestive heart failure and certain cardiac arrhythmias for more than 200 years. Despite the introduction of a variety of new classes of drugs for the management of heart failure, specifically angiotensin-converting enzyme (ACE inhibitors, b-adrenergic antagonists (bblockers, and the aldosterone antagonist spironolactone, digoxin continues to have an important role in long-term outpatient management. However, a narrow margin exists between therapeutic and toxic doses of digoxin, resulting in a high incidence of digoxin toxicity in clinical practice.A wide variety of placebo-controlled clinical trials have unequivocally shown that treatment with digoxin can improve symptoms, quality of life, and exercise tolerance in patients with mild, moderate, or severe heart failure. The clinical relevance of digoxin therapeutic monitoring is also proved but the SDC (Serum Digoxin Conentrations required for optimal clinical efficacy and acceptable toxicity remains controversial. In the last years, international guidelines recommend 1.2 ng/mL as acceptable high level.In this bibliographic synthesis, we aim to collect pertinent informations from MedLine database about exposure-effect relationship in order to assess the evidence level scientific of new digoxin therapeutic monitoring

  4. Use of PCR Signal and Therapeutic Drug Monitoring in a Switch Cohort Study to Tenofovir/Emtricitabine/Rilpivirine: A W96 Follow-Up.

    Science.gov (United States)

    Charpentier, Charlotte; Lê, Minh Patrick; Joly, Véronique; Visseaux, Benoit; Lariven, Sylvie; Phung, Bao; Yéni, Patrick; Yazdanpanah, Yazdan; Descamps, Diane; Peytavin, Gilles; Landman, Roland

    2015-01-01

    To assess, in a clinical cohort, the efficacy of switching treatment in virologically-suppressed patients to tenofovir/emtricitabine/rilpivirine as a single-tablet regimen (STR) using the PCR signal of the viral load (VL) assay and plasma drug determination (C24h). An observational single-centre study enrolling patients with VLinitiating rilpivirine-based STR. C24h and VL were performed until W48 and W96 of STR, respectively. PCRneg was defined as an undetected PCR signal. Medians (IQR) were presented. 116 patients were enrolled. At STR baseline, time since first antiretroviral therapy and time of virological suppression were 6 years (2-9) and 17 months (7-43), respectively. Before STR initiation, patients were receiving protease inhibitors and non-nucleoside reverse transcriptase inhibitors-based regimen in 44% and 47% of cases, respectively. Historical genotype showed virus resistant to one drug of the STR in 6 patients (5%). At W96, 17 (15%) discontinued STR due to adverse events. The proportion of patients maintaining VL 50 ng/mL, the target effective concentration. In this clinical cohort of virologically-suppressed patients switching to a new STR, most subjects had adequate rilpivirine C24h and displayed a high level of virological suppression with no residual viremia until W96.

  5. Therapeutic drug monitoring of carbamazepine and its metabolite in children from dried blood spots using liquid chromatography and tandem mass spectrometry.

    Science.gov (United States)

    Shokry, Engy; Villanelli, Fabio; Malvagia, Sabrina; Rosati, Anna; Forni, Giulia; Funghini, Silvia; Ombrone, Daniela; Della Bona, Maria; Guerrini, Renzo; la Marca, Giancarlo

    2015-05-10

    Carbamazepine (CBZ) is a first-line drug for the treatment of different forms of epilepsy and the first choice drug for trigeminal neuralgia. CBZ is metabolized in the liver by oxidation into carbamazepine-10,11-epoxide (CBZE), its major metabolite which is equipotent and known to contribute to the pharmacological activity of CBZ. The aim of the present study was to develop and validate a reliable, selective and sensitive liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of CBZ and its active metabolite in dried blood spots (DBS). The extraction process was carried out from DBS using methanol-water-formic acid (80:20:0.1, v/v/v). Chromatographic elution was achieved by using a linear gradient with a mobile phase consisting of acetonitrile-water-0.1% formic acid at a flow rate of 0.50mL/min. The method was linear over the range 1-40mg/L and 0.25-20mg/L for CBZ and CBZE, respectively. The limit of quantification was 0.75mg/L and 0.25mg/L for CBZ and CBZE. Intra-day and inter-day assay precisions were found to be lower than 5.13%, 6.46% and 11.76%, 4.72% with mean percentage accuracies of 102.1%, 97.5% and 99.2%, 97.8% for CBZ and CBZE. We successfully applied the method for determining DBS finger-prick samples in paediatric patients and confirmed the results with concentrations measured in matched plasma samples. This novel approach allows quantification of CBZ and its metabolite from only one 3.2mm DBS disc by LC-MS/MS thus combining advantages of DBS technique and LC-MS/MS in clinical practice. Copyright © 2015 Elsevier B.V. All rights reserved.

  6. Drug trafficking: recent advances in therapeutics and disease.

    Science.gov (United States)

    Sprowl, J A; Sparreboom, A

    2012-11-01

    Drug transporter proteins are of ever-increasing interest because of their role both in processes regulating pharmacokinetic properties of drugs (absorption, distribution, and elimination) and in the development of cellular drug resistance through decreased uptake or increased efflux of drugs in the target organ or tumor. Further understanding of the role of transporters in drug-drug interactions and identification of these proteins as possible therapeutic targets could contribute to improved treatment of a wide variety of diseases.

  7. Immunoassays in monitoring biotechnological drugs.

    Science.gov (United States)

    Gygax, D; Botta, L; Ehrat, M; Graf, P; Lefèvre, G; Oroszlan, P; Pfister, C

    1996-08-01

    For the evaluation and interpretation of pharmacokinetic data reliable quantitative determinations are a requirement that can only be met by well-characterized and fully validated analytical methods. To cope with these requirements a method is being established that is based on an integrated and automated fiber-optic biospecific interaction analysis system (FOBIA) for immunoassays. Performance characteristics of this system used in monitoring of recombinant hirudin (CGP 39 393) are presented. Recombinant hirudin is a highly potent and selective inhibitor of human thrombin. Owing to its size and charge, recombinant hirudin is mainly eliminated by glomerular filtration. But only a fraction of the hirudin dose seems to be reabsorbed at the proximal tubule by luminal endocytosis and hydrolyzed by lysosomal enzymes, leaving approximately 50% of the dose to be extracted in the urine. Thus, renal clearance of recombinant hirudin in the absence of renal insufficiency appears to depend primarily on the glomerular filtration rate. During a 3-month i.v. tolerability study in dogs, some of the dogs developed antibodies against recombinant hirudin. The hirudin-antibody complex accumulated in plasma and apparent hirudin plasma concentrations were therefore much higher than expected from single-dose kinetics. Hirudin captured by antibodies showed an extended half-life and the hirudin-antibody complex is still pharmacologically active, as demonstrated by the observed increase in thrombin time. In conclusion, only appropriate analytical methods allow adequate monitoring and pharmacokinetic characterization of biotechnology drugs in biological materials.

  8. [Drugs having latex and therapeutic alternatives in hospital formulary].

    Science.gov (United States)

    Damas Fuentes, Rosa María; Pérez León, Moisés; Piñero González, Marta; Sangil Monroy, Nayra; Molero Gómez, Rafael; Domínguez Lantigua, Pablo

    2015-01-01

    To analyze the latex content of drugs in hospital formulary and establish possible therapeutic alternatives. All drugs susceptible of having latex were selected and written information was obtained from manufacturers. A therapeutic alternative was found for each of them, if possible. Written information from manufacturer was obtained for 605 (97.9%) and from label information for 8 of 632 selected drugs. For 43.9% of not safe drugs (total 57) on patients with latex allergy, a therapeutic alternative was found in hospital formulary. Knowing drugs having latex improve the prescription security, while the therapeutic alternatives chart eases the validation. The published data updates the scarce and variable information for patients and healthcare professionals. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  9. Therapeutic drug monitoring of tacrolimus in pancreas transplantation at São Lucas Hospital Monitoramento terapêutico de tacrolimus em transplante de pâncreas no Hospital São Lucas

    Directory of Open Access Journals (Sweden)

    Luciana Mello de Oliveira

    2007-10-01

    Full Text Available Tacrolimus (FK 506, a potent immunosuppressive drug used in prevention and treatment of rejection of transplanted organs, exhibits efficacy related to its blood levels and has a narrow therapeutic index. These factors require frequent monitoring of patients blood levels, in attempt to adjust the dose to reach the best drug concentration with minimum side effects. In this historic study, the authors evaluated tacrolimus blood profile in patients submitted to pancreas transplantation between June 2002 and March 2004. The results show that blood levels were, mostly, within subtherapeutic (39.1% and toxic (43.4% ranges. Considering post-transplantation period, subtherapeutic levels were more frequent until three months after the graft receiving (51.1% and between three and six months (41.9%, whereas toxic levels were more common six months after the transplantation (63%. Patients who received pancreas/kidney transplantation showed a tendency to present toxic levels. The same did not happen with the patients who received isolated pancreas and pancreas after kidney; these patients presented subtherapeutic blood levels in all post-transplantation periods. The results found in this study reassure the importance of therapeutic monitoring to achieve the adequate blood levels of tacrolimus following pancreas transplantation.O tacrolimus (FK506, um potente imunossupressor utilizado na profilaxia e no tratamento de rejeições pós-transplante, exibe eficácia relacionada com sua concentração sangüínea e possui estreita janela terapêutica. Esses fatores requerem o freqüente monitoramento dos níveis sangüíneos em pacientes que fazem uso do fármaco, tendo como objetivo o ajuste de dose para uma concentração terapêutica ótima com efeitos colaterais mínimos. Este estudo retrospectivo foi realizado através do acesso à base de dados do Laboratório de Patologia Clínica do Hospital São Lucas, da Pontifícia Universidade Católica do Rio Grande do

  10. Therapeutic potential of cannabinoid-based drugs.

    Science.gov (United States)

    Klein, Thomas W; Newton, Catherine A

    2007-01-01

    Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer's disease, atherosclerosis, and osteoporosis.

  11. Monitoring therapeutic efficacy in breast carcinomas.

    Science.gov (United States)

    Tardivon, Anne A; Ollivier, Liliane; El Khoury, Carl; Thibault, Fabienne

    2006-11-01

    The aim of imaging during and after neoadjuvant therapy is to document and quantify tumor response: has the tumor size been accurately measured? Certainly, the most exciting information for the oncologists is: can we identify good or nonresponders, and can we predict the pathological response early after the initiation of treatment? This review article will discuss the role and the performance of the different imaging modalities (mammography, ultrasound, magnetic resonance imaging and FDG-PET imaging) for evaluating this therapeutic response. It is important to emphasize that, at this time, clinical examination and conventional imaging (mammography and ultrasound) are the only methods recognized by the international criteria. Magnetic resonance imaging and FDG-PET imaging are very promising for predicting the response early after the initiation of neoadjuvant chemotherapy.

  12. Monitoring therapeutic efficacy in breast carcinomas

    Energy Technology Data Exchange (ETDEWEB)

    Tardivon, Anne A.; Ollivier, Liliane; Khoury, Carl El; Thibault, Fabienne [Institut Curie, Department of Radiology, Paris (France)

    2006-11-15

    The aim of imaging during and after neoadjuvant therapy is to document and quantify tumor response: has the tumor size been accurately measured? Certainly, the most exciting information for the oncologists is: can we identify good or nonresponders, and can we predict the pathological response early after the initiation of treatment? This review article will discuss the role and the performance of the different imaging modalities (mammography, ultrasound, magnetic resonance imaging and FDG-PET imaging) for evaluating this therapeutic response. It is important to emphasize that, at this time, clinical examination and conventional imaging (mammography and ultrasound) are the only methods recognized by the international criteria. Magnetic resonance imaging and FDG-PET imaging are very promising for predicting the response early after the initiation of neoadjuvant chemotherapy. (orig.)

  13. A review on therapeutic contact lenses for ocular drug delivery.

    Science.gov (United States)

    Maulvi, Furqan A; Soni, Tejal G; Shah, Dinesh O

    2016-10-01

    Contact lenses for ophthalmic drug delivery have become very popular, due to their unique advantages like extended wear and more than 50% bioavailability. To achieve controlled and sustained drug delivery from contact lenses, researchers are working on various systems like polymeric nanoparticles, microemulsion, micelle, liposomes, use of vitamin E, etc. Numerous scientists are working on different areas of therapeutic contact lenses to treat ocular diseases by implementing techniques like soaking method, molecular imprinting, entrapment of drug-laden colloidal nanoparticles, drug plate/film, ion ligand polymeric systems, supercritical fluid technology, etc. Though sustained drug delivery was achieved using contact lens, the critical properties such as water content, tensile strength (mechanical properties), ion permeability, transparency and oxygen permeability were altered, which limit the commercialization of therapeutic contact lenses. Also issues like drug stability during processing/fabrication (drug integrity test), zero order release kinetics (prevent burst release), drug release during monomer extraction step after fabrication (to remove un-reacted monomers), protein adherence, drug release during storage in packaging solution, shelf life study, cost-benefit analysis, etc. are still to be addressed. This review provides an expert opinion on different methodology to develop therapeutic contact lenses with special remark of their advantages and limitations.

  14. Monitoring drug markets in the Internet age and the evolution of drug monitoring systems in Australia.

    Science.gov (United States)

    Burns, Lucy; Roxburgh, Amanda; Bruno, Raimondo; Van Buskirk, Joe

    2014-01-01

    In Australia, drug monitoring systems have been in place for more than a decade allowing for the measurement of ongoing trends in drug use and the detection of new drugs. The Drug Trends Unit at the National Drug and Alcohol Research Centre monitors drugs through four separate systems. The Illicit Drug Reporting System (IDRS) measures the price, purity, and availability of drugs that are primarily injected. The Ecstasy and Related Drugs Reporting System (EDRS) monitors psychostimulants that are used recreationally. The National Illicit Drugs Indicator Project (NIDIP) analyzes indicator data including drug-related hospitalizations and deaths. Finally, the Drugs and Emerging Technologies Project (DNeT) analyzes the role of the Internet in the procurement and use of novel psychoactive substances. This paper provides an overview of each component of the system, demonstrating how the system has evolved over time. Copyright © 2014 John Wiley & Sons, Ltd.

  15. Drug assessment by a Pharmacy and Therapeutics committee: from drug selection criteria to use in clinical practice.

    Science.gov (United States)

    Lozano-Blázquez, Ana; Calvo-Pita, Cecilia; Carbajales-Álvarez, Mónica; Suárez-Gil, Patricio; Martínez-Martínez, Fernando; Calleja-Hernández, Miguel Ángel

    2014-01-01

    In Spain, hospital medicines are assessed and selected by local Pharmacy and Therapeutics committees (PTCs). Of all the drugs assessed, cancer drugs are particularly important because of their budgetary impact and the sometimes arguable added value with respect to existing alternatives. This study analyzed the PTC drug selection process and the main objective was to evaluate the degree of compliance of prescriptions for oncology drugs with their criteria for use. This was a retrospective observational study (May 2007 to April 2010) of PTC-assessed drugs. The variables measured to describe the committee's activity were number of drugs assessed per year and number of drugs included in any of these settings: without restrictions, with criteria for use, and not included in formulary. These drugs were also analyzed by therapeutic group. To assess the degree of compliance of prescriptions, a score was calculated to determine whether prescriptions for bevacizumab, cetuximab, trastuzumab, and bortezomib were issued in accordance with PTC drug use criteria. The PTC received requests for inclusion of 40 drugs, of which 32 were included in the hospital formulary (80.0%). Criteria for use were established for 28 (87.5%) of the drugs included. In total, 293 patients were treated with the four cancer drugs in eight different therapeutic indications. The average prescription compliance scores were as follows: bevacizumab, 83% for metastatic colorectal cancer, 100% for metastatic breast cancer, and 82.3% for non-small-cell lung cancer; cetuximab, 62.0% for colorectal cancer and 50% for head and neck cancer; trastuzumab, 95.1% for early breast cancer and 82.4% for metastatic breast cancer; and bortezomib, 63.7% for multiple myeloma. The degree of compliance with criteria for use of cancer drugs was reasonably high. PTC functions need to be changed so that they can carry out more innovative tasks, such as monitoring conditions for drug use.

  16. Effect of CYP2B6*6 on Steady-State Serum Concentrations of Bupropion and Hydroxybupropion in Psychiatric Patients: A Study Based on Therapeutic Drug Monitoring Data.

    Science.gov (United States)

    Høiseth, Gudrun; Haslemo, Tore; Uthus, Linda H; Molden, Espen

    2015-10-01

    The clinical effect of bupropion is mediated by its active metabolite hydroxybupropion. Previous studies have reported conflicting impact of the CYP2B6*6 variant allele on the formation of hydroxybupropion from bupropion. The aim of this study was to clarify the effect of CYP2B6*6 and secondarily CYP2D6 genotype on steady-state serum concentrations of bupropion and hydroxybupropion in a large population of psychiatric patients. Retrospective information about dose-adjusted serum concentrations (C/D ratios) of bupropion and hydroxybupropion, CYP2B6 genotype (ie, data on the 2B6*6 polymorphisms 516G>T and 785A>G) and CYP2D6 genotype, was obtained from a therapeutic drug monitoring database (n = 132 patients). C/D ratios of bupropion and hydroxybupropion, and metabolic ratios, were compared between CYP2B6 genotype subgroups by multivariate mixed-model analyses (2B6*1/*1 was defined as control group). In the analyses, CYP2D6 genotype was also included as a covariate. Homozygous 2B6*6 carriers (n = 7) had significantly lower C/D ratios of hydroxybupropion compared with controls (n = 79), that is, estimated mean 5.8 versus 13.0 nmol·L·mg (P bupropion metabolic ratios in heterozygous and homozygous 2B6*6 carriers were significantly lower than in controls (P = 0.001 and P bupropion values were observed in poor versus extensive CYP2D6 metabolizers (P = 0.020). This study shows that the CYP2B6*6 variant allele is associated with significantly reduced formation of the active bupropion metabolite in psychiatric patients. Our findings suggest that dose-adjusted serum concentrations of hydroxybupropion at steady state is approximately halved in homozygous CYP2B6*6 carriers, which might imply risk of reduced clinical response in this patient subgroup. The CYP2D6 genotype does not affect hydroxybupropion concentrations and is therefore unlikely to impact bupropion treatment.

  17. Monitoring drug promiscuity over time.

    Science.gov (United States)

    Hu, Ye; Bajorath, Jürgen

    2014-01-01

    Drug promiscuity and polypharmacology are much discussed topics in pharmaceutical research. Experimentally, promiscuity can be studied by profiling of compounds on arrays of targets. Computationally, promiscuity rates can be estimated by mining of compound activity data. In this study, we have assessed drug promiscuity over time by systematically collecting activity records for approved drugs. For 518 diverse drugs, promiscuity rates were determined over different time intervals. Significant differences between the number of reported drug targets and the promiscuity rates derived from activity records were frequently observed. On the basis of high-confidence activity data, an increase in average promiscuity rates from 1.5 to 3.2 targets per drug was detected between 2000 and 2014. These promiscuity rates are lower than often assumed. When the stringency of data selection criteria was reduced in subsequent steps, non-realistic increases in promiscuity rates from ~6 targets per drug in 2000 to more than 28 targets were obtained. Hence, estimates of drug promiscuity significantly differ depending on the stringency with which target annotations and activity data are considered.

  18. Soft Interaction in Liposome Nanocarriers for Therapeutic Drug Delivery

    Directory of Open Access Journals (Sweden)

    Domenico Lombardo

    2016-06-01

    Full Text Available The development of smart nanocarriers for the delivery of therapeutic drugs has experienced considerable expansion in recent decades, with the development of new medicines devoted to cancer treatment. In this respect a wide range of strategies can be developed by employing liposome nanocarriers with desired physico-chemical properties that, by exploiting a combination of a number of suitable soft interactions, can facilitate the transit through the biological barriers from the point of administration up to the site of drug action. As a result, the materials engineer has generated through the bottom up approach a variety of supramolecular nanocarriers for the encapsulation and controlled delivery of therapeutics which have revealed beneficial developments for stabilizing drug compounds, overcoming impediments to cellular and tissue uptake, and improving biodistribution of therapeutic compounds to target sites. Herein we present recent advances in liposome drug delivery by analyzing the main structural features of liposome nanocarriers which strongly influence their interaction in solution. More specifically, we will focus on the analysis of the relevant soft interactions involved in drug delivery processes which are responsible of main behaviour of soft nanocarriers in complex physiological fluids. Investigation of the interaction between liposomes at the molecular level can be considered an important platform for the modeling of the molecular recognition processes occurring between cells. Some relevant strategies to overcome the biological barriers during the drug delivery of the nanocarriers are presented which outline the main structure-properties relationships as well as their advantages (and drawbacks in therapeutic and biomedical applications.

  19. Therapeutic approaches to drug targets in atherosclerosis.

    Science.gov (United States)

    Jamkhande, Prasad G; Chandak, Prakash G; Dhawale, Shashikant C; Barde, Sonal R; Tidke, Priti S; Sakhare, Ram S

    2014-07-01

    Non-communicable diseases such as cancer, atherosclerosis and diabetes are responsible for major social and health burden as millions of people are dying every year. Out of which, atherosclerosis is the leading cause of deaths worldwide. The lipid abnormality is one of the major modifiable risk factors for atherosclerosis. Both genetic and environmental components are associated with the development of atherosclerotic plaques. Immune and inflammatory mediators have a complex role in the initiation and progression of atherosclerosis. Understanding of all these processes will help to invent a range of new biomarkers and novel treatment modalities targeting various cellular events in acute and chronic inflammation that are accountable for atherosclerosis. Several biochemical pathways, receptors and enzymes are involved in the development of atherosclerosis that would be possible targets for improving strategies for disease diagnosis and management. Earlier anti-inflammatory or lipid-lowering treatments could be useful for alleviating morbidity and mortality of atherosclerotic cardiovascular diseases. However, novel drug targets like endoglin receptor, PPARα, squalene synthase, thyroid hormone analogues, scavenger receptor and thyroid hormone analogues are more powerful to control the process of atherosclerosis. Therefore, the review briefly focuses on different novel targets that act at the starting stage of the plaque form to the thrombus formation in the atherosclerosis.

  20. β-lactam Therapeutic Drug Management in the PICU.

    Science.gov (United States)

    Cies, Jeffrey J; Moore, Wayne S; Enache, Adela; Chopra, Arun

    2017-11-03

    To determine whether contemporary β-lactam anti-infective dosing recommendations in critically ill children achieve concentrations associated with maximal anti-infective activity. The secondary objective was to describe the microbiological and clinical outcomes associated with β-lactam therapeutic drug management. Electronic Medical Record Review. A 189-bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA. Patients admitted to the PICU from September 1, 2014, to May 31, 2017, with sepsis and those receiving extracorporal therapy with either extracorporeal membrane oxygenation or continuous renal replacement therapy that had routine β-lactam therapeutic drug management. None. Eighty-two patients were in the total cohort and 23 patients in the infected cohort accounting for 248 samples for therapeutic drug management analysis. The median age was 1 year (range, 4 d to 18 yr) with a mean weight of 19.7 ± 22.3 kg (range, 2.7-116 kg). Twenty-three patients (28%) had growth of an identified pathogen from a normally sterile site. Seventy-eight of 82 patients (95%) had subtherapeutic anti-infective concentrations and did not attain the primary pharmacodynamic endpoint. All patients in the infected cohort achieved a microbiological response, and 22 of 23 (95.7%) had a positive clinical response. Overall, 95% of patients had subtherapeutic anti-infective concentrations and did not achieve the requisite pharmacodynamic exposure with current pediatric dosing recommendations. All patients achieved a microbiological response, and 95.7% achieved clinical response with active β-lactam therapeutic drug management. These data suggest β-lactam therapeutic drug management is a potentially valuable intervention to optimize anti-infective pharmacokinetics and the pharmacodynamic exposure. Further, these data also suggest the need for additional research in specific pediatric populations and assessing clinical outcomes associated with

  1. Early Warning Indicators for Population-Based Monitoring of HIV Drug Resistance in 6 African Countries

    NARCIS (Netherlands)

    Sigaloff, Kim C. E.; Hamers, Raph L.; Menke, Jack; Labib, Moheb; Siwale, Margaret; Ive, Prudence; Botes, Mariette E.; Kityo, Cissy; Mandaliya, Kishor; Wellington, Maureen; Osibogun, Akin; Geskus, Ronald B.; Stevens, Wendy S.; van Vugt, Michèle; Rinke de Wit, Tobias F.

    2012-01-01

    Human immunodeficiency virus (HIV) RNA testing and HIV drug resistance (HIVDR) testing are not routinely available for therapeutic monitoring of patients receiving antiretroviral therapy (ART) in resource-limited settings. World Health Organization HIVDR early warning indicators (EWIs) assess ART

  2. Evaluation of pharmacy and therapeutics committee drug evaluation reports.

    Science.gov (United States)

    Majercik, P L; May, J R; Longe, R L; Johnson, M H

    1985-05-01

    Pharmacy and therapeutics (P & T) committee drug evaluation reports prepared by pharmacies and drug information centers (DICs) and product package inserts were compared with standard guidelines to evaluate their quality. Letters were sent to 143 hospital pharmacies asking them to submit a previously prepared drug evaluation report on temazepam, moxalactam disodium, or atenolol. The reports and package inserts for these three drugs were evaluated by the presence of 40 elements derived from the published ASHP guidelines for drug evaluation report preparation. Responses were obtained from 124 (87%) pharmacies; however, only 80 reports (60 DIC-prepared and 20 pharmacy-prepared) were received. The reports contained a mean of 28 of the 40 (70%) possible elements. The most frequently omitted elements were AHFS number, potential unlabeled uses, drug-drug interactions, drug-disease-laboratory test interactions, risk and benefit data, prevention and treatment of side effects, comparisons with established treatment, and disadvantages of the drug under consideration. Although the reports prepared by the DICs and pharmacies contained the same amount of information, the DIC-prepared reports included data more frequently on supply sources, therapeutic indications, approved labeling, comparison with established treatment, bioavailability and pharmacokinetics, and recommendations. Most of the reports contained more elements than the corresponding package inserts. The product package inserts did not contain the comparative elements required for P & T committee decisions. Both the pharmacy- and DIC-prepared reports failed to contain all 40 elements recommended in the standard guidelines, suggesting the need for more thorough reports.

  3. ADVERSE DRUG REACTION (ADR) MONITORING AND PHARMACOVIGILANCE

    OpenAIRE

    D. KAVITHA

    2013-01-01

    The need for systematic follow up of medicines for adverse drug reactions once they are introduced into general use has been widely recognised today. Even in developing countries like India, national pharmacovigilance programme has been started for monitoring adverse drug reactions. In its first year this program mainly aimed to foster the culture of ADR notification among health care professionals. As a part of health care team every pharmacist must have knowledge about adverse drug reaction...

  4. Developmental neurotoxicity induced by therapeutic and illicit drugs.

    OpenAIRE

    Vorhees, C V

    1994-01-01

    The developmental neurotoxicity of phenytoin, isotretinoin, and methamphetamine has been reviewed to illustrate effects from both therapeutic and illicit drugs to which people are exposed and which either induce or show the potential for inducing learning disabilities following in utero exposure. In each case both human and experimental animal data are presented and compared where possible. The findings point to several conclusions. First, some drugs in current use induce developmental neurot...

  5. CEP biomarkers as potential tools for monitoring therapeutics.

    Directory of Open Access Journals (Sweden)

    Kutralanathan Renganathan

    Full Text Available BACKGROUND: Carboxyethylpyrrole (CEP adducts are oxidative modifications derived from docosahexaenoate-containing lipids that are elevated in ocular tissues and plasma in age-related macular degeneration (AMD and in rodents exposed to intense light. The goal of this study was to determine whether light-induced CEP adducts and autoantibodies are modulated by pretreatment with AL-8309A under conditions that prevent photo-oxidative damage of rat retina. AL-8309A is a serotonin 5-HT1A receptor agonist. METHODS: Albino rats were dark adapted prior to blue light exposure. Control rats were maintained in normal cyclic light. Rats were injected subcutaneously 3x with 10 mg/kg AL-8309A (2 days, 1 day and 0 hours before light exposure for 6 h (3.1 mW/cm(2, λ=450 nm. Animals were sacrificed immediately following light exposure and eyes, retinas and plasma were collected. CEP adducts and autoantibodies were quantified by Western analysis or ELISA. RESULTS: ANOVA supported significant differences in mean amounts of CEP adducts and autoantibodies among the light + vehicle, light + drug and dark control groups from both retina and plasma. Light-induced CEP adducts in retina were reduced ~20% following pretreatment with AL-8309A (n = 62 rats, p = 0.006 and retinal CEP immunoreactivity was less intense by immunohistochemistry. Plasma levels of light-induced CEP adducts were reduced at least 30% (n = 15 rats, p = 0.004 by drug pretreatment. Following drug treatment, average CEP autoantibody titer in light exposed rats (n = 22 was unchanged from dark control levels, and ~20% (p = 0.046 lower than in vehicle-treated rats. CONCLUSIONS: Light-induced CEP adducts in rat retina and plasma were significantly decreased by pretreatment with AL-8309A. These results are consistent with and extend previous studies showing AL-8309A reduces light-induced retinal lesions in rats and support CEP biomarkers as possible tools for monitoring the efficacy of select therapeutics.

  6. Therapeutic applications of hydrogels in oral drug delivery.

    Science.gov (United States)

    Sharpe, Lindsey A; Daily, Adam M; Horava, Sarena D; Peppas, Nicholas A

    2014-06-01

    Oral delivery of therapeutics, particularly protein-based pharmaceutics, is of great interest for safe and controlled drug delivery for patients. Hydrogels offer excellent potential as oral therapeutic systems due to inherent biocompatibility, diversity of both natural and synthetic material options and tunable properties. In particular, stimuli-responsive hydrogels exploit physiological changes along the intestinal tract to achieve site-specific, controlled release of protein, peptide and chemotherapeutic molecules for both local and systemic treatment applications. This review provides a wide perspective on the therapeutic use of hydrogels in oral delivery systems. General features and advantages of hydrogels are addressed, with more considerable focus on stimuli-responsive systems that respond to pH or enzymatic changes in the gastrointestinal environment to achieve controlled drug release. Specific examples of therapeutics are given. Last, in vitro and in vivo methods to evaluate hydrogel performance are discussed. Hydrogels are excellent candidates for oral drug delivery, due to the number of adaptable parameters that enable controlled delivery of diverse therapeutic molecules. However, further work is required to more accurately simulate physiological conditions and enhance performance, which is important to achieve improved bioavailability and increase commercial interest.

  7. Injectable nanomaterials for drug delivery: carriers, targeting moieties, and therapeutics.

    Science.gov (United States)

    Webster, David M; Sundaram, Padma; Byrne, Mark E

    2013-05-01

    Therapeutics such as nucleic acids, proteins/peptides, vaccines, anti-cancer, and other drugs have disadvantages of low bio-availability, rapid clearance, and high toxicity. Thus, there is a significant need for the development of efficient delivery methods and carriers. Injectable nanocarriers have received much attention due to their vast range of structures and ability to contain multiple functional groups, both within the bulk material and on the surface of the particles. Nanocarriers may be tailored to control drug release and/or increase selective cell targeting, cellular uptake, drug solubility, and circulation time, all of which lead to a more efficacious delivery and action of therapeutics. The focus of this review is injectable, targeted nanoparticle drug delivery carriers highlighting the diversity of nanoparticle materials and structures as well as highlighting current therapeutics and targeting moieties. Structures and materials discussed include liposomes, polymersomes, dendrimers, cyclodextrin-containing polymers (CDPs), carbon nanotubes (CNTs), and gold nanoparticles. Additionally, current clinical trial information and details such as trial phase, treatment, active drug, carrier sponsor, and clinical trial identifier for different materials and structures are presented and discussed. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. Remote monitoring of heart failure: benefits for therapeutic decision making.

    Science.gov (United States)

    Martirosyan, Mihran; Caliskan, Kadir; Theuns, Dominic A M J; Szili-Torok, Tamas

    2017-07-01

    Chronic heart failure is a cardiovascular disorder with high prevalence and incidence worldwide. The course of heart failure is characterized by periods of stability and instability. Decompensation of heart failure is associated with frequent and prolonged hospitalizations and it worsens the prognosis for the disease and increases cardiovascular mortality among affected patients. It is therefore important to monitor these patients carefully to reveal changes in their condition. Remote monitoring has been designed to facilitate an early detection of adverse events and to minimize regular follow-up visits for heart failure patients. Several new devices have been developed and introduced to the daily practice of cardiology departments worldwide. Areas covered: Currently, special tools and techniques are available to perform remote monitoring. Concurrently there are a number of modern cardiac implantable electronic devices that incorporate a remote monitoring function. All the techniques that have a remote monitoring function are discussed in this paper in detail. All the major studies on this subject have been selected for review of the recent data on remote monitoring of HF patients and demonstrate the role of remote monitoring in the therapeutic decision making for heart failure patients. Expert commentary: Remote monitoring represents a novel intensified follow-up strategy of heart failure management. Overall, theoretically, remote monitoring may play a crucial role in the early detection of heart failure progression and may improve the outcome of patients.

  9. [Therapeutic techniques and subjectivation in treatment with drug users].

    Science.gov (United States)

    Garbi, Silvana Laura; Touris, María Cecilia; Epele, María

    2012-07-01

    The internment process in therapeutic communities (TC) involves a multiplicity of therapeutic practices and strategies geared to abstinence from drug usage. According to the specialists' own regulations and explicit objectives, the residents must not only abandon the consumption of substances but also adopt new practices, attitudes, emotions and significances through the use of therapeutic techniques that allow them to adapt to the structure of the organization that these institutions impose. Based on the results of the ethnographic survey carried out between 2009 and 2010 in three TCs of the metropolitan area of Buenos Aires, Argentina, the scope of this article is to analyze from a sociological and anthropological standpoint the "therapeutic tools" that comprise the treatment, the subject models that underlie these tools, the consequences that they may produce and their participation in the subjectivity production processes. For this purpose, we focus on analysis of "confrontation" as a privileged and omnipresent strategy of subjectivation in these therapeutic contexts, in order to reveal the epistemological, economic, political and ethical dimensions in the de-subjectivation process of the institutionalized drug user.

  10. The AGNP-TDM Expert Group Consensus Guidelines: focus on therapeutic monitoring of antidepressants.

    Science.gov (United States)

    Baumann, Pierre; Ulrich, Sven; Eckermann, Gabriel; Gerlach, Manfred; Kuss, Hans-Joachim; Laux, Gerd; Müller-Oerlinghausen, Bruno; Rao, Marie Luise; Riederer, Peter; Zernig, Gerald; Hiemke, Christoph

    2005-01-01

    Therapeutic drug monitoring (TDM) of psychotropic drugs such as antidepressants has been widely introduced for optimization of pharmacotherapy in psychiatric patients. The interdisciplinary TDM group of the Arbeitsgemeinschaft für Neuropsychopharmakologie und Pharmakopsychiatrie (AGNP) has worked out consensus guidelines with the aim of providing psychiatrists and TDM laboratories with a tool to optimize the use of TDM. Five research-based levels of recommendation were defined with regard to routine monitoring of drug plasma concentrations: (i) strongly recommended; (ii) recommended; (iii) useful; (iv) probably useful; and (v) not recommended. In addition, a list of indications that justify the use of TDM is presented, eg, control of compliance, lack of clinical response or adverse effects at recommended doses, drug interactions, pharmacovigilance programs, presence of a genetic particularity concerning drug metabolism, and children, adolescents, and elderly patients. For some drugs, studies on therapeutic ranges are lacking, but target ranges for clinically relevant plasma concentrations are presented for most drugs, based on pharmacokinetic studies reported in the literature. For many antidepressants, a thorough analysis of the literature on studies dealing with the plasma concentration-clinical effectiveness relationship allowed inclusion of therapeutic ranges of plasma concentrations. In addition, recommendations are made with regard to the combination of pharmacogenetic (phenotyping or genotyping) tests with TDM. Finally, practical instructions are given for the laboratory practitioners and the treating physicians how to use TDM: preparation of TDM, drug analysis, reporting and interpretation of results, and adequate use of information for patient treatment TDM is a complex process that needs optimal interdisciplinary coordination of a procedure implicating patients, treating physicians, clinical pharmacologists, and clinical laboratory specialists. These

  11. Therapeutic monitoring of unfractionated heparin - trials and tribulations.

    Science.gov (United States)

    Baluwala, Israfil; Favaloro, Emmanuel J; Pasalic, Leonardo

    2017-07-01

    Heparin is one of the oldest biological medicines with an established role in prevention and treatment of arterial and venous thromboembolism. Published therapeutic ranges for unfractionated heparin (UFH) mostly precede the large increase in the number of activated partial thromboplastin time (APTT) reagent/instrument combinations that now show wide variability. Areas covered: This paper explores the use of UFH, the development of heparin therapeutic ranges (HTRs), and the strengths and limitations of the methods used to monitor heparin's anticoagulant effect. Expert commentary: Despite longstanding use of UFH for management of thromboembolic conditions, the optimal test for monitoring UFH remains undetermined. Although used extensively for monitoring UFH, routine APTT-derived HTRs are based on limited science that may have little relevance to current laboratory practice. Anti-FXa levels may provide better and more reliable HTRs; however, even these levels show considerable inter-laboratory variation, and there are insufficient clinical studies proving improved clinical efficacy. Alternative tests for monitoring UFH reported over time have not been proven effective nor feasible, secondary to technical or cost issues, or lack of general adoption. Thus, despite limited evidence of clinical utility, an uncomfortable marriage of convenience represented by heparin laboratory monitoring is unlikely to be terminated in the immediate future.

  12. Multifunctional porous silicon for therapeutic drug delivery and imaging.

    Science.gov (United States)

    Santos, Hélder A; Bimbo, Luis M; Lehto, Vesa-Pekka; Airaksinen, Anu J; Salonen, Jarno; Hirvonen, Jouni

    2011-09-01

    Major challenges in drug formulation are the poor solid state stability of drug molecules, poor dissolution/solubility and/or poor pharmacokinetic properties (bioavailability), which may lead to unreliable in vitro-in vivo (IVIV) correlation. To improve current therapeutical strategies, novel means to deliver poorly water soluble active pharmaceutical ingredients, as well as to target them to specific sites or cells in the body are needed. Biomedical applications of porous silicon (PSi) have been actively investigated during the last 10 years, especially in the areas of drug delivery and imaging, due to the biocompatibility and biodegradability of PSi materials, which makes them a potential candidate for controlled drug release. In addition, the unique pore sizes and easily functionalized surface properties of PSi materials allow high drug payloads and controlled kinetics from the drug release formulations. Modification of the PSi surface properties also facilitates biofunctionalization of the surface and the possibility to attach targeting moieties (e.g., antibodies and peptides), thus enabling effective targeting of the payload. In this review, we briefly address the production methodologies of PSi, and we will mainly present and discuss several examples about the biocompatibility of PSi, the most recent in vitro and in vivo applications of PSi as a carrier in drug/protein/peptide delivery and tissue engineering, as well as PSi as a platform for drug targeting and imaging.

  13. Developmental neurotoxicity induced by therapeutic and illicit drugs.

    Science.gov (United States)

    Vorhees, C V

    1994-06-01

    The developmental neurotoxicity of phenytoin, isotretinoin, and methamphetamine has been reviewed to illustrate effects from both therapeutic and illicit drugs to which people are exposed and which either induce or show the potential for inducing learning disabilities following in utero exposure. In each case both human and experimental animal data are presented and compared where possible. The findings point to several conclusions. First, some drugs in current use induce developmental neurotoxicity, and it cannot safely be assumed that there are not more as yet unidentified. Second, of the types of neurotoxicity induced by drugs, learning disabilities figure prominently. Third, the effects observed are dependent on both the drug's mechanism of action and the period of brain development during which exposure occurs. Fourth, with the exception of CNS teratogens, it is not yet possible to predict which periods of brain development are the most vulnerable for the induction of learning disabilities, as seen by the different patterns of critical periods for phenytoin and isotretinoin compared to methamphetamine. Fifth, as seen with isotretinoin, existing drugs that cause developmental neurotoxicity are not the only problem; new drugs with such effects are still being introduced. Sixth, only a small fraction of the drugs currently in use have ever been examined for developmental neurotoxicity; hence, the full scope of the problem cannot even be accurately estimated based on current information. It is concluded that prevention of new cases caused by drugs such as isotretinoin should be a high priority for future regulatory action.

  14. Protein and Peptide in Drug Targeting and its Therapeutic Approach

    Directory of Open Access Journals (Sweden)

    Raj K. Keservani

    2015-09-01

    Full Text Available Aim: The main aim of this review article is to provide information like advantages of protein and peptides via different routes of drug administration, targeted to a particular site and its implication in drug delivery system. Methods: To that aim, from the web sites of PubMed, HCAplus, Thomson, and Registry were used as the main sources to perform the search for the most significant research articles published on the subject. The information was then carefully analyzed, highlighting the most important results in the development of protein and peptide drug targeting as well as its therapeutic activity. Results: In recent years many researchers use protein and peptide as a target site of drug by a different delivery system. Proteins and peptides are used as specific and effective therapeutic agents, due to instability and side effects their use is complicated. Protein kinases are important regulators of most, if not all, biological processes. Abnormal activity of proteins and peptides has been implicated in many human diseases, such as diabetes, cancer and neurodegenerative disorders. Conclusions: It is concluded that the protein and peptide were used in drug targeting to specific site and also used in different diseased states like cancer, diabetes, immunomodulating, neurodegenerative effects and antimicrobial activity.

  15. Factors influencing GPs’ choice between drugs in a therapeutic drug group. A qualitative study

    DEFF Research Database (Denmark)

    Buusman, Allan; Andersen, Morten; Merrild, Camilla Hoffmann

    2007-01-01

    Objective. To explore how GPs choose between drugs in a therapeutic drug group. Design. A qualitative study based on semi-structured ethnographic interviews. Setting and subjects. General practitioners from the counties of both Funen and West Zealand in Denmark. A total of 15 general practitioners...

  16. The therapeutic potential of psychedelic drugs: past, present and future

    OpenAIRE

    Carhart-Harris, RL; Goodwin, G

    2017-01-01

    Plant-based psychedelics such as psilocybin have an ancient history of medicinal use. After the first English-language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aides to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programmes. Since the...

  17. Drug safety in pregnancy - monitoring congenital anomalies

    NARCIS (Netherlands)

    Morgan, Margery; De Jong-Van Den Berg, Lolkje T. W.; Jordan, Sue

    Aim This paper outlines research into the causes of congenital anomalies, and introduces a pan-European study. The potential roles of nurses and midwives in this area are illustrated by a case report. Background Since the thalidomide disaster, use of drugs in pregnancy has been carefully monitored

  18. Stealth Properties to Improve Therapeutic Efficacy of Drug Nanocarriers

    Directory of Open Access Journals (Sweden)

    Stefano Salmaso

    2013-01-01

    Full Text Available Over the last few decades, nanocarriers for drug delivery have emerged as powerful tools with unquestionable potential to improve the therapeutic efficacy of anticancer drugs. Many colloidal drug delivery systems are underdevelopment to ameliorate the site specificity of drug action and reduce the systemic side effects. By virtue of their small size they can be injected intravenously and disposed into the target tissues where they release the drug. Nanocarriers interact massively with the surrounding environment, namely, endothelium vessels as well as cells and blood proteins. Consequently, they are rapidly removed from the circulation mostly by the mononuclear phagocyte system. In order to endow nanosystems with long circulation properties, new technologies aimed at the surface modification of their physicochemical features have been developed. In particular, stealth nanocarriers can be obtained by polymeric coating. In this paper, the basic concept underlining the “stealth” properties of drug nanocarriers, the parameters influencing the polymer coating performance in terms of opsonins/macrophages interaction with the colloid surface, the most commonly used materials for the coating process and the outcomes of this peculiar procedure are thoroughly discussed.

  19. Chitosan in nasal delivery systems for therapeutic drugs.

    Science.gov (United States)

    Casettari, Luca; Illum, Lisbeth

    2014-09-28

    There is an obvious need for efficient and safe nasal absorption enhancers for the development of therapeutically efficacious nasal products for small hydrophilic drugs, peptides, proteins, nucleic acids and polysaccharides, which do not easily cross mucosal membranes, including the nasal. Recent years have seen the development of a range of nasal absorption enhancer systems such as CriticalSorb (based on Solutol HS15) (Critical Pharmaceuticals Ltd), Chisys based on chitosan (Archimedes Pharma Ltd) and Intravail based on alkylsaccharides (Aegis Therapeutics Inc.), that is presently being tested in clinical trials for a range of drugs. So far, none of these absorption enhancers have been used in a marketed nasal product. The present review discusses the evaluation of chitosan and chitosan derivatives as nasal absorption enhancers, for a range of drugs and in a range of formulations such as solutions, gels and nanoparticles and finds that chitosan and its derivatives are able to efficiently improve the nasal bioavailability. The revirtew also questions whether chitosan nanoparticles for systemic drug delivery provide any real improvement over simpler chitosan formulations. Furthermore, the review also evaluates the use of chitosan formulations for the improvement of transport of drugs directly from the nasal cavity to the brain, based on its mucoadhesive characteristics and its ability to open tight junctions in the olfactory and respiratory epithelia. It is found that the use of chitosan nanoparticles greatly increases the transport of drugs from nose to brain over and above the effect of simpler chitosan formulations. Copyright © 2014 Elsevier B.V. All rights reserved.

  20. Therapeutic drug monitoring of levetiracetam by high-performance liquid chromatography with photodiode array ultraviolet detection: preliminary observations on correlation between plasma concentration and clinical response in patients with refractory epilepsy.

    Science.gov (United States)

    Lancelin, Frédérique; Franchon, Emilie; Kraoul, Linda; Garciau, Isabelle; Brovedani, Sophie; Tabaouti, Khalid; Landré, Elisabeth; Chassoux, Francine; Paubel, Pascal; Piketty, Marie-Liesse

    2007-10-01

    Levetiracetam is a new antiepileptic drug prescribed for the treatment of patients with refractory partial seizures with or without secondary generalization as well as for the treatment of juvenile myoclonic epilepsy. A rapid and specific method by high-performance liquid chromatography diode array detection was developed to measure the concentration of levetiracetam in human plasma. The trough plasma concentrations measured in 69 epileptic patients treated with 500 to 3000 mg/d of levetiracetam ranged from 1.1 to 33.5 microg/mL. The mean (range) levetiracetam plasma concentrations in responders and nonresponders were 12.9 microg/mL (4.6-21 microg/mL) and 9.5 microg/mL (1.1-20.9 microg/mL), respectively. A wide variability in concentration-response relationships was observed in patients. Using a receiver operating characteristic curve, the threshold levetiracetam concentration for a therapeutic response was 11 microg/mL. The sensitivity and specificity for this threshold levetiracetam concentration were 73% and 71%, respectively. According to chi analysis, this finding was not significant probably because of the small number of patients and because of their refractory seizure type. Nevertheless, the levetiracetam plasma concentration could be used to help clinicians detect severe intoxication or to verify compliance by repeating the measurement in patients.

  1. Mitragynine (Kratom) - monitoring in sports drug testing.

    Science.gov (United States)

    Guddat, Sven; Görgens, Christian; Steinhart, Vanessa; Schänzer, Wilhelm; Thevis, Mario

    2016-11-01

    In 2014, mitragynine (Kratom) was placed on the Monitoring List of the World Anti-Doping Agency to gain information of its current use in professional sports. Therefore, analytical strategies in sports drug testing are presented and the first Kratom case in professional sports is described. It is outlined that thorough monitoring by anti-doping laboratories is of utmost importance to obtain data on Kratom's misuse and to protect athletes from potential health hazards. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  2. Therapeutic approach to bronchiolitis: why pediatricians continue to overprescribe drugs?

    Directory of Open Access Journals (Sweden)

    de Seta Federica

    2010-10-01

    Full Text Available Abstract Background Bronchiolitis guidelines suggest that neither bronchodilators nor corticosteroids, antiviral and antibacterial agents should be routinely used. Although recommendations, many clinicians persistently prescribe drugs for bronchiolitis. Aim of the study To unravel main reasons of pediatricians in prescribing drugs to infants with bronchiolitis, and to possibly correlate therapeutic choices to the severity of clinical presentation. Also possible influence of socially deprived condition on therapeutic choices is analyzed. Methods Patients admitted to Pediatric Division of 2 main Hospitals of Naples because of bronchiolitis in winter season 2008-2009 were prospectively analyzed. An RDAI (Respiratory Distress Assessment Instrument score was assessed at different times from admission. Enrolment criteria were: age 1-12 months; 1st lower respiratory infection with cough and rhinitis with/without fever, wheezing, crackles, tachypnea, use of accessory muscles, and/or nasal flaring, low oxygen saturation, cyanosis. Social deprivation status was assessed by evaluating school graduation level of the origin area of the patients. A specific questionnaire was submitted to clinicians to unravel reasons of their therapeutic behavior. Results Eighty-four children were enrolled in the study. Mean age was 3.5 months. Forty-four per cent of patients presented with increased respiratory rate, 70.2% with chest retractions, and 7.1% with low SaO2. Mean starting RDAI score was 8. Lung consolidation was found in 3.5% on chest roentgenogram. Data analysis also unraveled that 64.2% matched clinical admission criteria. Social deprivation status analysis revealed that 72.6% of patients were from areas "at social risk". Evaluation of length of stay vs. social deprivation status evidenced no difference between "at social risk" and "not at social risk" patients. Following therapeutic interventions were prescribed: nasal suction (64.2%, oxygen administration (7

  3. Neuroprotective peptide drug delivery and development: potential new therapeutics.

    Science.gov (United States)

    Gozes, I

    2001-12-01

    Alzheimer's disease and related neurodegenerative disorders are prevalent among the elderly and might be considered as the plague of the 21st century. It is thus imperative to find cures for these conditions. The use of nerve growth factor proteins as neuroprotective therapeutics is limited by their hindered mobility through the blood-brain barrier. Peptides provide an attractive alternative. However, do peptide derivatives retain the activity of the entire protein? Are they stable? Would peptides cross the blood-brain barrier and what are the potential side effects? Examples are put forth to strengthen our opinion that peptides are important candidates for future drug development.

  4. Monitoring Therapeutic Treatments against Burkholderia Infections Using Imaging Techniques

    Directory of Open Access Journals (Sweden)

    Tiffany M. Mott

    2013-05-01

    Full Text Available Burkholderia mallei, the etiologic agent of glanders, are Category B select agents with biothreat potential, and yet effective therapeutic treatments are lacking. In this study, we showed that CpG administration increased survival, demonstrating protection in the murine glanders model. Bacterial recovery from infected lungs, liver and spleen was significantly reduced in CpG-treated animals as compared with non-treated mice. Reciprocally, lungs of CpG-treated infected animals were infiltrated with higher levels of neutrophils and inflammatory monocytes, as compared to control animals. Employing the B. mallei bioluminescent strain CSM001 and the Neutrophil-Specific Fluorescent Imaging Agent, bacterial dissemination and neutrophil trafficking were monitored in real-time using multimodal in vivo whole body imaging techniques. CpG-treatment increased recruitment of neutrophils to the lungs and reduced bioluminescent bacteria, correlating with decreased bacterial burden and increased protection against acute murine glanders. Our results indicate that protection of CpG-treated animals was associated with recruitment of neutrophils prior to infection and demonstrated, for the first time, simultaneous real time in vivo imaging of neutrophils and bacteria. This study provides experimental evidence supporting the importance of incorporating optimized in vivo imaging methods to monitor disease progression and to evaluate the efficacy of therapeutic treatment during bacterial infections.

  5. Risk evaluation and monitoring in multiple sclerosis therapeutics.

    Science.gov (United States)

    Clanet, Michel C; Wolinsky, Jerry S; Ashton, Raymond J; Hartung, Hans-Peter; Reingold, Stephen C

    2014-09-01

    Risk for multiple sclerosis (MS) disease-modifying therapies (DMT) must be assessed on an ongoing basis. Early concerns regarding the first-approved DMTs for MS have been mitigated, but recently licensed therapies have been linked to possibly greater risks. The objective of this review is to discuss risk assessment in MS therapeutics based on an international workshop and comprehensive literature search and recommend strategies for risk assessment/monitoring. Assessment and perception of therapeutic risks vary between patients, doctors and regulators. Acceptability of risk depends on the magnitude of risk and the demonstrated clinical benefits of any agent. Safety signals must be distinguishable from chance occurrences in a clinical trial and in long-term use of medications. Post-marketing research is crucial for assessing longer-term safety in large patient cohorts. Reporting of adverse events is becoming more proactive, allowing more rapid identification of risks. Communication about therapeutic risks and their relationship to clinical benefit must involve patients in shared decision making. It is difficult to produce a general risk-assessment algorithm for all MS therapies. Specific algorithms are required for each DMT in every treated-patient population. New and evolving risks must be evaluated and communicated rapidly to allow patients and physicians to be well informed and able to share treatment decisions. © The Author(s) 2013.

  6. Adapting drug approval pathways for bacteriophage-based therapeutics

    Directory of Open Access Journals (Sweden)

    Callum Cooper

    2016-08-01

    Full Text Available The global rise of multi-drug resistant bacteria has resulted in the notion that an antibiotic apocalypse is fast approaching. This has led to a number of well publicized calls for global funding initiatives to develop new antibacterial agents. The long clinical history of phage therapy in Eastern Europe, combined with more recent in vitro and in vivo success, demonstrates the potential for whole phage or phage based antibacterial agents. To date, no whole phage or phage derived products are approved for human therapeutic use in the EU or USA. There are at least three reasons for this: (i phages possess different biological, physical and pharmacological properties compared to conventional antibiotics. Phages need to replicate in order to achieve a viable antibacterial effect, resulting in complex pharmacodynamics / pharmacokinetics. (ii The specificity of individual phages requires multiple phages to treat single species infections, often as part of complex cocktails. (iii The current approval process for antibacterial agents has evolved with the development of chemically based drugs at its core, and is not suitable for phages. Due to similarities with conventional antibiotics, phage derived products such as endolysins are suitable for approval under current processes as biological therapeutic proteins. These criteria render the approval of phages for clinical use theoretically possible but not economically viable. In this review, pitfalls of the current approval process will be discussed for whole phage and phage derived products, in addition to the utilization of alternative approval pathways including adaptive licensing and Right to try legislation.

  7. Drug assessment by a Pharmacy and Therapeutics committee: from drug selection criteria to use in clinical practice

    Directory of Open Access Journals (Sweden)

    Lozano-Blázquez A

    2014-07-01

    therapeutic indications. The average prescription compliance scores were as follows: bevacizumab, 83% for metastatic colorectal cancer, 100% for metastatic breast cancer, and 82.3% for non-small-cell lung cancer; cetuximab, 62.0% for colorectal cancer and 50% for head and neck cancer; trastuzumab, 95.1% for early breast cancer and 82.4% for metastatic breast cancer; and bortezomib, 63.7% for multiple myeloma.Conclusion: The degree of compliance with criteria for use of cancer drugs was reasonably high. PTC functions need to be changed so that they can carry out more innovative tasks, such as monitoring conditions for drug use.Keywords: decision-making, drug selection, drug utilization, formulary, neoplasm, Pharmacy and Therapeutics committee

  8. Perspectives on Drug and Therapeutics Committee policy implementation.

    Science.gov (United States)

    Tan, Ee Lyn; Day, Richard O; Brien, Jo-anne E

    2005-12-01

    Drug and therapeutics committees (DTCs) are expected to make difficult decisions that may have an impact on the clinical and economic outcomes of drug use. There have been few studies investigating the barriers to DTC policy implementation, and little is known about ways to improve the process. The specific objectives of this qualitative study were to explore stakeholder opinions with respect to (1) the perceptions of barriers to Drug and Therapeutics Committee (DTC) policy implementation and (2) ways to improve DTC policy implementation. Stakeholders of Australian DTCs participated in focus group discussions. Discussions were audiotaped and transcribed verbatim. Thematic content analysis was conducted. Six focus group discussions were conducted. A number of barriers were identified (lack of resources, lack of follow-up, lack of ownership, low DTC profile within the organization, and overreliance on pharmacy to implement policy). Participants were of the opinion that prioritizing decisions, optimizing pharmacy roles, provision of real-time information, and active procurement of organizational commitment were some of the ways to improve DTC policy implementation. Although this study was conducted in an Australian setting, the challenges facing DTCs in other countries are likely to be similar. Ownership, social influence, and resources are important issues in the implementation of policy/guidelines for many DTCs, both in Australia and internationally. It is expected that these issues will have an impact on policy implementation. Therefore, the findings of this study may be widely applicable. This work reinforced the notion that the significance of DTCs lies beyond decision making alone. The time and expertise invested in decision making could be undermined, if DTC policies are not effectively implemented.

  9. Adverse drug events associated with vitamin K antagonists: factors of therapeutic imbalance

    Directory of Open Access Journals (Sweden)

    El-Helou N

    2013-03-01

    Full Text Available Nancy El-Helou, Amal Al-Hajje, Rola Ajrouche, Sanaa Awada, Samar Rachidi, Salam Zein, Pascale SalamehClinical and Epidemiological Research Laboratory, Faculty of Pharmacy, Lebanese University, Beirut, LebanonBackground: Adverse drug events (ADE occur frequently during treatment with vitamin K antagonists (AVK and contribute to increase hemorrhagic risks.Methods: A retrospective study was conducted over a period of 2 years. Patients treated with AVK and admitted to the emergency room of a tertiary care hospital in Beirut were included. The aim of the study was to identify ADE characterized by a high international normalized ratio (INR and to determine the predictive factors responsible for these events. Statistical analysis was performed with the SPSS statistical package.Results: We included 148 patients. Sixty-seven patients (47.3% with an INR above the therapeutic range were identified as cases. The control group consisted of 81 patients (54.7% with an INR within the therapeutic range. Hemorrhagic complications were observed in 53.7% of cases versus 6.2% of controls (P < 0.0001. No significant difference was noticed between cases and controls regarding the indication and the dose of AVK. Patients aged over 75 years were more likely to present an INR above the therapeutic range (58.2%, P = 0.049. Recent infection was present in 40.3% of cases versus 6.2% of controls (P < 0.0001 and hypoalbuminemia in 37.3% of cases versus 6.1% of controls (P < 0.0001. Treatment with antibiotics, amiodarone, and anti-inflammatory drugs were also factors of imbalance (P < 0.0001.Conclusion: Many factors may be associated with ADE related to AVK. Monitoring of INR and its stabilization in the therapeutic range are important for preventing these events.Keywords: adverse drug events, vitamin K antagonists, bleeding risks, therapeutic imbalance

  10. The Therapeutic Potential of Psychedelic Drugs: Past, Present, and Future.

    Science.gov (United States)

    Carhart-Harris, Robin L; Goodwin, Guy M

    2017-10-01

    Plant-based psychedelics, such as psilocybin, have an ancient history of medicinal use. After the first English language report on LSD in 1950, psychedelics enjoyed a short-lived relationship with psychology and psychiatry. Used most notably as aids to psychotherapy for the treatment of mood disorders and alcohol dependence, drugs such as LSD showed initial therapeutic promise before prohibitive legislature in the mid-1960s effectively ended all major psychedelic research programs. Since the early 1990s, there has been a steady revival of human psychedelic research: last year saw reports on the first modern brain imaging study with LSD and three separate clinical trials of psilocybin for depressive symptoms. In this circumspective piece, RLC-H and GMG share their opinions on the promises and pitfalls of renewed psychedelic research, with a focus on the development of psilocybin as a treatment for depression.

  11. Packaging protein drugs as bacterial inclusion bodies for therapeutic applications

    Directory of Open Access Journals (Sweden)

    Villaverde Antonio

    2012-06-01

    Full Text Available Abstract A growing number of insights on the biology of bacterial inclusion bodies (IBs have revealed intriguing utilities of these protein particles. Since they combine mechanical stability and protein functionality, IBs have been already exploited in biocatalysis and explored for bottom-up topographical modification in tissue engineering. Being fully biocompatible and with tuneable bio-physical properties, IBs are currently emerging as agents for protein delivery into mammalian cells in protein-replacement cell therapies. So far, IBs formed by chaperones (heat shock protein 70, Hsp70, enzymes (catalase and dihydrofolate reductase, grow factors (leukemia inhibitory factor, LIF and structural proteins (the cytoskeleton keratin 14 have been shown to rescue exposed cells from a spectrum of stresses and restore cell functions in absence of cytotoxicity. The natural penetrability of IBs into mammalian cells (reaching both cytoplasm and nucleus empowers them as an unexpected platform for the controlled delivery of essentially any therapeutic polypeptide. Production of protein drugs by biopharma has been traditionally challenged by IB formation. However, a time might have arrived in which recombinant bacteria are to be engineered for the controlled packaging of therapeutic proteins as nanoparticulate materials (nanopills, for their extra- or intra-cellular release in medicine and cosmetics.

  12. A Fibrous Localized Drug Delivery Platform with NIR-Triggered and Optically Monitored Drug Release

    Science.gov (United States)

    Liu, Heng; Fu, Yike; Li, Yangyang; Ren, Zhaohui; Li, Xiang; Han, Gaorong; Mao, Chuanbin

    2016-01-01

    Implantable localized drug delivery systems (LDDSs) with intelligent functionalities have emerged as a powerful chemotherapeutic platform in curing cancer. Developing LDDSs with rationally controlled drug release and real-time monitoring functionalities holds promise for personalized therapeutic protocols but suffers daunting challenges. To overcome such challenges, a series of porous Yb3+/Er3+ codoped CaTiO3 (CTO:Yb,Er) nanofibers, with specifically designed surface functionalization, were synthesized for doxorubicin (DOX) delivery. The content of DOX released could be optically monitored by increase in the intensity ratio of green to red emission (I550/I660) of upconversion photoluminescent nanofibers under 980 nm near-infrared (NIR) excitation owing to the fluorescence resonance energy transfer (FRET) effect between DOX molecules and the nanofibers. More importantly, the 808 nm NIR irradiation enabled markedly accelerated DOX release, confirming representative NIR-triggered drug release properties. In consequence, such CTO:Yb,Er nanofibers presented significantly enhanced in vitro anticancer efficacy under NIR irradiation. This study has thus inspired another promising fibrous LDDS platform with NIR-triggered and optics-monitored DOX releasing for personalized tumor chemotherapy. PMID:27557281

  13. New Perspectives on Antiacne Plant Drugs: Contribution to Modern Therapeutics

    Directory of Open Access Journals (Sweden)

    Priyam Sinha

    2014-01-01

    Full Text Available Acne is a common but serious skin disease, which affects approximately 80% adolescents and young adults in 11–30 age group. 42.5% of men and 50.9% of women continue to suffer from this disease into their twenties. Bacterial resistance is now at the alarming stage due to the irrational use of antibiotics. Hence, search for new lead molecule/bioactive and rational delivery of the existing drug (for better therapeutic effect to the site of action is the need of the hour. Plants and plant-derived products have been an integral part of health care system since time immemorial. Therefore, plants that are currently used for the treatment of acne and those with a high potential are summarized in the present review. Most active plant extracts, namely, P. granatum, M. alba, A. anomala, and M. aquifolium exhibit minimum inhibitory concentration (MIC in the range of 4–50 µg/mL against P. acnes, while aromatic oils of C. obovoides, C. natsudaidai, C. japonica, and C. nardus possess MICs 0.005–0.6 μL/mL and phytomolecules such as rhodomyrtone, pulsaquinone, hydropulsaquinone, honokiol, magnolol, xanthohumol lupulones, chebulagic acid and rhinacanthin-C show MIC in the range of 0.5–12.5 μg/mL. Novel drug delivery strategies of important plant leads in the treatment of acne have also been discussed.

  14. Ratiometric Monitoring of Intracellular Drug Release by an Upconversion Drug Delivery Nanosystem.

    Science.gov (United States)

    Li, Kai; Su, Qianqian; Yuan, Wei; Tian, Bo; Shen, Bin; Li, Yuhao; Feng, Wei; Li, Fuyou

    2015-06-10

    Nanoscale drug delivery systems have been widely investigated due to their well-recognized advantages including controlled delivery of chemotherapeutic agents, enhanced therapeutic effectiveness, and reduced adverse effects compared to conventional chemotherapy with small molecules. However, further progress in the use of nanoscale delivery systems in clinical applications has been hampered by pharmacokinetic studies in biological samples which were associated with significant experimental challenges. Here, we report a rational ratiometric approach to monitor drug release kinetics by quantitatively investigating luminescence resonance energy transfer (LRET) from upconversion nanoparticles to the antitumor drug doxorubicin (DOX). Specifically, DOX molecules within the shell of mesoporous silica-coated upconversion nanoparticles selectively quenched the green emission of upconversion nanoparticles, while the intensity of red emission was essentially unaltered. Consequently, when DOX was gradually released, a steady recovery of green emission was observed. The ability to monitor the intensity ratio of green-to-red luminescence enabled a rational design for real-time investigation of drug delivery release kinetics. Importantly, the internal standard effect of red emission made this ratiometric approach suitable for complex biological microenvironments.

  15. Drug delivery via lipoprotein-based carriers: answering the challenges in systemic therapeutics.

    Science.gov (United States)

    Sabnis, Nirupama; Lacko, Andras G

    2012-05-01

    Plasma lipoproteins are transporters of lipids and other hydrophobic molecules in the mammalian circulation. Lipoproteins also have a strong potential to serve as drug-delivery vehicles due to their small size, long residence time in the circulation and high-drug payload. Consequently, lipoproteins and synthetic/reconstituted lipoprotein preparations have been evaluated with increasing interest towards clinical applications, particularly for cancer diagnostics/imaging and chemotherapy. In this review, past and current studies on lipoproteins and similar alternative drug carriers are discussed regarding their suitability as agents to deliver drugs, primarily to cancer cells and tumors. A lipoprotein-based delivery strategy may also provide a novel platform for improving the therapeutic efficacy of drugs that have previously been judged unsuitable or had only limited application due to poor solubility. An additional, and perhaps the most important aspect of the drug-delivery process via lipoprotein-type carriers, is the receptor-mediated uptake of the payload from the lipoprotein complex. Monitoring the expression of specific receptors prior to treatment could, thus, give rise to efficient selection of optimally responsive patients, resulting in a successful personalized therapy regimen.

  16. Monitoring of NSAIDs adverse effects based on spontaneous reports from Wrocław regional adverse drug reactions monitoring center.

    Science.gov (United States)

    Jaźwińska-Tarnawska, Ewa; Wiela-Hojeńska, Anna; Wolańczyk-Medrala, Anna; Patkowski, Janusz; Nittner-Marszalska, Marita; Głowacka, Krystyna

    2012-01-01

    The mechanism of action of non-steroidal anti-inflammatory drugs (NSAIDs) in majority of cases is responsible for adverse reactions of these therapeutic agents. Obtaining post-registration information on adverse drug reactions (ADRs) by means of the Yellow Card System is a significant element in the process of enhancing the safety of pharmacotherapy. The aim of the study was to analyze ADRs of NSAIDs (anti-inflammatory and analgesic drugs) reported to the Regional Centre for the Monitoring of Adverse Drug Reactions (RCMADR) in Wrocław in the years 2007-2009. The study material included 232 spontaneous reports, which were sent by physicians and pharmacists to the RCMADR in Wrocław, out of which 80 concerned mentioned drugs. Analysis of the obtained data revealed a relationship between the incidence and kind of ADRs and the age, gender of the patients, centre from which the data were supplied, geographical region of administered medication. A significant role of post-registration monitoring of adverse drug reactions during therapy with antiinflammatory and analgesic drugs was confirmed in view of geographically conditioned differences affecting the profile of instituted therapy and the source of information. With an increasing global use of these medications, only thorough monitoring of every adverse reaction, encouraging spontaneous reports, as well as analysis at a global level may increase the knowledge on adverse drug reactions and enable correction of the safety profile of every drug from this group.

  17. Requirements for drug monitoring of verapamil: experience from an unselected group of patients with cardiovascular disease

    DEFF Research Database (Denmark)

    Husum, D; Johnsen, A; Jensen, Gorm Boje

    1990-01-01

    620 and D 617 indicated saturation of the first-pass metabolism. In conclusion, therapeutic drug monitoring is not indicated during routine verapamil treatment, whereas single measurements of verapamil may be warranted in patients not responding to treatment in order to identify fast metabolizers...

  18. Marijuana-based drugs: innovative therapeutics or designer drugs of abuse?

    Science.gov (United States)

    Seely, Kathryn A; Prather, Paul L; James, Laura P; Moran, Jeffery H

    2011-02-01

    The principal psychoactive component of marijuana, Δ(9)-tetrahydrocannabinol (THC), activates CB1 cannabinoid receptors (CB1Rs). Unfortunately, pharmacological research into the design of effective THC analogs has been hampered by psychiatric side effects. THC-based drug design of a less academic nature, however, has led to the marketing of "synthetic marijuana," labeled as K2 or "Spice," among other terms, which elicits psychotropic actions via CB1R activation. Because of structural dissimilarity to THC, the active ingredients of K2/Spice preparations are widely unregulated. The K2/Spice "phenomenon" provides a context for considering whether marijuana-based drugs will truly provide innovative therapeutics or merely perpetuate drug abuse.

  19. RFID Tag Helix Antenna Sensors for Wireless Drug Dosage Monitoring.

    Science.gov (United States)

    Huang, Haiyu; Zhao, Peisen; Chen, Pai-Yen; Ren, Yong; Liu, Xuewu; Ferrari, Mauro; Hu, Ye; Akinwande, Deji

    2014-01-01

    Miniaturized helix antennas are integrated with drug reservoirs to function as RFID wireless tag sensors for real-time drug dosage monitoring. The general design procedure of this type of biomedical antenna sensors is proposed based on electromagnetic theory and finite element simulation. A cost effective fabrication process is utilized to encapsulate the antenna sensor within a biocompatible package layer using PDMS material, and at the same time form a drug storage or drug delivery unit inside the sensor. The in vitro experiment on two prototypes of antenna sensor-drug reservoir assembly have shown the ability to monitor the drug dosage by tracking antenna resonant frequency shift from 2.4-2.5-GHz ISM band with realized sensitivity of 1.27 [Formula: see text] for transdermal drug delivery monitoring and 2.76-[Formula: see text] sensitivity for implanted drug delivery monitoring.

  20. Prioritising drug and therapeutics committee (DTC) decisions: a national survey.

    Science.gov (United States)

    Tan, Ee Lyn; Day, Richard O; Brien, Jo-anne E

    2007-04-01

    A national survey was conducted to explore stakeholder opinions about: (1) the domains of activity and criteria used to determine "important" decisions; (2) the "importance" of Drug and Therapeutics Committee (DTC) decisions as an appropriate approach for prioritising implementation and actions and (3) how DTC decisions could be prioritised for action. This is a study of DTCs conducted in the Australian health care setting. A semi-structured questionnaire was sent to Directors of Pharmacies or Chief Pharmacists in Australian hospitals. Questionnaires could be returned by email or by fax. Two weeks after initial mail-out, non-responders were followed-up. Responses were collated and analysed using descriptive statistics. Free-text responses were collated. QSR NVivo was used as a data management tool. The response rate was 61%. All respondents indicated that "patient safety" was a domain of importance for a decision. Other domains of important DTC decisions include: "ensuring the practice of evidence based medicine within their institution" (94%), "cost" (93%), "ensure practice according to legislative requirements" (87%). Most respondents agreed that some DTC decisions were more important than others. Given constraints on time and resources, the majority agreed that DTC decisions should be prioritised for implementation, although most had no suggestions about how this could be done. Some suggested that the domains of importance could be the basis for priority assignment. Currently DTC decisions and policies are implemented in an ad hoc manner. As a result implementation may be incomplete and ineffective, and may pose a risk of serious consequences in patient care. This study identifies the domains or criteria of DTC decisions so that DTCs may allocate scarce resources to the systematic implementation of important decisions.

  1. From evidence-based medicine to personalized medicine, with particular emphasis on drug-safety monitoring.

    Science.gov (United States)

    Ennezat, Pierre-Vladimir; Cosgrove, Shona; Bouvaist, Hélène; Maréchaux, Sylvestre; Guerbaai, Raphaëlle-Ashley; Le Jemtel, Thierry; Andréjak, Michel; Vital-Durand, Denis

    Nowadays, guidelines are derived from the findings of randomized controlled therapeutic trials. However, an overall significant P value does not exclude that some patients may be harmed by or will not respond to the therapeutic agent being studied. Trials in patients with a low risk of events and/or a limited chance of providing significant differences in therapeutic effects require a large patient population to demonstrate a beneficial effect. Composite efficacy endpoints are often employed to obviate the need for a large patient population when low rates of events or limited therapeutic efficacy are anticipated. Results of randomized controlled therapeutic trials are commonly expressed in terms of relative risk reduction, whereas absolute risk reduction allows the calculation of the "number needed to treat" to prevent an adverse outcome. The number needed to treat is a far more clinically relevant variable than relative risk reduction. The clinician's mission is to match treatment to patient with the goal of achieving optimal therapeutic response. Drug-safety monitoring is also of major importance to avoid exposing patients to irreversible adverse effects. Unfortunately, drug-safety monitoring is often overlooked in routine clinical practice. Finally, the lack of long-term therapeutic data (>5-10 years) is an unsolved dilemma, as most trials are limited to a duration of a few months or years. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  2. Value of Gallium-67 Scanning in Monitoring Therapeutic Effectiveness in a Patient with Relapsing Polychondritis

    Directory of Open Access Journals (Sweden)

    Ming-Che Chang

    2008-06-01

    Full Text Available We present a 57-year-old man who had low-grade fever and painful, swollen and erythematous ears. Gallium-67 citrate scintigraphy (gallium scan performed prior to the commencement of treatment showed increased gallium uptake in bilateral external ears, neck, mediastinum and bilateral pulmonary hili. The results of ultrasonography of both ears were compatible with the diagnosis of chondritis. The patient's clinical condition and laboratory data improved after a course of nonsteroidal anti-inflammatory drugs and steroids. Gallium scan performed after treatment showed a diminished uptake in the external ears, neck, and mediastinum. Gallium scintigraphy is a valuable tool for evaluating inflammatory activity and monitoring therapeutic response in patients with relapsing polychondritis.

  3. Adverse Drug Reaction Monitoring in Ethiopia: Analysis of case ...

    African Journals Online (AJOL)

    Bernt Lindtjørn

    Abstract. Background: Ensuring the health and safety of the public from adverse reaction of drugs is paramount. Adverse. Drug Reactions Monitoring (ADRM) is a system that is put in place to ensure the health and safety of the public from adverse reactions of drugs. It heavily relies on health professionals (HPs) reporting of ...

  4. Trichogram To Monitor Therapeutic Benefit In Hair Loss

    Directory of Open Access Journals (Sweden)

    Uppal Monica

    2004-01-01

    Full Text Available Trichogram is a method of quantifying hair. We report 3 cases of diffuse hair loss of varying etiology in whom the improvement after therapeutic intervention could be objectively documented using trichogram.

  5. Drug monitoring in child and adolescent psychiatry for improved efficacy and safety of psychopharmacotherapy

    Directory of Open Access Journals (Sweden)

    Fegert Jörg M

    2009-04-01

    Full Text Available Abstract Most psychotropic drugs used in the treatment of children and adolescents are applied "off label" with a direct risk of under- or overdosing and a delayed risk of long-term side effects. The selection of doses in paediatric psychiatric patients requires a consideration of pharmacokinetic parameters and the development of central nervous system, and warrants specific studies in children and adolescents. Because these are lacking for most of the psychotropic drugs applied in the Child and Adolescent and Psychiatry, therapeutic drug monitoring (TDM is a valid tool to optimise pharmacotherapy and to enable to adjust the dosage of drugs according to the characteristics of the individual patient. Multi-centre TDM studies enable the identification of age- and development-dependent therapeutic ranges of blood concentrations and facilitate a highly qualified standardized documentation in the child and adolescent health care system. In addition, they will provide data for future research on psychopharmacological treatment in children and adolescents, as a baseline for example for clinically relevant interactions with various co-medications. Therefore, a German-Austrian-Swiss "Competence Network on Therapeutic Drug Monitoring in Child and Adolescent Psychiatry" was founded 1 introducing a comprehensive internet data base for the collection of demographic, safety and efficacy data as well as blood concentrations of psychotropic drugs in children and adolescents.

  6. Simultaneous monitoring of the drug release and antitumor effect of a novel drug delivery system-MWCNTs/DOX/TC.

    Science.gov (United States)

    Dong, Xia; Sun, Zhiting; Wang, Xiaoxiao; Zhu, Dunwan; Liu, Lanxia; Leng, Xigang

    2017-11-01

    Monitoring drug release and therapeutic efficacy is crucial for developing drug delivery systems. Our preliminary study demonstrated that, as compared with pristine multiwalled carbon nanotubes (MWCNTs), transactivator of transcription (TAT)-chitosan functionalized MWCNTs (MWCNTs-TC) were a more promising candidate for drug delivery in cancer therapy. In the present study, a MWCNTs/TC-based drug delivery system was developed for an anticancer drug, doxorubicin (DOX). The drug loading and in vitro release profiles, cellular uptake and cytotoxicity were assessed. More importantly, the in vivo drug release and antitumor effect of MWCNTs/DOX/TC were evaluated by noninvasive fluorescence and bioluminescence imaging. It was demonstrated that MWCNTs/DOX/TC can be efficiently taken up by BEL-7402 hepatoma cells. The release of DOX from MWCNTs/DOX/TC was faster under lower pH condition, which was beneficial for intrcellular drug release. The in vivo release process of DOX and antitumor effect in animal model were monitored simultaneously by noninvasive fluorescence and luminescence imaging, which demonstrated the application potential of MWCNTs/DOX/TC for cancer therapy.

  7. The beginning of therapeutic communities in the Czech republic: Biographical narration of founders of therapeutic communities for drug addiction in the Czech republic.

    OpenAIRE

    Polzová, Alžběta

    2012-01-01

    The work focuses on the emergence of therapeutic communities for drug addicts in the Czech Republic. Describes the history of addiction treatment in 1989 and subsequently the emerging system of care for drug addicts in 1989. It charts the evolution of the concept of therapeutic community and using the oral history brings experience and individual stories of each of the founders of therapeutic communities.

  8. Methadone: The Drug and Its Therapeutic Uses In the Treatment of Addiction. Series 31, No. 1.

    Science.gov (United States)

    Gamage, James R.; Zerkin, E. Lief

    This fact sheet from the National Clearinghouse for Drug Abuse Information discusses methadone, a therapeutic drug for the treatment of narcotic addiction. It reviews the pharmacology of the drug as well as physiological and psychological effects, patterns of use, and adverse effects (toxicity and poisoning). It examines the success rates of…

  9. Therapeutic drug monitoring of nevirapine in resource-limited settings.

    NARCIS (Netherlands)

    L'homme, R.F.A.; Muro, E.P.; Droste, J.A.H.; Wolters, L.R.; Kolmer, NW van Ewijk-Benek; Schimana, W.; Burger, D.M.

    2008-01-01

    BACKGROUND: We developed a simple and inexpensive thin-layer chromatography (TLC) assay for semiquantitative detection of saliva concentrations of nevirapine in resource-limited settings. The method was validated in an African target population. METHODS: Paired plasma and saliva nevirapine

  10. Therapeutic drug monitoring of clozapine : An unexpected outcome

    NARCIS (Netherlands)

    Uges, DRA; Boom, K; Wientjes, GD; Versteege, J

    A patient is described who died with the diagnosis of septicemia. After her death the delayed results of a clozapine determination for TDM were sent to the clinician. The clozapine serum level was 4034 mu g/L, which was considered to be the primary cause of death. However, a forensic autopsy

  11. Depth-Sensor-Based Monitoring of Therapeutic Exercises

    Directory of Open Access Journals (Sweden)

    Mu-Chun Su

    2015-10-01

    Full Text Available In this paper, we propose a self-organizing feature map-based (SOM monitoring system which is able to evaluate whether the physiotherapeutic exercise performed by a patient matches the corresponding assigned exercise. It allows patients to be able to perform their physiotherapeutic exercises on their own, but their progress during exercises can be monitored. The performance of the proposed the SOM-based monitoring system is tested on a database consisting of 12 different types of physiotherapeutic exercises. An average 98.8% correct rate was achieved.

  12. Depth-Sensor-Based Monitoring of Therapeutic Exercises

    National Research Council Canada - National Science Library

    Su, Mu-Chun; Jhang, Jhih-Jie; Hsieh, Yi-Zeng; Yeh, Shih-Ching; Lin, Shih-Chieh; Lee, Shu-Fang; Tseng, Kai-Ping

    2015-01-01

    In this paper, we propose a self-organizing feature map-based (SOM) monitoring system which is able to evaluate whether the physiotherapeutic exercise performed by a patient matches the corresponding assigned exercise...

  13. Positron emission tomography in CNS drug discovery and drug monitoring.

    Science.gov (United States)

    Piel, Markus; Vernaleken, Ingo; Rösch, Frank

    2014-11-26

    Molecular imaging methods such as positron emission tomography (PET) are increasingly involved in the development of new drugs. Using radioactive tracers as imaging probes, PET allows the determination of the pharmacokinetic and pharmacodynamic properties of a drug candidate, via recording target engagement, the pattern of distribution, and metabolism. Because of the noninvasive nature and quantitative end point obtainable by molecular imaging, it seems inherently suited for the examination of a pharmaceutical's behavior in the brain. Molecular imaging, most especially PET, can therefore be a valuable tool in CNS drug research. In this Perspective, we present the basic principles of PET, the importance of appropriate tracer selection, the impact of improved radiopharmaceutical chemistry in radiotracer development, and the different roles that PET can fulfill in CNS drug research.

  14. Cytokines in cancer drug resistance: Cues to new therapeutic strategies.

    Science.gov (United States)

    Jones, Valerie Sloane; Huang, Ren-Yu; Chen, Li-Pai; Chen, Zhe-Sheng; Fu, Liwu; Huang, Ruo-Pan

    2016-04-01

    The development of oncoprotein-targeted anticancer drugs is an invaluable weapon in the war against cancer. However, cancers do not give up without a fight. They may develop multiple mechanisms of drug resistance, including apoptosis inhibition, drug expulsion, and increased proliferation that reduce the effectiveness of the drug. The collective work of researchers has highlighted the role of cytokines in the mechanisms of cancer drug resistance, as well as in cancer cell progression. Furthermore, recent studies have described how specific cytokines secreted by cancer stromal cells confer resistance to chemotherapeutic treatments. In order to gain a better understanding of mechanism of cancer drug resistance and a prediction of treatment outcome, it is imperative that correlations are established between global cytokine profiles and cancer drug resistance. Here we discuss the recent discoveries in this field of research and discuss their implications for the future development of effective anti-cancer medicines. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

  15. Psychedelic Drugs as Therapeutics: No Illusions About the Challenges.

    Science.gov (United States)

    Sellers, Edward M; Leiderman, Deborah B

    2017-08-24

    Interest in the potential therapeutic benefits of psychedelic agents has recently increased. In addition to psilocybin, a wide variety of agents with psychedelic properties have been proposed and partially tested. However, the challenges of obtaining approval to market a restricted psychotomimetic agent are formidable. © 2017 ASCPT.

  16. Postmarket Safety Events Among Novel Therapeutics Approved by the US Food and Drug Administration Between 2001 and 2010.

    Science.gov (United States)

    Downing, Nicholas S; Shah, Nilay D; Aminawung, Jenerius A; Pease, Alison M; Zeitoun, Jean-David; Krumholz, Harlan M; Ross, Joseph S

    2017-05-09

    Postmarket safety events of novel pharmaceuticals and biologics occur when new safety risks are identified after initial regulatory approval of these therapeutics. These safety events can change how novel therapeutics are used in clinical practice and inform patient and clinician decision making. To characterize the frequency of postmarket safety events among novel therapeutics approved by the US Food and Drug Administration (FDA), and to examine whether any novel therapeutic characteristics known at the time of FDA approval were associated with increased risk. Cohort study of all novel therapeutics approved by the FDA between January 1, 2001, and December 31, 2010, followed up through February 28, 2017. Novel therapeutic characteristics known at the time of FDA approval, including drug class, therapeutic area, priority review, accelerated approval, orphan status, near-regulatory deadline approval, and regulatory review time. A composite of (1) withdrawals due to safety concerns, (2) FDA issuance of incremental boxed warnings added in the postmarket period, and (3) FDA issuance of safety communications. From 2001 through 2010, the FDA approved 222 novel therapeutics (183 pharmaceuticals and 39 biologics). There were 123 new postmarket safety events (3 withdrawals, 61 boxed warnings, and 59 safety communications) during a median follow-up period of 11.7 years (interquartile range [IQR], 8.7-13.8 years), affecting 71 (32.0%) of the novel therapeutics. The median time from approval to first postmarket safety event was 4.2 years (IQR, 2.5-6.0 years), and the proportion of novel therapeutics affected by a postmarket safety event at 10 years was 30.8% (95% CI, 25.1%-37.5%). In multivariable analysis, postmarket safety events were statistically significantly more frequent among biologics (incidence rate ratio [IRR] = 1.93; 95% CI, 1.06-3.52; P = .03), therapeutics indicated for the treatment of psychiatric disease (IRR = 3.78; 95% CI, 1.77-8.06; P

  17. [Classic psychedelic drugs and their potential therapeutic effect].

    Science.gov (United States)

    Bayat, Michael

    2017-09-11

    Over the past decade we have witnessed a renewed scientific interest in the classic hallucinogens (psychedelic drugs). These are substances which exert their effects by an agonist action on the 5-HT2A receptors. The purpose of this paper is to provide a short review and discussion of the psychedelic drugs, their safety profile and their potential antidepressive, anxiolytic and antiaddictive effects. The article primarily focusses on the most recent clinical trials.

  18. Aptamer/Graphene Quantum Dots Nanocomposite Capped Fluorescent Mesoporous Silica Nanoparticles for Intracellular Drug Delivery and Real-Time Monitoring of Drug Release.

    Science.gov (United States)

    Zheng, Fen-Fen; Zhang, Peng-Hui; Xi, Yu; Chen, Jing-Jia; Li, Ling-Ling; Zhu, Jun-Jie

    2015-12-01

    Great challenges in investigating the release of drug in complex cellular microenvironments necessitate the development of stimuli-responsive drug delivery systems with real-time monitoring capability. In this work, a smart drug nanocarrier based on fluorescence resonance energy transfer (FRET) is fabricated by capping graphene quantum dots (GQDs, the acceptor) onto fluorescent mesoporous silica nanoparticles (FMSNs, the donor) via ATP aptamer for real-time monitoring of ATP-triggered drug release. Under extracellular conditions, the fluorescence of FMSNs remains in the "off" state in the low ATP level which is unable to trigger the release of drug. Once specifically recognized and internalized into the target tumor cells by AS1411 aptamer, in the ATP-rich cytoplasm, the conformation switch of the ATP aptamer causes the shedding of the GQDs from the nanocarriers, leading to the release of the loaded drugs and consequently severe cytotoxicity. Simultaneously, the fluorescence of FMSNs turns "on" along with the dissociation of GQDs, which allows real-time monitoring of the release of drug from the pores. Such a drug delivery system features high specificity of dual-target recognition with AS1411 and ATP aptamer as well as high sensitivity of the FRET-based monitoring strategy. Thus, the proposed multifunctional ATP triggered FRET-nanocarriers will find potential applications for versatile drug-release monitoring, efficient drug transport, and targeted cancer therapeutics.

  19. Intracellular trafficking of new anticancer therapeutics: antibody–drug conjugates

    Science.gov (United States)

    Kalim, Muhammad; Chen, Jie; Wang, Shenghao; Lin, Caiyao; Ullah, Saif; Liang, Keying; Ding, Qian; Chen, Shuqing; Zhan, Jinbiao

    2017-01-01

    Antibody–drug conjugate (ADC) is a milestone in targeted cancer therapy that comprises of monoclonal antibodies chemically linked to cytotoxic drugs. Internalization of ADC takes place via clathrin-mediated endocytosis, caveolae-mediated endocytosis, and pinocytosis. Conjugation strategies, endocytosis and intracellular trafficking optimization, linkers, and drugs chemistry present a great challenge for researchers to eradicate tumor cells successfully. This inventiveness of endocytosis and intracellular trafficking has given considerable momentum recently to develop specific antibodies and ADCs to treat cancer cells. It is significantly advantageous to emphasize the endocytosis and intracellular trafficking pathways efficiently and to design potent engineered conjugates and biological entities to boost efficient therapies enormously for cancer treatment. Current studies illustrate endocytosis and intracellular trafficking of ADC, protein, and linker strategies in unloading and also concisely evaluate practically applicable ADCs. PMID:28814834

  20. Intracellular trafficking of new anticancer therapeutics: antibody-drug conjugates.

    Science.gov (United States)

    Kalim, Muhammad; Chen, Jie; Wang, Shenghao; Lin, Caiyao; Ullah, Saif; Liang, Keying; Ding, Qian; Chen, Shuqing; Zhan, Jinbiao

    2017-01-01

    Antibody-drug conjugate (ADC) is a milestone in targeted cancer therapy that comprises of monoclonal antibodies chemically linked to cytotoxic drugs. Internalization of ADC takes place via clathrin-mediated endocytosis, caveolae-mediated endocytosis, and pinocytosis. Conjugation strategies, endocytosis and intracellular trafficking optimization, linkers, and drugs chemistry present a great challenge for researchers to eradicate tumor cells successfully. This inventiveness of endocytosis and intracellular trafficking has given considerable momentum recently to develop specific antibodies and ADCs to treat cancer cells. It is significantly advantageous to emphasize the endocytosis and intracellular trafficking pathways efficiently and to design potent engineered conjugates and biological entities to boost efficient therapies enormously for cancer treatment. Current studies illustrate endocytosis and intracellular trafficking of ADC, protein, and linker strategies in unloading and also concisely evaluate practically applicable ADCs.

  1. Intracellular trafficking of new anticancer therapeutics: antibody–drug conjugates

    Directory of Open Access Journals (Sweden)

    Kalim M

    2017-08-01

    Full Text Available Muhammad Kalim,1 Jie Chen,1 Shenghao Wang,1 Caiyao Lin,1 Saif Ullah,1 Keying Liang,1 Qian Ding,1 Shuqing Chen,2 Jinbiao Zhan1 1Department of Biochemistry and Genetics, School of Medicine, 2Department of Pharmaceutical Analysis, College of Pharmaceutical Science, Zhejiang University, Hangzhou, People’s Republic of China Abstract: Antibody–drug conjugate (ADC is a milestone in targeted cancer therapy that comprises of monoclonal antibodies chemically linked to cytotoxic drugs. Internalization of ADC takes place via clathrin-mediated endocytosis, caveolae-mediated endocytosis, and pinocytosis. Conjugation strategies, endocytosis and intracellular trafficking optimization, linkers, and drugs chemistry present a great challenge for researchers to eradicate tumor cells successfully. This inventiveness of endocytosis and intracellular trafficking has given consi­derable momentum recently to develop specific antibodies and ADCs to treat cancer cells. It is significantly advantageous to emphasize the endocytosis and intracellular trafficking pathways efficiently and to design potent engineered conjugates and biological entities to boost efficient therapies enormously for cancer treatment. Current studies illustrate endocytosis and intracellular trafficking of ADC, protein, and linker strategies in unloading and also concisely evaluate practically applicable ADCs. Keywords: antibody–drug conjugate, antibody, endocytosis, intracellular trafficking, clathrin

  2. The Effect of Common Therapeutic Drugs on Vision

    Science.gov (United States)

    1975-05-01

    since the 18th century. The effects on blood vessels to skin and digitalis group is one of the group of mucosa, salivary glands , etc.) than re- drugs...285-286, 1961. 447-451, 1969. Gentles, W. and E. Llewellyn Thomas. Fink, M. EEG classification of psy- Effect of benzodiazepines upon sac- choactive

  3. Retrospective monitoring of drug utilisation in cardiovascular ...

    African Journals Online (AJOL)

    This retrospective study was carried out to established drug prescribing trends in the management of cardiovascular diseases (CVDs) in the cardiovascular unit of the Department of Medicine, University of Port Harcourt Teaching Hospital, Rivers State, Nigeria. 100 folders of patients with various CVDs were randomly ...

  4. Monitoring drug therapy in hospitalized patients

    NARCIS (Netherlands)

    Uijtendaal, E.V.

    2014-01-01

    Prevention of adverse drug events that may result from medication errors is challenging. The safety of medication treatment is mostly determined on an average population and medication errors may be prevented when pharmacotherapy is better tailored to the individualized needs of the hospitalized

  5. WHAT IS THERAPEUTIC EQUIVALENCE OF GENERIC DRUG AND HOW TO PROVE IT

    Directory of Open Access Journals (Sweden)

    N. P. Kutishenko

    2011-01-01

    Full Text Available The problem of generic drugs use in clinical practice and confirmation of their therapeutic equivalence is discussed. The significance of studies on generic drugs bioequivalence, as well as details of international practice and regulations in this area is explained.

  6. Improving nurses' therapeutic attitude to patients who use illicit drugs: workplace drug and alcohol education is not enough.

    Science.gov (United States)

    Ford, Rosemary; Bammer, Gabriele; Becker, Niels

    2009-04-01

    This study examines the impact of workplace drug and alcohol education on nurses' therapeutic attitude to patients who use illicit drugs. It builds on a study of the generalist nursing workforce in the Australian Capital Territory in 2003, which showed that the interaction of role support with workplace drug and alcohol education facilitated nurses' therapeutic attitude. This paper explores this interaction in detail, showing that workplace education has no independent association with therapeutic attitude and that an effect from education only occurs when nurses have at least a moderate level of role support. Nursing workforce development needs to focus on strategies that provide role support for nurses as they work with this clinically challenging patient group. Without the ready availability of someone in the nurse's clinical field to advise and assist them, efforts to increase nurses' knowledge and skills are wasted.

  7. Voltage-gated Potassium Channels as Therapeutic Drug Targets

    Science.gov (United States)

    Wulff, Heike; Castle, Neil A.; Pardo, Luis A.

    2009-01-01

    The human genome contains 40 voltage-gated potassium channels (KV) which are involved in diverse physiological processes ranging from repolarization of neuronal or cardiac action potentials, over regulating calcium signaling and cell volume, to driving cellular proliferation and migration. KV channels offer tremendous opportunities for the development of new drugs for cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This review first discusses pharmacological strategies for targeting KV channels with venom peptides, antibodies and small molecules and then highlights recent progress in the preclinical and clinical development of drugs targeting KV1.x, KV7.x (KCNQ), KV10.1 (EAG1) and KV11.1 (hERG) channels. PMID:19949402

  8. Voltage-gated Potassium Channels as Therapeutic Drug Targets

    OpenAIRE

    Wulff, Heike; Castle, Neil A.; Pardo, Luis A.

    2009-01-01

    The human genome contains 40 voltage-gated potassium channels (KV) which are involved in diverse physiological processes ranging from repolarization of neuronal or cardiac action potentials, over regulating calcium signaling and cell volume, to driving cellular proliferation and migration. KV channels offer tremendous opportunities for the development of new drugs for cancer, autoimmune diseases and metabolic, neurological and cardiovascular disorders. This review first discusses pharmacologi...

  9. Homeopathic use of modern drugs: therapeutic application of the organism paradoxical reaction or rebound effect

    OpenAIRE

    Marcus Zulian Teixeira

    2011-01-01

    When Samuel Hahnemann systematized homeopathy and the effects of drugs on the state of human health, he described the primary action of drugs and the following secondary and opposite reaction of the organism. Seeking to apply this secondary action or vital reaction of the organism as therapeutic method, he postulated the principle of similitude, i.e. the prescription to ill individuals of drugs that cause similar symptoms in the healthy (similia similibus curentur). In modern pharmacology, se...

  10. Recent advances in (therapeutic protein drug development [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    H.A. Daniel Lagassé

    2017-02-01

    Full Text Available Therapeutic protein drugs are an important class of medicines serving patients most in need of novel therapies. Recently approved recombinant protein therapeutics have been developed to treat a wide variety of clinical indications, including cancers, autoimmunity/inflammation, exposure to infectious agents, and genetic disorders. The latest advances in protein-engineering technologies have allowed drug developers and manufacturers to fine-tune and exploit desirable functional characteristics of proteins of interest while maintaining (and in some cases enhancing product safety or efficacy or both. In this review, we highlight the emerging trends and approaches in protein drug development by using examples of therapeutic proteins approved by the U.S. Food and Drug Administration over the previous five years (2011–2016, namely January 1, 2011, through August 31, 2016.

  11. Combinatorial therapeutic approaches with RNAi and anticancer drugs using nanodrug delivery systems.

    Science.gov (United States)

    Babu, Anish; Munshi, Anupama; Ramesh, Rajagopal

    2017-09-01

    RNA interference (RNAi) is emerging as a powerful approach in cancer treatment. siRNA is an important RNAi tool that can be designed to specifically silence the expression of genes involved in drug resistance and chemotherapeutic inactivity. Combining siRNA and other therapeutic agents can overcome the multidrug resistance (MDR) phenomenon by simultaneously silencing genes and enhancing chemotherapeutic activity. Moreover, the therapeutic efficiency of anticancer drugs can be significantly improved by additive or synergistic effects induced by siRNA and combined therapies. Co-delivery of these diverse anticancer agents, however, requires specially designed nanocarriers. This review highlights the recent trends in siRNA/anticancer drug co-delivery systems under the major categories of liposomes/lipid, polymeric and inorganic nanoplatforms. The objective is to discuss the strategies for nanocarrier-based co-delivery systems using siRNA/anticancer drug combinations, emphasizing various siRNA targets that help overcome MDR and enhance therapeutic efficiency.

  12. Customising the therapeutic response of signalling networks to promote antitumor responses by drug combinations

    Directory of Open Access Journals (Sweden)

    Alexey eGoltsov

    2014-02-01

    Full Text Available Drug resistance, de novo and acquired, pervades cellular signalling networks from one signalling motif to another as a result of cancer progression and/or drug intervention. This resistance is one of the key determinants of efficacy in targeted anticancer drug therapy. Although poorly understood, drug resistance is already being addressed in combination therapy by selecting drug targets where sensitivity increases due to combination components or as a result of de novo or acquired mutations. Additionally, successive drug combinations have shown low resistance potency. To promote a rational, systematic development of combination therapies, it is necessary to establish the underlying mechanisms that drive the advantages of drug combinations and design methods to determine advanced targets for drug combination therapy. Based on a joint systems analysis of cellular signalling network (SN response and its sensitivity to drug action and oncogenic mutations, we describe an in silico method to analyse the targets of drug combinations. The method explores mechanisms of sensitizing the SN through combination of two drugs targeting vertical signalling pathways. We propose a paradigm of SN response customization by one drug to both maximize the effect of another drug in combination and promote a robust therapeutic response against oncogenic mutations. The method was applied to the customization of the response of the ErbB/PI3K/PTEN/AKT pathway by combination of drugs targeting HER2 receptors and proteins in the downstream pathway. The results of a computational experiment showed that the modification of the SN response from hyperbolic to smooth sigmoid response by manipulation of two drugs in combination leads to greater robustness in therapeutic response against oncogenic mutations determining cancer heterogeneity. The application of this method in drug combination co-development suggests a combined evaluation of inhibition effects along with the

  13. New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics

    Science.gov (United States)

    Pan, Si-Yuan; Zhou, Shu-Feng; Gao, Si-Hua; Yu, Zhi-Ling; Zhang, Shuo-Feng; Tang, Min-Ke; Sun, Jian-Ning; Han, Yi-Fan; Fong, Wang-Fun; Ko, Kam-Ming

    2013-01-01

    With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM) therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is “experience driven,” the search for a therapeutically useful synthetic drug, like “looking for a needle in a haystack,” is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development. PMID:23634172

  14. New Perspectives on How to Discover Drugs from Herbal Medicines: CAM's Outstanding Contribution to Modern Therapeutics

    Directory of Open Access Journals (Sweden)

    Si-Yuan Pan

    2013-01-01

    Full Text Available With tens of thousands of plant species on earth, we are endowed with an enormous wealth of medicinal remedies from Mother Nature. Natural products and their derivatives represent more than 50% of all the drugs in modern therapeutics. Because of the low success rate and huge capital investment need, the research and development of conventional drugs are very costly and difficult. Over the past few decades, researchers have focused on drug discovery from herbal medicines or botanical sources, an important group of complementary and alternative medicine (CAM therapy. With a long history of herbal usage for the clinical management of a variety of diseases in indigenous cultures, the success rate of developing a new drug from herbal medicinal preparations should, in theory, be higher than that from chemical synthesis. While the endeavor for drug discovery from herbal medicines is “experience driven,” the search for a therapeutically useful synthetic drug, like “looking for a needle in a haystack,” is a daunting task. In this paper, we first illustrated various approaches of drug discovery from herbal medicines. Typical examples of successful drug discovery from botanical sources were given. In addition, problems in drug discovery from herbal medicines were described and possible solutions were proposed. The prospect of drug discovery from herbal medicines in the postgenomic era was made with the provision of future directions in this area of drug development.

  15. Medication monitoring and drug testing ethics project.

    Science.gov (United States)

    Payne, Richard; Moe, Jeffrey L; Sevier, Catherine Harvey; Sevier, David; Waitzkin, Michael

    2015-01-01

    In 2012, Duke University initiated a research project, funded by an unrestricted research grant from Millennium Laboratories, a drug testing company. The project focused on assessing the frequency and nature of questionable, unethical, and illegal business practices in the clinical drug testing industry and assessing the potential for establishing a business code of ethics. Laboratory leaders, clinicians, industry attorneys, ethicists, and consultants participated in the survey, were interviewed, and attended two face-to-face meetings to discuss a way forward. The study demonstrated broad acknowledgment of variations in the legal and regulatory environment, resulting in inconsistent enforcement of industry practices. Study participants expressed agreement that overtly illegal practices sometimes exist, particularly when laboratory representatives and clinicians discuss reimbursement, extent of testing, and potential business incentives with medical practitioners. Most respondents reported directly observing probable violations involving marketing materials, contracts, or, in the case of some individuals, directly soliciting people with offers of clinical supplies and other "freebies." While many study respondents were skeptical that voluntary standards alone would eliminate questionable business practices, most viewed ethics codes and credentialing as an important first step that could potentially mitigate uneven enforcement, while improving quality of care and facilitating preferred payment options for credentialed parties. Many were willing to participate in future discussions and industry-wide initiatives to improve the environment.

  16. Optimizing Treatment with TNF Inhibitors in Inflammatory Bowel Disease by Monitoring Drug Levels and Antidrug Antibodies

    DEFF Research Database (Denmark)

    Steenholdt, Casper; Bendtzen, Klaus; Brynskov, Jørn

    2016-01-01

    BACKGROUND: Biological tumor necrosis factor (TNF) inhibitors have revolutionized the treatment of inflammatory bowel disease and redefined treatment goals to include mucosal healing. Clinicians are faced with challenges such as inadequate responses, treatment failures, side effects, and high drug...... costs. The objective is to review optimization of anti-TNF therapy by use of personalized treatment strategies based on circulating drug levels and antidrug antibodies (Abs), i.e. therapeutic drug monitoring (TDM). Furthermore, to outline TDM-related pitfalls and their prevention. METHODS: Literature...... review. RESULTS: Circulating anti-TNF drug trough level is a marker for the pharmacokinetics (PK) of TNF inhibitors. Because of a number of factors, including antidrug antibodies, PK varies between and within patients across time leading to variable clinical outcomes. Differences in intestinal...

  17. Therapeutic cancer drugs. 9-10 July 1998, London, UK.

    Science.gov (United States)

    Jackson, R

    1998-09-01

    In line with the SMi objective of 'linking business with information', this meeting addressed a number of aspects of oncological drug development that must be grappled with by companies that are attempting to build a business in this area. Some of the recurring themes of many of the presentations were summarized by the Chairman, Dr Roy Drucker (Technomark, UK) in his closing remarks. Many of the innovative new anticancer drugs have their origins in start-up companies, but their clinical development is generally in the hands of multinational pharmaceutical companies. Such alliances, while often productive and mutually advantageous, present management challenges. There were concerns expressed that the innovation from biotechnology and pharmaceutical companies might not be matched at the regulatory end. The increasing individualization of treatment is likely to expand in the future through the use of functional genomics tools, that may increase response rates, but will do so at the cost of complicating the development and regulatory process, and will result in an increasingly fragmented market. Cancer medicine is increasingly politicized: there are issues of "who gets what" and "who pays for it". Patient support groups are increasingly expecting to contribute to these decisions. As treatment gets more expensive and complex, the gulf between treatment practices in rich and poor countries widens; nevertheless, many emerging economies are generating a prosperous middle class who will expect first-world standards of care, and present a market opportunity. Finally, pharmaceutical industry management still tend to treat oncology as a poor relation to its more lavishly funded cardiovascular and CNS programs, an attitude that is not entirely market-driven but reflects confusion about this complex and rapidly-changing area.

  18. Therapeutic use of the rebound effect of modern drugs: "New homeopathic medicines"

    Directory of Open Access Journals (Sweden)

    Marcus Zulian Teixeira

    Full Text Available Summary The homeopathic treatment is based on the principle of therapeutic similitude, employing medicines that cause certain disorders to treat similar manifestations, stimulating a reaction of the organism against its own ailments. The occurrence of this secondary reaction of the organism, opposite in nature to the primary action of the medicines, is evidenced in the study of the rebound (paradoxical effect of several classes of modern drugs. In this work, in addition to substantiate the principle of similitude before the experimental and clinical pharmacology, we suggest a proposal to employ hundreds of conventional drugs according to homeopathic method, applying the therapeutic similitude between the adverse events of medicines and the clinical manifestations of patients. Describing existing lines of research and a specific method for the therapeutic use of the rebound effect of modern drugs (http://www.newhomeopathicmedicines.com, we hope to minimize prejudices related to the homeopathy and contribute to a broadening of the healing art.

  19. Therapeutic monitoring of pediatric transplant patients with conversion to generic tacrolimus.

    Science.gov (United States)

    Riva, Natalia; Cáceres Guido, Paulo; Licciardone, Nieves; Imventarza, Oscar; Monteverde, Marta; Staciuk, Raquel; Charroqui, Alberto; Schaiquevich, Paula

    2017-03-01

    Therapeutic monitoring during interchange of tacrolimus commercial formulations is essential to ensure similar exposure in transplant patients. However, there are limited data in the pediatric transplant population. This study aims to evaluate exposure, safety and efficacy in maintenance pediatric transplant patients under generic tacrolimus substitution. Pediatric patients who underwent interchange of tacrolimus formulations were detected by the Service of Pharmacy and included in this study. Tacrolimus trough levels (C0), laboratory parameters and clinical characteristics were recorded before and after the switch. Statistical analysis was performed using Wilcoxon matched pair t-test. In total, 10 patients with kidney, liver, heart and hematopoietic stem cell transplantation received the innovator and switched to the generic product. The median (range) of the C0 normalized by the dose before and after switch was 74.8 [(ng/ml)/(mg/kg)] (13.8-518.4) and 65.1 [(ng/ml)/(mg/kg)] (13.5-723.5), respectively (p>0.05). Tacrolimus dose was 0.070(mg/kg) (0.024-0.461) and 0.069(mg/kg) (0.017- 0.571) for the innovator and generic formulation, respectively, with no difference when comparing both values (p>0.05). Laboratory parameters did not change after conversion (p>0.05). Adverse events, acute rejection, death and graft loss were not observed. In our study population, no significant differences in terms of laboratory parameters, drug exposure and dose were observed. We emphasize the need of close monitoring to ensure a safe interchange, especially in vulnerable populations such as the pediatric. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

  20. Therapeutic monitoring of pediatric transplant patients with conversion to generic tacrolimus

    Directory of Open Access Journals (Sweden)

    Natalia Riva

    2017-03-01

    Full Text Available p>Objective: Therapeutic monitoring during interchange of tacrolimus commercial formulations is essential to ensure similar exposure in transplant patients. However, there are limited data in the pediatric transplant population. This study aims to evaluate exposure, safety and efficacy in maintenance pediatric transplant patients under generic tacrolimus substitution. Method: Pediatric patients who underwent interchange of tacrolimus formulations were detected by the Service of Pharmacy and included in this study. Tacrolimus trough levels (C0, laboratory parameters and clinical characteristics were recorded before and after the switch. Statistical analysis was performed using Wilcoxon matched pair t-test. Results: In total, 10 patients with kidney, liver, heart and hematopoietic stem cell transplantation received the innovator and switched to the generic product. The median (range of the C0 normalized by the dose before and after switch was 74.8 [(ng/ml/(mg/kg] (13.8-518.4 and 65.1 [(ng/ml/(mg/kg] (13.5-723.5, respectively (p>0.05. Tacrolimus dose was 0.070(mg/kg (0.024-0.461 and 0.069(mg/kg (0.017- 0.571 for the innovator and generic formulation, respectively, with no difference when comparing both values (p>0.05. Laboratory parameters did not change after conversion (p>0.05. Adverse events, acute rejection, death and graft loss were not observed. Conclusion: In our study population, no significant differences in terms of laboratory parameters, drug exposure and dose were observed. We emphasize the need of close monitoring to ensure a safe interchange, especially in vulnerable populations such as the pediatric.

  1. Review article: the safety of therapeutic drugs in male inflammatory bowel disease patients wishing to conceive.

    Science.gov (United States)

    Sands, K; Jansen, R; Zaslau, S; Greenwald, D

    2015-05-01

    Many therapeutic drugs are used by patients with inflammatory bowel disease, often around the time of conception. The pregnancy outcomes of males and females exposed to these therapeutics needs to be examined and this information is necessary to counsel patients appropriately. To review the literature describing male infertility and inflammatory bowel disease to educate practitioners of the impact of inflammatory bowel disease on male reproduction and the impact of therapeutics on pregnancy outcomes. We performed a PubMed search using the search terms 'male infertility,' 'Crohn's disease,' 'inflammatory bowel disease,' 'ulcerative colitis,' 'ciprofloxacin AND infertility,' 'metronidazole AND infertility,' 'sulfasalazine AND infertility,' 'azathioprine AND infertility,' 'methotrexate AND infertility,' 'ciclosporin AND infertility,' 'corticosteroids AND infertility,' 'infliximab AND male fertility,' 'infliximab AND infertility,' 'infliximab AND foetus,' 'infliximab AND paternal exposure' and 'infliximab AND sperm.' References from selected papers were reviewed and used if relevant. Over half of male patients with IBD have some degree of infertility, compared to 8-17% of the general population. Semen parameters including total count, motility and morphology may be adversely affected by therapeutics. IBD medications in males do not increase foetal risk with the possible exception of azathioprine and mercaptopurine; however, increased foetal risk is seen in other drugs if taken by female patients. It is recognised that male infertility is often impacted with therapeutic drugs used to treat inflammatory bowel disease; however, the effects of the paternal drug exposure at the time of conception and exposure in utero should be considered to counsel patients appropriately. © 2015 John Wiley & Sons Ltd.

  2. A hybrid method for prediction and repositioning of drug Anatomical Therapeutic Chemical classes.

    Science.gov (United States)

    Chen, Lei; Lu, Jing; Zhang, Ning; Huang, Tao; Cai, Yu-Dong

    2014-04-01

    In the Anatomical Therapeutic Chemical (ATC) classification system, therapeutic drugs are divided into 14 main classes according to the organ or system on which they act and their chemical, pharmacological and therapeutic properties. This system, recommended by the World Health Organization (WHO), provides a global standard for classifying medical substances and serves as a tool for international drug utilization research to improve quality of drug use. In view of this, it is necessary to develop effective computational prediction methods to identify the ATC-class of a given drug, which thereby could facilitate further analysis of this system. In this study, we initiated an attempt to develop a prediction method and to gain insights from it by utilizing ontology information of drug compounds. Since only about one-fourth of drugs in the ATC classification system have ontology information, a hybrid prediction method combining the ontology information, chemical interaction information and chemical structure information of drug compounds was proposed for the prediction of drug ATC-classes. As a result, by using the Jackknife test, the 1st prediction accuracies for identifying the 14 main ATC-classes in the training dataset, the internal validation dataset and the external validation dataset were 75.90%, 75.70% and 66.36%, respectively. Analysis of some samples with false-positive predictions in the internal and external validation datasets indicated that some of them may even have a relationship with the false-positive predicted ATC-class, suggesting novel uses of these drugs. It was conceivable that the proposed method could be used as an efficient tool to identify ATC-classes of novel drugs or to discover novel uses of known drugs.

  3. Completion of therapeutic and safety monitoring tests in Lebanese outpatients on chronic medications: a cross-sectional study

    Directory of Open Access Journals (Sweden)

    Ramia E

    2014-09-01

    Full Text Available Elsy Ramia, Rony Zeenny Department of Pharmacy Practice, School of Pharmacy, Lebanese American University, Byblos, Lebanon Purpose: To evaluate the appropriateness of laboratory-test monitoring recommended for patients on chronic medication therapies in the Lebanese community setting.Patients and methods: In October 2011, all outpatients visiting selected community pharmacies in Lebanon were screened by pharmacists to evaluate their use of one or more chronic medications requiring safety and/or therapeutic laboratory tests. The list of medications was elaborated after an extensive review of laboratory-test monitoring recommendations from pertinent up-to-date clinical guidelines, medications that have been issued black box warnings for monitoring, and the most current information from the US Food and Drug Administration website. Patients receiving these medications were subjected to a questionnaire assessing the appropriateness of their laboratory-test monitoring. The study was approved by the Lebanese American University’s Institutional Review Board.Results: A total of 284 outpatients, with almost equal distribution by sex, were identified during the aforementioned period to be on one or more of the specified medications. The majority of the sample (68% was younger than 65 years of age. Overall, most of the study group (65% were found to be partially monitored with laboratory tests, while only 27% were fully monitored and 8% were not monitored at all. The study group reported clinic-visit intervals as follows: more than a year (35%, on yearly basis (18%, every 6 months (25%, every 3 months (16%, less than 3 months (6%. Conclusion: Seventy-three percent (73% of the study group were receiving incomplete therapeutic/safety laboratory-test monitoring recommended for patients on chronic medication in the Lebanese community. It is concluded from the results that patients need to better understand the importance of recommended test monitoring for the

  4. Therapeutic Potential of Foldamers: From Chemical Biology Tools To Drug Candidates?

    Science.gov (United States)

    Gopalakrishnan, Ranganath; Frolov, Andrey I; Knerr, Laurent; Drury, William J; Valeur, Eric

    2016-11-10

    Over the past decade, foldamers have progressively emerged as useful architectures to mimic secondary structures of proteins. Peptidic foldamers, consisting of various amino acid based backbones, have been the most studied from a therapeutic perspective, while polyaromatic foldamers have barely evolved from their nascency and remain perplexing for medicinal chemists due to their poor drug-like nature. Despite these limitations, this compound class may still offer opportunities to study challenging targets or provide chemical biology tools. The potential of foldamer drug candidates reaching the clinic is still a stretch. Nevertheless, advances in the field have demonstrated their potential for the discovery of next generation therapeutics. In this perspective, the current knowledge of foldamers is reviewed in a drug discovery context. Recent advances in the early phases of drug discovery including hit finding, target validation, and optimization and molecular modeling are discussed. In addition, challenges and focus areas are debated and gaps highlighted.

  5. Recent Trends in Nanotechnology-Based Drugs and Formulations for Targeted Therapeutic Delivery.

    Science.gov (United States)

    Iqbal, Hafiz M N; Rodriguez, Angel M V; Khandia, Rekha; Munjal, Ashok; Dhama, Kuldeep

    2017-01-01

    In the recent past, a wider spectrum of nanotechnologybased drugs or drug-loaded devices and systems has been engineered and investigated with high interests. The key objective is to help for an enhanced/better quality of patient life in a secure way by avoiding/limiting drug abuse, or severe adverse effects of some in practice traditional therapies. Various methodological approaches including in vitro, in vivo, and ex vivo techniques have been exploited, so far. Among them, nanoparticles-based therapeutic agents are of supreme interests for an enhanced and efficient delivery in the current biomedical sector of the modern world. The development of new types of novel, effective and highly reliable therapeutic drug delivery system (DDS) for multipurpose applications is essential and a core demand to tackle many human health related diseases. In this context, nanotechnology-based several advanced DDS have been engineered with novel characteristics for biomedical, pharmaceutical and cosmeceutical applications that include but not limited to the enhanced/improved bioactivity, bioavailability, drug efficacy, targeted delivery, and therapeutically safer with an extra advantage of overcoming demerits of traditional drug formulations/designs. This review work is focused on recent trends/advances in nanotechnology-based drugs and formulations designed for targeted therapeutic delivery. Moreover, information is also reviewed and given from recent patents and summarized or illustrated diagrammatically to depict a better understanding. Recent patents covering various nanotechnology-based approaches for several applications have also been reviewed. The drug-loaded nanoparticles are among versatile candidates with multifunctional characteristics for potential applications in biomedical, and tissue engineering sector. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Drug taper during long-term video-EEG monitoring

    DEFF Research Database (Denmark)

    Guld, Asger Toke; Sabers, A; Kjaer, T W

    2017-01-01

    OBJECTIVES: Anti-epileptic drugs (AED) are often tapered to reduce the time needed to record a sufficient number of seizure during long-term video-EEG monitoring (LTM). Fast AED reduction is considered less safe, but few studies have examined this. Our goal is to examine whether the rate of AED r...

  7. Variability in activity and results from drug assessments by pharmacy and therapeutics committees in Spanish hospitals.

    Science.gov (United States)

    Puigventós Latorre, F; Santos-Ramos, B; Ortega Eslava, A; Durán-García, M E

    2011-01-01

    To quantify the Spanish Pharmacy and Therapeutics Committees (P&TC) activity with regard to assessing and selecting drugs and describing variability in decisions made to include them. Descriptive, cross-sectional study based on a questionnaire aimed to 513 hospitals with more than 75 beds. We included questions referring to the P&TC resolutions, the therapeutic positioning and assessment reports. Recruitment was carried out between November 2007 and January 2008. Variability among P&TC conclusions were presented in five categories or levels of coincidence. One hundred and seventy-five hospitals participated, with a response rate of 34% (54% of beds). The mean (SD) number of drug-indications assessed per hospital was 10.35 (7.45). The proportion of assessments that conclude with drug inclusion or rejection was 75.3 and 21.4%, respectively. 16.2% concluded with therapeutic equivalence. Conditions for use were established for 64% of them, and 33% were included in a clinical guide. With regard to variability, 81.0% of assessments coincided with the conclusion to include or reject the drug. A contradictory decision was made for 19.0%. Drug assessment and selection activity in hospitals involve an amount of work. The proportion of drugs approved is similar in different types of hospitals. There is extensive variability as regards deciding upon inclusion and is similar to studies conducted in other countries. They indicate that a standardising methodology would be recommendable. Copyright © 2010 SEFH. Published by Elsevier Espana. All rights reserved.

  8. Drug and Therapeutics (D & T) committees in Dutch hospitals : a nation-wide survey of structure, activities, and drug selection procedures

    NARCIS (Netherlands)

    Fijn, R; Brouwers, JRBJ; Knaap, RJ; De Jong-Van den Berg, LTW

    Aims To determine structure, activities and drug selection processes used by Dutch hospital drug and therapeutics (D & T) committees. Methods A pretested structured survey questionnaire based on the Australian process and impact indicators, previous research, and consultation of professionals was

  9. Drug safety in pregnancy--monitoring congenital anomalies.

    Science.gov (United States)

    Morgan, Margery; De Jong-van den Berg, Lolkje T W; Jordan, Sue

    2011-04-01

    This paper outlines research into the causes of congenital anomalies, and introduces a pan-European study. The potential roles of nurses and midwives in this area are illustrated by a case report. Since the thalidomide disaster, use of drugs in pregnancy has been carefully monitored to prevent anything similar happening again. However, monitoring is incomplete and questions remain unanswered. Many medicines are essential for the health of pregnant women. However, drug use in pregnancy requires surveillance. Methods include spontaneous reporting of adverse events, cohort studies and case control studies. It is hoped that a Europe-wide study, combining data from several congenital anomaly registers, will provide a sufficiently large population to assess the impact of selected drugs on congenital anomalies. However, this work depends on the consistency of reporting by nurses and midwives. Drug safety in pregnancy remains undetermined. Collaboration across Europe has the potential to provide a framework for safety evaluation. Prescribers should consider the possibility of pregnancy in women of child-bearing age. Careful review of maternal drug use in early pregnancy is essential. Midwives and nurses should be aware of adverse event drug reporting systems, including congenital anomaly registers. © 2011 The Authors. Journal compilation © 2011 Blackwell Publishing Ltd.

  10. Therapeutic Potential of Phytochemicals in Combination with Drugs for Cardiovascular Disorders.

    Science.gov (United States)

    Shen, James Z; Ng, Ting L J; Ho, Wing S

    2017-01-01

    The incidence of cardiovascular disorders is increasing worldwide. Heart disease is the leading cause of death for both men and women. High blood pressure, high low-density lipoprotein cholesterol level, and smoking are key risk factors for heart disease. Other medical conditions such as diabetes, overweight, obesity and lifestyle can put people at a higher risk for coronary heart disease. The preventive measures based on the common drugs may help reduce the risk of cardiovascular diseases. The present review highlights the contributions of therapeutic potential of phytochemicals in management of cardiovascular diseases. However, the delivery efficiency of therapeutic agents can be enhanced in order to improve the efficacy of phytochemicals as a therapeutic agent. The oral administration of phytochemicals as therapeutic agents is a common approach. The review highlights the recent development of natural products for the complementary treatment of cardiovascular diseases. These findings indicate that the combination of therapeutic drugs and natural products may improve the treatment efficacy of therapeutic agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  11. The role of expectation in the therapeutic outcomes of alcohol and drug addiction treatments.

    Science.gov (United States)

    Spagnolo, Primavera A; Colloca, Luana; Heilig, Markus

    2015-05-01

    Throughout history, patient-physician relationships have been acknowledged as an important component of the therapeutic effects of any pharmacological treatment. Here, we discuss the role of physicians' expectations in influencing the therapeutic outcomes of alcohol and drug addiction pharmacological treatments. As largely demonstrated, such expectations and attitudes may contribute to produce placebo and nocebo effects that in turn affect the course of the disease and the response to the therapy. This article is aimed at discussing the current insights into expectations, placebo and nocebo mechanisms and their impact on the therapeutic outcomes of alcohol and drug addiction treatments; with the goal of informing physicians and other health care providers about the potentially widespread implications for clinical practice and for a successful treatment regimen. Published by Oxford University Press on behalf of Medical Council on Alcohol 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

  12. Are therapeutic vaccines an answer to the global problem of drug and alcohol abuse?

    Science.gov (United States)

    Brashier, Dick B S; Sharma, Ashok Kumar; Akhoon, Neha

    2016-01-01

    Drug Abuse has become a major challenging problem for the society. It effects people of all countries economical strata's and all ages. According. Monetary loss all over the world regarding drug abuse is in million dollars, it not only has an impact on human productivity and healthcare cost but also on cost of crimes conducted by these drugs and alcohol abuse. Therapeutic vaccine has come as new approach to deal with this problem, after failures in search for a pharmaceutical agent to deal with drug of abuse and alcohol. Research in field of nicotine abuse has gone a way ahead with number of vaccines being tried clinically followed by cocaine, opioids, methamphetamine, phencyclidine and alcohol. All of them have a common mechanism of action by antibody production whereas alcohol acts by genetic intervention. None have being approved yet due to poor results in phase II trials, possibly due to not able to trigger an adequate immunological response. But still quest is on for cracking the ice by developing first successful vaccine against drug of abuse, that would follow for other drugs too. It would be great step in field of therapeutic vaccines for drug abuse after similar successful vaccines being approved for other diseases like cancer.

  13. A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity.

    Science.gov (United States)

    Johansen, Lisa M; DeWald, Lisa Evans; Shoemaker, Charles J; Hoffstrom, Benjamin G; Lear-Rooney, Calli M; Stossel, Andrea; Nelson, Elizabeth; Delos, Sue E; Simmons, James A; Grenier, Jill M; Pierce, Laura T; Pajouhesh, Hassan; Lehár, Joseph; Hensley, Lisa E; Glass, Pamela J; White, Judith M; Olinger, Gene G

    2015-06-03

    Currently, no approved therapeutics exist to treat or prevent infections induced by Ebola viruses, and recent events have demonstrated an urgent need for rapid discovery of new treatments. Repurposing approved drugs for emerging infections remains a critical resource for potential antiviral therapies. We tested ~2600 approved drugs and molecular probes in an in vitro infection assay using the type species, Zaire ebolavirus. Selective antiviral activity was found for 80 U.S. Food and Drug Administration-approved drugs spanning multiple mechanistic classes, including selective estrogen receptor modulators, antihistamines, calcium channel blockers, and antidepressants. Results using an in vivo murine Ebola virus infection model confirmed the protective ability of several drugs, such as bepridil and sertraline. Viral entry assays indicated that most of these antiviral drugs block a late stage of viral entry. By nature of their approved status, these drugs have the potential to be rapidly advanced to clinical settings and used as therapeutic countermeasures for Ebola virus infections. Copyright © 2015, American Association for the Advancement of Science.

  14. Macromolecular therapeutics: emerging strategies for drug discovery in the postgenome era.

    Science.gov (United States)

    Juliano, R L; Astriab-Fisher, A; Falke, D

    2001-04-01

    The postgenome era offers a plethora of potential therapeutic targets. Many of these targets will be addressable using small organic molecules as drug candidates. However, certain aspects of cell function, particularly those that rely on protein-protein or protein-nucleic acid interactions, will be difficult to influence using small molecules. Thus, the possibility of using highly specific macromolecules as potential therapeutic agents is an intriguing concept. Recent developments in several areas of research have brought this possibility closer to fruition. Peptide and nucleic acid combinatorial libraries allow the generation of novel molecules having exquisite selectivity. Structural information and molecular modeling also contribute to the design of new macromolecules with therapeutic potential. Perhaps most importantly, approaches for delivering macromolecules into the cell interior have been developed and applied with considerable success. Thus, the therapeutic use of macromolecules, including oligonucleotides, peptides, and proteins, may be an idea whose time has come.

  15. Enhanced therapeutic agent delivery through magnetic resonance imaging-monitored focused ultrasound blood-brain barrier disruption for brain tumor treatment: an overview of the current preclinical status.

    Science.gov (United States)

    Liu, Hao-Li; Yang, Hung-Wei; Hua, Mu-Yi; Wei, Kuo-Chen

    2012-01-01

    Malignant glioma is a severe primary CNS cancer with a high recurrence and mortality rate. The current strategy of surgical debulking combined with radiation therapy or chemotherapy does not provide good prognosis, tumor progression control, or improved patient survival. The blood-brain barrier (BBB) acts as a major obstacle to chemotherapeutic treatment of brain tumors by severely restricting drug delivery into the brain. Because of their high toxicity, chemotherapeutic drugs cannot be administered at sufficient concentrations by conventional delivery methods to significantly improve long-term survival of patients with brain tumors. Temporal disruption of the BBB by microbubble-enhanced focused ultrasound (FUS) exposure can increase CNS-blood permeability, providing a promising new direction to increase the concentration of therapeutic agents in the brain tumor and improve disease control. Under the guidance and monitoring of MR imaging, a brain drug-delivery platform can be developed to control and monitor therapeutic agent distribution and kinetics. The success of FUS BBB disruption in delivering a variety of therapeutic molecules into brain tumors has recently been demonstrated in an animal model. In this paper the authors review a number of critical studies that have demonstrated successful outcomes, including enhancement of the delivery of traditional clinically used chemotherapeutic agents or application of novel nanocarrier designs for actively transporting drugs or extending drug half-lives to significantly improve treatment efficacy in preclinical animal models.

  16. Obstetric therapeutics-how pharmacogenetics may inform drug therapy for pregnant women in the future.

    Science.gov (United States)

    Haas, David M

    2013-09-01

    Most pregnant women take prescription medications. There are many factors related to pregnancy that make finding the most effective and safe dose of a therapeutic drug difficult for providers. Genetic differences in drug-metabolizing enzymes, transporters, and receptors may also account for some of the differences in drug response. Single-nucleotide polymorphisms in drug-metabolizing enzymes, such as the cytochrome P450 families, have been studied in relation to drugs used in pregnancy. Combining clinical characteristics, physiologic parameters in pregnancy, and possibly pharmacogenetic models may allow for providers to individualize pharmacotherapy in pregnancy and get to the most effective and safe dose of medication more quickly than in the current practice model. This article discusses these issues along with helpful Web sites and references for providers.

  17. Enhanced Therapeutic Efficacy of iRGD-Conjugated Crosslinked Multilayer Liposomes for Drug Delivery

    Directory of Open Access Journals (Sweden)

    Yarong Liu

    2013-01-01

    Full Text Available Targeting nanoparticles by conjugating various specific ligands has shown potential therapeutic efficacy in nanomedicine. However, poor penetration of antitumor drugs into solid tumors remains a major obstacle. Here, we describe a targeting strategy for antitumor drug delivery by conjugating a crosslinked multilamellar liposomal vesicle (cMLV formulation with a tumor-penetrating peptide, iRGD. The results showed that iRGD peptides could facilitate the binding and cellular uptake of drug-loaded cMLVs and consequently enhance the antitumor efficacy in breast tumor cells, including multidrug-resistant cells. Moreover, colocalization data revealed that iRGD-conjugated cMLVs (iRGD-cMLVs entered cells via the clathrin-mediated pathway, followed by endosome-lysosome transport for efficient drug delivery. Finally, in vivo study indicated that iRGD-cMLVs could deliver anticancer drugs efficiently to mediate significant tumor suppression.

  18. The Therapeutic Utility of Employment in Treating Drug Addiction: Science to Application.

    Science.gov (United States)

    Silverman, Kenneth; Holtyn, August F; Morrison, Reed

    2016-06-01

    Research on a model Therapeutic Workplace has allowed for evaluation of the use of employment in the treatment of drug addiction. Under the Therapeutic Workplace intervention, adults with histories of drug addiction are hired and paid to work. To promote drug abstinence or adherence to addiction medications, participants are required to provide drug-free urine samples or take prescribed addiction medications, respectively, to gain access to the workplace and/or to maintain their maximum rate of pay. Research has shown that the Therapeutic Workplace intervention is effective in promoting and maintaining abstinence from heroin, cocaine and alcohol and in promoting adherence to naltrexone. Three models could be used to implement and maintain employment-based reinforcement in the treatment of drug addiction: A Social Business model, a Cooperative Employer model, and a Wage Supplement model. Under all models, participants initiate abstinence in a training and abstinence initiation phase (Phase 1). Under the Social Business model, Phase 1 graduates are hired as employees in a social business and required to maintain abstinence to maintain employment and/or maximum pay. Under the Cooperative Employer model, cooperating community employers hire graduates of Phase 1 and require them to maintain abstinence to maintain employment and/or maximum pay. Under the Wage Supplement Model, graduates of Phase 1 are offered abstinence-contingent wage supplements if they maintain competitive employment in a community job. Given the severity and persistence of the problem of drug addiction and the lack of treatments that can produce lasting effects, continued development of the Therapeutic Workplace is warranted.

  19. Similarity-based prediction for Anatomical Therapeutic Chemical classification of drugs by integrating multiple data sources.

    Science.gov (United States)

    Liu, Zhongyang; Guo, Feifei; Gu, Jiangyong; Wang, Yong; Li, Yang; Wang, Dan; Lu, Liang; Li, Dong; He, Fuchu

    2015-06-01

    Anatomical Therapeutic Chemical (ATC) classification system, widely applied in almost all drug utilization studies, is currently the most widely recognized classification system for drugs. Currently, new drug entries are added into the system only on users' requests, which leads to seriously incomplete drug coverage of the system, and bioinformatics prediction is helpful during this process. Here we propose a novel prediction model of drug-ATC code associations, using logistic regression to integrate multiple heterogeneous data sources including chemical structures, target proteins, gene expression, side-effects and chemical-chemical associations. The model obtains good performance for the prediction not only on ATC codes of unclassified drugs but also on new ATC codes of classified drugs assessed by cross-validation and independent test sets, and its efficacy exceeds previous methods. Further to facilitate the use, the model is developed into a user-friendly web service SPACE ( S: imilarity-based P: redictor of A: TC C: od E: ), which for each submitted compound, will give candidate ATC codes (ranked according to the decreasing probability_score predicted by the model) together with corresponding supporting evidence. This work not only contributes to knowing drugs' therapeutic, pharmacological and chemical properties, but also provides clues for drug repositioning and side-effect discovery. In addition, the construction of the prediction model also provides a general framework for similarity-based data integration which is suitable for other drug-related studies such as target, side-effect prediction etc. The web service SPACE is available at http://www.bprc.ac.cn/space. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Identification of Potential Therapeutics to Conquer Drug Resistance in Salmonella typhimurium: Drug Repurposing Strategy.

    Science.gov (United States)

    Preethi, Balasundaram; Shanthi, Veerappapillai; Ramanathan, Karuppasamy

    2016-12-01

    Salmonella typhimurium is the main cause of gastrointestinal illness in humans, and treatment options are decreasing because drug-resistant strains have emerged. The objective of this study was to use computational drug repurposing to identify a novel candidate with an effective mechanism of action to circumvent the drug resistance. We used the Mantra 2.0 database to initially screen drug candidates that share similar gene expression profiles to those of quinolones. Data were further reduced using pharmacophore mapping theory. Finally, we employed molecular-simulation studies to calculate the binding affinity of the screened candidates with DNA gyrase, alongside an analysis of side effects. A total of 16 drug candidates from the Mantra 2.0 database were screened. The pharmacophoric features of the screened candidates were examined and nalidixic acid features compared using the PharamGist program. A total of 11 compounds with the highest pharmacophore score were considered for binding energy calculation. Finally, we analysed the side effects of the eight drug candidates that showed significant binding affinity in the simulation study. Overall, flufenamic acid and sulconazole may be potential drug candidates that could be studied in vitro to assess their resistance profile against Salmonella enterica Typhimurium.

  1. Therapeutics for filovirus infection: traditional approaches and progress towards in silico drug design.

    Science.gov (United States)

    Shurtleff, Amy C; Nguyen, Tam L; Kingery, David A; Bavari, Sina

    2012-10-01

    Ebolaviruses and marburgviruses cause severe and often lethal human hemorrhagic fevers. As no FDA-approved therapeutics are available for these infections, efforts to discover new therapeutics are important, especially because these pathogens are considered biothreats and emerging infectious diseases. All methods for discovering new therapeutics should be considered, including compound library screening in vitro against virus and in silico structure-based drug design, where possible, if sufficient biochemical and structural information is available. This review covers the structure and function of filovirus proteins, as they have been reported to date, as well as some of the current antiviral screening approaches. The authors discuss key studies mapping small-molecule modulators that were found through library and in silico screens to potential sites on viral proteins or host proteins involved in virus trafficking and pathogenesis. A description of ebolavirus and marburgvirus diseases and available animal models is also presented. To discover novel therapeutics with potent efficacy using sophisticated computational methods, more high-resolution crystal structures of filovirus proteins and more details about the protein functions and host interaction will be required. Current compound screening efforts are finding active antiviral compounds, but an emphasis on discovery research to investigate protein structures and functions enabling in silico drug design would provide another avenue for finding antiviral molecules. Additionally, targeting of protein-protein interactions may be a future avenue for drug discovery since disrupting catalytic sites may not be possible for all proteins.

  2. Trends in therapeutic drug conjugates for bacterial diseases: a patent review.

    Science.gov (United States)

    Cal, Pedro M S D; Matos, Maria J; Bernardes, Gonçalo J L

    2017-02-01

    Drug conjugates are trend topics in Chemical Biology. These entities are an emerging class of highly potent biopharmaceutical drugs, best known in the field of oncology, that have been also designed as a targeted therapy/diagnosis for the treatment/prevention of several bacterial diseases. Antibiotic resistance is now a major threat to public health, and targeted strategies can reduce resistance. The following review aims at giving an overview of the patented therapeutic innovations covering these areas. Particular attention has been given to antibacterial drug conjugates in the last 30 years. Areas covered: The authors provide an overview of the scientific reports describing the research and development of new drug conjugates for bacterial diseases. The review emphasizes the rationale behind synthesis, biological activities and improvement of the new drug conjugates. New technologies applied for the research in this field have also been discussed. The article is based on the most relevant literature related to the development of new therapeutic solutions. The patents presented in this review have been collected from multiple electronic databases including SciFinder, Pubmed, Espacenet and Mendeley. Expert opinion: The new drug conjugates described in the current review proved to display improved delivery, efficacy, targeting abilities and fewer side effects. Versatile approaches were invented to achieve these goals.

  3. Do psychoactive drugs have a therapeutic role in compulsivity? Studies on schedule-induced polydipsia.

    Science.gov (United States)

    Martín-González, Elena; Prados-Pardo, Ángeles; Mora, Santiago; Flores, Pilar; Moreno, Margarita

    2018-02-01

    Clinical studies have shown that some psychoactive recreational drugs have therapeutic applications in anxiety, depression, and schizophrenia. However, to date, there are few studies on the therapeutic potential efficacy of recreational drugs in compulsive neuropsychiatric disorders. We explored the therapeutic potential of different psychoactive and psychedelic drugs in a preclinical model of compulsive behavior. Outbred male Wistar rats were selected as either high (HD) or low (LD) drinkers according to their behavior in schedule-induced polydipsia (SIP). Subsequently, we assessed the effects of acute administration of scopolamine (0.125, 0.25, and 0.5 mg/kg), methamphetamine (0.25, 0.5, 1.25, and 2.5 mg/kg), ketamine (1.25, 2.5, 5, and 10 mg/kg), cannabidiol (1 and 3 mg/kg), WIN21255-2 (0.5, 075, and 1 mg/kg), and AM404 (0.25 and 0.5 mg/kg) on compulsive drinking in SIP. Scopolamine reduced dose-dependent compulsive drinking in HD compared with LD rats in SIP. Methamphetamine induced a dose-dependent inverted U-curve effect in both groups, in which lower doses increased and higher doses reduced compulsive drinking in SIP. Ketamine, cannabidiol, WIN21255-2, and AM404 did not have any relevant effects in SIP. These data provide new evidence that low doses of scopolamine and intermediate doses of methamphetamine might therapeutically reduce compulsive behaviors and suggest that there is not a direct participation of the endocannabinoid system in compulsive behavior on SIP. The research in the underlying neurochemical mechanisms of these psychoactive drugs might provide an additional insight on new therapeutic targets in compulsive neuropsychiatric disorders.

  4. Ultrasound-Stimulated Drug Delivery Using Therapeutic Reconstituted High-Density Lipoprotein Nanoparticles.

    Science.gov (United States)

    Xiong, Fangyuan; Nirupama, Sabnis; Sirsi, Shashank R; Lacko, Andras; Hoyt, Kenneth

    2017-01-01

    method for monitoring the effects of US-stimulated drug delivery of IR-780 dye-loaded rHDL NPs in living animals. No change in optical imaging data was found in the control animals. However, there was considerable dye accumulation (surrogate drug) within 48 h in the low (5 µg), moderate (10 µg), and high (50 µg) rHDL NP concentration-dosed group animals (p 0.69, p < 0.003). IR-780 dye extraction from the tumor tissue samples confirmed the in vivo and ex vivo US therapy findings. Overall, the addition of US therapy considerably improved local rHDL NP accumulation in tumor tissue. This study concludes that US-mediated drug delivery can facilitate tumor uptake of rHDL NPs and more research is warranted to optimize the drug dosing schedule and the respective therapeutic protocols.

  5. Lessons Learned from Gemcitabine: Impact of Therapeutic Carrier Systems and Gemcitabine's Drug Conjugates on Cancer Therapy.

    Science.gov (United States)

    Dyawanapelly, Sathish; Kumar, Animesh; Chourasia, Manish K

    2017-01-01

    Currently, drug delivery systems have a high impact in cancer therapy and are receiving more attention than conventional cancer treatment modalities. Compared with current cancer therapies, gemcitabine (2', 2'-difluoro-2'-deoxycytidine) has been proven to be an effective chemotherapeutic agent against pancreatic, colon, bladder, breast, ovarian, non-small-cell lung, and head and neck cancers in combination with other anticancer agents. To improve the safety and efficacy of cytotoxic drugs, several drug delivery systems have been explored. This review outlines the recent work directed toward gemcitabine delivery systems for cancer therapy, including aerosols, polymeric nanoparticles, liposomes, microparticles, carbon nanotubes, and multifunctional theranostic nanomedicines. It also provides insight into the design and development of gemcitabine conjugation for safe and effective cancer therapy. Despite the clinical promises of gemcitabine, many therapeutic challenges remain. Specifically, its therapeutic use in cancer chemotherapy is impeded by a short biological half-life, caused by its rapid metabolism, and resistance due to increased expression of ribonucleotide reductase. In our opinion, many research investigations have contributed to improve the selectivity and efficacy of gemcitabine. This combined approach of drug delivery systems and gemcitabine conjugates has shown promising efficacy in preclinical models and significant potential for future clinical cancer-therapeutic applications. Also, these strategies overcome most of the aforementioned limits of gemcitabine.

  6. Potential effects of gamma irradiation on the stability and therapeutic activity of anticancer drug, doxorubicin

    Directory of Open Access Journals (Sweden)

    Fatmah M. Alshammari

    2017-04-01

    Full Text Available Cancer therapy has progressed dramatically in recent years. In order to decrease the dose and side effects of the anticancer drug, the therapeutic options for patients with cancer include increasingly complex combinations of chemotherapy and radiotherapy. This combination may cause overlapping interaction between the two types of treatment and affect the stability of the anticancer drug. In this study, the effect of gamma irradiation on the stability and therapeutic activity of one anticancer drug (Doxorubicin was studied. For this purpose, doxorubicin drug characterized by two methods, at first, in-vitro study, before and after drug irradiation with different doses of gamma rays (2, 5, 20, 100 GY which achieved through measuring the dielectric relaxation and absorption spectrum of drug solution. Secondly, in-vivo studies, where the unirradiated and the drug, which later exposed to gamma rays, were injected respectively into 6 groups of mice (3 mice in each group. The dielectric relaxation and absorption spectrum were studded for hemoglobin of the injected mice. The results for the in-vitro study indicate that the values of dielectric parameters show unnoticeable change for drug molecules before and after irradiation as compared with the control. The results for in-vivo study indicated an increase in the values of relaxation time and Cole- Cole parameter, that may as a result of changes in the conformational structure in hemoglobin molecules which may affect their properties and hence RBC's physiological functions. The absorption spectra of hemoglobin molecules show an increase in the amplitude of the characteristic bands with irradiation dose indicate an increase of the oxygen binding capacity with hemoglobin. It was concluded that combination between the drugs and gamma irradiation can be used as a powerful conjunction that may give us the benefit chemo and radiotherapy treatment.

  7. Therapeutic potential of histaminergic compounds in the treatment of addiction and drug-related cognitive disorders.

    Science.gov (United States)

    Alleva, Livia; Tirelli, Ezio; Brabant, Christian

    2013-01-15

    Addiction is a behavioral disorder characterized by the compulsive seeking and taking of drugs despite serious negative consequences. In particular, the chronic use of drugs impairs memory and cognitive functions, which aggravates the loss of control over drug use and complicates treatment outcome. Therefore, cognitive enhancers targeting acetylcholine have been proposed to treat addiction. Interestingly, histamine H(3) receptor (H(3)R) antagonists/inverse agonists stimulate acetylcholine transmission in different brain areas, facilitate memory in animal models and can reverse learning deficits induced by drugs such as scopolamine, dizocilpine and alcohol. Moreover, several studies found that compounds capable of activating the histaminergic system generally decrease the reinforcing effects of drugs, namely alcohol and opioids, in preclinical models of addiction. Finally, several H(3)R antagonists/inverse agonists increase histamine in the brain and have proven to be safe in humans. However, no studies have yet investigated the therapeutic potential of cognitive enhancing H(3)R antagonists/inverse agonists in the treatment of addiction in humans. The present review first describes the impact of addictive drugs on learning processes and cognitive functions that play an important role for addicts to remain abstinent. Second, our work briefly summarizes the relevant literature describing the function of histamine in learning, memory and drug addiction. Finally, the potential therapeutic use of histaminergic agents in the treatment of addiction is discussed. Our review suggests that histaminergic compounds like H(3)R antagonists/inverse agonists may improve the treatment outcome of addiction by reversing drug-induced cognitive deficits and/or diminishing the reinforcing properties of addictive drugs, especially opioids and alcohol. Copyright © 2012 Elsevier B.V. All rights reserved.

  8. A novel ingestible electronic drug delivery and monitoring device.

    Science.gov (United States)

    van der Schaar, Peter J; Dijksman, J Frits; Broekhuizen-de Gast, Henny; Shimizu, Jeff; van Lelyveld, Niels; Zou, Hans; Iordanov, Ventzeslav; Wanke, Christoph; Siersema, Peter D

    2013-09-01

    We developed an ingestible electronic drug delivery and monitoring system. This system includes an electronic capsule comprising a drug reservoir, a pH and temperature sensor, a microprocessor and wireless transceiver, a stepper motor, and batteries. The location of the capsule in the gut derived from pH data can be monitored in real time. The stepper motor can be remotely actuated to expel the contents of the drug reservoir. First human study. Two consecutive observational studies. University medical center. Twenty healthy volunteers. Study I: Ingestion and passage of the capsule. Study II: Ingestion and passage of the capsule, loaded with (99m)technetium-pertechnetate ((99m)Tc); remotely actuated expulsion of (99m)Tc in the gut. Study I: Safety, tolerability, and functionality (wireless pH and temperature recording). Study II: Tracing of the capsule and expulsion and distribution of (99m)Tc from the drug reservoir by scintigraphy. Correlating location pH with scintigraphy. Study I: Ingestion and passage of the capsule was safe and well tolerated. Transmitted pH and temperature data were received by the recorder in 96.5% ± 3%. Study II: pH-determined passage of the esophagogastric, gastroduodenal, and ileocolonic junction correlated well with scintigraphy. Expulsion of (99m)Tc from the capsule was successful in 9 of 10 subjects. Subjects with relatively low body mass index. This electronic drug delivery and monitoring system may be a promising tool for targeted delivery of substances to well-defined areas of the GI tract. Copyright © 2013 American Society for Gastrointestinal Endoscopy. Published by Mosby, Inc. All rights reserved.

  9. Drug-Level Monitoring on Admission for Presurgical Epilepsy Evaluation.

    Science.gov (United States)

    Constantinescu, Irina; Korff, Christian M; Vulliemoz, Serge; Picard, Fabienne; Seeck, Margitta

    2017-01-01

    Evaluation for surgical treatment is offered to patients who do not respond to antiepileptic drugs. Pseudo-pharmacoresistance (PPR) has been described in the context of impaired compliance, incorrect diagnosis of epilepsy or pharmacological interference resulting in too low blood levels. We were interested to determine the frequency and causes of PPR in patients admitted for presurgical evaluation. We reviewed 553 drug levels in 199 patients and analyzed the relative frequency of drugs below reference range (10 and 20% below the range). Patients who had at least one serum level below the 10% cut-off amounted to 33% and 9% of patients had at least one serum level below the 20% cut-off. Only in 2 patients (1%), this was due to poor compliance. Low levels were equally frequent in mono- or polytherapy. Drugs that were most frequently found out of range were phenytoin, valproate, and topiramate. In monotherapy, lamotrigine was often prescribed in too low dosages. Low drug levels are frequently observed in surgical candidates due to pharmacological interference or insufficient dosing. Poor compliance or incorrect diagnosis does not appear to be a significant concern in this patient group. Our data strengthen the need for regular drug monitoring even in advanced chronic epilepsy to avoid unnecessary health costs by too low and ineffective dosages. © 2017 S. Karger AG, Basel.

  10. Intelligent Janus nanoparticles for intracellular real-time monitoring of dual drug release

    Science.gov (United States)

    Cao, Han; Yang, Yuhong; Chen, Xin; Shao, Zhengzhong

    2016-03-01

    Stimuli-responsive nanomaterials have been receiving much attention as drug delivery carriers, however understanding of multi-drug release from the carriers for efficient therapeutics is highly challenging. Here, we report a novel nanosystem, Janus particle Dox-CMR-MS/Au-6MP (Dox: doxorubicin, CMR: 7-hydroxycoumarin-3-carboxylate, MS: mesoporous silica, Au: gold, 6MP: 6-mercaptopurine) with opposing MS and Au faces, which can monitor intracellular dual-drug (Dox and 6MP) controlled release in real time based on fluorescence resonance energy transfer (FRET) and surface-enhanced Raman scattering (SERS). The FRET acceptor Dox is attached to CMR (as a FRET donor) conjugated MS with a pH-responsive linker hydrazone, and 6MP is conjugated to the Au surface through the gold-thiol interaction. As the Janus nanoparticle enters into tumor cells, the breakage of the hydrazone bond in an acidic environment and the substitution of glutathione (GSH) overexpressed in cancer cells give rise to the release of Dox and 6MP, respectively. Thus, the change of the CMR fluorescence signal and the SERS decrease of 6MP can be used to monitor the dual-drug release within living cells in real time. In addition, this work demonstrates the enhanced anticancer effect of the designed dual-drug loaded nanosystem. Therefore, the current study may provide new perspectives for the real-time study of intelligent multi-drug delivery and release, as well as cellular responses to drug treatment.Stimuli-responsive nanomaterials have been receiving much attention as drug delivery carriers, however understanding of multi-drug release from the carriers for efficient therapeutics is highly challenging. Here, we report a novel nanosystem, Janus particle Dox-CMR-MS/Au-6MP (Dox: doxorubicin, CMR: 7-hydroxycoumarin-3-carboxylate, MS: mesoporous silica, Au: gold, 6MP: 6-mercaptopurine) with opposing MS and Au faces, which can monitor intracellular dual-drug (Dox and 6MP) controlled release in real time based on

  11. Repurposing FDA-approved drugs as therapeutics to treat Rift Valley fever virus infection

    Directory of Open Access Journals (Sweden)

    Ashwini eBenedict

    2015-07-01

    Full Text Available There are currently no FDA-approved therapeutics available to treat Rift Valley fever virus (RVFV infection. In an effort to repurpose drugs for RVFV treatment, a library of FDA-approved drugs was screened to determine their ability to inhibit RVFV. Several drugs from varying compound classes, including inhibitors of growth factor receptors, microtubule assembly/disassembly, and DNA synthesis, were found to reduce RVFV replication. The hepatocellular and renal cell carcinoma drug, sorafenib, was the most effective inhibitor, being non-toxic and demonstrating inhibition of RVFV in a cell-type and virus strain independent manner. Mechanism of action studies indicated that sorafenib targets at least two stages in the virus infectious cycle, RNA synthesis and viral egress. Computational modeling studies also support this conclusion. siRNA knockdown of Raf proteins indicated that non-classical targets of sorafenib are likely important for the replication of RVFV.

  12. Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer's Disease Therapeutic Agents.

    Science.gov (United States)

    Llorach-Pares, Laura; Nonell-Canals, Alfons; Sanchez-Martinez, Melchor; Avila, Conxita

    2017-11-27

    Computer-aided drug discovery/design (CADD) techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A-G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium, against various protein kinases involved in Alzheimer's disease (AD), a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT). Balance splitting between tau kinase and phosphate activities caused tau hyperphosphorylation and, thereby, its aggregation and NTF formation. Inhibition of specific kinases involved in its phosphorylation pathway could be one of the key strategies to reverse tau hyperphosphorylation and would represent an approach to develop drugs to palliate AD symptoms. Meridianins bind to the adenosine triphosphate (ATP) binding site of certain protein kinases, acting as ATP competitive inhibitors. These compounds show very promising scaffolds to design new drugs against AD, which could act over tau protein kinases Glycogen synthetase kinase-3 Beta (GSK3β) and Casein kinase 1 delta (CK1δ, CK1D or KC1D), and dual specificity kinases as dual specificity tyrosine phosphorylation regulated kinase 1 (DYRK1A) and cdc2-like kinases (CLK1). This work is aimed to highlight the role of CADD techniques in marine drug discovery and to provide precise information regarding the binding mode and strength of meridianins against several protein kinases that could help in the future development of anti-AD drugs.

  13. Drug convertarule.

    OpenAIRE

    Brodie, M. J.; Robson, A.; Murray, T.

    1983-01-01

    A convenient pocket ruler has been developed that allows conversion between metric and molar measurements of many of the drugs for which therapeutic monitoring in the circulation is commonly used. The ruler also gives information to the clinician on suggested therapeutic ranges for the incorporated drugs.

  14. Drug Vaping: From the Dangers of Misuse to New Therapeutic Devices.

    Science.gov (United States)

    Varlet, V

    2016-12-16

    Users of e-cigarettes are unwitting volunteers participating in a worldwide epidemiological study. Because of the obvious benefits of e-cigarettes compared with traditional cigarette smoking, these electronic devices have been introduced all around the world to support tobacco smoking cessation. Same potential harm reduction could be considered by cannabis vaping for marijuana smokers. However, the toxicities of liquids and aerosols remain under investigation because although the use of e-cigarettes is likely to be less harmful than traditional cigarette smoking, trace levels of contaminants have been identified. Simultaneously, other electronic devices, such as e-vaporisers, e-hookahs or e-pipes, have been developed and commercialised. Consequently, misuse of electronic devices has increased, and experimentation has been documented on Internet web fora. Although legal and illegal drugs are currently consumed with these e-devices, no scientific papers are available to support the observations reported by numerous media and web fora. Moreover, building on illegal drug vaping and vaporisation with e-devices (vaping misuse), legal drug vaping (an alternative use of vaping) could present therapeutic benefits, as occurs with medical cannabis vaporisation with table vaporisers. This review seeks to synthesise the problems of e-cigarette and liquid refill toxicity in order to introduce the dangers of illegal and legal drugs consumed using vaping and vaporisation for recreational purposes, and finally, to present the potential therapeutic benefits of vaping as a new administration route for legal drugs.

  15. Self-Microemulsifying Drug Delivery Systems: An Attractive Strategy for Enhanced Therapeutic Profile.

    Science.gov (United States)

    Akula, Samatha; Gurram, Aravind Kumar; Devireddy, Srinivas Reddy

    2014-01-01

    Ease of administration and painless approach made oral route the most preferred. Poor oral bioavailability is pronounced with the majority of recent active ingredients because of dissolution rate limited absorption. Failure to attain intended therapeutic effect of the poor water soluble drugs by this route led to development of novel drug delivery systems which will fulfill therapeutic needs with minimum dose. Although many formulation approaches like solid dispersions, complexation, pH modification, and cocrystals exist, lipid based delivery systems finding increased appliance with the apparent increase in absorption of drug. Among lipid based formulations, self-microemulsifying formulations (droplet size < 100 nm) are evident to improve the oral bioavailability of hydrophobic drugs primarily due to their efficiency in facilitating solubilization and in presenting the hydrophobic drug in solubilized form whereby dissolution process can be circumvented. Various components that are used to formulate these dosage forms like surfactants and lipids contribute to the overall improvement in oral bioavailability via promoting the lymphatic transport; thereby hepatic first pass metabolism can be surmounted. The present paper gives exhaustive information on the formulation design and characterization of SMEDDS along with the probable mechanisms by which the bioavailability can be improved with SMEDDS.

  16. Drug Vaping: From the Dangers of Misuse to New Therapeutic Devices

    Directory of Open Access Journals (Sweden)

    V. Varlet

    2016-12-01

    Full Text Available Users of e-cigarettes are unwitting volunteers participating in a worldwide epidemiological study. Because of the obvious benefits of e-cigarettes compared with traditional cigarette smoking, these electronic devices have been introduced all around the world to support tobacco smoking cessation. Same potential harm reduction could be considered by cannabis vaping for marijuana smokers. However, the toxicities of liquids and aerosols remain under investigation because although the use of e-cigarettes is likely to be less harmful than traditional cigarette smoking, trace levels of contaminants have been identified. Simultaneously, other electronic devices, such as e-vaporisers, e-hookahs or e-pipes, have been developed and commercialised. Consequently, misuse of electronic devices has increased, and experimentation has been documented on Internet web fora. Although legal and illegal drugs are currently consumed with these e-devices, no scientific papers are available to support the observations reported by numerous media and web fora. Moreover, building on illegal drug vaping and vaporisation with e-devices (vaping misuse, legal drug vaping (an alternative use of vaping could present therapeutic benefits, as occurs with medical cannabis vaporisation with table vaporisers. This review seeks to synthesise the problems of e-cigarette and liquid refill toxicity in order to introduce the dangers of illegal and legal drugs consumed using vaping and vaporisation for recreational purposes, and finally, to present the potential therapeutic benefits of vaping as a new administration route for legal drugs.

  17. Topical Nonsteroidal Anti-Inflammatory Drugs: The Importance of Drug, Delivery, and Therapeutic Outcome.

    Science.gov (United States)

    Barkin, Robert L

    2015-01-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of pain associated with a variety of indications, including arthritic conditions, but their usefulness is often limited by dose-dependent adverse events (AEs), such as gastrointestinal disturbances, cardiovascular events, and renal toxicity. The risk of such effects could be reduced by the use of topical formulations, which offer the potential to deliver analgesic concentrations locally, at the site of inflammation, while minimizing systemic concentrations. The topical preparations currently approved in the United States are diclofenac sodium 1.5% topical solution (containing dimethyl sulfoxide as a penetration enhancer), diclofenac sodium gel 1%, and a diclofenac hydroxyethylpyrrolidine 1.3% patch. Each of these topical NSAIDs provide drug delivery to subcutaneous tissues for the management of pain associated with osteoarthritis or soft-tissue injuries. Furthermore, these formulations are not significantly associated with the systemic AEs associated with oral NSAIDs; the most common AEs associated with topical formulations are local skin reactions, which are usually mild and self-limiting. Other topical NSAID preparations approved in the European Union include ibuprofen creams and gels, ketoprofen gel, felbinac gel and cutaneous foam, and piroxicam gel. Meta-analyses have confirmed the efficacy and safety of these preparations. However, it is important to recognize that pharmacokinetic absorption from topical formulations can vary markedly, even between different formulations of the same drug, depending on the agent, the underlying disorder, and the site of application. It is therefore essential to consider the patient, the drug, and the drug delivery mechanism when selecting a topical NSAID preparation.

  18. A Bioequivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-Scaled Approach and Variability Comparison Criterion

    OpenAIRE

    Jiang, Wenlei; Makhlouf, Fairouz; Schuirmann, Donald J.; Zhang, Xinyuan; Zheng, Nan; Conner, Dale; Yu, Lawrence X.; Lionberger, Robert

    2015-01-01

    Various health communities have expressed concerns regarding whether average bioequivalence (BE) limits (80.00–125.00%) for the 90% confidence interval of the test-to-reference geometric mean ratio are sufficient to ensure therapeutic equivalence between a generic narrow therapeutic index (NTI) drug and its reference listed drug (RLD). Simulations were conducted to investigate the impact of different BE approaches for NTI drugs on study power, including (1) direct tightening of average BE lim...

  19. In vivo gastrointestinal drug-release monitoring through second near-infrared window fluorescent bioimaging with orally delivered microcarriers

    Science.gov (United States)

    Wang, Rui; Zhou, Lei; Wang, Wenxing; Li, Xiaomin; Zhang, Fan

    2017-03-01

    Non-invasive monitoring of gastrointestinal drug release in vivo is extremely challenging because of the limited spatial resolution and long scanning time of existing bioimaging modalities, such as X-ray radiation and magnetic resonance. Here, we report a novel microcarrier that can retain drugs and withstand the harsh conditions of gastrointestinal tract. Significantly, we can track the microcarrier fate and semi-quantitatively monitor the content of drug released in vivo in real time by measuring the fluorescence signals in the second near-infrared window of lanthanide-based downconversion nanoparticles with an absorption competition-induced emission bioimaging system. The microcarriers show a prolonged residence time of up to 72 h in the gastrointestinal tract, releasing up to 62% of their content. Moreover, minimal deposition of the microcarriers is found in non-target organs, such as the liver, spleen and kidney. These findings provide novel insights for the development of therapeutic and bioimaging strategies of orally administered drugs.

  20. Complement therapeutics in inflammatory diseases: promising drug candidates for C3-targeted intervention.

    Science.gov (United States)

    Mastellos, D C; Ricklin, D; Hajishengallis, E; Hajishengallis, G; Lambris, J D

    2016-02-01

    There is increasing appreciation that complement dysregulation lies at the heart of numerous immune-mediated and inflammatory disorders. Complement inhibitors are therefore being evaluated as new therapeutic options in various clinical translation programs and the first clinically approved complement-targeted drugs have profoundly impacted the management of certain complement-mediated diseases. Among the many members of the intricate protein network of complement, the central component C3 represents a 'hot-spot' for complement-targeted therapeutic intervention. C3 modulates both innate and adaptive immune responses and is linked to diverse immunomodulatory systems and biological processes that affect human pathophysiology. Compelling evidence from preclinical disease models has shown that C3 interception may offer multiple benefits over existing therapies or even reveal novel therapeutic avenues in disorders that are not commonly regarded as complement-driven, such as periodontal disease. Using the clinically developed compstatin family of C3 inhibitors and periodontitis as illustrative examples, this review highlights emerging therapeutic concepts and developments in the design of C3-targeted drug candidates as novel immunotherapeutics for oral and systemic inflammatory diseases. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Addiction research centres and the nurturing of creativity. Monitoring the European drug situation: the ongoing challenge for the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).

    Science.gov (United States)

    Griffiths, Paul; Mounteney, Jane; Lopez, Dominique; Zobel, Frank; Götz, Wolfgang

    2012-02-01

    The European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) is the designated hub for drug-related information in the European Union. The organization's role is to provide the European Union (EU) and its Member States with a factual overview of European drug problems and a common information framework to support the drugs debate. In order to achieve its mission, the EMCDDA coordinates and relies on a network of 30 national monitoring centres, the Reitox National Focal Points. The Centre publishes on a wide range of drug-related topics, across epidemiology, interventions, laws and policies. Every November, the EMCDDA publishes its Annual Report, providing a yearly update on the European drug situation, translated into 23 EU languages. In line with its founding regulation, the EMCDDA has a role acting as an interface between the worlds of science and policy. While not a research centre in the formal sense, the results the Centre generates serve as catalysts for new research questions and help to identify priorities. Current challenges facing the agency include continuing to increase scientific standards while maintaining a strong institutional role, as well as supporting European efforts to identify, share and codify best practice in the drugs field. © 2011 EMCDDA.

  2. The benefits of antiepileptic drug (AED) blood level monitoring to complement clinical management of people with epilepsy.

    Science.gov (United States)

    Stepanova, Daria; Beran, Roy G

    2015-01-01

    Some argue that there is no evidence to support the use of antiepileptic drug (AED) blood level monitoring when treating people with epilepsy (PWE). This paper identifies how AED monitoring can be invaluable in such treatment. SPECIFIC EXAMPLES: (i) Compliance: Antiepileptic drug blood levels often confirm noncompliance rather than adequate seizure control, confirming subtherapeutic levels in PWE attending hospitals due to seizures. Routine monitoring of AED levels may prevent breakthrough seizures by identifying noncompliance and instituting heightened compliance measures before experiencing breakthrough seizures without modifying dosages. For PWE attending hospitals due to seizures, loading with the AED shown to be subtherapeutic may be all that is required. (ii) Cluster seizures and status epilepticus: When using long-acting AEDs to complement benzodiazepines, blood level monitoring confirms that an adequate dosage was given and, if not, a further bolus can be administered with further monitoring. This is particularly useful when using rectal administration of AEDs. (iii) Polypharmacy: Polypharmacy provokes drug interactions in which case AED monitoring helps in differentiating adequate dosing, offending AED with toxicity and free level measuring benefits when total levels are unhelpful. (iv) Generic substitution: Generic AEDs can fluctuate considerably from a parent compound, and even a parent compound, sourced from an alternative supplier, may have altered bioavailability for which blood level monitoring is very useful. While therapeutic blood level monitoring is not a substitute for good clinical judgment, it offers a valuable adjunct to patient care. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. The dopamine hypothesis of drug addiction and its potential therapeutic value.

    Directory of Open Access Journals (Sweden)

    Marco eDiana

    2011-11-01

    Full Text Available Dopamine (DA transmission is deeply affected by drugs of abuse, and alterations in DA function are involved in various phases of drug addiction and potentially exploitable therapeutically. In particular, basic studies have documented a reduction in the electrophysiological activity of DA neurons in alcohol, opiate, cannabinoid and other drug-dependent rats. Further, DA release in the Nacc is decreased in virtually all drug-dependent rodents. In parallel, these studies are supported by increments in intracranial self stimulation (ICSS thresholds during withdrawal from alcohol, nicotine, opiates, and other drugs of abuse, thereby suggesting a hypofunction of the neural substrate of ICSS. Accordingly, morphological evaluations fed into realistic computational analysis of the Medium Spiny Neuron (MSN of the Nucleus accumbens (Nacc, post-synaptic counterpart of DA terminals, show profound changes in structure and function of the entire mesolimbic system. In line with these findings, human imaging studies have shown a reduction of dopamine receptors accompanied by a lesser release of endogenous DA in the ventral striatum of cocaine, heroin and alcohol-dependent subjects, thereby offering visual proof of the ‘dopamine-impoverished’ addicted human brain.The reduction in physiological activity of the DA system leads to the idea that an increment in its activity, to restore pre-drug levels, may yield significant clinical improvements (reduction of craving, relapse and drug-seeking/taking. In theory, it may be achieved pharmacologically and/or with novel interventions such as Transcranial Magnetic Stimulation (TMS. Its anatomo-physiological rationale as a possible therapeutic aid in alcoholics and other addicts will be described and proposed as a theoretical framework to be subjected to experimental testing in human addicts.

  4. Coordination conjugates of therapeutic proteins with drug carriers: A new approach for versatile advanced drug delivery

    Czech Academy of Sciences Publication Activity Database

    Kejík, Z.; Bříza, T.; Králová, Jarmila; Poučková, P.; Kral, A.; Martásek, P.; Král, V.

    2011-01-01

    Roč. 21, č. 18 (2011), s. 5514-5520 ISSN 0960-894X R&D Projects: GA ČR GA203/09/1311 Grant - others:MPO(CZ) FR-TI3/521; AV ČR(CZ) KAN200100801 Program:FR; KA Institutional research plan: CEZ:AV0Z50520514 Keywords : combined cancer therapy * photodynamic therapy * targeted drug delivery Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.554, year: 2011

  5. EEG Monitoring and Antiepileptic Drugs in Children with Severe TBI.

    Science.gov (United States)

    Ruzas, Christopher M; DeWitt, Peter E; Bennett, Kimberly S; Chapman, Kevin E; Harlaar, Nicole; Bennett, Tellen D

    2017-04-01

    Traumatic brain injury (TBI) causes substantial morbidity and mortality in US children. Post-traumatic seizures (PTS) occur in 11-42% of children with severe TBI and are associated with unfavorable outcome. Electroencephalographic (EEG) monitoring may be used to detect PTS and antiepileptic drugs (AEDs) may be used to treat PTS, but national rates of EEG and AED use are not known. The purpose of this study was to describe the frequency and timing of EEG and AED use in children hospitalized after severe TBI. Retrospective cohort study of 2165 children at 30 hospitals in a probabilistically linked dataset from the National Trauma Data Bank (NTDB) and the Pediatric Health Information Systems (PHIS) database, 2007-2010. We included children (age 24 h, and non-missing disposition. The primary outcomes were EEG and AED use. Overall, 31.8% of the cohort had EEG monitoring. Of those, 21.8% were monitored on the first hospital day. The median duration of EEG monitoring was 2.0 (IQR 1.0, 4.0) days. AEDs were prescribed to 52.0% of the cohort, of whom 61.8% received an AED on the first hospital day. The median duration of AED use was 8.0 (IQR 4.0, 17.0) days. EEG monitoring and AED use were more frequent in children with known risk factors for PTS. EEG monitoring and AED use were not related to hospital TBI volume. EEG use is relatively uncommon in children with severe TBI, but AEDs are frequently prescribed. EEG monitoring and AED use are more common in children with known risk factors for PTS.

  6. How Parents of Teens Store and Monitor Prescription Drugs in the Home

    Science.gov (United States)

    Friese, Bettina; Moore, Roland S.; Grube, Joel W.; Jennings, Vanessa K.

    2013-01-01

    Qualitative interviews were conducted with parents of teens to explore how parents store and monitor prescription drugs in the home. Most parents had prescription drugs in the house, but took few precautions against teens accessing these drugs. Strategies for monitoring included moving the drugs to different locations, remembering how many pills…

  7. Silica Coated Paper Substrate for Paper-Spray Analysis of Therapeutic Drugs in Dried Blood Spots

    Science.gov (United States)

    Zhang, Zhiping; Xu, Wei; Manicke, Nicholas E.; Cooks, R. Graham; Ouyang, Zheng

    2011-01-01

    Paper spray is a newly developed ambient ionization method that has been applied for direct qualitative and quantitative analysis of biological samples. The properties of the paper substrate and spray solution have a significant impact on the release of chemical compounds from complex sample matrices, the diffusion of the analytes through the substrate, and the formation of ions for mass spectrometry analysis. In this study, a commercially available silica-coated paper was explored in an attempt to improve the analysis of therapeutic drugs in dried blood spots (DBS). The dichloromethane/isopropanol solvent has been identified as an optimal spray solvent for the analysis. The comparison was made with paper spray using chromatography paper as substrate with methanol/water as solvent for the analysis of verapamil, citalopram, amitriptyline, lidocaine and sunitinib in dried blood spots. It has been demonstrated the efficiency of recovery of the analytes was notably improved with the silica coated paper and the limit of quantitation (LOQ) for the drug analysis was 0.1 ng mL−1 using a commercial triple quadrupole mass spectrometer. The use of silica paper substrate also resulted in a sensitivity improvement of 5-50 fold in comparison with chromatography papers, including the Whatmann ET31 paper used for blood card. Analysis using a handheld miniature mass spectrometer Mini 11 gave LOQs of 10~20 ng mL−1 for the tested drugs, which is sufficient to cover the therapeutic ranges of these drugs. PMID:22145627

  8. Permeation of Therapeutic Drugs in Different Formulations across the Airway Epithelium In Vitro.

    Directory of Open Access Journals (Sweden)

    Claudia Meindl

    Full Text Available Pulmonary drug delivery is characterized by short onset times of the effects and an increased therapeutic ratio compared to oral drug delivery. This delivery route can be used for local as well as for systemic absorption applying drugs as single substance or as a fixed dose combination. Drugs can be delivered as nebulized aerosols or as dry powders. A screening system able to mimic delivery by the different devices might help to assess the drug effect in the different formulations and to identify potential interference between drugs in fixed dose combinations. The present study evaluates manual devices used in animal studies for their suitability for cellular studies.Calu-3 cells were cultured submersed and in air-liquid interface culture and characterized regarding mucus production and transepithelial electrical resistance. The influence of pore size and material of the transwell membranes and of the duration of air-liquid interface culture was assessed. Compounds were applied in solution and as aerosols generated by MicroSprayer IA-1C Aerosolizer or by DP-4 Dry Powder Insufflator using fluorescein and rhodamine 123 as model compounds. Budesonide and formoterol, singly and in combination, served as examples for drugs relevant in pulmonary delivery.Membrane material and duration of air-liquid interface culture had no marked effect on mucus production and tightness of the cell monolayer. Co-application of budesonide and formoterol, applied in solution or as aerosol, increased permeation of formoterol across cells in air-liquid interface culture. Problems with the DP-4 Dry Powder Insufflator included compound-specific delivery rates and influence on the tightness of the cell monolayer. These problems were not encountered with the MicroSprayer IA-1C Aerosolizer. The combination of Calu-3 cells and manual aerosol generation devices appears suitable to identify interactions of drugs in fixed drug combination products on permeation.

  9. Permeation of Therapeutic Drugs in Different Formulations across the Airway Epithelium In Vitro.

    Science.gov (United States)

    Meindl, Claudia; Stranzinger, Sandra; Dzidic, Neira; Salar-Behzadi, Sharareh; Mohr, Stefan; Zimmer, Andreas; Fröhlich, Eleonore

    2015-01-01

    Pulmonary drug delivery is characterized by short onset times of the effects and an increased therapeutic ratio compared to oral drug delivery. This delivery route can be used for local as well as for systemic absorption applying drugs as single substance or as a fixed dose combination. Drugs can be delivered as nebulized aerosols or as dry powders. A screening system able to mimic delivery by the different devices might help to assess the drug effect in the different formulations and to identify potential interference between drugs in fixed dose combinations. The present study evaluates manual devices used in animal studies for their suitability for cellular studies. Calu-3 cells were cultured submersed and in air-liquid interface culture and characterized regarding mucus production and transepithelial electrical resistance. The influence of pore size and material of the transwell membranes and of the duration of air-liquid interface culture was assessed. Compounds were applied in solution and as aerosols generated by MicroSprayer IA-1C Aerosolizer or by DP-4 Dry Powder Insufflator using fluorescein and rhodamine 123 as model compounds. Budesonide and formoterol, singly and in combination, served as examples for drugs relevant in pulmonary delivery. Membrane material and duration of air-liquid interface culture had no marked effect on mucus production and tightness of the cell monolayer. Co-application of budesonide and formoterol, applied in solution or as aerosol, increased permeation of formoterol across cells in air-liquid interface culture. Problems with the DP-4 Dry Powder Insufflator included compound-specific delivery rates and influence on the tightness of the cell monolayer. These problems were not encountered with the MicroSprayer IA-1C Aerosolizer. The combination of Calu-3 cells and manual aerosol generation devices appears suitable to identify interactions of drugs in fixed drug combination products on permeation.

  10. Computer-aided drug design to explore cyclodextrin therapeutics and biomedical applications.

    Science.gov (United States)

    Abdolmaleki, Azizeh; Ghasemi, Fatemeh; Ghasemi, Jahan B

    2017-02-01

    Cyclodextrin (CD) is a subset of the macrocyclic structural class, which is an important class of small organic agents that are useful functional excipients. They have wide range application possibilities in different fields of sciences such as material preparation, medicine, analytical chemistry, and separation processes. They are used widely in pharmaceutical formulations and drug delivery for increasing the water solubility of low soluble drugs and drug candidates. Due to the ring structure, they behave differently than smaller molecules and may be capable of hitting new classes of targets. A macrocyclic molecule presents varied functionality and stereochemical complexity in a pre-organized conformation of the ring structure. This can result in high selectivity and affinity for protein targets while conserving enough bioavailability to arrive at intracellular locations. Regardless of these valuable features, and the verified success of several marketed macrocycle drugs isolated from natural compounds, this class has been little explored in drug development. This study describes some of the key features of the CDs therapeutic discovery. Also, the application of computational chemistry approaches such as QSAR/QSPR, molecular docking, and molecular/quantum mechanics for modeling of CD-drug system is reviewed briefly. © 2017 John Wiley & Sons A/S.

  11. Drug delivery to the nail: therapeutic options and challenges for onychomycosis.

    Science.gov (United States)

    Barot, Bhavesh S; Parejiya, Punit B; Patel, Hetal K; Mehta, Dharmik M; Shelat, Pragna K

    2014-01-01

    Onychomycosis is one of the most common nail disorders. It affects 10-30% of the world population and is caused by dermatophytes, non-dermatophytes, molds, and yeasts. Present treatment methods of onychomycosis include oral therapy, topical therapy, and a combination of both; they have mild-to-moderate efficacy, with a relapse and reinfection rate of 20-25%. For oral therapy, newer antifungal compounds (azole class and allylamine class) are being investigated to increase efficacy and minimize side effects. Oral therapy with antifungal agents have severe side effects, with lesser bioavailability and longer duration of treatment. By contrast, topical therapy of onychomycosis is associated with greater patient compliance and fewer systemic side effects and drug interactions. Current topical treatment options of onychomycosis are nail lacquers, ointments, lotions, solutions, and gels, but these formulations have been unsuccessful due to poor penetration and distribution of drugs at the infected site. Therefore, novel therapeutic options are constantly being researched to improve the efficacy of onychomycosis treatment by enhancing the permeation of the drug across the nail to reach the infected site. Various physical and chemical enhancement methods have been studied to increase the permeation of drugs across the nail plate to the nail bed. Device-based therapeutic options have also been investigated to increase the antifungal drug concentration and its effects in the onychomycotic nail. Randomized clinical trials of these novel therapies have demonstrated better efficacy. The present review discusses the anatomy of the human nail, onychomycosis and its types, onycholysis, and conventional and novel therapies. We also review patents granted as well as design challenges facing optimal drug formulation for onychomycosis treatment.

  12. Responding to the challenge of antimalarial drug resistance by routine monitoring to update national malaria treatment policies

    DEFF Research Database (Denmark)

    Vestergaard, Lasse S; Ringwald, Pascal

    2007-01-01

    additional information about changing patterns of resistance. However, some of the tests are technically demanding, and thus there is a need for more resources for training and capacity building in endemic countries to be able to adequately respond to the challenge of drug resistance....... of rational and updated malaria treatment policies, but defining and updating such policies requires a sufficient volume of high-quality drug-resistance data collected at national and regional levels. Three main tools are used for drug resistance monitoring, including therapeutic efficacy tests, in vitro...... tests, and analyses of molecular markers. Data obtained with the therapeutic efficacy test conducted according to the standard protocol of the World Health Organization are most useful for updating national treatment policies, while the in vitro test and molecular markers can provide important...

  13. Biosensing Probe for Quality Control Monitoring of the Structural Integrity of Therapeutic Antibodies.

    Science.gov (United States)

    Watanabe, Hideki; Yageta, Seiki; Imamura, Hiroshi; Honda, Shinya

    2016-10-18

    Ideal quality control of therapeutic antibodies involves analytical techniques with high-sensitivity, high-resolution, and high-throughput performance. Few technologies that assess the physicochemical heterogeneity of antibodies, however, meet all the required demands. We developed a biosensing method for the quality control of therapeutic antibodies based on an artificial protein, AF.2A1, which discriminates between the native and the non-native three-dimensional structures of immunoglobulin G (IgG). AF.2A1 specifically recognized non-native IgG spiked into a solution of native IgG, thereby making it possible to detect contamination by a small amount of non-native IgG, which is difficult using conventional size-based separation or spectroscopic techniques. Using AF.2A1 as an analytical probe, we determined the concentration of non-native IgG formed under various pH conditions. The probe was also applicable to accelerated tests of the long-term stability of a therapeutic antibody, allowing monitoring of the formation of non-native IgG at elevated temperatures and extended periods of storage. AF.2A1, a proteinous probe, can be combined with established methods or devices to achieve high-throughput assays and provides the potential for probe-based biosensing for the quality control of therapeutic antibodies.

  14. Systems pharmacology in drug discovery and therapeutic insight for herbal medicines.

    Science.gov (United States)

    Huang, Chao; Zheng, Chunli; Li, Yan; Wang, Yonghua; Lu, Aiping; Yang, Ling

    2014-09-01

    Systems pharmacology is an emerging field that integrates systems biology and pharmacology to advance the process of drug discovery, development and the understanding of therapeutic mechanisms. The aim of the present work is to highlight the role that the systems pharmacology plays across the traditional herbal medicines discipline, which is exemplified by a case study of botanical drugs applied in the treatment of depression. First, based on critically examined pharmacology and clinical knowledge, we propose a large-scale statistical analysis to evaluate the efficiency of herbs used in traditional medicines. Second, we focus on the exploration of the active ingredients and targets by carrying out complex structure-, omics- and network-based systematic investigations. Third, specific informatics methods are developed to infer drug-disease connections, with purpose to understand how drugs work on the specific targets and pathways. Finally, we propose a new systems pharmacology method, which is further applied to an integrated platform (Herbal medicine Systems Pharmacology) of blended herbal medicine and omics data sets, allowing for the systematization of current and traditional knowledge of herbal medicines and, importantly, for the application of this emerging body of knowledge to the development of new drugs for complex human diseases. © The Author 2013. Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  15. Efficient drug-delivery using magnetic nanoparticles--biodistribution and therapeutic effects in tumour bearing rabbits.

    Science.gov (United States)

    Tietze, Rainer; Lyer, Stefan; Dürr, Stephan; Struffert, Tobias; Engelhorn, Tobias; Schwarz, Marc; Eckert, Elisabeth; Göen, Thomas; Vasylyev, Serhiy; Peukert, Wolfgang; Wiekhorst, Frank; Trahms, Lutz; Dörfler, Arnd; Alexiou, Christoph

    2013-10-01

    To treat tumours efficiently and spare normal tissues, targeted drug delivery is a promising alternative to conventional, systemic administered chemotherapy. Drug-carrying magnetic nanoparticles can be concentrated in tumours by external magnetic fields, preventing the nanomaterial from being cleared by metabolic burden before reaching the tumour. Therefore in Magnetic Drug Targeting (MDT) the favoured mode of application is believed to be intra-arterial. Here, we show that a simple yet versatile magnetic carrier-system (hydrodynamic particles diameter recovery from all investigated tissues: tumour region: 57.2%, liver: 14.4%, kidneys: 15.2%. Systemic intra-venous application revealed different results: tumour region: 0.7%, liver: 14.4 % and kidneys: 77.8%. The therapeutic outcome was demonstrated by complete tumour remissions and a survival probability of 26.7% (P=0.0075). These results are confirming former pilot experiments and implying a milestone towards clinical studies. This team of investigators studied drug carrying nanoparticles for magnetic drug targeting (MDT), demonstrating the importance of intra-arterial administration resulting in improved clinical outcomes in the studied animal model compared with intra-venous. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Drug discovery and therapeutic delivery for the treatment of B and T cell tumors.

    Science.gov (United States)

    Stephenson, Regan; Singh, Ankur

    2017-05-15

    Hematological malignancies manifest as lymphoma, leukemia, and myeloma, and remain a burden on society. From initial therapy to endless relapse-related treatment, societal burden is felt not only in the context of healthcare cost, but also in the compromised quality of life of patients. Long-term therapeutic strategies have become the standard in keeping hematological malignancies at bay as these cancers develop resistance to each round of therapy with time. As a result, there is a continual need for the development of new drugs to combat resistant disease in order to prolong patient life, if not to produce a cure. This review aims to summarize advances in targeting lymphoma, leukemia, and myeloma through both cutting-edge and well established platforms. Current standard of treatment will be reviewed for these malignancies and emphasis will be made on new therapy development in the areas of antibody engineering, epigenetic small molecule inhibiting drugs, vaccine development, and chimeric antigen receptor cell engineering. In addition, platforms for the delivery of these and other drugs will be reviewed including antibody-drug conjugates, micro- and nanoparticles, and multimodal hydrogels. Lastly, we propose that tissue engineered constructs for hematological malignancies are the missing link in targeted drug discovery alongside mouse and patient-derived xenograft models. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Differences in abuse potential of ADHD drugs measured by contrasting poison centre and therapeutic use data

    DEFF Research Database (Denmark)

    Jensen, Louise; Pagsberg, Anne Katrine; Dalhoff, Kim Peder

    2015-01-01

    CONTEXT: Atomoxetine (ATX) is the treatment of choice for attention deficit hyperactivity disorders with co-morbid risk of drug abuse, although its abuse potential needs to be qualified. The purpose of this study is to analyse ATX misuse in relation to therapeutic use and compare our results...... with that of methylphenidate (MPH). METHODS AND MATERIALS: Data on enquiries were extracted from the Danish Poison Information Centre database (January 2006 to June 2012), while data on therapeutic use were provided by the Danish State Serum Institute (2007-2011). RESULTS: The study included 28 ATX and 394 MPH enquiries....... Frequency of ATX enquiries did not show a significant correlation to either sale or number of treated patients but for MPH, both correlations were significant (p = 0.001 and p = 0.0008, respectively). The enquiries/number of treated patients relationship differed significantly between ATX and MPH (p = 0...

  18. DREADDs (designer receptors exclusively activated by designer drugs): chemogenetic tools with therapeutic utility.

    Science.gov (United States)

    Urban, Daniel J; Roth, Bryan L

    2015-01-01

    In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein-coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). As we show in this review, DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. Results from these studies have directly implicated GPCR signaling in a large number of therapeutically relevant contexts. We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics.

  19. Applications of biosensing atomic force microscopy in monitoring drug and nanoparticle delivery.

    Science.gov (United States)

    Lamprecht, Constanze; Hinterdorfer, Peter; Ebner, Andreas

    2014-08-01

    The therapeutic effects of medicinal drugs not only depend on their properties, but also on effective transport to the target receptor. Here we highlight recent developments in this discipline and show applications of atomic force microscopy (AFM) that enable us to track the effects of drugs and the effectiveness of nanoparticle delivery at the single molecule level. Physiological AFM imaging enables visualization of topographical changes to cells as a result of drug exposure and allows observation of cellular responses that yield morphological changes. When we upgrade the regular measuring tip to a molecular biosensor, it enables investigation of functional changes at the molecular level via single molecule force spectroscopy. Biosensing AFM techniques have generated powerful tools to monitor drug delivery in (living) cells. While technical developments in actual AFM methods have simplified measurements at relevant physiological conditions, understanding both the biological and technical background is still a crucial factor. However, due to its potential impact, we expect the number of application-based biosensing AFM techniques to further increase in the near future.

  20. Adverse drug reactions monitoring of psychotropic drugs: a tertiary care centre study

    Directory of Open Access Journals (Sweden)

    Hemendra Singh

    2017-06-01

    Full Text Available Background: Many new psychotropic drugs/ agents have been developed and found to be effective in the treatment of psychiatric disorders. However, these drugs also exhibit adverse drug reactions (ADRs which may affect compliance in psychiatric patients. Hence the present study was aimed at monitoring and assessing ADRs caused by psychotropic drugs. Methods: A hospital based prospective observational study was carried out in the psychiatry outpatient department of a tertiary care teaching hospital for the duration of six months. Two hundred and two patients were included in the study and ADRs were documented using a predesigned data collection form. The causality assessment was carried out as per the criteria of both the World Health Organization- Uppsala Monitoring Centre (WHO-UMC and Naranjo scale. Severity and predictability assessment of ADRs were also performed. Results: A total of 106 ADRs were observed during the study period with majority of them occurring in 25-35 years of age group (40.56%. Weight gain (18.86% followed by sedation (16.03% and insomnia (11.32% were found to be the commonest ADRs. Risperidone (19.8% and escitalopram (12.3% were the drugs responsible for majority of the ADRs. Causality assessment showed that most of ADRs were possible and probable. 94.33% of ADRs were found to be mild and 89% of them were predictable. Conclusion: A wide range of ADRs affecting central nervous and metabolic systems were reported with psychotropic drugs. The study findings necessitate the need for an active pharmacovigilance programme for the safe and effective use of psychotropics.

  1. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment.

    Science.gov (United States)

    Yoshida, Go J

    2017-03-09

    The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy-lysosome flux leads to endoplasmic reticulum (ER) stress and an unfolded protein response (UPR), which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a "double-edged sword" for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that "conventional" agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development strategy has attracted increasing

  2. Bioinspired therapeutic dendrimers as efficient peptide drugs based on supramolecular interactions for tumor inhibition.

    Science.gov (United States)

    Zhang, Xiao; Zhang, Zhijun; Xu, Xianghui; Li, Yunkun; Li, Yachao; Jian, Yeting; Gu, Zhongwei

    2015-03-27

    Bioinspired tryptophan-rich peptide dendrimers (TRPDs) are designed as a new type of dendritic peptide drugs for efficient tumor therapy. The TRPDs feature a precise molecular structure and excellent water solubility and are obtained in a facile process. Based on the unique features of peptide dendrimers, including highly branched structures, abundant terminal groups, and globular-protein-like architectures, the therapeutic dendrimers show significant supramolecular interactions with DNA through the tryptophan residues (indole rings and amino groups). Further experimental results indicate that TRPDs are efficient antitumor agents both in vitro and in vivo. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  3. Therapeutic strategies of drug repositioning targeting autophagy to induce cancer cell death: from pathophysiology to treatment

    Directory of Open Access Journals (Sweden)

    Go J. Yoshida

    2017-03-01

    Full Text Available Abstract The 2016 Nobel Prize in Physiology or Medicine was awarded to the researcher that discovered autophagy, which is an evolutionally conserved catabolic process which degrades cytoplasmic constituents and organelles in the lysosome. Autophagy plays a crucial role in both normal tissue homeostasis and tumor development and is necessary for cancer cells to adapt efficiently to an unfavorable tumor microenvironment characterized by hypo-nutrient conditions. This protein degradation process leads to amino acid recycling, which provides sufficient amino acid substrates for cellular survival and proliferation. Autophagy is constitutively activated in cancer cells due to the deregulation of PI3K/Akt/mTOR signaling pathway, which enables them to adapt to hypo-nutrient microenvironment and exhibit the robust proliferation at the pre-metastatic niche. That is why just the activation of autophagy with mTOR inhibitor often fails in vain. In contrast, disturbance of autophagy–lysosome flux leads to endoplasmic reticulum (ER stress and an unfolded protein response (UPR, which finally leads to increased apoptotic cell death in the tumor tissue. Accumulating evidence suggests that autophagy has a close relationship with programmed cell death, while uncontrolled autophagy itself often induces autophagic cell death in tumor cells. Autophagic cell death was originally defined as cell death accompanied by large-scale autophagic vacuolization of the cytoplasm. However, autophagy is a “double-edged sword” for cancer cells as it can either promote or suppress the survival and proliferation in the tumor microenvironment. Furthermore, several studies of drug re-positioning suggest that “conventional” agents used to treat diseases other than cancer can have antitumor therapeutic effects by activating/suppressing autophagy. Because of ever increasing failure rates and high cost associated with anticancer drug development, this therapeutic development

  4. HOW PARENTS OF TEENS STORE AND MONITOR PRESCRIPTION DRUGS IN THE HOME*

    OpenAIRE

    Friese, Bettina; Moore, Roland S; Grube, Joel W.; Jennings, Vanessa K.

    2013-01-01

    Qualitative interviews were conducted with parents of teens to explore how parents store and monitor prescription drugs in the home. Most parents had prescription drugs in the house, but took few precautions against teens accessing these drugs. Strategies for monitoring included moving the drugs to different locations, remembering how many pills were left, and how medication containers were positioned. Reasons given for not securing drugs were that parents did not think that their teens would...

  5. Alters Intratumoral Drug Distribution and Affects Therapeutic Synergy of Antiangiogenic Organoselenium Compound

    Directory of Open Access Journals (Sweden)

    Youcef M. Rustum

    2010-01-01

    Full Text Available Tumor differentiation enhances morphologic and microvascular heterogeneity fostering hypoxia that retards intratumoral drug delivery, distribution, and compromise therapeutic efficacy. In this study, the influence of tumor biologic heterogeneity on the interaction between cytotoxic chemotherapy and selenium was examined using a panel of human tumor xenografts representing cancers of the head and neck and lung along with tissue microarray analysis of human surgical samples. Tumor differentiation status, microvessel density, interstitial fluid pressure, vascular phenotype, and drug delivery were correlated with the degree of enhancement of chemotherapeutic efficacy by selenium. Marked potentiation of antitumor activity was observed in H69 tumors that exhibited a well-vascularized, poorly differentiated phenotype. In comparison, modulation of chemotherapeutic efficacy by antiangiogenic selenium was generally lower or absent in well-differentiated tumors with multiple avascular hypoxic, differentiated regions. Tumor histomorphologic heterogeneity was found prevalent in the clinical samples studied and represents a primary and critical physiological barrier to chemotherapy.

  6. Production of Electrospun Fast-Dissolving Drug Delivery Systems with Therapeutic Eutectic Systems Encapsulated in Gelatin.

    Science.gov (United States)

    Mano, Francisca; Martins, Marta; Sá-Nogueira, Isabel; Barreiros, Susana; Borges, João Paulo; Reis, Rui L; Duarte, Ana Rita C; Paiva, Alexandre

    2017-02-24

    Fast-dissolving delivery systems (FDDS) have received increasing attention in the last years. Oral drug delivery is still the preferred route for the administration of pharmaceutical ingredients. Nevertheless, some patients, e.g. children or elderly people, have difficulties in swallowing solid tablets. In this work, gelatin membranes were produced by electrospinning, containing an encapsulated therapeutic deep-eutectic solvent (THEDES) composed by choline chloride/mandelic acid, in a 1:2 molar ratio. A gelatin solution (30% w/v) with 2% (v/v) of THEDES was used to produce electrospun fibers and the experimental parameters were optimized. Due to the high surface area of polymer fibers, this type of construct has wide applicability. With no cytotoxicity effect, and showing a fast-dissolving release profile in PBS, the gelatin fibers with encapsulated THEDES seem to have promising applications in the development of new drug delivery systems.

  7. VALUE OF THERAPEUTIC EQUIVALENCE IN SUBSTITUTION OF ORIGINAL DRUG WITH GENERIC BY EXAMPLE OF FOSINIPRIL

    Directory of Open Access Journals (Sweden)

    N. P. Kutishenko

    2011-01-01

    Full Text Available Aim. To study the therapeutic equivalence of original and generic fosinopril in patients with arterial hypertension (HT of 1-2 degrees, and to evaluate the cost effectiveness of original drug substitution with generic. Material and methods. Patients (n=36 with HT of 1-2 degree aged 41-82 years and disease duration up 3 to 22 years included in an open, crossover , randomized trial. All patients had two courses of treatment: with generic (Fosicard and the original drug (Monopril; sequence of courses was determined by randomization. Wash-out period (10-14 days preceded each course. Treatment duration was 6 weeks; drugs were administered QD; initial dose - 10 mg/day. Blood pressure (BP and heart rate (HR were evaluated at the end of the wash-out period, and in 2, 4 and 6 weeks of therapy. In case of ineffective BP control (>140/90 mm Hg hydrochlorothiazide 12.5 mg was added initially and dose fosinopril was increased up to 20 mg/day next. Results. Patients in groups were comparable by basic clinical parameters. Both fosinopril based drugs have comparable antihypertensive effect. Differences between their effect on systolic and diastolic BP as well as HR at all steps of treatment were not significant. The individual analysis revealed a tendency to more pronounced Monopril antihypertensive effect compared with Fosicard, but the differences were not significant. An average dose of Monopril was 11.8±3.9 mg/day , and Fosicard — 13.2±4.7 mg/day (p=0.13; the rate of monotherapy with both drugs of fosinopril at dose of 10 mg/day was similar (in 41% and 44% of patients, respectively; the rate of combined therapies with various composition differed insignificantly. Reduction in BP <140/90 mmHg was recorded at the end of the study in 29 (85.3% patients treated with Monorpil and in 27 (79.4% — Fosicard (p=0.52. Both drugs showed a good safety profile. Conclusion. Fosicard or its combination with hydrochlorothiazide is therapeutically equivalent to

  8. Therapeutic drugs during healing after myocardial infarction modify infarct collagens and ventricular distensibility at elevated pressures.

    Science.gov (United States)

    Jugdutt, Bodh I; Idikio, Halliday; Uwiera, Richard R E

    2007-10-01

    We investigated whether therapeutic drugs given during healing following acute myocardial infarction (AMI) modify infarct collagens and left ventricular (LV) distensibility. We treated dogs with drugs from major classes (i.e., indomethacin, ibuprofen, captopril, enalapril, verapamil, amlodipine, propranolol, isosorbide dinitrate [ISDN] and digoxin) between day 2 and 6 weeks and measured hemodynamics, LV remodeling and function during healing over 6 weeks after transmural anterior AMI, and regional collagens, LV distensibility under increasing pressure, rupture threshold (RT), and topography at 6 weeks. Relative to sham, AMI controls showed infarct zone (IZ) expansion and thinning, 9.3-fold increase in IZ collagen, LV dilation and dysfunction, and no change in distensibility and RT. Relative to controls, indomethacin as well as enalapril, captopril and amlodipine decreased IZ collagen. Infarct expansion was attenuated by ibuprofen, captopril, amlodipine and ISDN but augmented by indomethacin. Infarct thinning was prevented by captopril, amlodipine and ISDN but enhanced by indomethacin. Importantly, indomethacin and enalapril enhanced LV distensibility and lowered RT. Distensibility correlated positively with IZ type III collagen and negatively with type I/III collagen ratio and pyridinoline cross-links whereas RT correlated positively with IZ type I collagen. Systolic volume and ejection fraction deteriorated with indomethacin but were improved or preserved with other therapies. The results demonstrate that different therapeutic drugs may produce different effects on IZ collagens during healing post-AMI: drugs that attenuate or adversely alter IZ collagens also enhance LV distensibility, augment adverse remodeling and lower RT, suggesting that testing for these effects post-AMI is warranted.

  9. Therapeutic Approaches to Genetic Ion Channelopathies and Perspectives in Drug Discovery.

    Science.gov (United States)

    Imbrici, Paola; Liantonio, Antonella; Camerino, Giulia M; De Bellis, Michela; Camerino, Claudia; Mele, Antonietta; Giustino, Arcangela; Pierno, Sabata; De Luca, Annamaria; Tricarico, Domenico; Desaphy, Jean-Francois; Conte, Diana

    2016-01-01

    In the human genome more than 400 genes encode ion channels, which are transmembrane proteins mediating ion fluxes across membranes. Being expressed in all cell types, they are involved in almost all physiological processes, including sense perception, neurotransmission, muscle contraction, secretion, immune response, cell proliferation, and differentiation. Due to the widespread tissue distribution of ion channels and their physiological functions, mutations in genes encoding ion channel subunits, or their interacting proteins, are responsible for inherited ion channelopathies. These diseases can range from common to very rare disorders and their severity can be mild, disabling, or life-threatening. In spite of this, ion channels are the primary target of only about 5% of the marketed drugs suggesting their potential in drug discovery. The current review summarizes the therapeutic management of the principal ion channelopathies of central and peripheral nervous system, heart, kidney, bone, skeletal muscle and pancreas, resulting from mutations in calcium, sodium, potassium, and chloride ion channels. For most channelopathies the therapy is mainly empirical and symptomatic, often limited by lack of efficacy and tolerability for a significant number of patients. Other channelopathies can exploit ion channel targeted drugs, such as marketed sodium channel blockers. Developing new and more specific therapeutic approaches is therefore required. To this aim, a major advancement in the pharmacotherapy of channelopathies has been the discovery that ion channel mutations lead to change in biophysics that can in turn specifically modify the sensitivity to drugs: this opens the way to a pharmacogenetics strategy, allowing the development of a personalized therapy with increased efficacy and reduced side effects. In addition, the identification of disease modifiers in ion channelopathies appears an alternative strategy to discover novel druggable targets.

  10. Therapeutic effects of orally administrated antioxidant drugs on acute noise-induced hearing loss.

    Science.gov (United States)

    Choi, C-H; Du, X; Floyd, R A; Kopke, R D

    2014-03-01

    The objective of this study was to investigate the dose-dependent therapeutic effect of the orally administrated antioxidant drugs [4-hydroxy alpha-phenyl-tert-butylnitrone (4-OHPBN) and N-acetyl-L-cysteine (NAC)] on acute noise-induced hearing loss because oral administration is the most commonly used method of drug administration due to its convenience, safety, and economical efficiency. Thirty chinchilla were exposed to a 105 dB octave band noise centered at 4 kHz for 6 h and randomly assigned to a control group (saline only) and three experimental groups [4-OHPBN (10 mg/kg) plus NAC (20 mg/kg), 4-OHPBN (20 mg/kg) plus NAC (50 mg/kg), and 4-OHPBN (50 mg/kg) plus NAC (100 mg/kg)]. The drugs were orally administrated beginning 4 h after noise exposure and then administered twice daily for the next 2 days. Permanent auditory brainstem response threshold shifts, distortion product otoacoustic emission threshold shifts, and the percentage of missing outer hair cell were determined. The oral administration significantly reduced permanent hearing threshold shift, distortion product otoacoustic emission threshold shift, and the percentage of missing outer hair cell in a dose-dependent manner. This result demonstrates that orally administered drugs can treat acute noise-induced hearing loss in a dose-dependent manner. This suggests that oral administration was effective in treating acute noise-induced hearing loss as in intraperitoneal administration.

  11. Sources and Targets for Drug Repurposing: Landscaping Transitions in Therapeutic Space.

    Science.gov (United States)

    Mucke, Hermann A M; Mucke, Eva

    2015-01-01

    Patent applications provide unique opportunities for landscaping ongoing medical innovation. In this analysis of drug repurposing patent applications published under the international Patent Convention Treaty during the years 2011-2014, we discuss what categories in the World Health Organization's International Classification of Diseases provide drugs and drug candidates for potential second medical uses, and how these proposed repurposed uses relate to each other and the original ones. Also discussed are the geographic origin of the patent assignees and their type and size. Beyond the expected interactions within the field of neuropsychiatry, frequent secondary use claims for oncology compounds to treat noninfectious respiratory diseases, and for cardiovascular compounds to treat neurological conditions, were unexpected findings derived from the repurposing heatmap. The relative absence of repurposing claims to treat parasitic or tropical diseases contrasts sharply with the broad attention this segment receives in the peer-reviewed literature. Equally notable are the dominance of universities and small pharmaceutical companies; a focus of large multinational companies to repurpose their own compounds; and the leading role of European-centered entities among the assignees. We believe that this investigation represents the first comprehensive cross-sectional attempt at mapping drug repurposing patterns across therapeutic fields, and could provide important clues that complement those obtained from the peer-reviewed literature.

  12. Clinical pharmacology and therapeutic uses of non-steroidal anti-inflammatory drugs in the horse.

    Science.gov (United States)

    Lees, P; Higgins, A J

    1985-03-01

    Weak organic acids possessing anti-inflammatory, analgesic and antipyretic properties--commonly known as aspirin-like drugs--have been used in equine medicine for almost 100 years. These non-steroidal anti-inflammatory drugs (NSAIDs) may be classified chemically into two groups; the enolic acids such as phenylbutazone and carboxylic acids like flunixin, meclofenamate and naproxen. All NSAIDs have similar and possibly identical modes of action accounting for both their therapeutic and their toxic effects. They block some part of the cyclo-oxygenase enzyme pathway and thereby suppress the synthesis of several chemical mediators of inflammation, collectively known as eicosanoids. The available evidence indicates that some of the newer NSAIDs have a reasonable safety margin but further studies are required. The toxicity of phenylbutazone in the horse has been investigated very thoroughly in recent years and it has been shown to cause renotoxicity and, most significantly, ulceration of the gastrointestinal tract when relatively high doses are administered. Several factors may predispose towards phenylbutazone toxicity in the horse, including breed and age, but high dosage is considered to be particularly important. The absorption into, and fate within, the body of NSAIDs are considered and particular attention is drawn to the ways in which these pharmacokinetic properties relate to the drugs' toxicity and clinical efficacy. In reviewing current knowledge of the clinical pharmacology of this important group of drugs, it is hoped to provide the clinician with a rational, scientific basis for their safe and effective use in equine practice.

  13. Therapeutic effects of acetylspiramycin and garlicin on cryptosporidiosis among drug users

    Directory of Open Access Journals (Sweden)

    Min-Zhu Huang

    2015-12-01

    Full Text Available Cryptosporidiosis affects humans of all ages, particularly malnourished children and those with compromised immune systems such as HIV/AIDS. This study investigated the therapeutic effects of acetylspiramycin and garlicin on Cryptosporidium infection in institutionalized male drug users receiving rehabilitative treatment. Examination of stool specimens from 903 drug users via modified acid-fast bacilli staining resulted in 172 positive cases. Among them 151 subjects consented to participate in a randomized trial of acetylspiramycin and garlicin in four groups: acetylspiramycin plus garlicin, acetylspiramycin only, garlicin only, and placebo control. The cryptosporidiosis rate was higher in younger subjects with longer drug use history than subjects who are older with shorter history of drug use. After two segments of treatments, 76.2% of the cases achieved negative test results, with the four groups achieving the rates of 92.1%, 76.7%, 72.2%, and 61.8%, respectively (χ2 = 9.517, P = 0.023. These results indicate clinical potential of garlicin in conjunction with acetylspiramycin in treating cryptosporidiosis.

  14. Drug delivery from therapeutic self-assembled monolayers (T-SAMs) on 316L stainless steel.

    Science.gov (United States)

    Mahapatro, Anil; Johnson, Dave M; Patel, Devang N; Feldman, Marc D; Ayon, Arturo A; Agrawal, C Mauli

    2008-01-01

    Delivery of therapeutic agents from self-assembled monolayers (SAMs) on 316L stainless steel (SS) has been demonstrated as a viable method to deliver drugs for localized coronary artery stent application. SAMs are highly-ordered, nano-sized molecular coatings, adding 1-10 nm thickness to a surface. Hydroxyl terminated alkanethiol SAMs of 11-mercapto-1-undecanol (-OH SAM) were formed on 316L SS with 48 hr immersion in ethanolic solutions. Attachment of ibuprofen (a model drug) to the functional SAMs was carried out in toluene for 5 hrs at 60 degrees C using Novozume-435 as a biocatalyst. SAM formation and subsequent attachment of ibuprofen was characterized collectively using X-ray photoelectron spectroscopy (XPS), Fourier transform infrared spectroscopy (FTIR), and contact angle (CA) measure-ments. The quantitative in vitro release of ibuprofen into a "physiological" buffer solution was characterized using reverse phase HPLC. Drug release kinetics showed that 14.1 microg of ibuprofen eluted over a period of 35 days with 2.7microg being eluted in the first day and the remaining being eluted over a period of 35 days. The drug release kinetics showed an increase in ibuprofen elution that occurred during first 14 days (2.7microg in 1 day to 9.5 microg in 14 days), following which there was a decrease in the rate of elution. Thus, functional SAMs on 316L SS could be used as tethers for drug attachment and could serve as a drug delivery mechanism from stainless steel implants such as coronary artery stents.

  15. PARENTING QUALITY IN DRUG-ADDICTED MOTHERS IN A THERAPEUTIC MOTHER-CHILD COMMUNITY: THE CONTRIBUTION OF ATTACHMENT AND PERSONALITY ASSESSMENT

    Directory of Open Access Journals (Sweden)

    Francesca eDe Palo

    2014-09-01

    Full Text Available Growing evidence shows that attachment is a key risk factor for the diagnosis and treatment of clinical diseases in Axis I, such as drug addiction. Recent literature regarding attachment, psychiatric pathology and drug addiction demonstrates that there is a clear prevalence of insecure attachment patterns in clinical and drug addicted subjects. Specifically, some authors emphasize that the anxious-insecure attachment pattern is prevalent among drug-addicted women with double diagnosis (Fonagy et al., 1996. The construct of attachment as a risk factor in clinical samples of drug-addicted mothers needs to be studied more in depth though. The present explorative study focused on the evaluation of parenting quality in a therapeutic mother-child community using attachment and personality assessment tools able to outline drug-addicted mothers’ profiles. This study involved 30 drug addicted mothers, inpatients of a therapeutic community. Attachment representations were assessed via the Adult Attachment Interview; personality diagnosis and symptomatic profiles were performed using the Structured Clinical Interview of the DSM-IV (SCID-II and the Symptom Check List-90-R (SCL-90-R respectively. Both instruments were administered during the first six months of residence in a therapeutic community. Results confirmed the prevalence of insecure attachment representations (90%, with a high presence of U patterns, prevalently scored for dangerous and/or not protective experiences in infanthood. Very high values (>5 were found for some experience scales (i.e. neglect and rejection scales. Data also showed very low values (1-3 in metacognitive monitoring, coherence of transcript and coherence of mind scales. Patients’ different profiles (U vs. E vs. Ds were linked to SCID-II diagnosis, providing insightful indications both for treatment planning and intervention on parenting functions and for deciding if to start foster care or adoption proceedings for

  16. Albumin Nanocarriers, γ- Irradiated Crosslinked, Combined with Therapeutic Drugs for Cancer Therapy>.

    Science.gov (United States)

    Siri, Macarena; Achilli, Estefania; Grasselli, Mariano; Del V Alonso, Silvia

    2017-01-01

    Albumin polymeric Nanoparticles (NPs) have opened a great expectancy as for controlled drug delivery due to their therapeutic potency. Concomitantly biodegradable NPs technologies with target linked structures to pave the way of personalised medicine are becoming increasingly important in sight of a therapeutically effective research technology. This is particularly attractive for nanoparticle-based cancer delivery systems, based on the known limitations and efforts to overcome. This new group of gamma irradiated-NPs inherited both the protein delivery properties and robustness of polymer forming structures, and gamma irradiation techniques that leave clean, innocuous and biodegradable NPs. These protein NPs made of serum albumin are referred to SA NPs that possesses several characteristics making them especially attractive to be considered as a drug delivery system. This review focused on methodologies actually being used in the synthesis and characterisation of albumin NPs and different author's opinions on strategic ways to treat cancerous cell-lines with NPs. Utterly, challenges being overthrown by researchers are brought up to anneal an effective, all in one targeted albumin NPs to passed through in vitro and preclinical trials. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Therapeutic Potential of Plants as Anti-Microbials for Drug Discovery

    Directory of Open Access Journals (Sweden)

    Ramar Perumal Samy

    2010-01-01

    Full Text Available The uses of traditional medicinal plants for primary health care have steadily increased worldwide in recent years. Scientists are in search of new phytochemicals that could be developed as useful anti-microbials for treatment of infectious diseases. Currently, out of 80% of pharmaceuticals derived from plants, very few are now being used as anti-microbials. Plants are rich in a wide variety of secondary metabolites that have found anti-microbial properties. This review highlights the current status of traditional medicine, its contribution to modern medicine, recent trends in the evaluation of anti-microbials with a special emphasis upon some tribal medicine, in vitro and in vivo experimental design for screening, and therapeutic efficacy in safety and human clinical trails for commercial outlet. Many of these commercially available compounds are crude preparations administered without performing human clinical trials. Recent methods are useful to standardize the extraction for scientific investigation of new phytochemicals and anti-microbials of traditionally used plants. It is concluded that once the local ethnomedical preparations of traditional sources are scientifically evaluated before dispensing they should replace existing drugs commonly used for the therapeutic treatment of infection. This method should be put into practice for future investigations in the field of ethnopharmacology, phytochemistry, ethnobotany and other biological fields for drug discovery.

  18. Dental implants modified with drug releasing titania nanotubes: therapeutic potential and developmental challenges.

    Science.gov (United States)

    Gulati, Karan; Ivanovski, Sašo

    2017-08-01

    The transmucosal nature of dental implants presents a unique therapeutic challenge, requiring not only rapid establishment and subsequent maintenance of osseointegration, but also the formation of resilient soft tissue integration. Key challenges in achieving long-term success are sub-optimal bone integration in compromised bone conditions and impaired trans-mucosal tissue integration in the presence of a persistent oral microbial biofilm. These challenges can be targeted by employing a drug-releasing implant modification such as TiO 2 nanotubes (TNTs), engineered on titanium surfaces via electrochemical anodization. Areas covered: This review focuses on applications of TNT-based dental implants towards achieving optimal therapeutic efficacy. Firstly, the functions of TNT implants will be explored in terms of their influence on osseointegration, soft tissue integration and immunomodulation. Secondly, the developmental challenges associated with such implants are reviewed including sterilization, stability and toxicity. Expert opinion: The potential of TNTs is yet to be fully explored in the context of the complex oral environment, including appropriate modulation of alveolar bone healing, immune-inflammatory processes, and soft tissue responses. Besides long-term in vivo assessment under masticatory loading conditions, investigating drug-release profiles in vivo and addressing various technical challenges are required to bridge the gap between research and clinical dentistry.

  19. [Therapeutic effect of early applying hydrotherapy with Chinese drugs on children hypoxic ischemic encephalopathy].

    Science.gov (United States)

    Ma, Yun-Zhi; Zhai, Hong-Yin; Su, Chun-Ya

    2009-02-01

    To observe the therapeutic effect of hydrotherapy with Chinese drugs (HT-C) in early intervention on children hypoxic ischemic encephalopathy (HIE). HIE children were assigned to the treatment group and the control group, 50 in each, at random depending on the willingness of patients' parents. Both groups received the conventional functional training, according to the "0 -3-year-old early intervention outline", but for the treatment group, HT-C was applied additionally. Indexes for quality of sleep, gross motor function, severity of spasm and intellectual development were observed and compared before and after treatment to assess the therapeutic effects. Therapeutic effect in the treatment group was better than that in the control group in all the indexes observed, showing statistical significance (all P <0.05). Early intervention of HT-C could improve clinical symptom, promote the functional recovery and intellectual development in children HIE, and also could reduce or prevent the sequelae occurrence of the nervous system in them.

  20. Human Disease Models in Drosophila melanogaster and the Role of the Fly in Therapeutic Drug Discovery

    Science.gov (United States)

    Pandey, Udai Bhan

    2011-01-01

    The common fruit fly, Drosophila melanogaster, is a well studied and highly tractable genetic model organism for understanding molecular mechanisms of human diseases. Many basic biological, physiological, and neurological properties are conserved between mammals and D. melanogaster, and nearly 75% of human disease-causing genes are believed to have a functional homolog in the fly. In the discovery process for therapeutics, traditional approaches employ high-throughput screening for small molecules that is based primarily on in vitro cell culture, enzymatic assays, or receptor binding assays. The majority of positive hits identified through these types of in vitro screens, unfortunately, are found to be ineffective and/or toxic in subsequent validation experiments in whole-animal models. New tools and platforms are needed in the discovery arena to overcome these limitations. The incorporation of D. melanogaster into the therapeutic discovery process holds tremendous promise for an enhanced rate of discovery of higher quality leads. D. melanogaster models of human diseases provide several unique features such as powerful genetics, highly conserved disease pathways, and very low comparative costs. The fly can effectively be used for low- to high-throughput drug screens as well as in target discovery. Here, we review the basic biology of the fly and discuss models of human diseases and opportunities for therapeutic discovery for central nervous system disorders, inflammatory disorders, cardiovascular disease, cancer, and diabetes. We also provide information and resources for those interested in pursuing fly models of human disease, as well as those interested in using D. melanogaster in the drug discovery process. PMID:21415126

  1. Educating Pharmacists on a Prescription Drug Monitoring Program.

    Science.gov (United States)

    Fleming, Marc L; Phan, Yen; Ferries, Erin A; Hatfield, Mark D

    2016-12-01

    To provide education to community pharmacists regarding the registration and use of the Texas prescription drug monitoring program (PDMP) and to assess the impact of the education on pharmacists' perceptions of the PDMP. The study design was a descriptive, pre and post, cross-sectional survey conducted among community pharmacists attending a PDMP education program. The program was designed to present the PDMP as a public health tool available to assist pharmacists with dispensing decisions related to controlled prescription drugs. Of the 24 pharmacists who completed the survey, 23 were already registered to use the PDMP. However, all 23 felt that the program successfully educated users regarding the PDMP and agreed that other community pharmacists would benefit from the program presented. After the program, 14 participants responded they would very likely use the PDMP in the next 30 days. Recognition of the use of PDMPs as a program for both pharmacists and physicians was increased from 12.5% (pre) to 73.9% (post). Pharmacists found the educational program beneficial and they were very likely to use the PDMP in the future. Perceptions of the Texas PDMP were changed from pre- to post-education program, with recognition that a PDMP can be a beneficial tool for pharmacy practice. © The Author(s) 2015.

  2. "We are people too": consumer participation and the potential transformation of therapeutic relations within drug treatment.

    Science.gov (United States)

    Rance, Jake; Treloar, Carla

    2015-01-01

    While there is growing recognition of the benefits of user involvement within drug treatment there is scant literature documenting the actual implementation of such initiatives. Nonetheless, the extant research is remarkably consistent in identifying poor relationships between service users and staff as a principal barrier to the successful implementation of consumer participation. Focussing on participants' accounts of change within the 'therapeutic alliance', this paper investigates a consumer participation initiative introduced within three Australian drug treatment services. In 2012, the New South Wales Users and AIDS Association (NUAA), a state-based drug user organisation, introduced a consumer participation initiative within three treatment facilities across the state. This paper draws on 57 semi-structured interviews with staff and service-user project participants. Approximately ten participants from each site were recruited and interviewed at baseline and six months later at evaluation. The enhanced opportunities for interaction enabled by the consumer participation initiative fostered a sense of service users and staff coming to know one another beyond the usual constraints and limitations of their relationship. Both sets of participants described a diminution of adversarial relations: an unsettling of the 'them and us' treatment divide. The routine separation of users and staff was challenged by the emergence of a more collaborative ethos of 'working together'. Participants noted 'seeing' one another--the other--differently; as people rather than simply an identity category. For service users, the opportunity to have 'a voice' began to disrupt the routine objectification or dehumanisation that consistently, if unintentionally, characterises the treatment experience. Having a voice, it seemed, was synonymous with being human, with having ones' 'humanness' recognised. We contend that not only did the introduction of consumer participation appear to

  3. The determinants of nurses' therapeutic attitude to patients who use illicit drugs and implications for workforce development.

    Science.gov (United States)

    Ford, Rosemary; Bammer, Gabriele; Becker, Niels

    2008-09-01

    To examine the determinants of generalist nurses' therapeutic attitude to patients who use illicit drugs, and to model workforce development initiatives. Individuals who use illicit drugs rely heavily on healthcare in emergency departments and inpatient hospital wards. Little is known about the determinants of generalist nurses' therapeutic attitude to provide care, therefore limiting our understanding of the important issues for workforce development. The study was a cross-sectional survey of registrants on the Australian Capital Territory Nurses Registration Roll 2002 (N = 3241, 50% response rate). The associations between variables and nurses' therapeutic attitude were examined by multi-variable linear regression analysis. Nurses' therapeutic attitude was assessed using a modified version of the Alcohol and Alcohol Problems Perception Questionnaire. Personal characteristics, attitudes to illicit drugs and professional practice variables such as drug and alcohol education, experience with the patient group and role support were examined using a mix of standardised and new questions. Professional practice variables explained 53% of the variation of nurses' therapeutic attitude, the most important being role support. Although a negative attitude to illicit drugs had a statistically significant association with therapeutic attitude, it added less than 1% to the variation explained. Personal characteristics showed no association. Generalist nurses struggle to provide care to this patient group. Role support was found to be the strongest driver of nurses' therapeutic attitude, and workplace illicit drug education was only useful in combination with high role support. Nurses' caring role with patients who use illicit drugs is complex and demanding. Nursing workforce development must focus on increasing nurses' role support, in terms of appropriately skilled staff readily available for consultation and advice. Support for nurses, in the form of evidence-based practice

  4. Tumor associated macrophages act as a slow-release reservoir of nano-therapeutic Pt(IV) pro-drug

    OpenAIRE

    Miller, Miles A.; Zheng, Yao-Rong; Gadde, Suresh; Pfirschke, Christina; Zope, Harshal; Engblom, Camilla; Kohler, Rainer H.; Iwamoto, Yoshiko; Yang, Katherine S.; Askevold, Bjorn; Kolishetti, Nagesh; Pittet, Mikael; Lippard, Stephen J.; Farokhzad, Omid C.; Weissleder, Ralph

    2015-01-01

    Therapeutic nanoparticles (TNPs) aim to deliver drugs more safely and effectively to cancers, yet clinical results have been unpredictable owing to limited in vivo understanding. Here we use single-cell imaging of intratumoral TNP pharmacokinetics and pharmacodynamics to better comprehend their heterogeneous behavior. Model TNPs comprised of a fluorescent platinum(IV) pro-drug and a clinically-tested polymer platform (PLGA-b-PEG) promote long drug circulation and alter accumulation by directi...

  5. Re-sensitizing drug-resistant bacteria to antibiotics by designing Antisense Therapeutics

    Science.gov (United States)

    Courtney, Colleen; Chatterjee, Anushree

    2014-03-01

    ``Super-bugs'' or ``multi-drug resistant organisms'' are a serious international health problem, with devastating consequences to patient health care. The Center for Disease Control has identified antibiotic resistance as one of the world's most pressing public health problems as a significant fraction of bacterial infections contracted are drug resistant. Typically, antibiotic resistance is encoded by ``resistance-genes'' which express proteins that carryout the resistance causing functions inside the bacterium. We present a RNA based therapeutic strategy for designing antimicrobials capable of re-sensitizing resistant bacteria to antibiotics by targeting labile regions of messenger RNAs encoding for resistance-causing proteins. We perform in silico RNA secondary structure modeling to identify labile target regions in an mRNA of interest. A synthetic biology approach is then used to administer antisense nucleic acids to our model system of ampicillin resistant Escherichia coli. Our results show a prolonged lag phase and decrease in viability of drug-resistant E. colitreated with antisense molecules. The antisense strategy can be applied to alter expression of other genes in antibiotic resistance pathways or other pathways of interest.

  6. P-glycoprotein trafficking as a therapeutic target to optimize CNS drug delivery.

    Science.gov (United States)

    Davis, Thomas P; Sanchez-Covarubias, Lucy; Tome, Margaret E

    2014-01-01

    The primary function of the blood-brain barrier (BBB)/neurovascular unit is to protect the central nervous system (CNS) from potentially harmful xenobiotic substances and maintain CNS homeostasis. Restricted access to the CNS is maintained via a combination of tight junction proteins as well as a variety of efflux and influx transporters that limits the transcellular and paracellular movement of solutes. Of the transporters identified at the BBB, P-glycoprotein (P-gp) has emerged as the transporter that is the greatest obstacle to effective CNS drug delivery. In this chapter, we provide data to support intracellular protein trafficking of P-gp within cerebral capillary microvessels as a potential target for improved drug delivery. We show that pain-induced changes in P-gp trafficking are associated with changes in P-gp's association with caveolin-1, a key scaffolding/trafficking protein that colocalizes with P-gp at the luminal membrane of brain microvessels. Changes in colocalization with the phosphorylated and nonphosphorylated forms of caveolin-1, by pain, are accompanied by dynamic changes in the distribution, relocalization, and activation of P-gp "pools" between microvascular endothelial cell subcellular compartments. Since redox-sensitive processes may be involved in signaling disassembly of higher-order structures of P-gp, we feel that manipulating redox signaling, via specific protein targeting at the BBB, may protect disulfide bond integrity of P-gp reservoirs and control trafficking to the membrane surface, providing improved CNS drug delivery. The advantage of therapeutic drug "relocalization" of a protein is that the physiological impact can be modified, temporarily or long term, despite pathology-induced changes in gene transcription. © 2014 Elsevier Inc. All rights reserved.

  7. A novel therapeutic design of microporous-structured biopolymer scaffolds for drug loading and delivery.

    Science.gov (United States)

    Dorj, Biligzaya; Won, Jong-Eun; Purevdorj, Odnoo; Patel, Kapil D; Kim, Joong-Hyun; Lee, Eun-Jung; Kim, Hae-Won

    2014-03-01

    Three-dimensional (3-D) open-channeled scaffolds of biopolymers are a promising candidate matrix for tissue engineering. When scaffolds have the capacity to deliver bioactive molecules the potential for tissue regeneration should be greatly enhanced. In order to improve drug-delivery capacity, we exploit 3-D poly(lactic acid) (PLA) scaffolds by creating microporosity within the scaffold network. Macroporous channeled PLA with a controlled pore configuration was obtained by a robotic dispensing technique. In particular, a room temperature ionic liquid (RTIL) bearing hydrophilic counter-anions, such as OTf and Cl, was introduced to the biopolymer solution at varying ratios. The RTIL-biopolymer slurry was homogenized by ultrasonication, and then solidified through the robotic dispensing process, during which the biopolymer and RTIL formed a bicontinuous interpenetrating network. After ethanol wash-out treatment the RTIL was completely removed to leave highly microporous open channels throughout the PLA network. The resultant pore size was observed to be a few micrometers (average 2.43 μm) and microporosity was determined to be ∼ 70%. The microporous surface was also shown to favor initial cell adhesion, stimulating cell anchorage on the microporous structure. Furthermore, in vivo tissue responses assessed in rat subcutaneous tissue revealed good tissue compatibility, with minimal inflammatory reactions, while gathering a larger population of fibroblastic cells than the non-microporous scaffolds, and even facilitating invasion of the cells within the microporous structure. The efficacy of the micropore networks generated within the 3-D scaffolds in loading and releasing therapeutic molecules was addressed using antibiotic sodium ampicillin and protein cytochrome C as model drugs. The microporous scaffolds exhibited significantly enhanced drug loading capacity: 4-5 times increase in ampicillin and 9-10 times increase in cytochrome C compared to the non

  8. Phytochemical-mediated Protein Expression Profiling and the Potential Applications in Therapeutic Drug Target Identifications.

    Science.gov (United States)

    Wong, Fai-Chu; Tan, Siok-Thing; Chai, Tsun-Thai

    2016-07-29

    Many phytochemicals derived from edible medicinal plants have been investigated intensively for their various bioactivities. However, the detailed mechanism and their corresponding molecular targets frequently remain elusive. In this review, we present a summary of the research works done on phytochemical-mediated molecular targets, identified via proteomic approach. Concurrently, we also highlighted some pharmaceutical drugs which could be traced back to their origins in phytochemicals. For ease of presentation, these identified protein targets were categorized into two important healthcare-related fields, namely anti-bacterial and anti-cancer research. Through this review, we hope to highlight the usefulness of comparative proteomic as a powerful tool in phytochemical-mediated protein target identifications. Likewise, we wish to inspire further investigations on some of these protein targets identified over the last few years. With contributions from all researchers, the accumulative efforts could eventually lead to the discovery of some target-specific, low-toxicity therapeutic agents.

  9. Recent Advances on Pathophysiology, Diagnostic and Therapeutic Insights in Cardiac Dysfunction Induced by Antineoplastic Drugs

    Directory of Open Access Journals (Sweden)

    Marilisa Molinaro

    2015-01-01

    Full Text Available Along with the improvement of survival after cancer, cardiotoxicity due to antineoplastic treatments has emerged as a clinically relevant problem. Potential cardiovascular toxicities due to anticancer agents include QT prolongation and arrhythmias, myocardial ischemia and infarction, hypertension and/or thromboembolism, left ventricular (LV dysfunction, and heart failure (HF. The latter is variable in severity, may be reversible or irreversible, and can occur soon after or as a delayed consequence of anticancer treatments. In the last decade recent advances have emerged in clinical and pathophysiological aspects of LV dysfunction induced by the most widely used anticancer drugs. In particular, early, sensitive markers of cardiac dysfunction that can predict this form of cardiomyopathy before ejection fraction (EF is reduced are becoming increasingly important, along with novel therapeutic and cardioprotective strategies, in the attempt of protecting cardiooncologic patients from the development of congestive heart failure.

  10. Use of an anti-viral drug, Ribavirin, as an anti-glioblastoma therapeutic.

    Science.gov (United States)

    Volpin, F; Casaos, J; Sesen, J; Mangraviti, A; Choi, J; Gorelick, N; Frikeche, J; Lott, T; Felder, R; Scotland, S J; Eisinger-Mathason, T S K; Brem, H; Tyler, B; Skuli, N

    2017-05-25

    The median survival for glioblastoma patients is ~15 months despite aggressive surgery and radio-chemotherapy approaches. Thus, developing new therapeutics is necessary to improve the treatment of these invasive brain tumors, which are known to show high levels of the eukaryotic initiation factor, eIF4E, a potent oncogene. Ribavirin, the only clinically approved drug known to target eIF4E, is an anti-viral molecule currently used in hepatitis C treatment. Here, we report the effect of ribavirin on proliferation, cell cycle, cell death and migration of several human and murine glioma cell lines, as well as human glioblastoma stem-like cells, in vitro. In addition, we tested ribavirin efficacy in vivo, alone and in combination with temozolomide and radiation. Our work showed that ribavirin inhibits glioma cell growth and migration, and increases cell cycle arrest and cell death, potentially through modulation of the eIF4E, EZH2 and ERK pathways. We also demonstrate that ribavirin treatment in combination with temozolomide or irradiation increases cell death in glioma cells. Finally and most importantly, ribavirin treatment in vivo significantly enhances chemo-radiotherapy efficacy and improves survival of rats and mice orthotopically implanted with gliosarcoma tumors or glioma stem-like cells, respectively. On the basis of these results, we propose that ribavirin represents a new therapeutic option for glioblastoma patients as an enhancer of the cytotoxic effects of temozolomide and radiotherapy.

  11. Peer and sexual relationships in the experience of drug-dependent adolescents in a therapeutic community.

    Science.gov (United States)

    Nathan, Sally; Foster, Michael; Ferry, Mark

    2011-07-01

    Evidence for success of adolescent treatment programs, including therapeutic communities, has been found among those who complete treatment. However, there is a lack of research examining peer relationships as part of treatment experience. Given the central role of 'community', including peers, as agents of change in therapeutic communities, there is a need to better understand peer relationships in treatment. This ethnographic study provides a window into the dynamics of adolescent relationships in a residential treatment program. Four months of participant observation, including 21 residents (15 male and 6 female) aged between 14 and 18 years-comprising all residents admitted during the study. All the data in this paper are from those who were 16 years or over. The data reveal the complex peer relationships that form for some residents. Peer groups were found to provide a space for residents to feel included but more often were a mechanism to ostracise or bully others. In contrast to past studies, our study found sexual activity was widespread, in particular among girls. A lack of sex caused frustrations for some and sexual encounters were found to coincide with overt conflict between residents. Treatment programs for adolescents need to more explicitly grapple with the complexity of resident's peer relationships, which may impact on treatment experience. Our study suggests sexual relationships may be common in treatment programs for adolescents and a cause of conflict. Further research about the mediating impact of peer relationships, including sexual relationships, is needed. © 2010 Australasian Professional Society on Alcohol and other Drugs.

  12. Inferences of drug responses in cancer cells from cancer genomic features and compound chemical and therapeutic properties

    Science.gov (United States)

    Wang, Yongcui; Fang, Jianwen; Chen, Shilong

    2016-09-01

    Accurately predicting the response of a cancer patient to a therapeutic agent is a core goal of precision medicine. Existing approaches were mainly relied primarily on genomic alterations in cancer cells that have been treated with different drugs. Here we focus on predicting drug response based on integration of the heterogeneously pharmacogenomics data from both cell and drug sides. Through a systematical approach, named as PDRCC (Predict Drug Response in Cancer Cells), the cancer genomic alterations and compound chemical and therapeutic properties were incorporated to determine the chemotherapeutic response in cancer patients. Using the Cancer Cell Line Encyclopedia (CCLE) study as the benchmark dataset, all pharmacogenomics data exhibited their roles in inferring the relationships between cancer cells and drugs. When integrating both genomic resources and compound information, the prediction coverage was significantly increased. The validity of PDRCC was also supported by its effective in uncovering the unknown cell-drug associations with database and literature evidences. It set the stage for clinical testing of novel therapeutic strategies, such as the sensitive association between cancer cell ‘A549_LUNG’ and compound ‘Topotecan’. In conclusion, PDRCC offers the possibility for faster, safer, and cheaper the development of novel anti-cancer therapeutics in the early-stage clinical trails.

  13. A therapeutic delivery system for chronic osteomyelitis via a multi-drug implant based on three-dimensional printing technology.

    Science.gov (United States)

    Wu, Weigang; Ye, Chenyi; Zheng, Qixin; Wu, Gui; Cheng, Zhaohui

    2016-08-01

    Chronic osteomyelitis is difficult to be cured and often relapses, which presents to be a great challenge to clinicians. We conducted this original study to explore the efficiency of therapeutic alliance for chronic osteomyelitis by a multi-drug implant based on three-dimensional printing technology. We designed and fabricated preciously a multi-drug implant with a multi-layered concentric cylinder construction by three-dimensional (3D) printing technology. Levofloxacin and tobramycin were incorporated into the drug implant in a specific sequence. The drug release property of the drug implant was assayed in vitro We also developed an animal model of chronic osteomyelitis to estimate the effect of the 3D printed multi-drug implant. The results showed that the multi-drug implant had a sustained and programmed drug release property. Levofloxacin and tobramycin which were released from the multi-drug implant worked in tandem to enhance pharmacodynamic action which was similar to a tumor chemotherapy program and were sufficient to treat chronic osteomyelitis. These findings imply that the administration of 3D printed multi-drug implant would be a potential therapeutic method for chronic osteomyelitis. Further studies are required. © The Author(s) 2016.

  14. Parenting quality in drug-addicted mothers in a therapeutic mother-child community: the contribution of attachment and personality assessment.

    Science.gov (United States)

    De Palo, Francesca; Capra, Nicoletta; Simonelli, Alessandra; Salcuni, Silvia; Di Riso, Daniela

    2014-01-01

    Growing evidence shows that attachment is a key risk factor for the diagnosis and treatment of clinical diseases in Axis I, such as drug addiction. Recent literature regarding attachment, psychiatric pathology, and drug addiction demonstrates that there is a clear prevalence of insecure attachment patterns in clinical and drug addicted subjects. Specifically, some authors emphasize that the anxious-insecure attachment pattern is prevalent among drug-addicted women with double diagnosis (Fonagy et al., 1996). The construct of attachment as a risk factor in clinical samples of drug-addicted mothers needs to be studied more in depth though. The present explorative study focused on the evaluation of parenting quality in a therapeutic mother-child community using attachment and personality assessment tools able to outline drug-addicted mothers' profiles. This study involved 30 drug addicted mothers, inpatients of a therapeutic community (TC). Attachment representations were assessed via the Adult Attachment Interview; personality diagnosis and symptomatic profiles were performed using the Structured Clinical Interview of the DSM-IV (SCID-II) and the Symptom Check List-90-R (SCL-90-R), respectively. Both instruments were administered during the first six months of residence in a TC. Results confirmed the prevalence of insecure attachment representations (90%), with a high presence of U patterns, prevalently scored for dangerous and/or not protective experiences in infanthood. Very high values (>5) were found for some experience scales (i.e., neglect and rejection scales). Data also showed very low values (1-3) in metacognitive monitoring, coherence of transcript and coherence of mind scales. Patients' different profiles (U vs. E vs. Ds) were linked to SCID-II diagnosis, providing insightful indications both for treatment planning and intervention on parenting functions and for deciding if to start foster care or adoption proceedings for children.

  15. Evaluation of the activated partial thromboplastin time (APTT) sensitivity to heparin using five commercial reagents: implications for therapeutic monitoring.

    Science.gov (United States)

    Manzato, F; Mengoni, A; Grilenzoni, A; Lippi, G

    1998-12-01

    Heparin is an effective drug for prevention and treatment of thromboembolic conditions. Although several biological assays have been proposed for monitoring unfractionated heparin therapy, the measurement of the activated partial thromboplastin time (APTT) is the most widely employed test, and the overall risk of thromboembolic episodes was markedly reduced by maintaining APTT ratios above 1.5. However, the adjustment of the heparin therapy on the basis of APTT presents several questions which are still unresolved. Major discrepancies were found in APTTs performed using different reagents in both ex vivo and in vitro heparinized samples and occasionally with different lots of the same reagents; poor correlation was observed between APTT values and plasma heparin concentrations. In order to gain further insights into this phenomenon, we analysed the sensitivity to heparin of five commercial reagents for APTT measurement in 19 ex vivo heparinized samples. Differences were observed; correlation coefficients ranged from 0.820 to 0.985 and slopes of linear regressions from 0.26 to 1.14. Moreover, unsatisfactory correlations were obtained when APTT ratios were compared with heparin plasma concentrations in the same patients' samples. In the heparin therapeutic range of 0.35 - 0.70 U/ml, reagent-dependent differences were observed in the corresponding APTT values. These results point out a critical role of the assay methodology in monitoring heparin therapy by APTT. We suggest that reference materials and methods should be urgently identified, a universally agreed scale for reporting results should be established and reference ranges for the unfractionated heparin therapy should be reconsidered taking on account the reagent employed.

  16. Analysis of the functioning of a therapeutic comunity for drug users

    Directory of Open Access Journals (Sweden)

    Mariane Capellato Melo

    2016-11-01

    Full Text Available Prolonged hospitalization of drug users in Therapeutic Communities (TC has become a public policy in Brazil. The aim of this study was to understand and analyze the functioning of a TC, considering the activities carried out there, the relationships established and the intervention process. Five visits to a TC were carried out. These visits were registered in a field diary. The notes were analyzed seeking to understand discursive features of the functioning of the TC and the impact of its functioning on the subjectivity of the users. The activities were labor therapy and group activities, and the Christian religious believes were explored. Relations were hierarchical, using strategies of control, confrontation and construction of guilt. Activities positioned the users as impulsive, addicts and deviants. The influence of the limited access to consumer goods and citizenship rights in the life trajectories of the users were not taken into consideration. Their problems with drugs were treated only as something internal, creating only strategies towards reconstructing the user's identity.

  17. Self-Assembling Peptide Amphiphiles for Therapeutic Delivery of Proteins, Drugs, and Stem Cells

    Science.gov (United States)

    Lee, Sungsoo Seth

    Biomaterials are used to help regenerate or replace the structure and function of damaged tissues. In order to elicit desired therapeutic responses in vivo, biomaterials are often functionalized with bioactive agents, such as growth factors, small molecule drugs, or even stem cells. Therefore, the strategies used to incorporate these bioactive agents in the microstructures and nanostructures of biomaterials can strongly influence the their therapeutic efficacy. Using self-assembling peptide amphiphiles (PAs), this work has investigated supramolecular nanostructures with improved interaction with three types of therapeutic agents: bone morphogenetic protein 2 (BMP-2) which promotes osteogenic differentiation and bone growth, anti-inflammatory drug naproxen which is used to treat osteo- and rheumatoid arthritis, and neural stem cells that could differentiate into neurons to treat neurodegenerative diseases. For BMP-2 delivery, two specific systems were investigated with affinity for BMP-2: 1) heparin-binding nanofibers that display the natural ligand of the osteogenic protein, and 2) nanofibers that display a synthetic peptide ligand discovered in our laboratory through phage display to directly bind BMP-2. Both systems promoted enhanced osteoblast differentiation of pluripotent C2C12 cells and augmented bone regeneration in two in vivo models, a rat critical-size femur defect model and spinal arthrodesis model. The thesis also describes the use of PA nanofibers to improve the delivery of the anti-inflammatory drug naproxen. To promote a controlled release, naproxen was chemically conjugated to the nanofiber surface via an ester bond that would only be cleaved by esterases, which are enzymes found naturally in the body. In the absence of esterases, the naproxen remained conjugated to the nanofibers and was non-bioactive. On the other hand, in the presence of esterases, naproxen was slowly released and inhibited cyclooxygenase-2 (COX-2) activity, an enzyme responsible

  18. The sigma-2 receptor as a therapeutic target for drug delivery in triple negative breast cancer

    Energy Technology Data Exchange (ETDEWEB)

    Makvandi, Mehran; Tilahun, Estifanos D.; Lieberman, Brian P.; Anderson, Redmond-Craig; Zeng, Chenbo; Xu, Kuiying; Hou, Catherine; McDonald, Elizabeth S.; Pryma, Daniel A.; Mach, Robert H., E-mail: rmach@mail.med.upenn.edu

    2015-11-27

    Background: Triple-negative breast cancer (TNBC) is associated with high relapse rates and increased mortality when compared with other breast cancer subtypes. In contrast to receptor positive breast cancers, there are no approved targeted therapies for TNBC. Identifying biomarkers for TNBC is of high importance for the advancement of patient care. The sigma-2 receptor has been shown to be overexpressed in triple negative breast cancer in vivo and has been characterized as a marker of proliferation. The aim of the present study was to define the sigma-2 receptor as a target for therapeutic drug delivery and biomarker in TNBC. Methods: Three TNBC cell lines were evaluated: MDA-MB-231, HCC1937 and HCC1806. Sigma-2 compounds were tested for pharmacological properties specific to the sigma-2 receptor through competitive inhibition assays. Sigma-2 receptor expression was measured through radioligand receptor saturation studies. Drug sensitivity for taxol was compared to a sigma-2 targeting compound conjugated to a cytotoxic payload, SW IV-134. Cell viability was assessed after treatments for 2 or 48 h. Sigma-2 blockade was assessed to define sigma-2 mediated cytotoxicity of SW IV-134. Caspase 3/7 activation induced by SW IV-134 was measured at corresponding treatment time points. Results: SW IV-134 was the most potent compound tested in two of the three cell lines and was similarly effective in all three. MDA-MB-231 displayed a statistically significant higher sigma-2 receptor expression and also was the most sensitive cell line evaluated to SW IV-134. Conclusion: Targeting the sigma-2 receptor with a cytotoxic payload was effective in all the three cell lines evaluated and provides the proof of concept for future development of a therapeutic platform for the treatment of TNBC. - Highlights: • TNBC cells are sensitive to sigma-2 receptor targeted drug conjugate SW IV-134. • MDA-MB-231 displayed the highest amount of sigma-2 receptors and corresponded well with

  19. Photosensitizer-mediated mitochondria-targeting nanosized drug carriers: Subcellular targeting, therapeutic, and imaging potentials.

    Science.gov (United States)

    Choi, Yeon Su; Kwon, Kiyoon; Yoon, Kwonhyeok; Huh, Kang Moo; Kang, Han Chang

    2017-03-30

    Mitochondria-targeting drug carriers have considerable potential because of the presence of many molecular drug targets in the mitochondria and their pivotal roles in cellular viability, metabolism, maintenance, and death. To compare the mitochondria-targeting abilities of triphenylphosphonium (TPP) and pheophorbide a (PhA) in nanoparticles (NPs), this study prepared mitochondria-targeting NPs using mixtures of methoxy poly(ethylene glycol)-(SS-PhA)2 [mPEG-(SS-PhA)2 or PPA] and TPP-b-poly(ε-caprolactone)-b-TPP [TPP-b-PCL-b-TPP or TPCL], which were designated PPAn-TPCL4-n (0≤n≤4) NPs. With increasing TPCL content, the formed PPAn-TPCL4-n NPs decreased in size from 33nm to 18nm and increased in terms of positive zeta-potentials from -12mV to 33mV. Although the increased TPCL content caused some dark toxicity of the PPAn-TPCL4-n NPs due to the intrinsic positive character of TPCL, the NPs showed strong light-induced killing effects in tumor cells. In addition, the mitochondrial distribution of the PPAn-TPCL4-n NPs was analyzed and imaged by flow cytometry and confocal microscopy, respectively. Thus, the PhA-containing NPs specifically targeted the mitochondria, and light stimulation caused PhA-mediated therapeutic effects and imaging functions. Expanding the capabilities of these nanocarriers by incorporating other drugs should enable multiple potential applications (e.g., targeting, therapy, and imaging) for combination and synergistic treatments. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Severe Drug Hypersensitivity Reactions: Clinical Pattern, Diagnosis, Etiology and Therapeutic Options.

    Science.gov (United States)

    Paulmann, Maren; Mockenhaupt, Maja

    2016-01-01

    Severe cutaneous adverse reactions (SCAR) are known for a high morbidity and mortality. They may be life-threatening for the affected patient and difficult to accomplish for the patient's family and the treating physician. Such conditions include not only bullous reactions like toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), but also acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS). Since clinical pattern, etiology, prognosis and treatment differ among these severe skin reactions, a clear diagnosis based on a comprehensive clinical examination, skin biopsy, and specific laboratory tests is necessary. Because most of these reactions are caused by drug intake, a thorough history of medication use has to be obtained. However, there are cases with an infectious or idiopathic cause. In any case it is crucial to identify the most likely cause and rapidly discontinue the inducing agent, if a drug cause is suspected. This is associated with the patient`s prognosis which is often poor for bullous reaction. In addition, patient's age, underlying conditions, and the extent of skin detachment play a major role in terms of prognosis. Severe cutaneous adverse reactions are T-cell-mediated reactions, and certain alleles of human leukocyte antigens (HLA) are involved in the activation of T-cells with cytotoxic effect. The therapeutic options depend on the clinical diagnosis. For all reactions a symptomatic and adequate supportive therapy is necessary, in some cases a systemic immunomodulating therapy can be useful. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  1. HOW PARENTS OF TEENS STORE AND MONITOR PRESCRIPTION DRUGS IN THE HOME*

    Science.gov (United States)

    FRIESE, BETTINA; MOORE, ROLAND S.; GRUBE, JOEL W.; JENNINGS, VANESSA K.

    2014-01-01

    Qualitative interviews were conducted with parents of teens to explore how parents store and monitor prescription drugs in the home. Most parents had prescription drugs in the house, but took few precautions against teens accessing these drugs. Strategies for monitoring included moving the drugs to different locations, remembering how many pills were left, and how medication containers were positioned. Reasons given for not securing drugs were that parents did not think that their teens would be interested in their prescription drugs and did not believe that they could be used to get high. This study highlights the need for parents to be educated about securing prescription drugs, the dangers of non-medical prescription drug use by teens, and which drugs might be used for non-medical purposes. PMID:25429166

  2. Tuberculosis therapeutics: Engineering of nanomedicinal systems for local delivery of targeted drug cocktails

    Science.gov (United States)

    D'Addio, Suzanne M.

    In this thesis, a multifunctional nanocarrier drug delivery system was investigated and optimized to improve tuberculosis therapy by promoting the intracellular delivery of high payloads of antibiotics. To meet the needs of a patient population which continues to grow by close to 10 million people a year, innovative therapeutics must be formulated by robust and scalable processes. We use Flash NanoPrecipitation for the continuous precipitation of nanocarriers by block copolymer directed assembly, which enables the development of nanocarriers with tunable properties. Stable nanocarriers of Rifampicin and a hydrophobic Rifampicin prodrug have efficacy against tuberculosis in vitro that is equivalent to the soluble Rifampicin. To overcome poor in vivo efficacy of the recently discovered antitubercular drug SQ641, we co-encapsulate SQ641 and Cyclosporine A in a stable aqueous nanocarrier suspension, which enables drug administration and also enhances intracellular accumulation and antitubercular efficacy relative to SQ641 in solution. Since the mannose receptor is involved in the phagocytosis of tuberculosis bacilli, we modify the surface of nanocarriers with mannoside residues to target specific intracellular accumulation in macrophages. The surface density of mannoside terminated polyethylene glycol chains was controlled between 0 and 75% and in vitro cellular association reveals a 9% surface density is optimal for internalization mediated by the mannose receptor. We explore the preparation of large, porous aerosol carrier particles of with tunable deposition characteristics by spray freeze drying with ultrasonic atomization for direct dosing to the lungs. Nanocarriers are loaded at 3 - 50 wt% in mannitol particles with constant size, limited nanocarrier aggregation, and 63% dose delivered to the lungs, as determined by in vitro cascade impaction. There has been a lag in the development of new technologies to facilitate development and commercialization of

  3. Drug delivery from engineered organisms and nanocarriers as monitored by multimodal imaging technologies

    NARCIS (Netherlands)

    Calle, Daniel; Yilmaz, Duygu; Cerdan, Sebastian; Kocer, Armagan

    2017-01-01

    In recent years, while the research budget and development times increased for different phases of drug development, the number of clinically approved new medicines declined. In fact, many promising drug candidates failed to demonstrate their full therapeutic potential in vivo. Reasons for

  4. Anticancer Drug-Incorporated Layered Double Hydroxide Nanohybrids and Their Enhanced Anticancer Therapeutic Efficacy in Combination Cancer Treatment

    Directory of Open Access Journals (Sweden)

    Tae-Hyun Kim

    2014-01-01

    Full Text Available Objective. Layered double hydroxide (LDH nanoparticles have been studied as cellular delivery carriers for anionic anticancer agents. As MTX and 5-FU are clinically utilized anticancer drugs in combination therapy, we aimed to enhance the therapeutic performance with the help of LDH nanoparticles. Method. Anticancer drugs, MTX and 5-FU, and their combination, were incorporated into LDH by reconstruction method. Simply, LDHs were thermally pretreated at 400°C, and then reacted with drug solution to simultaneously form drug-incorporated LDH. Thus prepared MTX/LDH (ML, 5-FU/LDH (FL, and (MTX + 5-FU/LDH (MFL nanohybrids were characterized by X-ray diffractometer, scanning electron microscopy, infrared spectroscopy, thermal analysis, zeta potential measurement, dynamic light scattering, and so forth. The nanohybrids were administrated to the human cervical adenocarcinoma, HeLa cells, in concentration-dependent manner, comparing with drug itself to verify the enhanced therapeutic efficacy. Conclusion. All the nanohybrids successfully accommodated intended drug molecules in their house-of-card-like structures during reconstruction reaction. It was found that the anticancer efficacy of MFL nanohybrid was higher than other nanohybrids, free drugs, or their mixtures, which means the multidrug-incorporated LDH nanohybrids could be potential drug delivery carriers for efficient cancer treatment via combination therapy.

  5. Two-drug combinations of memory enhancers: effect of dose ratio upon potency and therapeutic window, in mice.

    Science.gov (United States)

    Flood, J F; Smith, G E; Cherkin, A

    1988-01-01

    Two-drug combinations have been reported to enhance retention more effectively than when either drug was administered alone at the same dose. Some combinations of cholinergic drugs enhance retention even though the total drug dosage is reduced by as much as 97% compared to the dose needed to improve retention when the same drugs are administered singly. The choice of dose ratio is usually arbitrary or based on empirical results. The present study systematically varied the ratio of two drugs in a combination and at the same time varied the dosage of each drug. The drug combinations were administered to mice immediately after training on T-maze footshock avoidance task. Retention was tested one week later. Three two-drug combinations were selected for presentation because they differed considerably as to (a) the lowest effective total dose that improved memory-retention, (b) the optimal ratio that improved retention and (c) the width of the therapeutic window. The effect of a drug combination on retention was found to be dependent on the particular drugs in the combination, the ratio and the dose administered.

  6. Electrochemotherapy with cisplatin enhances local control after surgical ablation of fibrosarcoma in cats: an approach to improve the therapeutic index of highly toxic chemotherapy drugs

    Directory of Open Access Journals (Sweden)

    Cardelli Pierluigi

    2011-09-01

    Full Text Available Abstract Background Cancer is one of the most difficult current health challenges, being responsible for millions of deaths yearly. Systemic chemotherapy is the most common therapeutic approach, and the prevailing orientation calls for the administration of the maximum tolerated dose; however, considerable limitations exist including toxicities to healthy tissues and low achievable drug concentrations at tumor sites. Electrochemotherapy (ECT is a tumor treatment that combines the systemic or local delivery of anticancer drugs with the application of permeabilizing electric pulses. In this article we evaluate the capability of ECT to allow the use of cisplatin despite its high toxicity in a spontaneous feline model of soft tissue sarcoma. Methods A cohort of sixty-four cats with incompletely excised sarcomas were treated with cisplatin-based adjuvant ECT and monitored for side effects. Their response was compared to that of fourteen cats treated with surgery alone. Results The toxicities were minimal and mostly treated symptomatically. ECT resulted in increased local control (median not reached at the time of writing with a mean time to recurrence of 666 days versus 180 of controls. Conclusions We conclude that ECT is a safe and efficacious therapy for solid tumors; its use may be considered as part of strategies for the reintroduction of drugs with a narrow therapeutic index in the clinical protocols.

  7. Breath Ketone Testing: A New Biomarker for Diagnosis and Therapeutic Monitoring of Diabetic Ketosis

    Directory of Open Access Journals (Sweden)

    Yue Qiao

    2014-01-01

    Full Text Available Background. Acetone, β-hydroxybutyric acid, and acetoacetic acid are three types of ketone body that may be found in the breath, blood, and urine. Detecting altered concentrations of ketones in the breath, blood, and urine is crucial for the diagnosis and treatment of diabetic ketosis. The aim of this study was to evaluate the advantages of different detection methods for ketones, and to establish whether detection of the concentration of ketones in the breath is an effective and practical technique. Methods. We measured the concentrations of acetone in the breath using gas chromatography-mass spectrometry and β-hydroxybutyrate in fingertip blood collected from 99 patients with diabetes assigned to groups 1 (−, 2 (±, 3 (+, 4 (++, or 5 (+++ according to urinary ketone concentrations. Results. There were strong relationships between fasting blood glucose, age, and diabetic ketosis. Exhaled acetone concentration significantly correlated with concentrations of fasting blood glucose, ketones in the blood and urine, LDL-C, creatinine, and blood urea nitrogen. Conclusions. Breath testing for ketones has a high sensitivity and specificity and appears to be a noninvasive, convenient, and repeatable method for the diagnosis and therapeutic monitoring of diabetic ketosis.

  8. The experience of drug-dependent adolescents in a therapeutic community.

    Science.gov (United States)

    Foster, Michael; Nathan, Sally; Ferry, Mark

    2010-09-01

    Drug treatment programs for adolescents are now more widespread with some evidence of success. However, there has been little in-depth exploration of factors that may encourage or hinder program completion. This ethnographic study of an adolescent therapeutic community aimed to provide insights into the experience of the adolescent residents. Four months of participant observation at a program for drug-dependent adolescents in a metropolitan city in Australia. Twenty-one residents (15 boys and six girls) aged between 14 and 18 years participated, comprising all residents admitted during the study period. Vocational Education and Art Therapy are activities that universally engaged residents whereas frustration was evident in Journaling-a core program activity. Group sessions were often used to set up or dismantle social cliques, although they were also useful to expose difficult inter-personal relationships. The risk of residents 'taking off' was heightened during breaks from program activities when strong emotions surfaced. There needs to be a more central role for creative and vocational activities in adolescent programs and a variety of ways for them to document their journey. Group encounters need to be skillfully facilitated by staff to handle fluid inter-personal dynamics and residents need support outside of formal program time to minimise drop-out. The concept of a navigation-engagement continuum is discussed and the need to see treatment as a series of encounters that may be 'successful' despite 'non-completion'. This study gives adolescents a voice in program evaluation which may help improve retention.

  9. [Soluble guanylate cyclase in the molecular mechanism underlying the therapeutic action of drugs].

    Science.gov (United States)

    Piatakova, N V; Severina, I S

    2012-01-01

    The influence of ambroxol--a mucolytic drug--on the activity of human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase and activation of both enzymes by NO-donors (sodium nitroprusside and Sin-1) were investigated. Ambroxol in the concentration range from 0.1 to 10 microM had no effect on the basal activity of both enzymes. Ambroxol inhibited in a concentration-dependent manner the sodium nitroprusside-induced human platelet soluble guanylate cyclase and rat lung soluble guanylate cyclase with the IC50 values 3.9 and 2.1 microM, respectively. Ambroxol did not influence the stimulation of both enzymes by protoporphyrin IX. The influence of artemisinin--an antimalarial drug--on human platelet soluble guanylate cyclase activity and the enzyme activation by NO-donors were investigated. Artemisinin (0.1-100 microM) had no effect on the basal activity of the enzyme. Artemisinin inhibited in a concentration-dependent manner the sodium nitroprusside-induced activation of human platelet guanylate cyclase with an IC50 value 5.6 microM. Artemisinin (10 microM) also inhibited (by 71 +/- 4.0%) the activation of the enzyme by thiol-dependent NO-donor the derivative of furoxan, 3,4-dicyano-1,2,5-oxadiazolo-2-oxide (10 microM), but did not influence the stimulation of soluble guanylate cyclase by protoporphyrin IX. It was concluded that the sygnalling system NO-soluble guanylate cyclase-cGMP is involved in the molecular mechanism of the therapeutic action of ambroxol and artemisinin.

  10. Slow accumulation of psychotropic substances in the human brain. Relationship to therapeutic latency of neuroleptic and antidepressant drugs?

    Science.gov (United States)

    Kornhuber, J; Retz, W; Riederer, P

    1995-01-01

    The mechanism of therapeutic latency of antidepressant and neuroleptic drugs is not clearly understood. Current hypotheses include slow adaptive processes after fast access to primary drug targets. Here, we present a hypothesis explaining therapeutic latency by slow accumulation of the drugs in acidic intracellular compartments. We have studied the pharmacokinetics of amantadine, a lysosomotropic model substance. It's fast therapeutic response is mediated by fast access to cell surface receptors. However, it slowly accumulates intracellularly in human brain tissue. Half-maximal and plateau concentrations are reached after 8 and at least 70 days of treatment, respectively. The concentration in brain tissue relative to CSF and serum is about 20:1. The high storage capacity of brain tissue is probably related to lysosomotropic properties of amantadine. This means that amantadine, as other lysosomotropic substances, is trapped by protonation in acidic intracellular compartments and may disturb biochemical processes that require an acidic milieu, such as the proton-driven transport of monoamines into synaptic vesicles. The mean daily oral dose of amantadine is low compared to the high storage capacity of brain and other tissues thus explaining the slow accumulation. Many psychotropic drugs including antidepressant and neuroleptic substances also have lysosomotropic properties. A slow accumulation in brain tissue is therefore likely for many antidepressant and neuroleptic drugs and has been directly demonstrated for fluoxetine. While lysosomotropism alone is not a sufficient explanation for antidepressant or neuroleptic properties of a certain drug, it contributes to high storage capacity and slow accumulation in brain tissue and results in disturbances of several biochemical processes. Slow accumulation in brain tissue might be related to the therapeutic latency of neuroleptic and antidepressant drugs.

  11. Key factors influencing ADME properties of therapeutic proteins: A need for ADME characterization in drug discovery and development

    Science.gov (United States)

    Tibbitts, Jay; Canter, David; Graff, Ryan; Smith, Alison; Khawli, Leslie A.

    2016-01-01

    abstract Protein therapeutics represent a diverse array of biologics including antibodies, fusion proteins, and therapeutic replacement enzymes. Since their inception, they have revolutionized the treatment of a wide range of diseases including respiratory, vascular, autoimmune, inflammatory, infectious, and neurodegenerative diseases, as well as cancer. While in vivo pharmacokinetic, pharmacodynamic, and efficacy studies are routinely carried out for protein therapeutics, studies that identify key factors governing their absorption, distribution, metabolism, and excretion (ADME) properties have not been fully investigated. Thorough characterization and in-depth study of their ADME properties are critical in order to support drug discovery and development processes for the production of safer and more effective biotherapeutics. In this review, we discuss the main factors affecting the ADME characteristics of these large macromolecular therapies. We also give an overview of the current tools, technologies, and approaches available to investigate key factors that influence the ADME of recombinant biotherapeutic drugs, and demonstrate how ADME studies will facilitate their future development. PMID:26636901

  12. Activity of the hypoxia‐activated pro‐drug TH‐302 in hypoxic and perivascular regions of solid tumors and its potential to enhance therapeutic effects of chemotherapy

    National Research Council Canada - National Science Library

    Saggar, Jasdeep K; Tannock, Ian F

    2014-01-01

    Many chemotherapy drugs have poor therapeutic activity in regions distant from tumor blood vessels because of poor tissue penetration and low cytotoxic activity against slowly‐proliferating cells. The hypoxia‐activated pro‐drug TH...

  13. Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Paula I. Moreira

    2009-12-01

    Full Text Available Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ. Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.

  14. Impact of Seasons and Dioecy on Therapeutic Phytoconstituents of Tinospora cordifolia, a Rasayana Drug

    Directory of Open Access Journals (Sweden)

    Namrta Choudhry

    2014-01-01

    Full Text Available Tinospora cordifolia (Thunb. Miers, Menispermaceae, is a dioecious creeper, commonly known as “Giloe” or “Guduchi” with significant medicinal importance in the traditional systems of medicine. It is designated as Rasayana drug in Ayurveda and recommended for a number of diseases and also as adaptogen and immunomodulator. The safety and efficacy of herbal medicines are closely correlated with the quality of the source materials. The aim of this study is to see the effect of seasons on phytoconstituents and how these vary in male and female stem samples of T. cordifolia. The study revealed that total phenolics and total sugar concentration obtained highest values in summer season while starch and tannin content were found maximum in winter season in both the genders. However, biomarkers, tinosporaside and berberine, reached to their highest concentration in monsoon season. Further, antioxidant potential revealed the highest inhibition percentage in winter season as well as in late summer season. The results of this study suggest that the female plant is best for its therapeutic phytoconstituents and the best harvesting seasons may be either winter or late summer for antioxidant potential and immunomodulator activities and monsoon for antidiabetic activity of T. cordifolia.

  15. Impact of seasons and dioecy on therapeutic phytoconstituents of Tinospora cordifolia, a Rasayana drug.

    Science.gov (United States)

    Choudhry, Namrta; Singh, Shweta; Siddiqui, Mohammad Badruzzaman; Khatoon, Sayyada

    2014-01-01

    Tinospora cordifolia (Thunb.) Miers, Menispermaceae, is a dioecious creeper, commonly known as "Giloe" or "Guduchi" with significant medicinal importance in the traditional systems of medicine. It is designated as Rasayana drug in Ayurveda and recommended for a number of diseases and also as adaptogen and immunomodulator. The safety and efficacy of herbal medicines are closely correlated with the quality of the source materials. The aim of this study is to see the effect of seasons on phytoconstituents and how these vary in male and female stem samples of T. cordifolia. The study revealed that total phenolics and total sugar concentration obtained highest values in summer season while starch and tannin content were found maximum in winter season in both the genders. However, biomarkers, tinosporaside and berberine, reached to their highest concentration in monsoon season. Further, antioxidant potential revealed the highest inhibition percentage in winter season as well as in late summer season. The results of this study suggest that the female plant is best for its therapeutic phytoconstituents and the best harvesting seasons may be either winter or late summer for antioxidant potential and immunomodulator activities and monsoon for antidiabetic activity of T. cordifolia.

  16. Drug delivery from engineered organisms and nanocarriers as monitored by multimodal imaging technologies

    Directory of Open Access Journals (Sweden)

    Daniel Calle

    2017-03-01

    Full Text Available In recent years, while the research budget and development times increased for different phases of drug development, the number of clinically approved new medicines declined. In fact, many promising drug candidates failed to demonstrate their full therapeutic potential in vivo. Reasons for unfavorable outcome include some intrinsic properties of drugs, like biodegradation, solubility, and systemic toxicity, as well as the ways in which they are administered or the time elapsed until therapeutic efficiency is demonstrated. Therefore, to develop the full therapeutic potential of drug candidates in vivo, there is a need for advanced drug delivery systems that would carry the drug specifically to the target and release it there at desired concentrations. In addition, there is a requirement for non-invasive biomedical imaging technologies allowing for rapid and sensitive evaluations of drug performance in vivo. This review will present recent developments in bioengineered drug delivery systems, highlighting the biomedical imaging tools needed to evaluate the success of drug delivery strategies.

  17. Targeted anti-cancer prodrug based on carbon nanotube with photodynamic therapeutic effect and pH-triggered drug release

    Energy Technology Data Exchange (ETDEWEB)

    Fan, Jianquan; Zeng, Fang, E-mail: mcfzeng@scut.edu.cn; Xu, Jiangsheng; Wu, Shuizhu, E-mail: shzhwu@scut.edu.cn [South China University of Technology, College of Materials Science and Engineering, State Key Laboratory of Luminescent Materials and Devices (China)

    2013-09-15

    Herein, we describe a multifunctional anti-cancer prodrug system based on water-dispersible carbon nanotube (CNT); this prodrug system features active targeting, pH-triggered drug release, and photodynamic therapeutic properties. For this prodrug system (with the size of {approx}100-300 nm), an anti-cancer drug, doxorubicin (DOX), was incorporated onto CNT via a cleavable hydrazone bond; and a targeting ligand (folic acid) was also coupled onto CNT. This prodrug can preferably enter folate receptor (FR)-positive cancer cells and undergo intracellular release of the drug triggered by the reduced pH. The targeted CNT-based prodrug system can cause lower cell viability toward FR-positive cells compared to the non-targeted ones. Moreover, the CNT carrier exhibits photodynamic therapeutic (PDT) action; and the cell viability of FR-positive cancer cells can be further reduced upon light irradiation. The dual effects of pH-triggered drug release and PDT increase the therapeutic efficacy of the DOX-CNT prodrug. This study may offer some useful insights on designing and improving the applicability of CNT for other drug delivery systems.

  18. Development and application of a system for monitoring drug abuse: the Malaysian experience.

    Science.gov (United States)

    Navaratnam, V; Foong, K

    1989-01-01

    Monitoring systems are useful epidemiological instruments for assessing the problem of drug abuse. The rapid growth of the drug dependence problem in Malaysia led to increased awareness of the need for a system for continuous monitoring of the situation. Preliminary work on the design of an appropriate monitoring system was initiated in 1976. A fully integrated national reporting system was established in 1978, linking all public services and agencies coming into contact with drug-dependent persons, including law enforcement agencies, drug abuse treatment and rehabilitation centres, and social and welfare institutions. The information system included a mechanism for systematic gathering, processing, analysing and presenting essential data on the prevention, control and management of drug abuse problems. It also included reporting on drug-related events, such as hospitalizations and arrests, as well as data on known drug-dependent persons and new cases of dependence. The system has been used for routine monitoring of the extent, trends, patterns and other characteristics of drug abuse problems in Malaysia, providing basic information for policy-making and programme planning. On the basis of data generated by the system, it was estimated that the prevalence rate of drug-dependent persons per 100,000 population increased from 84.3 in 1976 to 754.6 in 1986. It was estimated that there were 119,001 drug-dependent persons in Malaysia in 1986.

  19. In vivo confocal microscopy for the detection of canine fungal keratitis and monitoring of therapeutic response.

    Science.gov (United States)

    Ledbetter, Eric C; Norman, Mary L; Starr, Jennifer K

    2016-05-01

    To describe in vivo corneal confocal microscopy of dogs during the clinical course of fungal keratitis and correlate findings with clinical evaluations and an ex vivo experimental canine fungal keratitis model. Seven dogs with naturally acquired fungal keratitis and ex vivo canine corneas experimentally infected with clinical fungal isolates. Dogs with naturally acquired fungal keratitis were examined by in vivo laser scanning confocal microscopy. Initial confocal microscopic examinations were performed to assist in establishing the diagnosis of fungal keratitis. Serial confocal microscopic examinations were performed to guide antifungal chemotherapy. Confocal microscopy images of canine corneal fungal isolates were obtained by examination of experimentally infected ex vivo canine corneas to corroborate in vivo findings. Fungi cultured and detected by PCR from canine corneal samples included Candida albicans, Fusarium incarnatum-equiseti, Malassezia pachydermatis, and a Rhodotorula sp. Linear, branching, interlocking, hyperreflective structures were detected by confocal microscopy in dogs with filamentous fungal keratitis and round to oval hyperreflective structures were detected in dogs with yeast fungal keratitis. Antifungal chemotherapy was associated with a progressive reduction in the distribution and density of corneal fungal elements, alterations to fungal morphology, decreased leukocyte numbers, restoration of epithelial layers, and an increased number of visible keratocyte nuclei. No dogs had a recurrence of fungal keratitis following medication discontinuation. Confocal microscopic fungal morphologies were similar between in vivo and ex vivo examinations. In vivo corneal confocal microscopy is a rapid method of diagnosing fungal keratitis in dogs and provides a noninvasive mechanism for monitoring therapeutic response. © 2015 American College of Veterinary Ophthalmologists.

  20. A study of harmful drug–drug interactions due to polypharmacy in hospitalized patients in Goa Medical College

    Directory of Open Access Journals (Sweden)

    Akshay Khandeparkar

    2017-01-01

    Conclusion: Patients taking multiple medications experience unique pharmacotherapy. Personalized drug prescribing strategies and close monitoring of patients taking drugs with potential DDIs are keys to optimal therapeutic result.

  1. Developments on drug discovery and on new therapeutics: highly diluted tinctures act as biological response modifiers

    Directory of Open Access Journals (Sweden)

    de Oliveira Carolina C

    2011-10-01

    Full Text Available Abstract Background In the search for new therapies novel drugs and medications are being discovered, developed and tested in laboratories. Highly diluted substances are intended to enhance immune system responses resulting in reduced frequency of various diseases, and often present no risk of serious side-effects due to its low toxicity. Over the past years our research group has been investigating the action of highly diluted substances and tinctures on cells from the immune system. Methods We have developed and tested several highly diluted tinctures and here we describe the biological activity of M1, M2, and M8 both in vitro in immune cells from mice and human, and in vivo in mice. Cytotoxicity, cytokines released and NF-κB activation were determined after in vitro treatment. Cell viability, oxidative response, lipid peroxidation, bone marrow and lymph node cells immunophenotyping were accessed after mice in vivo treatment. Results None of the highly diluted tinctures tested were cytotoxic to macrophages or K562. Lipopolysaccharide (LPS-stimulated macrophages treated with all highly diluted tinctures decreased tumour necrosis factor alpha (TNF-α release and M1, and M8 decreased IFN-γ production. M1 has decreased NF-κB activity on TNF-α stimulated reporter cell line. In vivo treatment lead to a decrease in reactive oxygen species (ROS, nitric oxide (NO production was increased by M1, and M8, and lipid peroxidation was induced by M1, and M2. All compounds enhanced the innate immunity, but M1 also augmented acquired immunity and M2 diminished B lymphocytes, responsible to acquired immunity. Conclusions Based on the results presented here, these highly diluted tinctures were shown to modulate immune responses. Even though further investigation is needed there is an indication that these highly diluted tinctures could be used as therapeutic interventions in disorders where the immune system is compromised.

  2. Common ocular effects reported to a poison control center after systemic absorption of drugs in therapeutic and toxic doses.

    Science.gov (United States)

    Slattery, Ann; Liebelt, Erica; Gaines, LaDonna A

    2014-11-01

    Ocular effects resulting from medications assist toxicologists in determining substances involved when treating a poisoned patient. The intention of this review is to discuss the most common ocular effects, the medications that cause them, and the mechanisms by which they occur. According to National Poison Data System, the most common reported ocular effects following a drug ingestion/injection/inhalation are mydriasis, miosis, and nystagmus. The most common drug/drug classes reported to a regional poison control center causing these ocular effects include the following: first, mydriasis - amphetamines and diphenhydramine; second, miosis - clonidine and opioids; third, nystagmus - dextromethorphan. However, many other drugs/substances can cause these effects along with other systemic effects. Ocular findings are a pertinent component of any patient assessment involving therapeutic and/or toxic exposure to medications and other substances.

  3. Accelerated approval of cancer drugs: improved access to therapeutic breakthroughs or early release of unsafe and ineffective drugs?

    Science.gov (United States)

    Richey, Elizabeth A; Lyons, E Alison; Nebeker, Jonathan R; Shankaran, Veena; McKoy, June M; Luu, Thanh Ha; Nonzee, Narissa; Trifilio, Steven; Sartor, Oliver; Benson, Al B; Carson, Kenneth R; Edwards, Beatrice J; Gilchrist-Scott, Douglas; Kuzel, Timothy M; Raisch, Dennis W; Tallman, Martin S; West, Dennis P; Hirschfeld, Steven; Grillo-Lopez, Antonio J; Bennett, Charles L

    2009-09-10

    Accelerated approval (AA) was initiated by the US Food and Drug Administration (FDA) to shorten development times of drugs for serious medical illnesses. Sponsors must confirm efficacy in postapproval trials. Confronted with several drugs that received AA on the basis of phase II trials and for which confirmatory trials were incomplete, FDA officials have encouraged sponsors to design AA applications on the basis of interim analyses of phase III trials. We reviewed data on orphan drug status, development time, safety, and status of confirmatory trials of AAs and regular FDA approvals of new molecular entities (NMEs) for oncology indications since 1995. Median development times for AA NMEs (n = 19 drugs) and regular-approval oncology NMEs (n = 32 drugs) were 7.3 and 7.2 years, respectively. Phase III trials supported efficacy for 75% of regular-approval versus 26% of AA NMEs and for 73% of non-orphan versus 45% of orphan drug approvals. AA accounted for 78% of approvals for oncology NMEs between 2001 and 2003 but accounted for 32% in more recent years. Among AA NMEs, confirmatory trials were nine-fold less likely to be completed for orphan drug versus non-orphan drug indications. Postapproval, black box warnings were added to labels for four oncology NMEs (17%) that had received AA and for two oncology NMEs (9%) that had received regular approval. AA oncology NMEs are safe and effective, although development times are not accelerated. A return to endorsing phase II trial designs for AA for oncology NMEs, particularly for orphan drug indications, may facilitate timely FDA approval of novel cancer drugs.

  4. Towards virological monitoring of HIV-1 drug resistance in resource-limited settings

    NARCIS (Netherlands)

    Aitken, S.C.

    2014-01-01

    HIV-1 treatment monitoring is important to ensure effective viral suppression and prevent the development of HIV-1 drug resistance. Commercial assays for HIV-1 treatment monitoring are generally costly and complex, and require plasma as a sample type for testing. The components of this thesis are

  5. A Web-Based Therapeutic Workplace for the Treatment of Drug Addiction and Chronic Unemployment

    Science.gov (United States)

    Silverman, Kenneth; Wong, Conrad J.; Grabinski, Michael J.; Hampton, Jacqueline; Sylvest, Christine E.; Dillon, Erin M.; Wentland, R. Daniel

    2005-01-01

    This article describes a Web-based therapeutic workplace intervention designed to promote heroin and cocaine abstinence and train and employ participants as data entry operators. Patients are paid to participate in training and then to perform data entry jobs in a therapeutic workplace business. Salary is linked to abstinence by requiring patients…

  6. Sub therapeutic drug levels among HIV/TB co-infected patients ...

    African Journals Online (AJOL)

    Daniel W. Gunda

    2016-11-01

    Nov 1, 2016 ... sub-therapeutic antiretroviral plasma levels of non nucleoside reverse transcriptase inhibitors and protease inhibitors which may ... therapeutic levels of both Non Nucleotide Reverse Transcrip- tase Inhibitors (NNRTIs) and .... ate logistic regression model followed by multivariate logistic regression model.

  7. Site-Specific Drug-Releasing Polypeptide Nanocarriers Based on Dual-pH Response for Enhanced Therapeutic Efficacy against Drug-Resistant Tumors.

    Science.gov (United States)

    Dong, Yaqiong; Yang, Jun; Liu, Hongmei; Wang, Tianyou; Tang, Suoqin; Zhang, Jinchao; Zhang, Xin

    2015-01-01

    To enhance effective drug accumulation in drug-resistant tumors, a site-specific drug-releasing polypeptide system (PEG-Phis/Pasp-DOX/CA4) was exploited in response to tumor extracellular and intracellular pH. This system could firstly release the embedded tumor vascular inhibitor (CA4) to transiently 'normalize' vasculature and facilitate drug internalization to tumors efficiently, and then initiate the secondary pH-response to set the conjugated active anticancer drug (DOX) free in tumor cells. The encapsulated system (PEG-Phis/DOX/CA4), both CA4 and DOX embedding in the nanoparticles, was used as a control. Comparing with PEG-Phis/DOX/CA4, PEG-Phis/Pasp-DOX/CA4 exhibited enhanced cytotoxicity against DOX-sensitive and DOX-resistant cells (MCF-7 and MCF-7/ADR). Moreover, PEG-Phis/Pasp-DOX/CA4 resulted in enhanced therapeutic efficacy in drug-resistant tumors with reduced toxicity. These results suggested that this site-specific drug-releasing system could be exploited as a promising treatment for cancers with repeated administration.

  8. Implications of central immune signaling caused by drugs of abuse: mechanisms, mediators and new therapeutic approaches for prediction and treatment of drug dependence.

    Science.gov (United States)

    Coller, Janet K; Hutchinson, Mark R

    2012-05-01

    In the past two decades a trickle of manuscripts examining the non-neuronal central nervous system immune consequences of the drugs of abuse has now swollen to a significant body of work. Initially, these studies reported associative evidence of central nervous system proinflammation resulting from exposure to the drugs of abuse demonstrating key implications for neurotoxicity and disease progression associated with, for example, HIV infection. However, more recently this drug-induced activation of central immune signaling is now understood to contribute substantially to the pharmacodynamic actions of the drugs of abuse, by enhancing the engagement of classical mesolimbic dopamine reward pathways and withdrawal centers. This review will highlight the key in vivo animal, human, biological and molecular evidence of these central immune signaling actions of opioids, alcohol, cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA). Excitingly, this new appreciation of central immune signaling activity of drugs of abuse provides novel therapeutic interventions and opportunities to identify 'at risk' individuals through the use of immunogenetics. Discussion will also cover the evidence of modulation of this signaling by existing clinical and pre-clinical drug candidates, and novel pharmacological targets. Finally, following examination of the breadth of central immune signaling actions of the drugs of abuse highlighted here, the current known common immune signaling components will be outlined and their impact on established addiction neurocircuitry discussed, thereby synthesizing a common neuroimmune hypothesis of addiction. Copyright © 2012 Elsevier Inc. All rights reserved.

  9. Therapeutic effects of local drug delivery systems - PerioChip® in the treatment of periodontal disease

    OpenAIRE

    Liljana Bogdanovska; Sahmedin Sali; Mirjana Popovska; Ilijana Muratovska; Aneta Dimitrovska; Rumenka Petkovska

    2014-01-01

    The primary goal of periodontal treatment is to stop periodontal disease progression and reduce future risks in disease recurrence. In order to overcome the limitations of the conventional treatment, controlled drug delivery systems for application in periodontal pockets have been developed. Their use offers several advantages: the therapeutic agent is targeted directly to the disease site and concentrations are 10-100 folds higher than the concentrations achieved by systemic administration, ...

  10. Giving Drugs a Second Chance: Overcoming Regulatory and Financial Hurdles in Repurposing Approved Drugs As Cancer Therapeutics

    Directory of Open Access Journals (Sweden)

    J. Javier Hernandez

    2017-11-01

    Full Text Available The repositioning or “repurposing” of existing therapies for alternative disease indications is an attractive approach that can save significant investments of time and money during drug development. For cancer indications, the primary goal of repurposed therapies is on efficacy, with less restriction on safety due to the immediate need to treat this patient population. This report provides a high-level overview of how drug developers pursuing repurposed assets have previously navigated funding efforts, regulatory affairs, and intellectual property laws to commercialize these “new” medicines in oncology. This article provides insight into funding programs (e.g., government grants and philanthropic organizations that academic and corporate initiatives can leverage to repurpose drugs for cancer. In addition, we highlight previous examples where secondary uses of existing, Food and Drug Administration- or European Medicines Agency-approved therapies have been predicted in silico and successfully validated in vitro and/or in vivo (i.e., animal models and human clinical trials for certain oncology indications. Finally, we describe the strategies that the pharmaceutical industry has previously employed to navigate regulatory considerations and successfully commercialize their drug products. These factors must be carefully considered when repurposing existing drugs for cancer to best benefit patients and drug developers alike.

  11. Navigating the Future of Cardiovascular Drug Development-Leveraging Novel Approaches to Drive Innovation and Drug Discovery: Summary of Findings from the Novel Cardiovascular Therapeutics Conference.

    Science.gov (United States)

    Povsic, Thomas J; Scott, Rob; Mahaffey, Kenneth W; Blaustein, Robert; Edelberg, Jay M; Lefkowitz, Martin P; Solomon, Scott D; Fox, Jonathan C; Healy, Kevin E; Khakoo, Aarif Y; Losordo, Douglas W; Malik, Fady I; Monia, Brett P; Montgomery, Rusty L; Riesmeyer, Jeffrey; Schwartz, Gregory G; Zelenkofske, Steven L; Wu, Joseph C; Wasserman, Scott M; Roe, Matthew T

    2017-08-01

    The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease. The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe. We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development. The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development.

  12. Old and new therapeutics for Rheumatoid Arthritis: in vivo models and drug development

    DEFF Research Database (Denmark)

    Sardar, Samra; Andersson, Åsa

    2016-01-01

    of in vivo models during development of anti-rheumatic drugs; from Methotrexate to various antibody treatments, to novel drugs that are, or have recently been, in clinical trials. For novel drugs, we have explored websites for clinical trials. Although one Rheumatoid Arthritis in vivo model cannot mirror...

  13. Self-carried curcumin nanoparticles for in vitro and in vivo cancer therapy with real-time monitoring of drug release

    Science.gov (United States)

    Zhang, Jinfeng; Li, Shengliang; An, Fei-Fei; Liu, Juan; Jin, Shubin; Zhang, Jin-Chao; Wang, Paul C.; Zhang, Xiaohong; Lee, Chun-Sing; Liang, Xing-Jie

    2015-08-01

    The use of different nanocarriers for delivering hydrophobic pharmaceutical agents to tumor sites has garnered major attention. Despite the merits of these nanocarriers, further studies are needed to improve their drug loading capacities (which are typically self-carried nanodrug delivery strategies without using inert carriers is highly desirable. In this study, we developed a self-carried curcumin (Cur) nanodrug for highly effective cancer therapy in vitro and in vivo with real-time monitoring of drug release. With a biocompatible C18PMH-PEG functionalization, the Cur nanoparticles (NPs) showed excellent dispersibility and outstanding stability in physiological environments with drug loading capacities >78 wt%. Both confocal microscopy and flow cytometry confirmed the cellular fluorescence ``OFF-ON'' activation and real-time monitoring of the Cur molecule release. In vitro and in vivo experiments clearly show that the therapeutic efficacy of the PEGylated Cur NPs is considerably better than that of free Cur. This self-carried strategy with real-time monitoring of drug release may open a new way for simultaneous cancer therapy and monitoring.The use of different nanocarriers for delivering hydrophobic pharmaceutical agents to tumor sites has garnered major attention. Despite the merits of these nanocarriers, further studies are needed to improve their drug loading capacities (which are typically self-carried nanodrug delivery strategies without using inert carriers is highly desirable. In this study, we developed a self-carried curcumin (Cur) nanodrug for highly effective cancer therapy in vitro and in vivo with real-time monitoring of drug release. With a biocompatible C18PMH-PEG functionalization, the Cur nanoparticles (NPs) showed excellent dispersibility and outstanding stability in physiological environments with drug loading capacities >78 wt%. Both confocal microscopy and flow cytometry confirmed the cellular fluorescence ``OFF-ON'' activation and real

  14. Effect of plasma treatment on the performance of two drug-loaded hydrogel formulations for therapeutic contact lenses.

    Science.gov (United States)

    Paradiso, Patrizia; Chu, Virginia; Santos, Luís; Serro, Ana Paula; Colaço, Rogério; Saramago, Benilde

    2015-07-01

    Although the plasma technology has long been applied to treat contact lenses, the effect of this treatment on the performance of drug-loaded contact lenses is still unclear. The objective of this work is to study the effect of nitrogen plasma treatment on two drug-loaded polymeric formulations which previously demonstrated to be suitable for therapeutic contact lenses: a poly-hydroxyethylmethacrylate (pHEMA) based hydrogel loaded with levofloxacin and a silicone-based hydrogel loaded with chlorhexidine. Modifications of the surface and the optical properties, and alterations in the drug release profiles and possible losses of the antimicrobial activities of the drugs induced by the plasma treatment were assessed. The results showed that, depending on the system and on the processing conditions, the plasma treatment may be beneficial for increasing wettability and refractive index, without degrading the lens surface. From the point of view of drug delivery, plasma irradiation at moderate power (200 W) decreased the initial release rate and the amount of released drug, maintaining the drug activity. For lower (100 W) and higher powers (300 W), almost no effect was detected because the treatment was, respectively, too soft and too aggressive for the lens materials. © 2014 Wiley Periodicals, Inc.

  15. Drug testing in Europe: monitoring results of the Trans European Drug Information (TEDI) project.

    Science.gov (United States)

    Brunt, Tibor M; Nagy, Constanze; Bücheli, Alexander; Martins, Daniel; Ugarte, Miren; Beduwe, Cécile; Ventura Vilamala, Mireia

    2017-02-01

    Drug testing is a harm reduction strategy that has been adopted by certain countries in Europe. Drug users are able to hand in their drugs voluntarily for chemical analysis of composition and dose. Drug users will be alerted about dangerous test results by the drug testing systems directly and through warning campaigns. An international collaborative effort was launched to combine data of drug testing systems, called the Trans European Drug Information (TEDI) project. Drug testing systems of Spain, Switzerland, Belgium, Austria, Portugal, and the Netherlands participated in this project. This study presents results of some of the main illicit drugs encountered: cocaine, ecstasy and amphetamine and also comments on new psychoactive substances (NPS) detected between 2008 and 2013. A total of 45 859 different drug samples were analyzed by TEDI. The drug markets of the distinct European areas showed similarities, but also some interesting differences. For instance, purity of cocaine and amphetamine powders was generally low in Austria, whilst high in Spain and the Netherlands. And the market for ecstasy showed a contrast: whereas in the Netherlands and Switzerland there was predominantly a market for ecstasy tablets, in Portugal and Spain MDMA (3,4-methylenedioxymethamphetamine) crystals were much more prevalent. Also, some NPS appearing in ecstasy seemed more specific for one country than another. In general, prevalence of NPS clearly increased between 2008 and 2013. Drug testing can be used to generate a global picture of drug markets and provides information about the pharmacological contents of drugs for the population at risk. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  16. Quantitative structural characterization of local N-glycan microheterogeneity in therapeutic antibodies by energy-resolved oxonium ion monitoring.

    Science.gov (United States)

    Toyama, Atsuhiko; Nakagawa, Hidewaki; Matsuda, Koichi; Sato, Taka-Aki; Nakamura, Yusuke; Ueda, Koji

    2012-11-20

    Site-specific characterization of glycoform heterogeneity currently requires glycan structure assignment and glycopeptide quantification in two independent experiments. We present here a new method combining multiple reaction monitoring mass spectrometry with energy-resolved structural analysis, which we termed "energy-resolved oxonium ion monitoring". We demonstrated that monitoring the yields of oligosaccharide-derived fragment ions (oxonium ions) over a wide range of collision induced dissociation (CID) energy applied to a glycopeptide precursor exhibits a glycan structure-unique fragmentation pattern. In the analysis of purified immunoglobulin glycopeptides, the energy-resolved oxonium ion profile was shown to clearly distinguish between isomeric glycopeptides. Moreover, limit of detection (LOD) of glycopeptide detection was 30 attomole injection, and quantitative dynamic range spanned 4 orders magnitude. Therefore, both quantification of glycopeptides and assignment of their glycan structures were achieved by a simple analysis procedure. We assessed the utility of this method for characterizing site-specific N-glycan microheterogeneity on therapeutic antibodies, including validation of lot-to-lot glycoform variability. A significant change in the degree of terminal galactosylation was observed in different production lots of trastuzumab and bevacizumab. Cetuximab Fab glycosylation, previously known to cause anaphylaxis, was also analyzed, and several causative antigens including Lewis X motifs were quantitatively detected. The data suggests that energy-resolved oxonium ion monitoring could fulfill the regulatory requirement on the routine quality control analysis of forthcoming biosimilar therapeutics.

  17. In Silico Systems Pharmacology to Assess Drug's Therapeutic and Toxic Effects

    DEFF Research Database (Denmark)

    Orozco, Alejandro Aguayo; Audouze, Karine; Brunak, Soren

    2016-01-01

    that consider the global physiological environment of protein targets and their modification by drugs. Studying drug action across multiple scales of complexity from molecular and cellular to tissue and organism levels may help identify new druggable disease genes and to design new drugs with a better efficacy......For many years, the "one target, one drug" paradigm has been the driving force behind developments in pharmaceutical research. With the recent advances in molecular biology and genomics technologies, the focus is shifting toward "drug-holistic" systems based approaches (i.e. systems pharmacology......). The integration of large and diverse amount of data from chemistry and biology coupled with the development and the application of network-based approaches to cope with these data is the next paradigm of drug discovery. Systems pharmacology offers a novel way of approaching drug discovery by developing models...

  18. In Silico Systems Pharmacology to Assess Drug's Therapeutic and Toxic Effects.

    Science.gov (United States)

    Aguayo-Orozco, Alejandro; Audouze, Karine; Brunak, Soren; Taboureau, Olivier

    2016-01-01

    For many years, the "one target, one drug" paradigm has been the driving force behind developments in pharmaceutical research. With the recent advances in molecular biology and genomics technologies, the focus is shifting toward "drug-holistic" systems based approaches (i.e. systems pharmacology). The integration of large and diverse amount of data from chemistry and biology coupled with the development and the application of network-based approaches to cope with these data is the next paradigm of drug discovery. Systems pharmacology offers a novel way of approaching drug discovery by developing models that consider the global physiological environment of protein targets and their modification by drugs. Studying drug action across multiple scales of complexity from molecular and cellular to tissue and organism levels may help identify new druggable disease genes and to design new drugs with a better efficacy and clinical safety. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  19. Monitoring of drug intake during pregnancy by questionnaires and LC-MS/MS drug urine screening: evaluation of both monitoring methods.

    Science.gov (United States)

    Hoeke, Henrike; Roeder, Stefan; Bertsche, Thilo; Lehmann, Irina; Borte, Michael; von Bergen, Martin; Wissenbach, Dirk K

    2015-08-01

    Various studies pointed towards a relationship between chronic diseases such as asthma and allergy and environmental risk factors, which are one aspect of the so-called Exposome. These environmental risk factors include also the intake of drugs. One critical step in human development is the prenatal period, in which exposures might have critical impact on the child's health outcome. Thereby, the health effects of drugs taken during gestation are discussed controversially with regard to newborns' disease risk. Due to this, the drug intake of pregnant women in the third trimester was monitored by questionnaire, in addition to biomonitoring using a local birth cohort study, allowing correlations of drug exposure with disease risk. Therefore, 622 urine samples were analyzed by an untargeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) urine screening and the results were compared to self-administered questionnaires. In total, 48% (n = 296) reported an intake of pharmaceuticals, with analgesics as the most frequent reported drug class in addition to dietary supplements. 182 times compounds were detected by urine screening, with analgesics (42%; n = 66) as the predominantly drug class. A comparison of reported and detected drug intake was performed for three different time spans between completion of the questionnaires and urine sampling. Even if the level of accordance was low in general, similar percentages (~25%, ~19%, and ~ 20%) were found for all groups. This study illustrates that a comprehensive evaluation of drug intake is neither achieved by questionnaires nor by biomonitoring alone. Instead, a combination of both monitoring methods, providing complementary information, should be considered. Copyright © 2014 John Wiley & Sons, Ltd.

  20. "Not just eliminating the mosquito but draining the swamp": A critical geopolitics of Turkish Monitoring Center for Drugs and Drug Addiction and Turkey's approach to illicit drugs.

    Science.gov (United States)

    Evered, Kyle T; Evered, Emine Ö

    2016-07-01

    In the 1970s, Turkey ceased to be a significant producer state of illicit drugs, but it continued to serve as a key route for the trade of drugs between East and West. Over the past decade, however, authorities identified two concerns beyond its continued transit state status. These reported problems entail both new modes of production and a rising incidence of drug abuse within the nation-state - particularly among its youth. Amid these developments, new law enforcement institutions emerged and acquired European sponsorship, leading to the establishment of TUBİM (the Turkish Monitoring Center for Drugs and Drug Addiction). Coordinating with and reporting to the European Union agency EMCDDA (the European Monitoring Center for Drugs and Drug Addiction), TUBİM's primary assigned duties entail the collection and analysis of data on drug abuse, trafficking, and prevention, the geographic identification of sites of concern (e.g. consumption, drug-related crimes, and peoples undergoing treatment), and the production of annual national reports. In this article, we examine the geopolitical origins of TUBİM as Turkey's central apparatus for confronting drug problems and its role as a vehicle for policy development, interpretation, and enforcement. In doing so, we emphasize the political and spatial dimensions inherent to the country's institutional and policy-driven approaches to contend with drug-related problems, and we assess how this line of attack reveals particular ambiguities in mission when evaluated from scales at world regional, national, and local levels. In sum, we assess how Turkey's new institutional and legislative landscapes condition the state's engagements with drug use, matters of user's health, and policy implementation at local scales and amid ongoing political developments. Copyright © 2016 Elsevier B.V. All rights reserved.

  1. A DT-diaphorase responsive theranostic prodrug for diagnosis, drug release monitoring and therapy.

    Science.gov (United States)

    Liu, Peilian; Xu, Jiangsheng; Yan, Donghang; Zhang, Peisheng; Zeng, Fang; Li, Bowen; Wu, Shuizhu

    2015-06-11

    A DT-diaphorase-activatable theranostic prodrug, which contains camptothecin, a self-immolative linker and a trigger group, has been developed for the detection of DT-diaphorase, tracking of drug release and selectively killing cancer cells over-expressed with DT-diaphorase. This strategy may offer a new approach for the development of enzyme-catalyzed theranostic anticancer therapeutics.

  2. [Which alternatives are at our disposal in the anti-infectious therapeutics face to multi-drug resistant bacteria?].

    Science.gov (United States)

    Bourlioux, P

    2013-05-01

    The development of multi-drug resistance to antibiotics during the last years and the few number of new active molecules launched on the market have limited the treatment of some infectious diseases. Which alternatives are at our disposal in the anti-infectious therapeutics face to multi-drug resistant bacteria? Considering the bibliographic data, we can note different facts: (1) some alternatives already exist, but correspond more to targeted useful and usable therapeutics as phage therapy, honey therapy, or maggot therapy; (2) some "old" antibiotics can find new bacterial targets and reinforce the anti-infectious therapy towards some multi-drug resistant bacteria; (3) new formulations can allow targeted drug delivery via nanoparticles and the association of molecules can reinforce the antibiotic antimicrobial effect; (4) new treatment could be potentially usable as: antimicrobial peptides, probiotics, herbal medicines, statins, phosphonosulfonates, fecal transplants...; (5) at least, we must not forget that "it's better to prevent than cure". So, besides the principles of hygiene that must be respected, it is necessary to promote (if possible) the development of new vaccines against bacteria responsible for nosocomial infections. Facing with this potential, we can say that new orientations are open with very different levels of success and that it is urgent to find new targets ignored or forgotten until now. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  3. A Bioequivalence Approach for Generic Narrow Therapeutic Index Drugs: Evaluation of the Reference-Scaled Approach and Variability Comparison Criterion.

    Science.gov (United States)

    Jiang, Wenlei; Makhlouf, Fairouz; Schuirmann, Donald J; Zhang, Xinyuan; Zheng, Nan; Conner, Dale; Yu, Lawrence X; Lionberger, Robert

    2015-07-01

    Various health communities have expressed concerns regarding whether average bioequivalence (BE) limits (80.00-125.00%) for the 90% confidence interval of the test-to-reference geometric mean ratio are sufficient to ensure therapeutic equivalence between a generic narrow therapeutic index (NTI) drug and its reference listed drug (RLD). Simulations were conducted to investigate the impact of different BE approaches for NTI drugs on study power, including (1) direct tightening of average BE limits and (2) a scaled average BE approach where BE limits are tightened based on the RLD's within-subject variability. Addition of a variability comparison (using a one-tailed F test) increased the difficulty for generic NTIs more variable than their corresponding RLDs to demonstrate bioequivalence. Based on these results, the authors evaluate the fully replicated, 2-sequence, 2-treatment, 4-period crossover study design for NTI drugs where the test product demonstrates BE based on a scaled average bioequivalence criterion and a within-subject variability comparison criterion.

  4. Targeted Drug Delivery Systems and Their Therapeutic Applications in Cancer and Immune Pathological Conditions.

    Science.gov (United States)

    Iqbal, Jamshed; Anwar, Fareeha; Afridi, Saifullah

    2017-01-01

    More than a century ago, Paul Ehrlich proposed the idea of a drug working as a "magic bullet" that selectively eliminates diseased cells without harming the surrounding normal cells. Since then, much progress has been made in this field to broaden the scope for targeted delivery of drugs. A major problem remain the toxic effects of targeted drugs on healthy cells. In order to reduce the adverse effects of chemotherapy on healthy tissues, we survey the use of recent drug delivery systems for targeted therapy. The selective delivery of the drugs to specific diseased cells or tissues still is a daunting task. Ideally, for target drug delivery systems, the system should be made up of carriers and drugs, where carriers precisely target the desired drug. This issue covers the recent advancements in modern techniques for such purposes. It encompasses advances, benefits and limitations in state of art work of targeted drug delivery through hydrogels, microfluidics, nanoparticles, carbon nanotubes, polymeric micelles, liposomes, lipoprotein based drug carriers and dendrites. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  5. Novel drug and soluble target tolerant antidrug antibody assay for therapeutic antibodies bearing the P329G mutation.

    Science.gov (United States)

    Wessels, Uwe; Schick, Eginhard; Ritter, Mirko; Kowalewsky, Frank; Heinrich, Julia; Stubenrauch, Kay

    2017-06-01

    Bridging immunoassays for detection of antidrug antibodies (ADAs) are typically susceptible to high concentrations of residual drug. Sensitive drug-tolerant assays are, therefore, needed. An immune complex assay to detect ADAs against therapeutic antibodies bearing Pro329Gly mutation was established. The assay uses antibodies specific for the Pro329Gly mutation for capture and human soluble Fcγ receptor for detection. When compared with a bridging assay, the new assay showed similar precision, high sensitivity to IgG1 ADA and dramatically improved drug tolerance. However, it was not able to detect early (IgM-based) immune responses. Applied in combination with a bridging assay, the novel assay serves as orthogonal assay for immunogenicity assessment and allows further characterization of ADA responses.

  6. Multi-drug resistance (MDR1 gene and P-glycoprotein influence on pharmacokinetic and pharmacodymanic of therapeutic drugs

    Directory of Open Access Journals (Sweden)

    Linardi Renata Lehn

    2006-01-01

    Full Text Available (MDR1 gene expressed in tumor cells and also in several normal tissues, such as intestine, liver, kidney, blood-brain barrier, spinal cord, and placenta. P-gp has been identified in mice, rat, bovine, monkey, rodents, and human beings and has been receiving a particular clinical relevance because this protein expression limits brain access and intestinal absorption of many drugs. This protein plays a role as a protective barrier against a wide variety of substrates, avoiding drug entry into the central nervous system. P-glycoprotein also interferes with drug bioavailability and disposition, including absorption, distribution, metabolization, and excretion, influencing pharmacokinetic and pharmacodynamic of drugs. Modulation of P-gp may help the efficacy of treatment of several diseases and can explain some adverse central nervous system effects induced by drugs after intravenous administration and the poor response of oral administration in patients. Alteration in P-gp expression or function has been associated with several diseases susceptibility in humans and animals. Furthermore, additional studies relating MDR1 and P-gp expression has an important clinical implication also in terms of treatment efficacy.

  7. Interest of a drug and therapeutics committee for the operation of a hospital in a developing country: Dapaong, Togo.

    Science.gov (United States)

    Ben Yahya, M

    2016-05-01

    The department of pharmacy of the Regional Hospital of Dapaong is responsible for delivery of health products. We sought to assess the department's avoidable costs to optimize the hospital's drug policies and thereby improve patient care. This cost-forecasting study is intended to convince the hospital staff of the utility of setting up a drug and therapeutics committee and more particularly of developing a drug handbook for use within the public health institutions of the Savanna region. This prospective study seeks to improve the efficiency, quality, and availability of medicines by listing the references currently available at the Regional Hospital to demonstrate the percentage of duplicates and to show the references currently unavailable via "lost" sales. A retrospective study then estimated the loss of income from sales due to expired drugs. Our studies indicate that optimized management of the pharmacy would result in a potential gain of 14,914,397 FCFA, that is, 22,770 €. This significant savings could be used to improve the quality of care and promote quality assurance at the CHRD. The elimination of duplicates would allow the purchase of currently unavailable pharmaceutical classes (12,369,701 FCFA, that is, 18,885 € for reinvestment), and multidisciplinary collaboration with prescribers could reduce the losses associated with expired drugs (2,544,696 FCFA, or 3,885 €). These changes would improve the matching of the drugs prescribed at the CHRD and those delivered by the pharmacy.

  8. Japan-China Joint Medical Workshop on Drug Discoveries and Therapeutics 2008: The need of Asian pharmaceutical researchers' cooperation.

    Science.gov (United States)

    Nakata, M; Tang, W

    2008-10-01

    The Japan-China Joint Medical Workshop on Drug Discoveries and Therapeutics 2008 (JCMWDDT 2008) was held from September 29 to October 1, 2008 at The University of Tokyo, Tokyo, Japan. JCMWDDT is an international workshop that is mainly organized by Asian editorial members of Drug Discoveries & Therapeutics (http://www.ddtjournal.com/home) for the purpose of promoting research exchanges in the field of drug discovery and therapeutic. This year's JCMWDDT is the second workshop and focused particularly on novel development and technological innovation of anti-influenza agents. The workshop began with an announcement by the Japanese Co-chairperson, Dr. Sekimizu (Department of Microbiology, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Japan; Editorin- Chief of Drug Discoveries & Therapeutics, DDT) followed by a speech by the Chinese Co-chairperson, Dr. Wenfang Xu (School of Pharmaceutical Sciences, Shandong University, Shandong, China; Editor in China Office of DDT), with additional speeches by Dr. Norio Matsuki (The University of Tokyo, Japan; Editor of DDT) and Dr. Guanhua Du (Chinese Academy of Medical Science, China; Editor of DDT). Fifty-nine titles were presented in 6 specialized sessions (Research Advances in Drug Discoveries and Therapeutics, Drug Synthesis/Clinical Therapeutics, Medicinal Chemistry/Natural Products, Anti-influenza Drugs, Anti-infection/antiviral Drugs, Biochemistry/Molecular Biology /Pharmacology) and a poster session (Drug Discov Ther 2008; 2, Suppl; available at http://www.ddtjournal.com/Announce/index.htm). An annual outbreak of avian influenza in Asian countries including China and Japan has sparked fears that the virus will mutate and then cause an epidemic in humans. Therefore, Asian researchers need to work together to control this infection. This year's JCMWDDT helped provide an opportunity to reiterate the crucial role of medicinal chemistry in conquering influenza and created an environment for cooperative

  9. Therapeutic indications and other use-case-driven updates in the drug ontology: anti-malarials, anti-hypertensives, opioid analgesics, and a large term request.

    Science.gov (United States)

    Hogan, William R; Hanna, Josh; Hicks, Amanda; Amirova, Samira; Bramblett, Baxter; Diller, Matthew; Enderez, Rodel; Modzelewski, Timothy; Vasconcelos, Mirela; Delcher, Chris

    2017-03-03

    The Drug Ontology (DrOn) is an OWL2-based representation of drug products and their ingredients, mechanisms of action, strengths, and dose forms. We originally created DrOn for use cases in comparative effectiveness research, primarily to identify historically complete sets of United States National Drug Codes (NDCs) that represent packaged drug products, by the ingredient(s), mechanism(s) of action, and so on contained in those products. Although we had designed DrOn from the outset to carefully distinguish those entities that have a therapeutic indication from those entities that have a molecular mechanism of action, we had not previously represented in DrOn any particular therapeutic indication. In this work, we add therapeutic indications for three research use cases: resistant hypertension, malaria, and opioid abuse research. We also added mechanisms of action for opioid analgesics and added 108 classes representing drug products in response to a large term request from the Program for Resistance, Immunology, Surveillance and Modeling of Malaria in Uganda (PRISM) project. The net result is a new version of DrOn, current to May 2016, that represents three major therapeutic classes of drugs and six new mechanisms of action. A therapeutic indication of a drug product is represented as a therapeutic function in DrOn. Adverse effects of drug products, as well as other therapeutic uses for which the drug product was not designed are dispositions. Our work provides a framework for representing additional therapeutic indications, adverse effects, and uses of drug products beyond their design. Our work also validated our past modeling decisions for specific types of mechanisms of action, namely effects mediated via receptor and/or enzyme binding. DrOn is available at: http://purl.obolibrary.org/obo/dron.owl . A smaller version without NDCs is available at: http://purl.obolibrary.org/obo/dron/dron-lite.owl.

  10. Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer’s Disease Therapeutic Agents

    Directory of Open Access Journals (Sweden)

    Laura Llorach-Pares

    2017-11-01

    Full Text Available Computer-aided drug discovery/design (CADD techniques allow the identification of natural products that are capable of modulating protein functions in pathogenesis-related pathways, constituting one of the most promising lines followed in drug discovery. In this paper, we computationally evaluated and reported the inhibitory activity found in meridianins A–G, a group of marine indole alkaloids isolated from the marine tunicate Aplidium, against various protein kinases involved in Alzheimer’s disease (AD, a neurodegenerative pathology characterized by the presence of neurofibrillary tangles (NFT. Balance splitting between tau kinase and phosphate activities caused tau hyperphosphorylation and, thereby, its aggregation and NTF formation. Inhibition of specific kinases involved in its phosphorylation pathway could be one of the key strategies to reverse tau hyperphosphorylation and would represent an approach to develop drugs to palliate AD symptoms. Meridianins bind to the adenosine triphosphate (ATP binding site of certain protein kinases, acting as ATP competitive inhibitors. These compounds show very promising scaffolds to design new drugs against AD, which could act over tau protein kinases Glycogen synthetase kinase-3 Beta (GSK3β and Casein kinase 1 delta (CK1δ, CK1D or KC1D, and dual specificity kinases as dual specificity tyrosine phosphorylation regulated kinase 1 (DYRK1A and cdc2-like kinases (CLK1. This work is aimed to highlight the role of CADD techniques in marine drug discovery and to provide precise information regarding the binding mode and strength of meridianins against several protein kinases that could help in the future development of anti-AD drugs.

  11. Improved Tumor-Specific Drug Accumulation by Polymer Therapeutics with pH-Sensitive Drug Release Overcomes Chemotherapy Resistance.

    Science.gov (United States)

    Heinrich, Anne-Kathrin; Lucas, Henrike; Schindler, Lucie; Chytil, Petr; Etrych, Tomáš; Mäder, Karsten; Mueller, Thomas

    2016-05-01

    The success of chemotherapy is limited by poor selectivity of active drugs combined with occurrence of tumor resistance. New star-like structured N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based drug delivery systems containing doxorubicin attached via a pH-sensitive hydrazone bond were designed and investigated for their ability to overcome chemotherapy resistance. These conjugates combine two strategies to achieve a high drug concentration selectively at the tumor site: (I) high accumulation by passive tumor targeting based on enhanced permeability and retention effect and (II) pH-sensitive site-specific drug release due to an acidic tumor microenvironment. Mice bearing doxorubicin-resistant xenograft tumors were treated with doxorubicin, PBS, poly HPMA (pHPMA) precursor or pHPMA-doxorubicin conjugate at different equivalent doses of 5 mg/kg bodyweight doxorubicin up to a 7-fold total dose using different treatment schedules. Intratumoral drug accumulation was analyzed by fluorescence imaging utilizing intrinsic fluorescence of doxorubicin. Free doxorubicin induced significant toxicity but hardly any tumor-inhibiting effects. Administering at least a 3-fold dose of pHPMA-doxorubicin conjugate was necessary to induce a transient response, whereas doses of about 5- to 6-fold induced strong regressions. Tumors completely disappeared in some cases. The onset of response was differential delayed depending on the tumor model, which could be ascribed to distinct characteristics of the microenvironment. Further fluorescence imaging-based analyses regarding underlying mechanisms of the delayed response revealed a related switch to a more supporting intratumoral microenvironment for effective drug release. In conclusion, the current study demonstrates that the concept of tumor site-restricted high-dose chemotherapy is able to overcome therapy resistance. Mol Cancer Ther; 15(5); 998-1007. ©2016 AACR. ©2016 American Association for Cancer Research.

  12. [Therapeutic effect of phages on extensively drug-resistant Acinetobacter baumannii-induced sepsis in mice].

    Science.gov (United States)

    Deng, L Y; Yang, Z C; Gong, Y L; Huang, G T; Yin, S P; Jiang, B; Peng, Y Z

    2016-09-20

    To study the therapeutic effect of phages on extensively drug-resistant Acinetobacter baumannii-induced sepsis in mice. (1) Sixty BALB/c mice were divided into blank control group, sepsis control group, antibiotics treatment group, phage treatment group, and phage control group according to the random number table, with 12 mice in each group. Mice in blank control group were intraperitoneally (the same injection position below) injected with 1 mL normal saline. Mice in sepsis control group, antibiotics treatment group, and phage treatment group were injected with 1 mL extensively drug-resistant Acinetobacter baumannii (the strain was isolated from the blood of a severely burned patient hospitalized in our unit) in the concentration of 5×10(7) colony-forming unit/mL to reproduce sepsis model. Two hours later, mice in sepsis control group, antibiotics treatment group, and phage treatment group were injected with 1 mL saline, 1 mg/mL imipenem/cilastatin, and 1×10(8) plaque-forming unit (PFU)/mL phages screened based on above-mentioned Acinetobacter baumannii (the same phages below) respectively. Mice in phage control group were injected with 1 mL phages in the titer of 1×10(8) PFU/mL. The injection was performed continuously for 7 days in each living mouse, and the survival situation of mice was observed each day to calculate the survival ratio in one week. (2) Another 60 BALB/c mice were grouped and treated as in experiment (1), and the injection was performed continuously for 5 days in each living mouse. On experiment day 2, 4, and 6, 3 mice from each group were selected (if the number of survived mouse in any group was less than 3 at sample collecting, all the survived mice were selected), and blood was drawn to determine white blood cell count (WBC, with 3 samples at each time point in each group). On experiment day 2, blood was drawn from the mice that had their blood taken earlier for bacterial culture, and lung, liver, kidney, and spleen tissue was collected

  13. Approaches to transport therapeutic drugs across the blood-brain barrier to treat brain diseases.

    Science.gov (United States)

    Gabathuler, Reinhard

    2010-01-01

    The central nervous system is protected by barriers which control the entry of compounds into the brain, thereby regulating brain homeostasis. The blood-brain barrier, formed by the endothelial cells of the brain capillaries, restricts access to brain cells of blood-borne compounds and facilitates nutrients essential for normal metabolism to reach brain cells. This very tight regulation of the brain homeostasis results in the inability of some small and large therapeutic compounds to cross the blood-brain barrier (BBB). Therefore, various strategies are being developed to enhance the amount and concentration of therapeutic compounds in the brain. In this review, we will address the different approaches used to increase the transport of therapeutics from blood into the brain parenchyma. We will mainly concentrate on the physiologic approach which takes advantage of specific receptors already expressed on the capillary endothelial cells forming the BBB and necessary for the survival of brain cells. Among all the approaches used for increasing brain delivery of therapeutics, the most accepted method is the use of the physiological approach which takes advantage of the transcytosis capacity of specific receptors expressed at the BBB. The low density lipoprotein receptor related protein (LRP) is the most adapted for such use with the engineered peptide compound (EPiC) platform incorporating the Angiopep peptide in new therapeutics the most advanced with promising data in the clinic.

  14. Oral antidiabetic therapy in a large Italian sample: drug supply and compliance for different therapeutic regimens.

    Science.gov (United States)

    Vittorino Gaddi, A; Benedetto, D; Capello, F; Di Pietro, C; Cinconze, E; Rossi, E; De Sando, V; Cevenini, M; D'Alò, G

    2014-01-01

    .34); and LDCT, 0.64 (IQR 0.39). Compliance was better for FDCT than the other therapeutic regimens in the study population. The same trend was observed in both the prevalent and incident patient cohorts. As type 2 diabetes is a chronic lifelong pathology, and multiple agents are often required to achieve glycaemic control, the preference for FDCT in the population, when clinically applicable, could be an effective strategy for functional administration of clinical outcome and sources. Evaluation of specific population fractions (age, sex, compliance, etc.) and specific agents or drug combinations could also be relevant in order to reach the healthcare objectives. Copyright © 2013 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

  15. Optimizing therapeutics in the management of patients with multiple sclerosis: a review of drug efficacy, dosing, and mechanisms of action

    Directory of Open Access Journals (Sweden)

    Damal K

    2013-11-01

    Full Text Available Kavitha Damal, Emily Stoker, John F FoleyRocky Mountain Multiple Sclerosis Research Group, Salt Lake City, UT, USAAbstract: Multiple sclerosis (MS is a debilitating neurological disorder that affects nearly 2 million adults, mostly in their prime of youth. An environmental trigger, such as a viral infection, is hypothesized to initiate the abnormal behavior of host immune cells: to attack and damage the myelin sheath surrounding the neurons of the central nervous system. While several other pathways and disease triggers are still being investigated, it is nonetheless clear that MS is a heterogeneous disease with multifactorial etiologies that works independently or synergistically to initiate the aberrant immune responses to myelin. Although there are still no definitive markers to diagnose the disease or to cure the disease per se, research on management of MS has improved many fold over the past decade. New disease-modifying therapeutics are poised to decrease immune inflammatory responses and consequently decelerate the progression of MS disease activity, reduce the exacerbations of MS symptoms, and stabilize the physical and mental status of individuals. In this review, we describe the mechanism of action, optimal dosing, drug administration, safety, and efficacy of the disease-modifying therapeutics that are currently approved for MS therapy. We also briefly touch upon the new drugs currently under investigation, and discuss the future of MS therapeutics.Keywords: multiple sclerosis, immunomodulation, interferons, glatiramer acetate, monoclonal antibodies, dimethyl fumarate

  16. Drug-Encoded Biomarkers for Monitoring Biological Therapies.

    Directory of Open Access Journals (Sweden)

    Desislava Tsoneva

    Full Text Available Blood tests are necessary, easy-to-perform and low-cost alternatives for monitoring of oncolytic virotherapy and other biological therapies in translational research. Here we assessed three candidate proteins with the potential to be used as biomarkers in biological fluids: two glucuronidases from E. coli (GusA and Staphylococcus sp. RLH1 (GusPlus, and the luciferase from Gaussia princeps (GLuc. The three genes encoding these proteins were inserted individually into vaccinia virus GLV-1h68 genome under the control of an identical promoter. The three resulting recombinant viruses were used to infect tumor cells in cultures and human tumor xenografts in nude mice. In contrast to the actively secreted GLuc, the cytoplasmic glucuronidases GusA and GusPlus were released into the supernatants only as a result of virus-mediated oncolysis. GusPlus resulted in the most sensitive detection of enzyme activity under controlled assay conditions in samples containing as little as 1 pg/ml of GusPlus, followed by GusA (25 pg/ml and GLuc (≥375 pg/ml. Unexpectedly, even though GusA had a lower specific activity compared to GusPlus, the substrate conversion in the serum of tumor-bearing mice injected with the GusA-encoding virus strains was substantially higher than that of GusPlus. This was attributed to a 3.2 fold and 16.2 fold longer half-life of GusA in the blood stream compared to GusPlus and GLuc respectively, thus a more sensitive monitor of virus replication than the other two enzymes. Due to the good correlation between enzymatic activity of expressed marker gene and virus titer, we conclude that the amount of the biomarker protein in the body fluid semiquantitatively represents the amount of virus in the infected tumors which was confirmed by low light imaging. We found GusA to be the most reliable biomarker for monitoring oncolytic virotherapy among the three tested markers.

  17. National Drug Formulary review of statin therapeutic group using the multiattribute scoring tool

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    Ramli A

    2013-12-01

    Full Text Available Azuana Ramli,1,3 Syed Mohamed Aljunid,1,2 Saperi Sulong,2 Faridah Aryani Md Yusof31United Nations University International Institute for Global Health (UNU-IIGH, Kuala Lumpur, Malaysia; 2International Centre for Casemix and Clinical Coding (ITCC, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia; 3Pharmaceutical Services Division, Ministry of Health, Petaling Jaya, MalaysiaPurpose: HMG-CoA reductase inhibitors (statins are extensively used in treating hypercholesterolemia. The statins available in Malaysia include atorvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, and fluvastatin. Over the years, they have accumulated in the National Drug Formulary; hence, the need for review. Effective selection of the best drugs to remain in the formulary can become complex due to the multiple drug attributes involved, and is made worse by the limited time and resources available. The multiattribute scoring tool (MAST systematizes the evaluation of the drug attributes to facilitate the drug selection process. In this study, a MAST framework was developed to rank the statins based on their utilities or benefits.Methods: Published literature on multicriteria decision analysis (MCDA were studied and five sessions of expert group discussions were conducted to build the MAST framework and to review the evidence. The attributes identified and selected for analysis were efficacy (clinical efficacy, clinical endpoints, safety (drug interactions, serious side effects and documentation, drug applicability (drug strength/formulation, indications, dose frequency, side effects, food–drug interactions, and dose adjustments, and cost. The average weights assigned by the members for efficacy, safety, drug applicability and cost were 32.6%, 26.2%, 24.1%, and 17.1%, respectively. The utility values of the attributes were scored based on the published evidence or/and agreements during the group discussions. The attribute scores were added up

  18. Digital drug safety surveillance: monitoring pharmaceutical products in twitter.

    Science.gov (United States)

    Freifeld, Clark C; Brownstein, John S; Menone, Christopher M; Bao, Wenjie; Filice, Ross; Kass-Hout, Taha; Dasgupta, Nabarun

    2014-05-01

    Traditional adverse event (AE) reporting systems have been slow in adapting to online AE reporting from patients, relying instead on gatekeepers, such as clinicians and drug safety groups, to verify each potential event. In the meantime, increasing numbers of patients have turned to social media to share their experiences with drugs, medical devices, and vaccines. The aim of the study was to evaluate the level of concordance between Twitter posts mentioning AE-like reactions and spontaneous reports received by a regulatory agency. We collected public English-language Twitter posts mentioning 23 medical products from 1 November 2012 through 31 May 2013. Data were filtered using a semi-automated process to identify posts with resemblance to AEs (Proto-AEs). A dictionary was developed to translate Internet vernacular to a standardized regulatory ontology for analysis (MedDRA(®)). Aggregated frequency of identified product-event pairs was then compared with data from the public FDA Adverse Event Reporting System (FAERS) by System Organ Class (SOC). Of the 6.9 million Twitter posts collected, 4,401 Proto-AEs were identified out of 60,000 examined. Automated, dictionary-based symptom classification had 86 % recall and 72 % precision [corrected]. Similar overall distribution profiles were observed, with Spearman rank correlation rho of 0.75 (p Twitter and FAERS by SOC. Patients reporting AEs on Twitter showed a range of sophistication when describing their experience. Despite the public availability of these data, their appropriate role in pharmacovigilance has not been established. Additional work is needed to improve data acquisition and automation.

  19. Therapeutic effects of antibiotic drug tigecycline against cervical squamous cell carcinoma by inhibiting Wnt/β-catenin signaling

    Energy Technology Data Exchange (ETDEWEB)

    Li, Hui; Jiao, Shun [Department of Obstetrics and Gynaecology, JingZhou Hospital Affiliated to Huazhong University of Science and Technology, Jingzhou (China); Li, Xin [Department of Obstetrics and Gynaecology, RenMin Hospital of Wuhan University, Wuhan (China); Banu, Hasina; Hamal, Shreejana [Department of Clinical Medicine, Medical School of Yangtze University, Jingzhou (China); Wang, Xianrong, E-mail: Dr.XianRong.Wang@hotmail.com [Department of Obstetrics and Gynaecology, JingZhou Hospital Affiliated to Huazhong University of Science and Technology, Jingzhou (China)

    2015-11-06

    Aberrant activation of the Wnt/β-catenin signaling pathway is common in human cervical cancers and has great potential therapeutic value. We show that tigecycline, a FDA-approved antibiotic drug, targets cervical squamous cell carcinoma through inhibiting Wnt/β-catenin signaling pathway. Tigecycline is effective in inducing apoptosis, inhibiting proliferation and anchorage-independent colony formation of Hela cells. The inhibitory effects of tigecycline are further enhanced upon combination with paclitaxel, a most commonly used chemotherapeutic drug for cervical cancer. In a cervical xenograft model, tigecycline inhibits tumor growth as a single agent and its combination with paclitaxel significantly inhibits more tumor growth throughout the duration of treatment. We further show that tigecycline decreases level of both cytoplasmic and nuclear β-catenin and suppressed Wnt/β-catenin-mediated transcription through increasing levels of Axin 1 in Hela cells. In addition, stabilization or overexpression of β-catenin using pharmacological and genetic approaches abolished the effects of tigecycline in inhibiting proliferation and inducing apoptosis of Hela cells. Our study suggests that tigecycline is a useful addition to the treatment armamentarium for cervical cancer and targeting Wnt/β-catenin represents a potential therapeutic strategy in cervical cancer. - Highlights: • We repurposed the antibiotic drug tigecycline for cervical cancer treatment. • Tigecycline is effectively against cervical cancer cells in vitro and in vivo. • Combination of tigecycline and paclitaxel is synergistic in targeting Hela cells. • Tigecycline acts on Hela cells through inhibiting Wnt/β-catenin signaling.

  20. Using PEGylated magnetic nanoparticles to describe the EPR effect in tumor for predicting therapeutic efficacy of micelle drugs.

    Science.gov (United States)

    Chen, Ling; Zang, Fengchao; Wu, Haoan; Li, Jianzhong; Xie, Jun; Ma, Ming; Gu, Ning; Zhang, Yu

    2018-01-08

    Micelle drugs based on a polymeric platform offer great advantages over liposomal drugs for tumor treatment. Although nearly all of the nanomedicines approved in the clinical use can passively target to the tumor tissues on the basis of an enhanced permeability and retention (EPR) effect, the nanodrugs have shown heterogenous responses in the patients. This phenomenon may be traced back to the EPR effect of tumor, which is extremely variable in the individuals from extensive studies. Nevertheless, there is a lack of experimental data describing the EPR effect and predicting its impact on therapeutic efficacy of nanoagents. Herein, we developed 32 nm magnetic iron oxide nanoparticles (MION) as a T2-weighted contrast agent to describe the EPR effect of each tumor by in vivo magnetic resonance imaging (MRI). The MION were synthesized by a thermal decomposition method and modified with DSPE-PEG2000 for biological applications. The PEGylated MION (Fe3O4@PEG) exhibited high r2 of 571 mM-1 s-1 and saturation magnetization (Ms) of 94 emu g-1 Fe as well as long stability and favorable biocompatibility through the in vitro studies. The enhancement intensities of the tumor tissue from the MR images were quantitatively measured as TNR (Tumor/Normal tissue signal Ratio) values, which were correlated with the delay of tumor growth after intravenous administration of the PLA-PEG/PTX micelle drug. The results demonstrated that the group with the smallest TNR values (TNR enhanced by Fe3O4@PEG (d = 32 nm) could be used to predict the therapeutic efficacy of the micelle drugs (d ≤ 32 nm) in a certain period of time. Fe3O4@PEG has a potential to serve as an ideal MRI contrast agent to visualize the EPR effect in patients for accurate medication guidance of micelle drugs in the future treatment of tumors.

  1. [Common physiological basis for post-traumatic stress disorder and dependence to drugs of abuse: Implications for new therapeutic approaches].

    Science.gov (United States)

    Gisquet-Verrier, Pascale; Tolédano, Daniel; Le Dorze, Claire

    2017-06-01

    Post-traumatic stress disorder (PTSD) and addiction to drugs of abuse are two common diseases, showing high comorbidity rates. This review presents a number of evidence showing similarities between these two pathologies, especially the hyper-responsiveness to environmental cues inducing a reactivation of the target memory leading either to re-experiencing (PTSD), or drug craving. Accordingly, PTSD and addiction to drug of abuse might by considered as memory pathologies, underlined by the same physiological process. We propose that these two pathologies rely on an uncoupling of the monoaminergic systems. According to this hypothesis, exposure to extreme conditions, either negative (trauma) or positive (drugs) induced a loss of the reciprocal control that one system usually exerts on the other monoaminergic system, resulting to an uncoupling between the noradrenergic and the serotonergic systems. Results obtained in our laboratory, using animal models of these pathologies, demonstrate that after a trauma, such as after repeated drug injections, rats developed both a behavioral sensitization (increases of the locomotion in response to a stimulation of the monoaminergic systems) and a pharmacological sensitization (increases of noradrenergic release within the prefrontal cortex). These results support our hypothesis and led us to propose new and innovative therapeutic approaches consisting either to induce a re-coupling of the monoaminergic systems, or to modify the pathological memories by using an emotional memory remodeling. Extremely encouraging results have already been obtained in rats and in humans, opening new and promising therapeutic avenues. Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  2. Transdermal Drug Delivery: Opportunities and Challenges for Controlled Delivery of Therapeutic Agents Using Nanocarriers.

    Science.gov (United States)

    Kurmi, Balak Das; Tekchandani, Pawan; Paliwal, Rishi; Paliwal, Shivani Rai

    2017-01-01

    Transdermal drug delivery represents an extremely attractive and innovative route across the skin owing to the possibility for achieving systemic effect of drugs. The present scenario demands a special focus on developing safe medicine with minimized toxic adverse effects related to most of the pharmacologically active agents. Transdermal drug delivery would be a focal paradigm which provides patient convenience, first-pass hepatic metabolism avoidance, local targeting and reduction in toxic effect related to various categories of drugs like, analgesics, antiinflammatory, antibiotics, antiviral, anaesthetic, anticancer etc. Even this route has challenges due to highly organized structure of skin which acts as a main barrier to penetration of drug via the skin. Several alternative possible strategies are available which overcome these barriers, including use of penetration enhancer, eletroporation, iontophoresis and various nanotechnologically developed nanocarrier systems. The latest one includes employing liposome, dendrimers, nanoparticles, ethosome, carbon nanotube and many more to avoid associated limitations of conventional formulations. Numerous transdermal products such as Estrasorb, Diractin, VivaGel®, Daytrana®, Aczone, Sileryst® are available in the market having a novel strategy to achieve higher penetration of drugs. This encourages formulation fraternity to develop structurally deformable and stable nanocarriers as an alternative approach for controlled and reliable drug delivery across the skin barrier. In this review, we will discuss nanocarriers mediated approaches that come-up with the solutions to the different challenges towards transdermal drug delivery, its clinical importance and latest insight to research in it. The reports presented in this review confirm the wide application of nanocarriers for transdermal delivery of drug/gene. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  3. Effect of Intratumoral Injection on the Biodistribution, the Therapeutic Potential of HPMA Copolymer-Based Drug Delivery Systems

    Directory of Open Access Journals (Sweden)

    Twan Lammers

    2006-10-01

    Full Text Available The direct intratumoral (i.t. injection of anticancer agents has been evaluated extensively in the past few decades. Thus far, however, it has failed to become established as an alternative route of administration in routine clinical practice. In the present report, the impact of i.t. injection on the biodistribution, the therapeutic potential of N-(2-hydroxypropylmethacrylamide (HPMA copolymer-based drug delivery systems was investigated. It was found that, compared to intravenous injection, both the tumor concentrations, the tumor-to-organ ratios of carriers improved substantially. In addition, compared to intravenously, intratumorally applied free doxorubicin, to intravenously applied poly(HPMA-glycylphenylalanylleucylglycine- doxorubicin, intratumorally injected poly(HPMA-glycylphenylalanylleucylglycine-doxorubicin presented a significantly increased antitumor efficacy, as well as an improved therapeutic index. Based on these findings, we propose intratumorally injected carrier-based chemotherapy as an interesting alternative to routinely used chemotherapy regimens, routes of administration.

  4. Drug vaping applied to cannabis: Is "Cannavaping" a therapeutic alternative to marijuana?

    Science.gov (United States)

    Varlet, Vincent; Concha-Lozano, Nicolas; Berthet, Aurélie; Plateel, Grégory; Favrat, Bernard; De Cesare, Mariangela; Lauer, Estelle; Augsburger, Marc; Thomas, Aurélien; Giroud, Christian

    2016-05-26

    Therapeutic cannabis administration is increasingly used in Western countries due to its positive role in several pathologies. Dronabinol or tetrahydrocannabinol (THC) pills, ethanolic cannabis tinctures, oromucosal sprays or table vaporizing devices are available but other cannabinoids forms can be used. Inspired by the illegal practice of dabbing of butane hashish oil (BHO), cannabinoids from cannabis were extracted with butane gas, and the resulting concentrate (BHO) was atomized with specific vaporizing devices. The efficiency of "cannavaping," defined as the "vaping" of liquid refills for e-cigarettes enriched with cannabinoids, including BHO, was studied as an alternative route of administration for therapeutic cannabinoids. The results showed that illegal cannavaping would be subjected to marginal development due to the poor solubility of BHO in commercial liquid refills (especially those with high glycerin content). This prevents the manufacture of liquid refills with high BHO concentrations adopted by most recreational users of cannabis to feel the psychoactive effects more rapidly and extensively. Conversely, "therapeutic cannavaping" could be an efficient route for cannabinoids administration because less concentrated cannabinoids-enriched liquid refills are required. However, the electronic device marketed for therapeutic cannavaping should be carefully designed to minimize potential overheating and contaminant generation.

  5. Drug vaping applied to cannabis: Is “Cannavaping” a therapeutic alternative to marijuana?

    Science.gov (United States)

    Varlet, Vincent; Concha-Lozano, Nicolas; Berthet, Aurélie; Plateel, Grégory; Favrat, Bernard; De Cesare, Mariangela; Lauer, Estelle; Augsburger, Marc; Thomas, Aurélien; Giroud, Christian

    2016-01-01

    Therapeutic cannabis administration is increasingly used in Western countries due to its positive role in several pathologies. Dronabinol or tetrahydrocannabinol (THC) pills, ethanolic cannabis tinctures, oromucosal sprays or table vaporizing devices are available but other cannabinoids forms can be used. Inspired by the illegal practice of dabbing of butane hashish oil (BHO), cannabinoids from cannabis were extracted with butane gas, and the resulting concentrate (BHO) was atomized with specific vaporizing devices. The efficiency of “cannavaping,” defined as the “vaping” of liquid refills for e-cigarettes enriched with cannabinoids, including BHO, was studied as an alternative route of administration for therapeutic cannabinoids. The results showed that illegal cannavaping would be subjected to marginal development due to the poor solubility of BHO in commercial liquid refills (especially those with high glycerin content). This prevents the manufacture of liquid refills with high BHO concentrations adopted by most recreational users of cannabis to feel the psychoactive effects more rapidly and extensively. Conversely, “therapeutic cannavaping” could be an efficient route for cannabinoids administration because less concentrated cannabinoids-enriched liquid refills are required. However, the electronic device marketed for therapeutic cannavaping should be carefully designed to minimize potential overheating and contaminant generation. PMID:27228348

  6. Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

    NARCIS (Netherlands)

    Lemos, A.; Melo, Rita; de Sousa Moreira, I.|info:eu-repo/dai/nl/412025000; Cordeiro, Maria Natália D S

    2017-01-01

    Alzheimer’s Disease (AD) is one of the most common and complex age-related neurodegenerative disorders in elderly people. Currently there is no cure for AD, and available therapeutic alternatives only improve both cognitive and behavioral functions. For that reason, the search for anti-AD

  7. Gang Membership and Subsequent Engagement into a Drug Free Therapeutic Community

    Science.gov (United States)

    Widlitz, Michelle; Dermatis, Helen; Galanter, Marc; Bunt, Gregory

    2007-01-01

    The purpose of the present study was to assess the relationship of history of gang involvement to engagement in Therapeutic Community (TC) treatment. Residents (N = 222) at two Daytop facilities completed a survey assessing sociodemographic characteristics, prior gang involvement and multiple aspects of TC functioning. Residents with prior gang…

  8. Salvinorin a and related compounds as therapeutic drugs for psychostimulant-related disorders.

    Science.gov (United States)

    dos Santos, R G; Crippa, J A S; Machado-de-Sousa, J P; Hallak, J E C

    2014-01-01

    Pharmacological treatments are available for alcohol, nicotine, and opioid dependence, and several drugs for cannabis-related disorders are currently under investigation. On the other hand, psychostimulant abuse and dependence lacks pharmacological treatment. Mesolimbic dopaminergic neurons mediate the motivation to use drugs and drug-induced euphoria, and psychostimulants (cocaine, amphetamine, and methamphetamine) produce their effects in these neurons, which may be modulated by the opioid system. Salvinorin A is a κ-opioid receptor agonist extracted from Salvia divinorum, a hallucinogenic plant used in magico-ritual contexts by Mazateca Indians in México. Salvinorin A and its analogues have demonstrated anti-addiction effects in animal models using psychostimulants by attenuating dopamine release, sensitization, and other neurochemical and behavioral alterations associated with acute and prolonged administration of these drugs. The objective of the present article is to present an overview of the preclinical evidence suggesting anti-addictive effects of salvinorin A and its analogues.

  9. Impact of Freeze/Thaw Process on Drug Substance Storage of Therapeutics.

    Science.gov (United States)

    Rayfield, William J; Kandula, Sunitha; Khan, Heera; Tugcu, Nihal

    2017-08-01

    The storage of drug substance at subzero temperatures mitigates potential risks associated with liquid storage, such as degradation and shipping stress, making it the best solution for long-term storage. However, slower (generally uncontrolled) rates of freezing and thawing of drug substance in conventional large storage containers (>2L) can lead to greater cryoconcentration (exclusion of solute molecules) resulting in zones of higher protein and excipient concentrations and changes to the desired formulation pH and excipient concentration. These conditions can negatively impact product quality, thus changing the target product profile. Freeze/thaw studies can provide valuable knowledge on the molecule even when performed from an early formulation image. This study attempts to provide guidance and strategy for planning of drug substance freeze and thaw studies in early development using a scale-down model, evaluating the impact of the (1) freeze/thaw rate, (2) mode of freezing, (3) drug substance container, (4) drug substance concentration, and (5) formulation on the drug substance product quality. Data presented in this study showed no impact on drug substance product quality after undergoing the typical one freeze/thaw cycle process for the variables evaluated. These findings suggest that a qualified scale-down model is not required for early phases of process development and that existing small-scale models can be used for drug substance storage development studies. Based on our experience, a workflow is suggested with minimal experimental design to reduce the material requirement by >70% at early stages of product development to reduce constraints. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  10. Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics

    Science.gov (United States)

    2014-01-01

    Background The demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. Results We use this approach to prioritize genes as drug target candidates in a set of ER + breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER + breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process. Conclusions Influence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use. PMID:24495353

  11. Therapeutic adherence: A prospective drug utilization study of oral hypoglycemic in patients with type 2 diabetes mellitus

    Directory of Open Access Journals (Sweden)

    Gulam Haidar Khan

    2014-02-01

    Full Text Available Objective: To determine the drug utilization patterns and outcomes of treatment in terms of metabolic control in the type 2 diabetic patients on oral hypoglycemic agents in the outpatient department in the teaching hospital of Hamdard University, New Delhi, India. Methods: Patients with established type 2 diabetes (n=184 visiting the outpatient department were interviewed using a structured questionnaire over a period of five months. Results: Majority of the type 2 diabetic patients in this setting were treated with a multiple oral hypoglycemic agents. The most commonly prescribed oral hypoglycemic agent was biguanides (metformin followed by sulfonylureas (glimepiride, thiazolidinediones (pioglitazone, alphaglucosidase inhibitors (miglitol and dipeptidyl peptidase-4 inhibitors (vildagliptin. As monotherapy metformin was the most common choice followed by glimepiride and voglibose, the most prevalent multiple therapy was a three-drug combination of glimepiride + metformin + pioglitazone. The study showed poor compliance to the prescribed therapy. Conclusions: This study prospected the need of patient education and counselled to enhance the patient compliance for prescribed oral hypoglycemic agents and concomitant drugs. There is need for diet control as well as blood glucose and HbA1c monitoring. Metabolic control was found to be poor in the study population. HbA1c monitoring was underutilized. Clinical monitoring of patien t’s adherence to the prescribed treatment to achieve good glycemic control is recommended. Measures should be taken to improve patient's adherence to the prescribed treatment.

  12. The Analytical Chemistry of Drug Monitoring in Athletes

    Science.gov (United States)

    Bowers, Larry D.

    2009-07-01

    The detection and deterrence of the abuse of performance-enhancing drugs in sport are important to maintaining a level playing field among athletes and to decreasing the risk to athletes’ health. The World Anti-Doping Program consists of six documents, three of which play a role in analytical development: The World Anti-Doping Code, The List of Prohibited Substances and Methods, and The International Standard for Laboratories. Among the classes of prohibited substances, three have given rise to the most recent analytical developments in the field: anabolic agents; peptide and protein hormones; and methods to increase oxygen delivery to the tissues, including recombinant erythropoietin. Methods for anabolic agents, including designer steroids, have been enhanced through the use of liquid chromatography/tandem mass spectrometry and gas chromatography/combustion/isotope-ratio mass spectrometry. Protein and peptide identification and quantification have benefited from advances in liquid chromatography/tandem mass spectrometry. Incorporation of techniques such as flow cytometry and isoelectric focusing have supported the detection of blood doping.

  13. Amine bridges grafted mesoporous silica, as a prolonged/controlled drug release system for the enhanced therapeutic effect of short life drugs.

    Science.gov (United States)

    Rehman, Fozia; Ahmed, Khalid; Airoldi, Claudio; Gaisford, Simon; Buanz, Asma; Rahim, Abdur; Muhammad, Nawshad; Volpe, Pedro L O

    2017-03-01

    Hybrid mesoporous silica SBA-15, with surface incorporated cross-linked long hydrophobic organic bridges was synthesized using stepwise synthesis. The synthesized materials were characterized by elemental analysis, infrared spectroscopy, nuclear magnetic resonance spectroscopy, nitrogen adsorption, X-rays diffraction, thermogravimetry and scanning and transmission electron microscopy. The functionalized material showed highly ordered mesoporous network with a surface area of 629.0m2g-1. The incorporation of long hydrophobic amine chains on silica surface resulted in high drug loading capacity (21% Mass/Mass) and prolonged release of ibuprofen up till 75.5h. The preliminary investigations suggests that the synthesized materials could be proposed as controlled release devices to prolong the therapeutic effect of short life drugs such as ibuprofen to increase its efficacy and to reduce frequent dosage. Copyright © 2016 Elsevier B.V. All rights reserved.

  14. Recovery Journeys of Counselors and Clients: A Case Study of the Therapeutic Alliance in a Drug Treatment and Rehabilitation Center in Malaysia

    Science.gov (United States)

    Amat, Mohamad Isa

    2013-01-01

    The therapeutic alliance is a significant research area in counseling. The understanding of the therapeutic alliance, particularly in drug treatment settings helps counselors and clients to increase the treatment outcomes and its treatment process. The present study investigated the journeys of recovering counselors and clients in a private…

  15. Microencapsulation for the Therapeutic Delivery of Drugs, Live Mammalian and Bacterial Cells, and Other Biopharmaceutics: Current Status and Future Directions.

    Science.gov (United States)

    Tomaro-Duchesneau, Catherine; Saha, Shyamali; Malhotra, Meenakshi; Kahouli, Imen; Prakash, Satya

    2013-01-01

    Microencapsulation is a technology that has shown significant promise in biotherapeutics, and other applications. It has been proven useful in the immobilization of drugs, live mammalian and bacterial cells and other cells, and other biopharmaceutics molecules, as it can provide material structuration, protection of the enclosed product, and controlled release of the encapsulated contents, all of which can ensure efficient and safe therapeutic effects. This paper is a comprehensive review of microencapsulation and its latest developments in the field. It provides a comprehensive overview of the technology and primary goals of microencapsulation and discusses various processes and techniques involved in microencapsulation including physical, chemical, physicochemical, and other methods involved. It also summarizes the state-of-the-art successes of microencapsulation, specifically with regard to the encapsulation of microorganisms, mammalian cells, drugs, and other biopharmaceutics in various diseases. The limitations and future directions of microencapsulation technologies are also discussed.

  16. Microencapsulation for the Therapeutic Delivery of Drugs, Live Mammalian and Bacterial Cells, and Other Biopharmaceutics: Current Status and Future Directions

    Directory of Open Access Journals (Sweden)

    Catherine Tomaro-Duchesneau

    2013-01-01

    Full Text Available Microencapsulation is a technology that has shown significant promise in biotherapeutics, and other applications. It has been proven useful in the immobilization of drugs, live mammalian and bacterial cells and other cells, and other biopharmaceutics molecules, as it can provide material structuration, protection of the enclosed product, and controlled release of the encapsulated contents, all of which can ensure efficient and safe therapeutic effects. This paper is a comprehensive review of microencapsulation and its latest developments in the field. It provides a comprehensive overview of the technology and primary goals of microencapsulation and discusses various processes and techniques involved in microencapsulation including physical, chemical, physicochemical, and other methods involved. It also summarizes the state-of-the-art successes of microencapsulation, specifically with regard to the encapsulation of microorganisms, mammalian cells, drugs, and other biopharmaceutics in various diseases. The limitations and future directions of microencapsulation technologies are also discussed.

  17. Neuroinflammation in the pathophysiology of Parkinson’s disease and therapeutic evidence of anti-inflammatory drugs

    Directory of Open Access Journals (Sweden)

    Taysa Bervian Bassani

    2015-07-01

    Full Text Available Parkinson’s disease (PD is the second most common neurodegenerative disease affecting approximately 1.6% of the population over 60 years old. The cardinal motor symptoms are the result of progressive degeneration of substantia nigra pars compacta dopaminergic neurons which are involved in the fine motor control. Currently, there is no cure for this pathology and the cause of the neurodegeneration remains unknown. Several studies suggest the involvement of neuroinflammation in the pathophysiology of PD as well as a protective effect of anti-inflammatory drugs both in animal models and epidemiological studies, although there are controversial reports. In this review, we address evidences of involvement of inflammatory process and possible therapeutic usefulness of anti-inflammatory drugs in PD.

  18. Microencapsulation for the Therapeutic Delivery of Drugs, Live Mammalian and Bacterial Cells, and Other Biopharmaceutics: Current Status and Future Directions

    Science.gov (United States)

    Saha, Shyamali; Malhotra, Meenakshi; Kahouli, Imen; Prakash, Satya

    2013-01-01

    Microencapsulation is a technology that has shown significant promise in biotherapeutics, and other applications. It has been proven useful in the immobilization of drugs, live mammalian and bacterial cells and other cells, and other biopharmaceutics molecules, as it can provide material structuration, protection of the enclosed product, and controlled release of the encapsulated contents, all of which can ensure efficient and safe therapeutic effects. This paper is a comprehensive review of microencapsulation and its latest developments in the field. It provides a comprehensive overview of the technology and primary goals of microencapsulation and discusses various processes and techniques involved in microencapsulation including physical, chemical, physicochemical, and other methods involved. It also summarizes the state-of-the-art successes of microencapsulation, specifically with regard to the encapsulation of microorganisms, mammalian cells, drugs, and other biopharmaceutics in various diseases. The limitations and future directions of microencapsulation technologies are also discussed. PMID:26555963

  19. Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis

    NARCIS (Netherlands)

    Sturkenboom, M.G.; Mulder, L.W.; Jager, A de; Altena, R. van; Aarnoutse, R.E.; Lange, W.C. de; Proost, J.H.; Kosterink, J.G.W.; Werf, T.S. van der; Alffenaar, J.W.C.

    2015-01-01

    Rifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC0-24) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of

  20. Pharmacokinetic Modeling and Optimal Sampling Strategies for Therapeutic Drug Monitoring of Rifampin in Patients with Tuberculosis

    NARCIS (Netherlands)

    Sturkenboom, Marieke G. G.; Mulder, Leonie W.; de Jager, Arthur; van Altena, Richard; Aarnoutse, Rob E.; de Lange, Wiel C. M.; Proost, Johannes H.; Kosterink, Jos G. W.; van der Werf, Tjip S.; Alffenaar, Jan-Willem C.

    Rifampin, together with isoniazid, has been the backbone of the current first-line treatment of tuberculosis (TB). The ratio of the area under the concentration-time curve from 0 to 24 h (AUC(0-24)) to the MIC is the best predictive pharmacokinetic-pharmacodynamic parameter for determinations of

  1. Therapeutic Drug-Monitoring of Methotrexate-Polyglutamates in Rheumatoid Arthritis

    NARCIS (Netherlands)

    E. den Boer (Ethan)

    2014-01-01

    markdownabstract__Abstract__ Rheumatoid Arthritis (RA) is a chronic autoimmune disease, characterized by the swelling of joints, uncontrolled proliferation of synovial tissue and multisystem co-morbidities. RA mainly affects the joints of the hands, feet, knees, wrist and elbows, with joint

  2. Limited sampling strategies for therapeutic drug monitoring of mycophenolate mofetil therapy in patients with autoimmune disease

    NARCIS (Netherlands)

    de Winter, Brenda C. M.; Neumann, Irmgard; van Hest, Reinier M.; van Gelder, Teun; Mathot, Ron A. A.

    2009-01-01

    Mycophenolate mofetil (MMF) is increasingly used for the treatment of autoimmune diseases (AID). In renal transplant recipients, it has been demonstrated that adjustment of the MMF dose according to the area under the plasma concentration versus time curve (AUC) of mycophenolic acid (MPA), the

  3. Individualized treatment of multidrug-resistant tuberculosis using therapeutic drug monitoring

    Directory of Open Access Journals (Sweden)

    Mathieu S Bolhuis

    2016-01-01

    Conclusion: TDM is highly valuable to individualize and optimize treatment of complex MDR-TB patients. TDM is routinely applied in Tuberculosis Center Beatrixoord, and high success rates for treatment of MDR-TB patients have been achieved. DBS and LSS make implementation of TDM feasible, even in low- and middle-income countries.

  4. Non-Invasive Monitoring for Optimization of Therapeutic Drug Delivery by Biodegradable Fiber to Prostate Tumor

    Science.gov (United States)

    2007-02-01

    who ha hnique to investig ynskis from the University d the tec oc l mu measure s of tissuesared to the norma a few h dvant ours before the a th fl in...report of four cases,” World Journal of Surgical l e on edings of the 26th Annual International Conference of the IEEE EMBS, 2004 ley R M, “A...Glukhovsky, R. Davis, “Battery Powered BION FES Network,” Proce [24] Akin T, Najafi K and Brad sieve electrode,” IEEE Tran [2 Texas at Arlington, 2005

  5. Cytoprotection by omega-3 fatty acids as a therapeutic drug vehicle when combined with nephrotoxic drugs in an intravenous emulsion: Effects on intraglomerular mesangial cells

    Directory of Open Access Journals (Sweden)

    Gabriel Alejandro Bonaterra

    2014-01-01

    Full Text Available During therapeutic interventions, blood concentrations of intravenously applied drugs are higher, and their onset of pharmacological action is faster than with other routes of drug administration. However, acute drug therapy often produces nephrotoxic side effects, as commonly seen after treatment with Ketorolac or Gentamicin leading to questions about their use, especially for patients at risk for acute renal failure. Omega-6(n-6 and omega-3(n-3 polyunsaturated fatty acids (PUFA affect eicosanoid metabolism, which plays a role in the regulation of inflammation. Eicosanoids derived from n-6 FA have proinflammatory and immunoactive functions, whereas eicosanoids derived from n-3 PUFA have anti-inflammatory and cytoprotective properties. We hypothesized that providing such injectable drugs with nephrotoxic potential in combination with n3-PUFAs from the outset, might afford rapid cytoprotection of renal cells, given the recent evidence that intravenously administered n3-PUFAs are rapidly incorporated into cell membranes. We used intraglomerular mesangial cells (MES13 that are sensitive to treatment with Ketorolac or Gentamicin instead of proximal tubular cells which do not respond to Ketorolac. We found a significant inhibition of Ketorolac (0.25, 0.5, 1 mM or Gentamicin (2.5, 5 mM induced cytotoxicity after pretreatment of MES13 cells with 0.01% of 20%w/v LipOmega-3 Emulsion 9/1, containing 90:10 wt/wt mixture of fish oil derived triglycerides to medium chain triglycerides.

  6. An inevitable wave of prescription drug monitoring programs in the context of prescription opioids: pros, cons and tensions.

    Science.gov (United States)

    Islam, M Mofizul; McRae, Ian S

    2014-08-16

    In an effort to control non-medical use and/or medical abuse of prescription drugs, particularly prescription opioids, electronic prescription drug monitoring programs (PDMP) have been introduced in North-American countries, Australia and some parts of Europe. Paradoxically, there are simultaneous pressures to increase opioid prescribing for the benefit of individual patients and to reduce it for the sake of public health, and this pressure warrants a delicate balance of appropriate therapeutic uses of these drugs with the risk of developing dependence. This article discusses pros and cons of PDMP in reducing diversion of prescription opioids, without hampering access to those medications for those with genuine needs, and highlights tensions around PDMP implementation. PDMPs may help alleviate diversion, over-prescription and fraudulent prescribing/dispensing; prompt drug treatment referrals; avoid awkward drug urine test; and inform spatial changes in prescribing practices and help designing tailored interventions. Fear of legal retribution, privacy and data security, potential confusion about addiction and pseudo-addiction, and potential undue pressure of detecting misuse/diversion - are the major problems. There are tensions about unintended consequence of excessive regulatory enforcements, corresponding collateral damages particularly about inadequate prescribing for patients with genuine needs, and mandatory consultation requirements of PDMP. In this era of information technology PDMP is likely to flourish and remain with us for a long time. A clear standard of practice against which physicians' care will be judged may expedite the utilisation of PDMP. In addition, adequate training on addiction and pain management along with public awareness, point-of-supply data entry from pharmacy, point-of-care real-time access to data, increasing access to addiction treatment and appropriate regulatory enforcement preferably through healthcare administration, together

  7. Open Innovation Drug Discovery (OIDD): a potential path to novel therapeutic chemical space.

    Science.gov (United States)

    Alvim-Gaston, Maria; Grese, Timothy; Mahoui, Abdelaziz; Palkowitz, Alan D; Pineiro-Nunez, Marta; Watson, Ian

    2014-01-01

    The continued development of computational and synthetic methods has enabled the enumeration or preparation of a nearly endless universe of chemical structures. Nevertheless, the ability of this chemical universe to deliver small molecules that can both modulate biological targets and have drug-like physicochemical properties continues to be a topic of interest to the pharmaceutical industry and academic researchers alike. The chemical space described by public, commercial, in-house and virtual compound collections has been interrogated by multiple approaches including biochemical, cellular and virtual screening, diversity analysis, and in-silico profiling. However, current drugs and known chemical probes derived from these efforts are contained within a remarkably small volume of the predicted chemical space. Access to more diverse classes of chemical scaffolds that maintain the properties relevant for drug discovery is certainly needed to meet the increasing demands for pharmaceutical innovation. The Lilly Open Innovation Drug Discovery platform (OIDD) was designed to tackle barriers to innovation through the identification of novel molecules active in relevant disease biology models. In this article we will discuss several computational approaches towards describing novel, biologically active, drug-like chemical space and illustrate how the OIDD program may facilitate access to previously untapped molecules that may aid in the search for innovative pharmaceuticals.

  8. Cathepsin B is a New Drug Target for Traumatic Brain Injury Therapeutics: Evidence for E64d as a Promising Lead Drug Candidate

    Directory of Open Access Journals (Sweden)

    Gregory eHook

    2015-09-01

    Full Text Available There currently is no therapeutic drug treatment for traumatic brain injury (TBI despite decades of experimental clinical trials. This may be because the mechanistic pathways for improving TBI outcomes have yet to be identified and exploited. As such, there remains a need to seek out new molecular targets and their drug candidates to find new treatments for TBI. This review presents supporting evidence for cathepsin B, a cysteine protease, as a potentially important drug target for TBI. Cathepsin B expression is greatly up-regulated in TBI animal models, as well as in trauma patients. Importantly, knockout of the cathepsin B gene in TBI mice results in substantial improvements of TBI-caused deficits in behavior, pathology, and biomarkers, as well as improvements in related injury models. During the process of TBI-induced injury, cathepsin B likely escapes the lysosome, its normal subcellular location, into the cytoplasm or extracellular matrix (ECM where its unleashed proteolytic power causes destruction via necrotic, apoptotic, autophagic, and activated glia-induced cell death, together with ECM breakdown and inflammation. Significantly, chemical inhibitors of cathepsin B are effective for improving deficits in TBI and related injuries including ischemia, cerebral bleeding, cerebral aneurysm, edema, pain, infection, nephritis, epilepsy, rheumatoid arthritis, pancreatitis, Huntington’s disease, and Alzheimer’s disease. The inhibitor E64d shows prominent efficacy for amelioration of TBI-caused deficits in preclinical models. In clinical trials, E64d has been shown to be safe based on its toxicological profile and, thus, illustrates the compound as an excellent candidate for drug development. These data support the overall conclusion that drug development of cathepsin B inhibitors, with E64d or a novel analog as a lead drug candidate, should be accelerated to improve the outcomes of TBI and related injuries.

  9. Drug addiction: targeting dynamic neuroimmune receptor interactions as a potential therapeutic strategy.

    Science.gov (United States)

    Jacobsen, Jonathan Henry W; Hutchinson, Mark R; Mustafa, Sanam

    2016-02-01

    Drug addiction and dependence have proven to be difficult psychiatric disorders to treat. The limited efficacy of neuronally acting medications, such as acamprosate and naltrexone, highlights the need to identify novel targets. Recent research has underscored the importance of the neuroimmune system in many behavioural manifestations of drug addiction. In this review, we propose that our appreciation for complex phenotypes such as drug addiction and dependence will come with a greater understanding that these disorders are the result of intricate, interconnected signalling pathways that are, if only partially, determined at the receptor level. The idea of receptor heteromerisation and receptor mosaics will be introduced to explain cross talk between the receptors and signalling molecules implicated in neuroimmune signalling pathways. Copyright © 2015 Elsevier Ltd. All rights reserved.

  10. Noninvasive ocular drug delivery: potential transcorneal and other alternative delivery routes for therapeutic molecules in glaucoma.

    Science.gov (United States)

    Foldvari, Marianna

    2014-01-01

    Drug delivery to the eye is made difficult by multiple barriers (such as the tear film, cornea, and vitreous) between the surface of the eye and the treatment site. These barriers are difficult to surmount for the purposes of drug delivery without causing toxicity. Using nanotechnology tools to control, manipulate, and study delivery systems, new approaches to delivering drugs, genes, and antigens that are effective and safe can be developed. Topical administration to the ocular surface would be the safest method for delivery, as it is noninvasive and painless compared with other delivery methods. However, there is only limited success using topical delivery methods, especially for gene therapy. Current thinking on treatments of the future enabled by nanodelivery systems and the identification of target specificity parameters that require deeper understanding to develop successful topical delivery systems for glaucoma is highlighted.

  11. Monitoring Disease Progression and Therapeutic Response in a Disseminated Tumor Model for Non-Hodgkin Lymphoma by Bioluminescence Imaging

    Directory of Open Access Journals (Sweden)

    Margarethe Köberle

    2015-07-01

    Full Text Available Xenograft tumor models are widely studied in cancer research. Our aim was to establish and apply a model for aggressive CD20-positive B-cell non-Hodgkin lymphomas, enabling us to monitor tumor growth and shrinkage in a noninvasive manner. By stably transfecting a luciferase expression vector, we created two bioluminescent human non-Hodgkin lymphoma cell lines, Jeko1(luci and OCI-Ly3(luci, that are CD20 positive, a prerequisite to studying rituximab, a chimeric anti-CD20 antibody. To investigate the therapy response in vivo, we established a disseminated xenograft tumor model injecting these cell lines in NOD/SCID mice. We observed a close correlation of bioluminescence intensity and tumor burden, allowing us to monitor therapy response in the living animal. Cyclophosphamide reduced tumor burden in mice injected with either cell line in a dose-dependent manner. Rituximab alone was effective in OCI-Ly3(luci-injected mice and acted additively in combination with cyclophosphamide. In contrast, it improved the therapeutic outcome of Jeko1(luci-injected mice only in combination with cyclophosphamide. We conclude that well-established bioluminescence imaging is a valuable tool in disseminated xenograft tumor models. Our model can be translated to other cell lines and used to examine new therapeutic agents and schedules.

  12. Nanoscale monitoring of drug actions on cell membrane using atomic force microscopy

    Science.gov (United States)

    Li, Mi; Liu, Lian-qing; Xi, Ning; Wang, Yue-chao

    2015-01-01

    Knowledge of the nanoscale changes that take place in individual cells in response to a drug is useful for understanding the drug action. However, due to the lack of adequate techniques, such knowledge was scarce until the advent of atomic force microscopy (AFM), which is a multifunctional tool for investigating cellular behavior with nanometer resolution under near-physiological conditions. In the past decade, researchers have applied AFM to monitor the morphological and mechanical dynamics of individual cells following drug stimulation, yielding considerable novel insight into how the drug molecules affect an individual cell at the nanoscale. In this article we summarize the representative applications of AFM in characterization of drug actions on cell membrane, including topographic imaging, elasticity measurements, molecular interaction quantification, native membrane protein imaging and manipulation, etc. The challenges that are hampering the further development of AFM for studies of cellular activities are aslo discussed. PMID:26027658

  13. The glucose ketone index calculator: a simple tool to monitor therapeutic efficacy for metabolic management of brain cancer.

    Science.gov (United States)

    Meidenbauer, Joshua J; Mukherjee, Purna; Seyfried, Thomas N

    2015-01-01

    Metabolic therapy using ketogenic diets (KD) is emerging as an alternative or complementary approach to the current standard of care for brain cancer management. This therapeutic strategy targets the aerobic fermentation of glucose (Warburg effect), which is the common metabolic malady of most cancers including brain tumors. The KD targets tumor energy metabolism by lowering blood glucose and elevating blood ketones (β-hydroxybutyrate). Brain tumor cells, unlike normal brain cells, cannot use ketone bodies effectively for energy when glucose becomes limiting. Although plasma levels of glucose and ketone bodies have been used separately to predict the therapeutic success of metabolic therapy, daily glucose levels can fluctuate widely in brain cancer patients. This can create difficulty in linking changes in blood glucose and ketones to efficacy of metabolic therapy. A program was developed (Glucose Ketone Index Calculator, GKIC) that tracks the ratio of blood glucose to ketones as a single value. We have termed this ratio the Glucose Ketone Index (GKI). The GKIC was used to compute the GKI for data published on blood glucose and ketone levels in humans and mice with brain tumors. The results showed a clear relationship between the GKI and therapeutic efficacy using ketogenic diets and calorie restriction. The GKIC is a simple tool that can help monitor the efficacy of metabolic therapy in preclinical animal models and in clinical trials for malignant brain cancer and possibly other cancers that express aerobic fermentation.

  14. Recent Advances in Delivery Systems and Therapeutics of Cinnarizine: A Poorly Water Soluble Drug with Absorption Window in Stomach

    Directory of Open Access Journals (Sweden)

    Smita Raghuvanshi

    2014-01-01

    Full Text Available Low solubility causing low dissolution in gastrointestinal tract is the major problem for drugs meant for systemic action after oral administration, like cinnarizine. Pharmaceutical products of cinnarizine are commercialized globally as immediate release preparations presenting low absorption with low and erratic bioavailability. Approaches to enhance bioavailability are widely cited in the literature. An attempt has been made to review the bioavailability complications and clinical therapeutics of poorly water soluble drug: cinnarizine. The interest of writing this paper is to summarize the pharmacokinetic limitations of drug with special focus on strategies to improvise bioavailability along with effectiveness of novel dosage forms to circumvent the obstacle. The paper provides insight to the approaches to overcome low and erratic bioavailability of cinnarizine by cyclodextrin complexes and novel dosage forms: self-nanoemulsifying systems and buoyant microparticulates. Nanoformulations need to systematically explored in future, for their new clinical role in prophylaxis of migraine attacks in children. Clinical reports have affirmed the role of cinnarizine in migraine prophylaxis. Research needs to be dedicated to develop dosage forms for efficacious bioavailability and drug directly to brain.

  15. Therapeutic Response for Functional Abdominal Pain in Children with Occult Constipation: Laxatives versus Prokinetic Drugs.

    Science.gov (United States)

    Ha, Eun Kyo; Jang, Homin; Jeong, Su Jin

    2017-01-01

    The relationship between functional abdominal pain (FAP) and occult constipation (OC) in children who did not meet the Rome III criteria for constipation has rarely been reported. This study aimed to estimate the prevalence of OC in patients with FAP and to compare the effectiveness of prokinetic drugs and laxatives for FAP and OC. Pediatric outpatients (n = 212; aged 4-15 years) who satisfied the Rome III criteria for childhood FAP were divided into 2 groups based on Leech scores: group 1 children with FAP. Laxatives can be more effective than prokinetic drugs for relieving symptoms of FAP in children with a Leech score ≥ 8 and suspected OC.

  16. Self-management of psychiatric symptoms using over-the-counter (OTC) psychopharmacology: the S-DTM therapeutic model--Self-diagnosis, self-treatment, self-monitoring.

    Science.gov (United States)

    Charlton, Bruce G

    2005-01-01

    Pharmacological self-management is becoming more widespread in modernizing societies, as part of a general expansion of health care. This may exert a vital corrective balance to the professionalization of health by ensuring that the individual perspective of patients is not neglected. There are many 'good ideas' for new treatments being published which have a plausible scientific rationale for effectiveness and a low likelihood of harm, yet are essentially ignored by mainstream medical research. The most likely avenue for progress is probably the spread of self-management, together with increased sharing of experience via the internet. There is considerable scope for self-management of psychiatric symptoms with psychoactive medication purchased 'over-the-counter' (OTC) and without prescription. A surprisingly wide range of effective psychoactive agents are available with the potential to self-treat many of the common psychiatric problems. These include 'medical' psychopharmacological agents such as analgesics and antihistamines, a plant extract called St. John's Wort (Hypericum), and physical treatments such as early morning bright light therapy. But self-management currently lacks an explicit therapeutic model. A three stage process of S-DTM - self-diagnosis, self-treatment and self-monitoring is proposed and described in relation to psychiatric symptoms. Self-diagnosis describes the skill of introspection to develop awareness of inner bodily states and emotions. A specific sensation is identified and isolated as the 'focal symptom' for subsequent treatment and monitoring. Self-treatment involves choosing a drug (or other therapy) which is intended to alleviate the focal symptom. Self-monitoring entails a continued awareness of the focal system and of general well-being in order to evaluate effect of therapy. Self-monitoring could involve repeated cycles of dose-adjustment, and on-off ('challenge-dechallenge-rechallenge') therapeutic trials. An example of S

  17. Psychotropic Drug Use among College Students: Patterns of Use, Misuse, and Medical Monitoring

    Science.gov (United States)

    Oberleitner, Lindsay M. S.; Tzilos, Golfo K.; Zumberg, Kathryn M.; Grekin, Emily R.

    2011-01-01

    Objective: To assess whether college students who use psychotropic drugs are (1) aware of potential side effects, (2) appropriately monitored by prescribing physicians, and (3) taking medications as prescribed. Participants: Fifty-five college students, currently taking psychotropic medications, were recruited between Summer 2008 and Fall 2009.…

  18. Treponema pallidum putative novel drug target identification and validation: rethinking syphilis therapeutics with plant-derived terpenoids.

    Science.gov (United States)

    Dwivedi, Upendra N; Tiwari, Sameeksha; Singh, Priyanka; Singh, Swati; Awasthi, Manika; Pandey, Veda P

    2015-02-01

    Syphilis, a slow progressive and the third most common sexually transmitted disease found worldwide, is caused by a spirochete gram negative bacteria Treponema pallidum. Emergence of antibiotic resistant T. pallidum has led to a search for novel drugs and their targets. Subtractive genomics analyses of pathogen T. pallidum and host Homo sapiens resulted in identification of 126 proteins essential for survival and viability of the pathogen. Metabolic pathway analyses of these essential proteins led to discovery of nineteen proteins distributed among six metabolic pathways unique to T. pallidum. One hundred plant-derived terpenoids, as potential therapeutic molecules against T. pallidum, were screened for their drug likeness and ADMET (absorption, distribution, metabolism, and toxicity) properties. Subsequently the resulting nine terpenoids were docked with five unique T. pallidum targets through molecular modeling approaches. Out of five targets analyzed, D-alanine:D-alanine ligase was found to be the most promising target, while terpenoid salvicine was the most potent inhibitor. A comparison of the inhibitory potential of the best docked readily available natural compound, namely pomiferin (flavonoid) with that of the best docked terpenoid salvicine, revealed that salvicine was a more potent inhibitor than that of pomiferin. To the best of our knowledge, this is the first report of a terpenoid as a potential therapeutic molecule against T. pallidum with D-alanine:D-alanine ligase as a novel target. Further studies are warranted to evaluate and explore the potential clinical ramifications of these findings in relation to syphilis that has public health importance worldwide.

  19. Intoxication with therapeutic and illicit drug substances and hospital admission to a Dutch university hospital

    NARCIS (Netherlands)

    A. Vermes (Andras); E.M. Roelofsen (Erik); G. Sabadi; B.W. van den Berg (Bart); M. de Quelerij (Marcel); A.G. Vulto (Arnold)

    2003-01-01

    textabstractBACKGROUND: This article describes the retrospective analysis of the patients who presented with a drug-related intoxication to the emergency department of the Erasmus Medical Centre in 2000. METHODS: Data were collected from the emergency department's electronic database and the medical

  20. Brain-derived neurotrophic factor and addiction: Pathological versus therapeutic effects on drug seeking

    NARCIS (Netherlands)

    Barker, J.M.; Taylor, J.R.; de Vries, T.J.; Peters, J.

    2015-01-01

    Many abused drugs lead to changes in endogenous brain-derived neurotrophic factor (BDNF) expression in neural circuits responsible for addictive behaviors. BDNF is a known molecular mediator of memory consolidation processes, evident at both behavioral and neurophysiological levels. Specific neural

  1. Effects of formulation design on niacin therapeutics: mechanism of action, metabolism, and drug delivery.

    Science.gov (United States)

    Cooper, Dustin L; Murrell, Derek E; Roane, David S; Harirforoosh, Sam

    2015-07-25

    Niacin is a highly effective, lipid regulating drug associated with a number of metabolically induced side effects such as prostaglandin (PG) mediated flushing and hepatic toxicity. In an attempt to reduce the development of these adverse effects, scientists have investigated differing methods of niacin delivery designed to control drug release and alter metabolism. However, despite successful formulation of various orally based capsule and tablet delivery systems, patient adherence to niacin therapy is still compromised by adverse events such as PG-induced flushing. While the primary advantage of orally dosed formulations is ease of use, alternative delivery options such as transdermal delivery or polymeric micro/nanoparticle encapsulation for oral administration have shown promise in niacin reformulation. However, the effectiveness of these alternative delivery options in reducing inimical effects of niacin and maintaining drug efficacy is still largely unknown and requires more in-depth investigation. In this paper, we present an overview of niacin applications, its metabolic pathways, and current drug delivery formulations. Focus is placed on oral immediate, sustained, and extended release niacin delivery as well as combined statin and/or prostaglandin antagonist niacin formulation. We also examine and discuss current findings involving transdermal niacin formulations and polymeric micro/nanoparticle encapsulated niacin delivery. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. Convection-enhanced drug delivery to the brain: therapeutic potential and neuropathological considerations.

    Science.gov (United States)

    Barua, Neil U; Gill, Steven S; Love, Seth

    2014-03-01

    Convection-enhanced delivery (CED) describes a direct method of drug delivery to the brain through intraparenchymal microcatheters. By establishing a pressure gradient at the tip of the infusion catheter in order to exploit bulk flow through the interstitial spaces of the brain, CED offers a number of advantages over conventional drug delivery methods-bypass of the blood-brain barrier, targeted distribution through large brain volumes and minimization of systemic side effects. Despite showing early promise, CED is yet to fulfill its potential as a mainstream strategy for the treatment of neurological disease. Substantial research effort has been dedicated to optimize the technology for CED and identify the parameters, which govern successful drug distribution. It seems likely that successful clinical translation of CED will depend on suitable catheter technology being used in combination with drugs with optimal physicochemical characteristics, and on neuropathological analysis in appropriate preclinical models. In this review, we consider the factors most likely to influence the success or failure of CED, and review its application to the treatment of high-grade glioma, Parkinson's disease (PD) and Alzheimer's disease (AD). © 2013 International Society of Neuropathology.

  3. Quantitative electrophysiological monitoring of anti-histamine drug effects on live cells via reusable sensor platforms.

    Science.gov (United States)

    Pham Ba, Viet Anh; Cho, Dong-Guk; Kim, Daesan; Yoo, Haneul; Ta, Van-Thao; Hong, Seunghun

    2017-08-15

    We demonstrated the quantitative electrophysiological monitoring of histamine and anti-histamine drug effects on live cells via reusable sensor platforms based on carbon nanotube transistors. This method enabled us to monitor the real-time electrophysiological responses of a single HeLa cell to histamine with different concentrations. The measured electrophysiological responses were attributed to the activity of histamine type 1 receptors on a HeLa cell membrane by histamine. Furthermore, the effects of anti-histamine drugs such as cetirizine or chlorphenamine on the electrophysiological activities of HeLa cells were also evaluated quantitatively. Significantly, we utilized only a single device to monitor the responses of multiple HeLa cells to each drug, which allowed us to quantitatively analyze the antihistamine drug effects on live cells without errors from the device-to-device variation in device characteristics. Such quantitative evaluation capability of our method would promise versatile applications such as drug screening and nanoscale bio sensor researches. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Addressing the challenge of high-priced prescription drugs in the era of precision medicine: A systematic review of drug life cycles, therapeutic drug markets and regulatory frameworks

    Science.gov (United States)

    van der Gronde, Toon; Uyl-de Groot, Carin A.

    2017-01-01

    Context Recent public outcry has highlighted the rising cost of prescription drugs worldwide, which in several disease areas outpaces other health care expenditures and results in a suboptimal global availability of essential medicines. Method A systematic review of Pubmed, the Financial Times, the New York Times, the Wall Street Journal and the Guardian was performed to identify articles related to the pricing of medicines. Findings Changes in drug life cycles have dramatically affected patent medicine markets, which have long been considered a self-evident and self-sustainable source of income for highly profitable drug companies. Market failure in combination with high merger and acquisition activity in the sector have allowed price increases for even off-patent drugs. With market interventions and the introduction of QALY measures in health care, governments have tried to influence drug prices, but often encounter unintended consequences. Patent reform legislation, reference pricing, outcome-based pricing and incentivizing physicians and pharmacists to prescribe low-cost drugs are among the most promising short-term policy options. Due to the lack of systematic research on the effectiveness of policy measures, an increasing number of ad hoc decisions have been made with counterproductive effects on the availability of essential drugs. Future challenges demand new policies, for which recommendations are offered. Conclusion A fertile ground for high-priced drugs has been created by changes in drug life-cycle dynamics, the unintended effects of patent legislation, government policy measures and orphan drug programs. There is an urgent need for regulatory reform to curtail prices and safeguard equitable access to innovative medicines. PMID:28813502

  5. Addressing the challenge of high-priced prescription drugs in the era of precision medicine: A systematic review of drug life cycles, therapeutic drug markets and regulatory frameworks.

    Science.gov (United States)

    Gronde, Toon van der; Uyl-de Groot, Carin A; Pieters, Toine

    2017-01-01

    Recent public outcry has highlighted the rising cost of prescription drugs worldwide, which in several disease areas outpaces other health care expenditures and results in a suboptimal global availability of essential medicines. A systematic review of Pubmed, the Financial Times, the New York Times, the Wall Street Journal and the Guardian was performed to identify articles related to the pricing of medicines. Changes in drug life cycles have dramatically affected patent medicine markets, which have long been considered a self-evident and self-sustainable source of income for highly profitable drug companies. Market failure in combination with high merger and acquisition activity in the sector have allowed price increases for even off-patent drugs. With market interventions and the introduction of QALY measures in health care, governments have tried to influence drug prices, but often encounter unintended consequences. Patent reform legislation, reference pricing, outcome-based pricing and incentivizing physicians and pharmacists to prescribe low-cost drugs are among the most promising short-term policy options. Due to the lack of systematic research on the effectiveness of policy measures, an increasing number of ad hoc decisions have been made with counterproductive effects on the availability of essential drugs. Future challenges demand new policies, for which recommendations are offered. A fertile ground for high-priced drugs has been created by changes in drug life-cycle dynamics, the unintended effects of patent legislation, government policy measures and orphan drug programs. There is an urgent need for regulatory reform to curtail prices and safeguard equitable access to innovative medicines.

  6. The therapeutic index of locally acting inhaled drugs as a function of their fine particle mass and particle size distribution - A literature review

    NARCIS (Netherlands)

    Weda, Marjolein; Zanen, Pieter; De Boer, Anne H.; Barends, Dirk M.; Frijlink, Henderik W.

    2008-01-01

    The therapeutic index (TI) of locally acting inhaled drug products depends on a number of parameters and processes: the particle size distribution of the inhaled aerosol, the dose-efficacy response curves at the deposition sites, the amount of drug absorbed into the systemic circulation from the

  7. Nanomedicine: nanoparticles, molecular biosensors, and targeted gene/drug delivery for combined single-cell diagnostics and therapeutics

    Science.gov (United States)

    Prow, Tarl W.; Salazar, Jose H.; Rose, William A.; Smith, Jacob N.; Reece, Lisa; Fontenot, Andrea A.; Wang, Nan A.; Lloyd, R. Stephen; Leary, James F.

    2004-07-01

    Next generation nanomedicine technologies are being developed to provide for continuous and linked molecular diagnostics and therapeutics. Research is being performed to develop "sentinel nanoparticles" which will seek out diseased (e.g. cancerous) cells, enter those living cells, and either perform repairs or induce those cells to die through apoptosis. These nanoparticles are envisioned as multifunctional "smart drug delivery systems". The nanosystems are being developed as multilayered nanoparticles (nanocrystals, nanocapsules) containing cell targeting molecules, intracellular re-targeting molecules, molecular biosensor molecules, and drugs/enzymes/gene therapy. These "nanomedicine systems" are being constructed to be autonomous, much like present-day vaccines, but will have sophisticated targeting, sensing, and feedback control systems-much more sophisticated than conventional antibody-based therapies. The fundamental concept of nanomedicine is to not to just kill all aberrant cells by surgery, radiation therapy, or chemotherapy. Rather it is to fix cells, when appropriate, one cell-at-a-time, to preserve and re-build organ systems. When cells should not be fixed, such as in cases where an improperly repaired cell might give rise to cancer cells, the nanomedical therapy would be to induce apoptosis in those cells to eliminate them without the damagin bystander effects of the inflammatory immune response system reacting to necrotic cells or those which have died from trauma or injury. The ultimate aim of nanomedicine is to combine diagnostics and therapeutics into "real-time medicine", using where possible in-vivo cytometry techniques for diagnostics and therapeutics. A number of individual components of these multi-component nanoparticles are already working in in-vitro and ex-vivo cell and tissue systems. Work has begun on construction of integrated nanomedical systems.

  8. Improving global monitoring of vaccine safety: a survey of national centres participating in the WHO Programme for International Drug Monitoring.

    Science.gov (United States)

    Letourneau, Megan; Wells, George; Walop, Wikke; Duclos, Philippe

    2008-01-01

    The WHO Programme for International Drug Monitoring (PIDM) was established in 1968 following the thalidomide disaster. The PIDM has had considerable success in analyzing drug-related adverse event reports, but more limited progress has been made in analyzing vaccine-related reports. In June 2005, the Global Advisory Committee on Vaccine Safety, acknowledging these limitations, called for a global consultation to address the need for improved monitoring and analysis of vaccine-related adverse event reports on an international level. In preparation for this consultation and as part of a larger study designed to evaluate the PIDM, a survey of the National Pharmacovigilance Centres of all 76 countries participating in the PIDM at the time the survey was conducted. Thirty-six countries (47%) responded. Of the 36 responding countries, 16 (44%) reported having a separate surveillance system for adverse events following immunizations (AEFIs) and 30 (83%) reported forwarding AEFI reports to the PIDM. Seven of the 36 countries (19%) indicated that one or more population subgroups are systematically excluded from their country's AEFI surveillance system. Five of the seven countries exclude reports concerning recipients of travellers' vaccines; three exclude recipients of vaccines administered by private physicians outside the national immunization programme and supply scheme; and five exclude reports from the military sector. Only half of the respondents knew of the Brighton Collaboration, a major international initiative aimed at the standardization of AEFI definitions. The survey identified critical elements that should be addressed quickly to improve global vaccine safety monitoring. Communication between national adverse drug reaction and AEFI surveillance authorities, ability to pay for advancing technology in developing countries, and proper use of services and terminologies are issues of concern.

  9. Discovery and therapeutic potential of drugs that shift energy metabolism from mitochondrial respiration to glycolysis

    Science.gov (United States)

    Gohil, Vishal M.; Sheth, Sunil A.; Nilsson, Roland; Wojtovich, Andrew P.; Lee, Jeong Hyun; Perocchi, Fabiana; Chen, William; Clish, Clary B.; Ayata, Cenk; Brookes, Paul S.; Mootha, Vamsi K.

    2010-01-01

    Most cells can dynamically shift their relative reliance on glycolytic versus oxidative metabolism in response to nutrient availability, during development, and in disease. Studies in model systems have shown that re-directing energy metabolism from respiration to glycolysis can suppress oxidative damage and cell death in ischemic injury. At present we have a limited set of drugs that safely toggle energy metabolism in humans. Here, we introduce a quantitative, nutrient sensitized screening strategy that can identify such compounds based on their ability to selectively impair growth and viability of cells grown in galactose versus glucose. We identify several FDA approved agents never before linked to energy metabolism, including meclizine, which blunts cellular respiration via a mechanism distinct from canonical inhibitors. We further show that meclizine pretreatment confers cardioprotection and neuroprotection against ischemia-reperfusion injury in murine models. Nutrient-sensitized screening may offer a useful framework for understanding gene function and drug action within the context of energy metabolism. PMID:20160716

  10. Therapeutic potential of antiviral drugs targeting chemorefractory colorectal adenocarcinoma cells overexpressing endogenous retroviral elements.

    Science.gov (United States)

    Díaz-Carballo, David; Acikelli, Ali Haydar; Klein, Jacqueline; Jastrow, Holger; Dammann, Philipp; Wyganowski, Thomas; Guemues, Cihan; Gustmann, Sebastian; Bardenheuer, Walter; Malak, Sascha; Tefett, Nora Sophia; Khosrawipour, Veria; Giger-Pabst, Urs; Tannapfel, Andrea; Strumberg, Dirk

    2015-08-12

    Endoretroviruses account for circa 8 % of all transposable elements found in the genome of humans and other animals. They represent a genetic footprint of ancestral germ-cell infections of exoviruses that is transmittable to the progeny by Mendelian segregation. Traces of human endogenous retroviruses are physiologically expressed in ovarial, testicular and placental tissues as well as in stem cells. In addition, a number of these fossil viral elements have also been related to carcinogenesis. However, a relation between endoretroviruses expression and chemoresistance has not been reported yet. Twenty colorectal carcinoma patient samples were scrutinized for HERV-WE1 and HERV-FRD1 endoretroviruses using immunohistochemical approaches. In order to search for differential expression of these elements in chemotherapy refractory cells, a resistant HCT8 colon carcinoma subline was developed by serial etoposide exposure. Endoretroviral