WorldWideScience

Sample records for beta-blocking drugs implications

  1. Current status of beta-blocking drugs in the treatment of anxiety disorders.

    Science.gov (United States)

    Tyrer, P

    1988-12-01

    beta-Adrenoceptor blocking drugs have been used for the treatment of acute stress reactions, adjustment disorders, generalised anxiety, panic disorder and agoraphobia. In general they are effective in these disorders if somatic or autonomic symptoms are prominent but not extreme in degree. Thus, they are of more value for the relatively mild tremor of the anxious violinist in public performance than in the severe shaking noticed during a panic attack. It is most likely that beta-blockers act primarily by blocking peripheral adrenergic beta-receptors; symptoms that are mediated through beta-stimulation, such as tremor and palpitations, are helped most. Improvement is noted within 1 to 2 hours and with relatively low doses (e.g. propranolol 40 mg/day). Some recent studies, however, have suggested that when longer treatment using higher doses (e.g. propranolol 160 mg/day) is given, improvement in other forms of anxiety is noted after several weeks of treatment. beta-blocking drugs are useful adjuncts to existing treatments for anxiety and are likely to enjoy wider use now that benzodiazepines are being avoided due to their dependence risks.

  2. Beta-blocking agents during electroconvulsive therapy: a review.

    Science.gov (United States)

    Boere, E; Birkenhäger, T K; Groenland, T H N; van den Broek, W W

    2014-07-01

    Electroconvulsive therapy (ECT) is associated with at least transient episodes of hypertension and tachycardia. Beta-blocking agents may be indicated to prevent cardiovascular complications and may shorten seizure duration. This review evaluates studies that used beta-blocking agents during ECT to determine which agent has the most favourable outcomes on cardiovascular variables and seizure duration. A Medline database search was made using the combined keywords 'adrenergic beta-antagonists' and 'electroconvulsive therapy'. The search was restricted to double-blind randomized controlled trials and yielded 29 original studies. With the use of esmolol, significant attenuating effects were found on cardiovascular parameters in the first 5 min after stimulation; its shortening effects on seizure duration may be dose-related. With the use of labetalol, findings on cardiovascular effects were inconsistent during the first minutes after stimulation but were significant after 5 min and thereafter; seizure duration was scarcely studied. Landiolol attenuates heart rate but with inconsistent findings regarding arterial pressure (AP); seizure duration was mostly unaffected. Esmolol appears to be effective in reducing the cardiovascular response, although seizure duration may be affected with higher dosages. Landiolol can be considered a suitable alternative, but effects on AP need further investigation. Labetalol has been studied to a lesser extent and may have prolonged cardiovascular effects. The included studies varied in design, methodology, and the amount of exact data provided in the publications. Further study of beta-blocking agents in ECT is clearly necessary. © The Author [2014]. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  3. [The use of beta-blocking agents in psychiatry and neurology (author's transl)].

    Science.gov (United States)

    Floru, L

    1977-02-01

    This paper is an up-to-date review of the literature on the subject, as well as of own research. The paper discusses pharmacological and experimental data concerning the central nervous activity of beta-blocking agents. Their use in anxiolysis - in adults and children -, ethological research, their indications in the treatment of various psychoses, withdrawal syndromes of opiate, alcohol, hypnotics, tranquilizers, marihuana and amphetamine addiction, Parkinson, essential, familiar, senile and lithium induced tremors, as well as in side effects of other psychopharmacological drugs is analysed. The relevance of different studies and therapeutical indications is discussed. Finally, tha paper points to the side-effects, advantages and disadvantages of the above substances in neuro-psychiatric therapy and stresses their importance for future research.

  4. Patterns of drug distribution: implications and issues.

    Science.gov (United States)

    Johnson, Bruce D

    2003-01-01

    This article delineates various patterns of illicit sales of drugs, especially at the retail (and near-retail) level, addressing a variety of central issues about drug sales and distribution documented during the past 30 years. including: a) the links between drug consumption and drug distribution activities; b) the various distribution roles; c) various levels of the distribution hierarchy; d) types of retail and wholesale markets; e) the association of drug distribution with nondrug associated criminality and violence. The article also will address the implications of drug distribution: whether various public policies such as supply reduction and source interdiction affect illicit drug markets, and how policing strategies and various law enforcement strategies can influence the involvement of individual participation in drug distribution activities. The overlooked contribution of treatment for "drug abuse" to reducing drug sales and distribution activities also will be considered as will other critical unresolved issues.

  5. Implications of Drug Testing Cheerleaders

    Science.gov (United States)

    Trachsler, Tracy A.; Birren, Genevieve

    2016-01-01

    With the untimely death of a University of Louisville cheerleader due to an accidental drug overdose in the summer of 2014, the athletic department representatives took steps to prevent future incidents by adding cheerleaders to the randomized drug testing protocols conducted at the university for the student-athletes involved in National…

  6. Policy implications of drug importation.

    Science.gov (United States)

    Palumbo, Francis B; Mullins, C Daniel; Slagle, Ashley F; Rizer, Jessica

    2007-12-01

    Importation of prescription drugs into the United States has been a major health policy issue for some time. The original objective of personal importation was to allow patients to have access to drugs that were not available to them in the United States either for continuation of therapy begun in another country or when all US Food and Drug Administration (FDA)-approved drug options for their condition had been exhausted. An increasing proportion of personally imported drugs are currently marketed in the United States, but imported drugs are presumably available at a lower cost to the consumer. As US consumers opt for importation through Internet sites and other means of purchase from other countries, potential risks of exposure to counterfeit products have increased, presenting challenges to both the US regulatory system and pharmaceutical companies. This commentary summarizes the current state of importation of prescription drugs into the United States. Regulators and policymakers are under increasing pressure to address the high cost of branded drugs in the United States and the desires of many US patients to purchase less expensive formulations of these products through importation. In many cases, the historical policies surrounding personal importation of prescription drugs that are not sold in the United States have been blatantly ignored, leaving the FDA in a quandary. While current legislative proposals would allow for greater access to drugs directly to consumers from other countries, they do not address the fact that the FDA has no ability to monitor the safety and efficacy of imported products. As such, the possibility of the entry of counterfeit medications and the related potential harm remain concerns.

  7. Heart rate dynamics during a treadmill cardiopulmonary exercise test in optimized beta-blocked heart failure patients

    OpenAIRE

    Vitor Oliveira Carvalho; Guilherme Veiga Guimarães; Emmanuel Gomes Ciolac; Edimar Alcides Bocchi

    2008-01-01

    BACKGROUND: Calculating the maximum heart rate for age is one method to characterize the maximum effort of an individual. Although this method is commonly used, little is known about heart rate dynamics in optimized beta-blocked heart failure patients. AIM: The aim of this study was to evaluate heart rate dynamics (basal, peak and % heart rate increase) in optimized beta-blocked heart failure patients compared to sedentary, normal individuals (controls) during a treadmill cardiopulmonary exer...

  8. Reference drug programs: effectiveness and policy implications.

    Science.gov (United States)

    Schneeweiss, Sebastian

    2007-04-01

    In the current economic environment, health care systems are constantly struggling to contain rapidly rising costs. Drug costs are targeted by a wide variety of measures. Many jurisdictions have implemented reference drug programs (RDPs) or similar therapeutic substitution programs. This paper summarizes the mechanism and rationale of RDPs and presents evidence of their economic effectiveness and clinical safety. RDPs for pharmaceutical reimbursement are based on the assumption that drugs within specified medication groups are therapeutically equivalent and clinically interchangeable and that a common reimbursement level can thus be established. If the evidence documents that a higher price for a given drug does not buy greater effectiveness or reduced toxicity, then under RDP such extra costs are not covered. RDPs or therapeutic substitutions based on therapeutic equivalence are seen as logical extensions of generic substitution that is based on bioequivalence of drugs. If the goal is to achieve full drug coverage for as many patients as possible in the most efficient manner, then RDPs in combination with prior authorization programs are safer and more effective than simplistic fiscal drug policies, including fixed co-payments, co-insurances, or deductibles. RDPs will reduce spending in the less innovative but largest market, while fully covering all patients. Prior authorization will ensure that patients with a specified indication will benefit from the most innovative therapies with full coverage. In practice, however, not all patients and drugs will fit exactly into one of the two categories. Therefore, a process of medically indicated exemptions that will consider full coverage should accompany an RDP. In the current economic environment, health care systems are constantly struggling to contain rapidly rising costs. Drug costs are targeted by a wide variety of measures. Many jurisdictions have implemented reference drug programs, and others are considering

  9. Drug: D08600 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08600 Drug Timolol (INN); Timolol (TN); Betimol (TN) C13H24N4O3S 316.1569 316.4197... S01ED Beta blocking agents S01ED01 Timolol D08600 Timolol (INN) USP drug classification [BR:br08302] Antimi...TS C07A BETA BLOCKING AGENTS C07AA Beta blocking agents, non-selective C07AA06 Timolol D08600 Timolol (INN) ...graine Agents Prophylactic Timolol D08600 Timolol (INN) Cardiovascular Agents Beta-adrenergic Blocking Agents Timolol D08600 Tim...olol (INN) Ophthalmic Agents Ophthalmic Antiglaucoma Agents Timolol D08600 Timolol (INN)

  10. Drug: D00378 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00378 Drug Timolol (USAN); Timolol hemihydrate; Betimol (TN) (C13H24N4O3S)2. H2O 6...ONS AND MIOTICS S01ED Beta blocking agents S01ED01 Timolol D00378 Timolol (USAN) USP drug classification [BR:br08302] Antim... BLOCKING AGENTS C07A BETA BLOCKING AGENTS C07AA Beta blocking agents, non-selective C07AA06 Timolol D00378 Tim...igraine Agents Prophylactic Timolol D00378 Timolol (USAN) Cardiovascular Agents Beta-adrenergic Blocking Agents Tim...olol D00378 Timolol (USAN) Ophthalmic Agents Ophthalmic Antiglaucoma Agents Timolol D00378 Tim

  11. Drug: D00603 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available classification [BR:br08302] Antimigraine Agents Prophylactic Timolol D00603 Timolol maleate (JP16/USP) Cardi...D00603 Drug Timolol maleate (JP16/USP); Blocadren (TN); Istalol (TN); Timoptic (TN)...g sensory organs 131 Ophthalmic agents 1319 Others D00603 Timolol maleate (JP16/U...ING AGENTS C07A BETA BLOCKING AGENTS C07AA Beta blocking agents, non-selective C07AA06 Timolol D00603 Timolo... Beta blocking agents S01ED01 Timolol D00603 Timolol maleate (JP16/USP) USP drug

  12. Drug: D09372 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09372 Drug Ranagengliotucel-T (USAN); Glionix (TN) Cell therapy treatment for brain cancer Autologous vacci...ne cocktail of TGF-beta blocked, whole brain cancer tumor cells PubChem: 96026052 ...

  13. Glutamatergic transmission in drug reward: implications for drug addiction.

    Science.gov (United States)

    D'Souza, Manoranjan S

    2015-01-01

    Individuals addicted to drugs of abuse such as alcohol, nicotine, cocaine, and heroin are a significant burden on healthcare systems all over the world. The positive reinforcing (rewarding) effects of the above mentioned drugs play a major role in the initiation and maintenance of the drug-taking habit. Thus, understanding the neurochemical mechanisms underlying the reinforcing effects of drugs of abuse is critical to reducing the burden of drug addiction in society. Over the last two decades, there has been an increasing focus on the role of the excitatory neurotransmitter glutamate in drug addiction. In this review, pharmacological and genetic evidence supporting the role of glutamate in mediating the rewarding effects of the above described drugs of abuse will be discussed. Further, the review will discuss the role of glutamate transmission in two complex heterogeneous brain regions, namely the nucleus accumbens (NAcc) and the ventral tegmental area (VTA), which mediate the rewarding effects of drugs of abuse. In addition, several medications approved by the Food and Drug Administration that act by blocking glutamate transmission will be discussed in the context of drug reward. Finally, this review will discuss future studies needed to address currently unanswered gaps in knowledge, which will further elucidate the role of glutamate in the rewarding effects of drugs of abuse.

  14. Glutamatergic transmission in drug reward: Implications for drug addiction

    Directory of Open Access Journals (Sweden)

    Manoranjan S Dsouza

    2015-11-01

    Full Text Available Individuals addicted to drugs of abuse such as alcohol, nicotine, cocaine, and heroin are a significant burden on healthcare systems all over the world. The positive reinforcing (rewarding effects of the above mentioned drugs play a major role in the initiation and maintenance of the drug-taking habit. Thus, understanding the neurochemical mechanisms underlying the reinforcing effects of drugs of abuse is critical to reducing the burden of drug addiction in society. Over the last two decades, there has been an increasing focus on the role of the excitatory neurotransmitter glutamate in drug addiction. In this review, pharmacological and genetic evidence supporting the role of glutamate in mediating the rewarding effects of the above described drugs of abuse will be discussed. Further, the review will discuss the role of glutamate transmission in two complex heterogeneous brain regions, namely the nucleus accumbens (NAcc and the ventral tegmental area (VTA, which mediate the rewarding effects of drugs of abuse. In addition, several medications approved by the Food and Drug Administration that act by blocking glutamate transmission will be discussed in the context of drug reward. Finally, this review will discuss future studies needed to address currently unanswered gaps in knowledge, which will further elucidate the role of glutamate in the rewarding effects of drugs of abuse.

  15. Perceptions of Imprisoned Drug Abusers: Implications for Counseling

    Science.gov (United States)

    Page, Richard C.; Myrick, Robert D.

    1977-01-01

    This study investigated the attitudes of 85 imprisoned drug abusers. The responses of the subjects on the activity, evaluative, and potency scales of a semantic differential were analyzed. Implications for counseling are discussed. (Author)

  16. pH-dependent drug-drug interactions for weak base drugs: potential implications for new drug development.

    Science.gov (United States)

    Zhang, L; Wu, F; Lee, S C; Zhao, H; Zhang, L

    2014-08-01

    Absorption of an orally administered drug with pH-dependent solubility may be altered when it is coadministered with a gastric acid-reducing agent (ARA). Assessing a drug's potential for pH-dependent drug-drug interactions (DDIs), considering study design elements for such DDI studies, and interpreting and communicating study results in the drug labeling to guide drug dosing are important for drug development. We collected pertinent information related to new molecular entities approved from January 2003 to May 2013 by the US Food and Drug Administration for which clinical DDI studies with ARAs were performed. On the basis of assessments of data on pH solubility and in vivo DDIs with ARAs, we proposed a conceptual framework for assessing the need for clinical pH-dependent DDI studies for weak base drugs (WBDs). Important study design considerations include selection of ARAs and timing of dosing of an ARA relative to the WBD in a DDI study. Labeling implications for drugs having DDIs with ARAs are also illustrated.

  17. Toxic Epidermal Necrolysis induced by rarely implicated drugs

    Directory of Open Access Journals (Sweden)

    Sujit Rajagopalan

    2012-01-01

    Full Text Available Toxic Epidermal Necrolysis (TEN and Steven-Johnson Syndrome (SJS are serious disorders commonly caused as idiosyncratic reactions to drugs, the most common ones being oxicams, anticonvulsants, allopurinol, and sulfonamides. We present a case of TEN in a patient who developed the lesions after ingesting multiple drugs including paracetamol, metoclopramide, antihistamines, and multivitamins. These drugs have rarely been implicated in this disorder. The suspected drugs in this case were paracetamol and metoclopramide. However, the role of other drugs could not be ruled out definitely. The patient was managed with antibiotics, corticosteroids, and parenteral fluids and recovered well.

  18. Critical drug shortages: implications for emergency medicine.

    Science.gov (United States)

    Mazer-Amirshahi, Maryann; Pourmand, Ali; Singer, Steven; Pines, Jesse M; van den Anker, John

    2014-06-01

    Prescription drug shortages have become increasingly common and more severe over the past decade. In addition, reported shortages are longer in duration and have had a greater effect on patient care. Some of the causes of current drug shortages are multifactorial, including the consolidation of drug manufacturers, quality problems at production plants that restrict the supply of drugs, and a lack of financial incentives for manufacturers to produce certain products, particularly generic medications. Generic injectable medications are most commonly affected by shortages because the production process is complex and costly for these drugs, and profit margins are often smaller than for branded medications. Many commonly used emergency department (ED) generic injectables have been affected by shortages, including multiple resuscitation and critical care drugs. Several reports have shown that shortages can potentially have major effects on the quality of medical care, including medication errors, treatment delays, adverse outcomes, and increased health care costs. Currently, no published data exist outside of case reports that directly link ED-based drug shortages to overall patient safety events; however, there are several examples in the ED where first-line therapies for life-saving medications have been in short supply, and alternatives have higher rates of adverse events, narrower therapeutic indexes, or both. Aside from increasing notification about shortages, the U.S. Food and Drug Administration has little power to coerce manufacturers to produce medications during a shortage. Therefore, ED providers must learn to mitigate the effects of shortages locally, through active communication with pharmacy staff to identify safe and effective alternatives for commonly used medications when possible. Particularly given the effect on critical care medications, therapeutic alternatives should be clearly communicated to all staff so that providers have easy access to this

  19. Drug: D08493 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08493 Mixture, Drug Dorzolamide hydrochloride - timolol maleate mixt; Cosopt (TN) ...Dorzolamide hydrochloride [DR:D00653], Timolol maleate [DR:D00603] carbonic anhydrase inhibitor / beta-block...gans 13 Agents affecting sensory organs 131 Ophthalmic agents 1319 Others D08493 Dorzolamide hydrochloride - tim... OPHTHALMOLOGICALS S01E ANTIGLAUCOMA PREPARATIONS AND MIOTICS S01ED Beta blocking agents S01ED51 Tim...olol, combinations D08493 Dorzolamide hydrochloride - timolol maleate mixt PubChem: 124490301 ...

  20. Hepatotoxicity by Drugs: The Most Common Implicated Agents

    Directory of Open Access Journals (Sweden)

    Einar S. Björnsson

    2016-02-01

    Full Text Available Idiosyncratic drug-induced liver injury (DILI is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov. According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab.

  1. Hepatotoxicity by Drugs: The Most Common Implicated Agents.

    Science.gov (United States)

    Björnsson, Einar S

    2016-02-06

    Idiosyncratic drug-induced liver injury (DILI) is an underreported and underestimated adverse drug reaction. Information on the documented hepatotoxicity of drugs has recently been made available by a website that can be accessed in the public domain: LiverTox (http://livertox.nlm.nih.gov). According to critical analysis of the hepatotoxicity of drugs in LiverTox, 53% of drugs had at least one case report of convincing reports of liver injury. Only 48 drugs had more than 50 case reports of DILI. Amoxicillin-clavulanate is the most commonly implicated agent leading to DILI in the prospective series. In a recent prospective study, liver injury due to amoxicillin-clavulanate was found to occur in approximately one out of 2300 users. Drugs with the highest risk of DILI in this study were azathioprine and infliximab.

  2. Spider venomics: implications for drug discovery.

    Science.gov (United States)

    Pineda, Sandy S; Undheim, Eivind A B; Rupasinghe, Darshani B; Ikonomopoulou, Maria P; King, Glenn F

    2014-10-01

    Over a period of more than 300 million years, spiders have evolved complex venoms containing an extraordinary array of toxins for prey capture and defense against predators. The major components of most spider venoms are small disulfide-bridged peptides that are highly stable and resistant to proteolytic degradation. Moreover, many of these peptides have high specificity and potency toward molecular targets of therapeutic importance. This unique combination of bioactivity and stability has made spider-venom peptides valuable both as pharmacological tools and as leads for drug development. This review describes recent advances in spider-venom-based drug discovery pipelines. We discuss spider-venom-derived peptides that are currently under investigation for treatment of a diverse range of pathologies including pain, stroke and cancer.

  3. Primary prevention of posttraumatic stress disorder:drugs and implications

    Institute of Scientific and Technical Information of China (English)

    Joachim C Burbiel

    2015-01-01

    Because posttraumatic stress disorder (PTSD) is a highly debilitating condition, prevention is an important research topic. This article reviews possible prevention approaches that involve the administration of drugs before the traumatic event takes place. The considered approaches include drugs that address the sympathetic nervous system, drugs interfere with the hypothalamic-pituitary-adrenal (HPA) axis, narcotics and other psychoactive drugs, as well as modulators of protein synthesis. Furthermore, some thoughts on potential ethical implications of the use of drugs for the primary prevention of PTDS are presented. While there are many barriers to overcome in this field of study, this paper concludes with a call for additional research, as there are currently no approaches that are well-suited for regular daily use.

  4. GIRK Channel Plasticity and Implications for Drug Addiction.

    Science.gov (United States)

    Marron Fernandez de Velasco, Ezequiel; McCall, Nora; Wickman, Kevin

    2015-01-01

    Drugs of abuse can "hijack" synaptic plasticity, a physiological basis of learning and memory, establishing maladaptations that can promote drug addiction. A wealth of data supports the existence and importance of neuroadaptations in excitatory neurotransmission upon drug exposure. Recent discoveries, however, have shown that inhibitory neurotransmission mediated by G protein-gated inwardly rectifying potassium (K(+)) (GIRK/Kir3) channels is also subject to adaptation triggered by exposure to drugs of abuse. GIRK channels are expressed in neuronal populations relevant to reward and reward-related behaviors, where their activation by neurotransmitters such as GABA, dopamine, and adenosine reduces neuronal excitability. Studies in animal models have implicated GIRK channels in a number of behaviors including reward. Drugs of abuse also affect the inhibitory neurotransmission mediated by GIRK channels. These changes might be important for the development, maintenance, or relapse of addiction, making GIRK channels promising targets for novel addiction therapies. © 2015 Elsevier Inc. All rights reserved.

  5. Drug rechallenge and treatment beyond progression—implications for drug resistance

    Science.gov (United States)

    Kuczynski, Elizabeth A.; Sargent, Daniel J.; Grothey, Axel; Kerbel, Robert S.

    2015-01-01

    The established dogma in oncology for managing recurrent or refractory disease dictates that therapy is changed at disease progression, because the cancer is assumed to have become drug-resistant. Drug resistance, whether pre-existing or acquired, is largely thought to be a stable and heritable process; thus, reuse of therapeutic agents that have failed is generally contraindicated. Over the past few decades, clinical evidence has suggested a role for unstable, non-heritable mechanisms of acquired drug resistance pertaining to chemotherapy and targeted agents. There are many examples of circumstances where patients respond to reintroduction of the same therapy (drug rechallenge) after a drug holiday following disease relapse or progression during therapy. Additional, albeit limited, evidence suggests that, in certain circumstances, continuing a therapy beyond disease progression can also have antitumour activity. In this Review, we describe the anticancer agents used in these treatment strategies and discuss the potential mechanisms explaining the apparent tumour re-sensitization with reintroduced or continued therapy. The extensive number of malignancies and drugs that challenge the custom of permanently switching to different drugs at each line of therapy warrants a more in-depth examination of the definitions of disease progression and drug resistance and the resulting implications for patient care. PMID:23999218

  6. Clinical drugs that interact with St. John's wort and implication in drug development.

    Science.gov (United States)

    Di, Yuan Ming; Li, Chun Guang; Xue, Charlie Changli; Zhou, Shu-Feng

    2008-01-01

    St. John's wort (Hypericum perforatum, SJW) is one of the most commonly used herbal antidepressants for the treatment of minor to moderate depression. A major safety concern about SJW is its ability to alter the pharmacokinetics and/or clinical response of a variety of clinically important drugs that have distinctive chemical structure, mechanism of action and metabolic pathways. This review highlights and updates the knowledge on clinical interactions of prescribed drugs with SJW and the implication in drug development. A number of clinically significant interactions of SJW have been identified with conventional drugs, including anticancer agents (imatinib and irinotecan), anti-HIV agents (e.g. indinavir, lamivudine and nevirapine), anti-inflammatory agents (e.g. ibuprofen and fexofenadine), antimicrobial agents (e.g. erythromycin and voriconazole), cardiovascular drugs (e.g. digoxin, ivabradine, warfarin, verapamil, nifedipine and talinolol), central nervous system agents (e.g. amitriptyline, buspirone, phenytoin, methadone, midazolam, alprazolam, and sertraline), hypoglycaemic agents (e.g. tolbutamide and gliclazide), immuno-modulating agents (e.g. cyclosporine and tacrolimus), oral contraceptives, proton pump inhibitor (e.g. omeprazole), respiratory system agent (e.g. theophylline), statins (e.g. atorvastatin and pravastatin). Both pharmacokinetic and pharmacodynamic components may play a role in the interactions of drugs with SJW. For pharmacokinetic changes of drugs by SJW, induction of cytochrome P450s (e.g. CYP2C9 and 3A4) and P-glycoprotein (P-gp) are considered the major mechanism. Thus, it is not a surprise that many drugs that interact with SJW are substrates of CYP3A4, CYP2C9 and P-gp. A comprehensive understanding of clinical drugs that interact with SJW has important implications in drug development. New drugs may be designed to minimize interactions with SJW; and new SJW formulations may be designed to avoid drug interactions. Further clinical and

  7. Drug: D00255 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00255 Drug Carvedilol (JAN/USAN/INN); Artist (TN); Coreg (TN) C24H26N2O4 406.1893 ...idual organs 21 Cardiovascular agents 214 Antihypertensives 2149 Others D00255 Carvedilol (JAN/USAN/INN) Ana...NTS C07A BETA BLOCKING AGENTS C07AG Alpha and beta blocking agents C07AG02 Carvedilol D00255 Carvedilol...edilol D00255 Carvedilol (JAN/USAN/INN) Target-based classification of drugs [BR:br...receptor [HSA:146 147 148] [KO:K04137 K04136 K04135] Carvedilol [ATC:C07AG02] D00255 Carvedilol (JAN/USAN/IN

  8. Pharmacokinetic drug-drug interaction and their implication in clinical management

    Directory of Open Access Journals (Sweden)

    Palleria Caterina

    2013-01-01

    Full Text Available Drug-drug interactions (DDIs are one of the commonest causes of medication error in developed countries, particularly in the elderly due to poly-therapy, with a prevalence of 20-40%. In particular, poly-therapy increases the complexity of therapeutic management and thereby the risk of clinically important DDIs, which can both induce the development of adverse drug reactions or reduce the clinical efficacy. DDIs can be classify into two main groups: pharmacokinetic and pharmacodynamic. In this review, using Medline, PubMed, Embase, Cochrane library and Reference lists we searched articles published until June 30 2012, and we described the mechanism of pharmacokinetic DDIs focusing the interest on their clinical implications.

  9. Implications of Chirality of Drugs and Excipients in Physical Pharmacy.

    Science.gov (United States)

    Duddu, Sarma P.

    1993-01-01

    entities leads to significant, interpretable changes in the physicochemical properties of the drug, which may have important implications in the design and development of reliable and effective solid dosage forms.

  10. Drug: D09815 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09815 Mixture, Drug Travoprost - timolol maleate mixt; Duotrav (TN) Travoprost [DR...ensory organs 131 Ophthalmic agents 1319 Others D09815 Travoprost - timolol maleate mixt Anatomical Therapeu...ARATIONS AND MIOTICS S01ED Beta blocking agents S01ED51 Timolol, combinations D09815 Travoprost - timolol maleate mixt PubChem: 124490555 ...

  11. Drug: D10298 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available S01ED Beta blocking agents S01ED51 Timolol, combinations D10298 Brimonidine tartrate - timolol maleate mixt PubChem: 163312329 ... ...D10298 Mixture, Drug Brimonidine tartrate - timolol maleate mixt; Combigan (TN) Bri...monidine tartrate [DR:D02076], Timolol maleate [DR:D00603] Treatment of glaucoma, ocular hypertension ATC co

  12. Drug: D10273 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10273 Mixture, Drug Metoprolol - hydrochlorothiazide mixt; Dutoprol (TN); Lopresso...r hct (TN) (Metoprolol tartrate [DR:D00601] | Metoprolol succinate [DR:D00635]), Hydrochlorothiazide [DR:D00...ZIDES C07BB Beta blocking agents, selective, and thiazides C07BB02 Metoprolol and thiazides D10273 Metoprolol - hydrochlorothiazide mixt PubChem: 163312304 ...

  13. Drug: D06563 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D06563 Drug Belagenpumatucel-L (USAN); Lucanix (TN) Cell therapy treatment of non-small cell lung cancer... Allogeneic vaccine cocktail of TGF-beta blocked, whole non-small cell lung cancer tumor cells. PubChem: 47208219 ...

  14. Drug therapy during pregnancy: implications for dental practice.

    Science.gov (United States)

    Ouanounou, A; Haas, D A

    2016-04-22

    Pregnancy is accompanied by various physiological and physical changes, including those found in the cardiovascular, respiratory, gastrointestinal, renal and haematological systems. These alterations in the pregnant patient may potentially affect drug pharmacokinetics. Also, pharmacotherapy presents a unique matter due to the potential teratogenic effects of certain drugs. Although medications prescribed by dentists are generally safe during pregnancy, some modifications may be needed. In this article we will discuss the changes in the physiology during pregnancy and its impact on drug therapy. Specific emphasis will be given to the drugs commonly given by dentists, namely, local anaesthetics, analgesics, antibiotics and sedatives.

  15. Acoustic behavior of microbubbles and implications for drug delivery

    NARCIS (Netherlands)

    Kooiman, K.; Vos, H.J.; Versluis, M.; Jong, de N.

    2014-01-01

    Ultrasound contrast agents are valuable in diagnostic ultrasound imaging, and they increasingly show potential for drug delivery. This review focuses on the acoustic behavior of flexible-coated microbubbles and rigid-coated microcapsules and their contribution to enhanced drug delivery. Phenomena re

  16. The pricing of breakthrough drugs: theory and policy implications.

    Directory of Open Access Journals (Sweden)

    Moshe Levy

    Full Text Available Pharmaceutical sales exceed $850 billion a year, of which 84% are accounted for by brand drugs. Drug prices are the focus of an ongoing heated debate. While some argue that pharmaceutical companies exploit monopolistic power granted by patent protection to set prices that are "too high", others claim that these prices are necessary to motivate the high R&D investments required in the pharmaceutical industry. This paper employs a recently documented utility function of health and wealth to derive the theoretically optimal pricing of monopolistic breakthrough drugs. This model provides a framework for a quantitative discussion of drug price regulation. We show that mild price regulation can substantially increase consumer surplus and the number of patients who purchase the drug, while having only a marginal effect on the revenues of the pharmaceutical company.

  17. Biophysics of Cell Membrane Lipids in Cancer Drug Resistance: Implications for Drug Transport and Drug Delivery with Nanoparticles

    Science.gov (United States)

    Peetla, Chiranjeevi; Vijayaraghavalu, Sivakumar; Labhasetwar, Vinod

    2013-01-01

    In this review, we focus on the biophysics of cell membrane lipids, particularly when cancers develop acquired drug resistance, and how biophysical changes in resistant cell membrane influence drug transport and nanoparticle-mediated drug delivery. Recent advances in membrane lipid research show the varied roles of lipids in regulating membrane P-glycoprotein function, membrane trafficking, apoptotic pathways, drug transport, and endocytic functions, particularly endocytosis, the primary mechanism of cellular uptake of nanoparticle-based drug delivery systems. Since acquired drug resistance alters lipid biosynthesis, understanding the role of lipids in cell membrane biophysics and its effect on drug transport is critical for developing effective therapeutic and drug delivery approaches to overcoming drug resistance. Here we discuss novel strategies for (a) modulating the biophysical properties of membrane lipids of resistant cells to facilitate drug transport and regain endocytic function and (b) developing effective nanoparticles based on their biophysical interactions with membrane lipids to enhance drug delivery and overcome drug resistance. PMID:24055719

  18. Severe iatrogenic bradycardia related to the combined use of beta-blocking agents and sodium channel blockers

    Directory of Open Access Journals (Sweden)

    Kawabata M

    2015-02-01

    Full Text Available Mihoko Kawabata,1 Yasuhiro Yokoyama,1 Takeshi Sasaki,1 Susumu Tao,1 Kensuke Ihara,1 Yasuhiro Shirai,1 Tetsuo Sasano,2 Masahiko Goya,1 Tetsushi Furukawa,3 Mitsuaki Isobe,4 Kenzo Hirao1 1Heart Rhythm Center, Tokyo Medical and Dental University, Tokyo, Japan; 2Department of Biofunctional Informatics, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, Tokyo, Japan; 3Department of Bio-informational Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan; 4Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan Purpose: Drug-induced bradycardia is common during antiarrhythmic therapy; the major culprits are beta-blockers. However, whether other antiarrhythmic drugs are also a significant cause of this, alone or in combination with beta-blockers, is not well known. Methods: We retrospectively investigated the records of all patients hospitalized at our institution for drug-related bradycardia from the years 2004 to 2012. Patients with cardiac disease and electrolytic or hormonal abnormalities that could cause bradyarrhythmias were excluded. Results: Eight patients were identified (mean age, 79±5 years; range, 71–85 years; 6 women. Three patients were taking only beta-blockers (hereafter referred to as the BB group, while five patients were on both beta-blockers and Na channel blockers (hereafter referred to as the BB + Na group. Heart rates ranged from 20~49 beats/minute on arrival. The initial electrocardiogram showed sinus bradycardia (n=6 or sinus arrest with escape beats (n=2. QRS duration was 80–100 ms. The clinical presentation of the BB + Na group was considerably worse than that of the BB group, and included cardiogenic shock and heart failure. Four of the BB + Na patients had been on their medications for over 300 days. The BB group recovered solely with drug discontinuation, while 4 of the 5 patients in the BB + Na group needed additional

  19. Implications of Recent Drug Approvals for Older Adults

    Science.gov (United States)

    Eisenhower, Christine; Koronkowski, Michael; Marcum, Zachary

    2016-01-01

    More than 100 medications were approved by the US Food and Drug Administration as new drugs or for new indications in 2014 and 2015. Several of the new drugs may benefit older adults, but adverse events and pharmacokinetic changes due to aging must be considered. This article will focus on three recently approved drugs that are marketed for chronic conditions that can affect older adults: suvorexant, for treatment of insomnia; edoxaban, for prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for treatment of venous thromboembolism; and droxidopa, for treatment of symptomatic neurogenic orthostatic hypotension. Information about indications, mechanisms of action, dosing, efficacy, and safety are reviewed. The place of each agent in therapy for older adults is also discussed. PMID:27340374

  20. Impaired fitness of drug-resistant malaria parasites: evidence and implication on drug-deployment policies.

    Science.gov (United States)

    Babiker, Hamza A; Hastings, Ian M; Swedberg, Göte

    2009-06-01

    Malaria, a leading parasitic disease, inflicts an enormous toll on human lives and is caused by protozoal parasites belonging to the genus Plasmodium. Antimalarial drugs targeting essential biochemical processes in the parasite are the primary resources for management and control. However, the parasite has established mutations, substantially reducing the efficacy of these drugs. First-line therapy is faced the with the consistent evolution of drug-resistant genotypes carrying these mutations. However, drug-resistant genotypes are likely to be less fit than the wild-type, suggesting that they might disappear by reducing the volume of drug pressure. A substantial body of epidemiological evidence confirmed that the frequency of resistant genotypes wanes when active drug selection declines. Drug selection on the parasite genome that removes genetic variation in the vicinity of drug-resistant genes (hitch-hiking) is common among resistant parasites in the field. This can further disadvantage drug-resistant strains and limit their variability in the face of a mounting immune response. Attempts to provide unequivocal evidence for the fitness cost of drug resistance have monitored the outcomes of laboratory competition experiments of deliberate mixtures of sensitive and resistant strains, in the absence of drug pressure, using isogenic clones produced either by drug selection or gene manipulation. Some of these experiments provided inconclusive results, but they all suggested reduced fitness of drug-resistant clones in the absence of drug pressure. In addition, biochemical analyses provided clearer information demonstrating that the mutation of some antimalarial-targeted enzymes lowers their activity compared with the wild-type enzyme. Here, we review current evidences for the disadvantage of drug-resistance mutations, and discuss some strategies of drug deployment to maximize the cost of resistance and limit its spread.

  1. The Visibility of Illicit Drugs: Implications for Community-based Drug Control Strategies.

    Science.gov (United States)

    Saxe, Leonard; Kadushin, Charles; Beveridge, Andrew; Livert, David; Tighe, Elizabeth; Rindskopf, David; Ford, Julie; Brodsky, Archie

    2001-01-01

    Examined differences between the visibility of drugs and drug use in over 2000 neighborhoods, surveying residents regarding drug- and alcohol-related behaviors and attitudes and comparing the responses of poor, urban, African Americans versus people from comparison neighborhoods. The most disadvantaged neighborhoods had the most visible drug…

  2. Justice implications of a proposed Medicare prescription drug policy.

    Science.gov (United States)

    Larkin, Heather

    2004-07-01

    Social justice is a core value to the mission of social work. Older people are among the most vulnerable populations for whom social workers are called on to advocate. Although Medicare prescription drug coverage has been a top legislative issue over the past few years, such a benefit expansion has yet to be implemented. This article examines the historical context of Medicare and reviews the proposals for prescription drug coverage, identifying the concerns raised. Literature critiquing the justice dimensions of health care for the elderly population is reviewed. Justice claims are identified and refined, and social justice theories are used in the analysis of the proposed policies.

  3. Tobacco, the Common Enemy and a Gateway Drug: Policy Implications

    Science.gov (United States)

    Torabi, Mohammad R.; Jun, Mi Kyung; Nowicke, Carole; de Martinez, Barbara Seitz; Gassman, Ruth

    2010-01-01

    For the four leading causes of death in the United States (heart disease, cancer, stroke and chronic respiratory disease), tobacco use is a common risk factor. Tobacco use is responsible for almost 450,000 deaths per year and impacts the health of every member of our society. Tobacco is a gateway drug for substance abuse. That role is critical to…

  4. Drugs and the Elderly: Implications for Exercise Indulgence.

    Science.gov (United States)

    Piscopo, John

    Many age-related biologic and physiologic changes can have important influences on drug pharmacology in elderly persons. Successful management depends upon good communications among health care providers, fitness instructors, and the medication user. Each exerciser should be monitored and reviewed at regular intervals. Medications may be a…

  5. Bioavailability of capsaicin and its implications for drug delivery.

    Science.gov (United States)

    Rollyson, William D; Stover, Cody A; Brown, Kathleen C; Perry, Haley E; Stevenson, Cathryn D; McNees, Christopher A; Ball, John G; Valentovic, Monica A; Dasgupta, Piyali

    2014-12-28

    The dietary compound capsaicin is responsible for the "hot and spicy" taste of chili peppers and pepper extracts. It is a valuable pharmacological agent with several therapeutic applications in controlling pain and inflammation. Emerging studies show that it displays potent anti-tumor activity in several human cancers. On a more basic research level, capsaicin has been used as a ligand to activate several types of ion-channel receptors. The pharmacological activity of capsaicin-like compounds is dependent on several factors like the dose, the route of administration and most importantly on its concentration at target tissues. The present review describes the current knowledge involving the metabolism and bioavailability of capsaicinoids in rodents and humans. Novel drug delivery strategies used to improve the bioavailability and therapeutic index of capsaicin are discussed in detail. The generation of novel capsaicin-mimetics and improved drug delivery methods will foster the hope of innovative applications of capsaicin in human disease.

  6. Atypical cytochrome p450 kinetics: implications for drug discovery.

    Science.gov (United States)

    Tracy, Timothy S

    2006-01-01

    The Michaelis-Menten model is commonly used to estimate a drug's potential in vivo hepatic clearance based on in vitro data obtained during drug discovery and development. This paradigm assumes that the drug obeys 'typical' enzyme kinetics and thus can be described by this model. However, it is increasingly being recognised that a number of drugs metabolised not only by the cytochrome P450 enzymes but also by other enzymes and transporters can exhibit atypical kinetic profiles, and thus are not accurately modeled with the Michaelis-Menten model. Application of an incorrect model can then lead to mis-estimation of in vitro intrinsic clearance and thus affect the prediction of in vivo clearance. This review discusses several types of atypical kinetic profiles that may be observed, including examples of homotropic cooperativity (i.e. sigmoidal kinetics, biphasic kinetics and substrate inhibition kinetics) as well as heterotropic cooperativity (i.e. activation). Application of the incorrect kinetic model may profoundly affect estimations of intrinsic clearance. For example, incorrectly applying the Michaelis-Menten model to a kinetic profile exhibiting substrate inhibition kinetics will result in an underestimation of Km (Michaelis-Menten constant) and V(max) (maximal velocity), whereas application of the Michaelis-Menten model to sigmoidal kinetic data typically results in an overestimation of Km and V(max) at the lower substrate concentrations that are typically therapeutically relevant. One must also be careful of potential artefactual causes of atypical kinetic profiles, such as enzyme activation by solvents, buffer dependent kinetic profiles, or altered kinetic parameter estimates due to nonspecific binding of the substrate to proteins. Despite a plethora of data on the effects of atypical kinetic profiles in vitro, only modest effects have been noted in vivo (with the exception of substrate dependent inhibition). Thus, the clinical relevance of these phenomena

  7. Analysis of drug prohibition and estimation of budgetary implications of marijuana legalization

    OpenAIRE

    Flegr, Jan

    2009-01-01

    This paper examines the impact of drug prohibition on society. It analyzes starting-points and aims of prohibition and shows, how prohibition attempts to achieve its goals. Furthermore, it explores social costs of prohibition, mainly the impact on potencial health risks of drug use and property and violent crimes. Then it presents main reasons of failure to achieve its goals. Furthemore, this paper estimates probable budgetary implications of marijuana legalization. This estimate is based on ...

  8. Drug targeting to myofibroblasts: Implications for fibrosis and cancer.

    Science.gov (United States)

    Yazdani, Saleh; Bansal, Ruchi; Prakash, Jai

    2017-07-16

    Myofibroblasts are the key players in extracellular matrix remodeling, a core phenomenon in numerous devastating fibrotic diseases. Not only in organ fibrosis, but also the pivotal role of myofibroblasts in tumor progression, invasion and metastasis has recently been highlighted. Myofibroblast targeting has gained tremendous attention in order to inhibit the progression of incurable fibrotic diseases, or to limit the myofibroblast-induced tumor progression and metastasis. In this review, we outline the origin of myofibroblasts, their general characteristics and functions during fibrosis progression in three major organs: liver, kidneys and lungs as well as in cancer. We will then discuss the state-of-the art drug targeting technologies to myofibroblasts in context of the above-mentioned organs and tumor microenvironment. The overall objective of this review is therefore to advance our understanding in drug targeting to myofibroblasts, and concurrently identify opportunities and challenges for designing new strategies to develop novel diagnostics and therapeutics against fibrosis and cancer. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  9. Antithyroid Drug Therapy for Graves’ Disease and Implications for Recurrence

    Directory of Open Access Journals (Sweden)

    Jia Liu

    2017-01-01

    Full Text Available Graves’ disease (GD is the most common cause of hyperthyroidism worldwide. Current therapeutic options for GD include antithyroid drugs (ATD, radioactive iodine, and thyroidectomy. ATD treatment is generally well accepted by patients and clinicians due to some advantages including normalizing thyroid function in a short time, hardly causing hypothyroidism, and ameliorating immune disorder while avoiding radiation exposure and invasive procedures. However, the relatively high recurrence rate is a major concern for ATD treatment, which is associated with multiple influencing factors like clinical characteristics, treatment strategies, and genetic and environmental factors. Of these influencing factors, some are modifiable but some are nonmodifiable. The recurrence risk can be reduced by adjusting the modifiable factors as much as possible. The titration regimen for 12–18 months is the optimal strategy of ATD. Levothyroxine administration after successful ATD treatment was not recommended. The addition of immunosuppressive drugs might be helpful to decrease the recurrence rate of GD patients after ATD withdrawal, whereas further studies are needed to address the safety and efficacy. This paper reviewed the current knowledge of ATD treatment and mainly focused on influencing factors for recurrence in GD patients with ATD treatment.

  10. Spread of anti-malarial drug resistance: Mathematical model with implications for ACT drug policies

    Directory of Open Access Journals (Sweden)

    Dondorp Arjen M

    2008-11-01

    Full Text Available Abstract Background Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT. The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. Methods A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. Results The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with

  11. Spread of anti-malarial drug resistance: mathematical model with implications for ACT drug policies.

    Science.gov (United States)

    Pongtavornpinyo, Wirichada; Yeung, Shunmay; Hastings, Ian M; Dondorp, Arjen M; Day, Nicholas P J; White, Nicholas J

    2008-11-02

    Most malaria-endemic countries are implementing a change in anti-malarial drug policy to artemisinin-based combination therapy (ACT). The impact of different drug choices and implementation strategies is uncertain. Data from many epidemiological studies in different levels of malaria endemicity and in areas with the highest prevalence of drug resistance like borders of Thailand are certainly valuable. Formulating an appropriate dynamic data-driven model is a powerful predictive tool for exploring the impact of these strategies quantitatively. A comprehensive model was constructed incorporating important epidemiological and biological factors of human, mosquito, parasite and treatment. The iterative process of developing the model, identifying data needed, and parameterization has been taken to strongly link the model to the empirical evidence. The model provides quantitative measures of outcomes, such as malaria prevalence/incidence and treatment failure, and illustrates the spread of resistance in low and high transmission settings. The model was used to evaluate different anti-malarial policy options focusing on ACT deployment. The model predicts robustly that in low transmission settings drug resistance spreads faster than in high transmission settings, and treatment failure is the main force driving the spread of drug resistance. In low transmission settings, ACT slows the spread of drug resistance to a partner drug, especially at high coverage rates. This effect decreases exponentially with increasing delay in deploying the ACT and decreasing rates of coverage. In the high transmission settings, however, drug resistance is driven by the proportion of the human population with a residual drug level, which gives resistant parasites some survival advantage. The spread of drug resistance could be slowed down by controlling presumptive drug use and avoiding the use of combination therapies containing drugs with mismatched half-lives, together with reducing malaria

  12. [Pharmacokinetic implications associated to the use of drugs as racemates or pure enantiomers].

    Science.gov (United States)

    Speisky, H; Squella, J A; Nuñez-Vergara, L J

    1995-07-01

    This article critically reviews the recent specialized literature concerning the influence of the stereochemical nature of quiral drugs on the pharmacokinetic processes and its pharmacological implications. Evidence is presented indicating that as a function of the type of enantiomer administered, profound differences in the pharmacokinetic profiles, e.g. absorption, distribution, biotransformation and elimination can occur. As a consequence of the enantioselective nature of the drug-organism interaction, major differences in the therapeutic responses can be envisaged depending on whether the drug is administered as a pure enantiomer or as a racemic mixture.

  13. Structural similarity between binding sites in influenza sialidase and isocitrate dehydrogenase: implications for an alternative approach to rational drug design.

    OpenAIRE

    Poirrette, A. R.; Artymiuk, P. J.; Grindley, H. M.; Rice, D.W.; Willett, P.

    1994-01-01

    Using searching techniques based on algorithms derived from graph theory, we have established a similarity between a 3-dimensional cluster of side chains implicated in drug binding in influenza sialidase and side chains involved in isocitrate binding in Escherichia coli isocitrate dehydrogenase. The possible implications of the use of such comparative methods in drug design are discussed.

  14. Drug: D10512 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10512 Mixture, Drug Brinzolamide - timolol maleate mixt; Azorga (TN) Brinzolamide [DR:D00652], Tim...rgans 13 Agents affecting sensory organs 131 Ophthalmic agents 1319 Others D10512 Brinzolamide - tim...SORY ORGANS S01 OPHTHALMOLOGICALS S01E ANTIGLAUCOMA PREPARATIONS AND MIOTICS S01ED Beta blocking agents S01ED51 Tim...olol, combinations D10512 Brinzolamide - timolol maleate mixt PubChem: 172232605 ...

  15. Drugs from the seas - current status and microbiological implications.

    Science.gov (United States)

    Proksch, P; Edrada, R A; Ebel, R

    2002-07-01

    The oceans are the source of a large group of structurally unique natural products that are mainly accumulated in invertebrates such as sponges, tunicates, bryozoans, and molluscs. Several of these compounds (especially the tunicate metabolite ET-743) show pronounced pharmacological activities and are interesting candidates for new drugs primarily in the area of cancer treatment. Other compounds are currently being developed as an analgesic (ziconotide from the mollusc Conus magus) or to treat inflammation. Numerous natural products from marine invertebrates show striking structural similarities to known metabolites of microbial origin, suggesting that microorganisms (bacteria, microalgae) are at least involved in their biosynthesis or are in fact the true sources of these respective metabolites. This assumption is corroborated by several studies on natural products from sponges that proved these compounds to be localized in symbiotic bacteria or cyanobacteria. Recently, molecular methods have successfully been applied to study the microbial diversity in marine sponges and to gain evidence for an involvement of bacteria in the biosynthesis of the bryostatins in the bryozoan Bugula neritina.

  16. Formation of the diuretic chlorazanil from the antimalarial drug proguanil--implications for sports drug testing.

    Science.gov (United States)

    Thevis, Mario; Geyer, Hans; Thomas, Andreas; Tretzel, Laura; Bailloux, Isabelle; Buisson, Corinne; Lasne, Francoise; Schaefer, Maximilian S; Kienbaum, Peter; Mueller-Stoever, Irmela; Schänzer, Wilhelm

    2015-11-10

    Chlorazanil (Ordipan, N-(4-chlorophenyl)-1,3,5-triazine-2,4-diamine) is a diuretic agent and as such prohibited in sport according to the regulations of the World Anti-Doping Agency (WADA). Despite its introduction into clinical practice in the late 1950s, the worldwide very first two adverse analytical findings were registered only in 2014, being motive for an in-depth investigation of these cases. Both individuals denied the intake of the drug; however, the athletes did declare the use of the antimalarial prophylactic agent proguanil due to temporary residences in African countries. A structural similarity between chlorazanil and proguanil is given but no direct metabolic relation has been reported in the scientific literature. Moreover, chlorazanil has not been confirmed as a drug impurity of proguanil. Proguanil however is metabolized in humans to N-(4-chlorophenyl)-biguanide, which represents a chemical precursor in the synthesis of chlorazanil. In the presence of formic acid, formaldehyde, or formic acid esters, N-(4-chlorophenyl)-biguanide converts to chlorazanil. In order to probe for potential sources of the chlorazanil detected in the doping control samples, drug formulations containing proguanil and urine samples of individuals using proguanil as antimalarial drug were subjected to liquid chromatography-high resolution/high accuracy mass spectrometry. In addition, in vitro simulations with 4-chlorophenyl-biguanide and respective reactants were conducted in urine and resulting specimens analyzed for the presence of chlorazanil. While no chlorazanil was found in drug formulations, the urine samples of 2 out of 4 proguanil users returned findings for chlorazanil at low ng/mL levels, similar to the adverse analytical findings in the doping control samples. Further, in the presence of formaldehyde, formic acid and related esters, 4-chlorophenyl-biguanide was found to produce chlorazanil in human urine, suggesting that the detection of the obsolete diuretic

  17. The acid-base profile of a contemporary set of drugs: implications for drug discovery.

    Science.gov (United States)

    Manallack, D T

    2009-10-01

    Acid-base ionization constant (pK(a)) values have considerable influence on the physicochemical and pharmacokinetic properties of therapeutic substances. A set of 907 drugs was examined to determine the proportion of drugs that contain an ionizable group and the distribution of their pK(a) values. Using this contemporary set of compounds it was found that 64% of these compounds contained an ionizable group. Within this group of ionizable compounds, 34% contained a single basic group while only 20% contained a single acidic functional group. The single acid and single base containing substances were investigated further to examine the distributions of their pK(a) values. These data are discussed and analyzed with a focus on the entire set as well as central nervous system, non-central nervous system and oral drugs. The findings from this research will prompt pharmaceutical companies to assess the constitution of their screening libraries, such that focus is placed on the proportion of ionizable substances, the ratio of acids to bases and the distribution of pK(a) values.

  18. Profiles of criminal-justice clients in drug treatment: implications for intervention.

    Science.gov (United States)

    Kline, A

    1997-01-01

    Psychosocial differences between criminal-justice-referred and voluntary clients, using a sample of 996 men and women in residential drug treatment in northern New Jersey, were explored. Results suggest differences in demographic characteristics between the two groups as well as differences in attitudes and behaviors likely to impact on treatment outcome. Demographically, criminal-justice clients are younger, more likely to be male, and less likely to be Black than other clients. They also report better health status and better social and psychological adjustment, reporting less homelessness, fewer health problems, lower levels of psychological distress, better family adjustment, and fewer medical, social, and drug problems requiring intervention. Implications for treatment are discussed.

  19. Evidence behind FDA alerts for drugs with adverse cardiovascular effects: implications for clinical practice.

    Science.gov (United States)

    Rackham, Daniel M; C Herink, Megan; Stevens, Ian G; Cardoza, Natalie M; Singh, Harleen

    2014-01-01

    The U.S. Food and Drug Administration (FDA) periodically publishes Drug Safety Communications and Drug Alerts notifying health care practitioners and the general public of important information regarding drug therapies following FDA approval. These alerts can result in both positive and negative effects on patient care. Most clinical trials are not designed to detect long-term safety end points, and postmarketing surveillance along with patient reported events are often instrumental in signaling the potential harmful effect of a drug. Recently, many cardiovascular (CV) safety announcements have been released for FDA-approved drugs. Because a premature warning could discourage a much needed treatment or prompt a sudden discontinuation, it is essential to evaluate the evidence supporting these FDA alerts to provide effective patient care and to avoid unwarranted changes in therapy. Conversely, paying attention to these warnings in cases involving high-risk patients can prevent adverse effects and litigation. This article reviews the evidence behind recent FDA alerts for drugs with adverse CV effects and discusses the clinical practice implications.

  20. Disease Control Implications of India's Changing Multi-Drug Resistant Tuberculosis Epidemic

    OpenAIRE

    Sze-Chuan Suen; Eran Bendavid; Goldhaber-Fiebert, Jeremy D.

    2014-01-01

    BACKGROUND: Multi-drug resistant tuberculosis (MDR TB) is a major health challenge in India that is gaining increasing public attention, but the implications of India's evolving MDR TB epidemic are poorly understood. As India's MDR TB epidemic is transitioning from a treatment-generated to transmission-generated epidemic, we sought to evaluate the potential effectiveness of the following two disease control strategies on reducing the prevalence of MDR TB: a) improving treatment of non-MDR TB;...

  1. Clinically relevant transmitted drug resistance to first line antiretroviral drugs and implications for recommendations.

    Directory of Open Access Journals (Sweden)

    Susana Monge

    Full Text Available BACKGROUND: The aim was to analyse trends in clinically relevant resistance to first-line antiretroviral drugs in Spain, applying the Stanford algorithm, and to compare these results with reported Transmitted Drug Resistance (TDR defined by the 2009 update of the WHO SDRM list. METHODS: We analysed 2781 sequences from ARV naive patients of the CoRIS cohort (Spain between 2007-2011. Using the Stanford algorithm "Low-level resistance", "Intermediate resistance" and "High-level resistance" categories were considered as "Resistant". RESULTS: 70% of the TDR found using the WHO list were relevant for first-line treatment according to the Stanford algorithm. A total of 188 patients showed clinically relevant resistance to first-line ARVs [6.8% (95%Confidence Interval: 5.8-7.7], and 221 harbored TDR using the WHO list [7.9% (6.9-9.0]. Differences were due to a lower prevalence in clinically relevant resistance for NRTIs [2.3% (1.8-2.9 vs. 3.6% (2.9-4.3 by the WHO list] and PIs [0.8% (0.4-1.1 vs. 1.7% (1.2-2.2], while it was higher for NNRTIs [4.6% (3.8-5.3 vs. 3.7% (3.0-4.7]. While TDR remained stable throughout the study period, clinically relevant resistance to first line drugs showed a significant trend to a decline (p = 0.02. CONCLUSIONS: Prevalence of clinically relevant resistance to first line ARVs in Spain is decreasing, and lower than the one expected looking at TDR using the WHO list. Resistance to first-line PIs falls below 1%, so the recommendation of screening for TDR in the protease gene should be questioned in our setting. Cost-effectiveness studies need to be carried out to inform evidence-based recommendations.

  2. Evaluating drug prices, availability, affordability, and price components: implications for access to drugs in Malaysia.

    OpenAIRE

    Zaheer Ud Din Babar; Mohamed Izham Mohamed Ibrahim; Harpal Singh; Nadeem Irfan Bukahri; Andrew Creese

    2007-01-01

    Editors' Summary Background. The World Health Organization has said that one-third of the people of the world cannot access the medicines they need. An important reason for this problem is that prices are often too high for people or government-funded health systems to afford. In developing countries, most people who need medicines have to pay for them out of their own pockets. Where the cost of drugs is covered by health systems, spending on medicines is a major part of the total healthcare ...

  3. Ultrasound and Microbubble Guided Drug Delivery: Mechanistic Understanding and Clinical Implications

    Science.gov (United States)

    Wang, Tzu-Yin; Wilson, Katheryne E.; Machtaler, Steven; Willmann, Jürgen K.

    2014-01-01

    Ultrasound mediated drug delivery using microbubbles is a safe and noninvasive approach for spatially localized drug administration. This approach can create temporary and reversible openings on cellular membranes and vessel walls (a process called “sonoporation”), allowing for enhanced transport of therapeutic agents across these natural barriers. It is generally believed that the sonoporation process is highly associated with the energetic cavitation activities (volumetric expansion, contraction, fragmentation, and collapse) of the microbubble. However, a thorough understanding of the process was unavailable until recently. Important progress on the mechanistic understanding of sonoporation and the corresponding physiological responses in vitro and in vivo has been made. Specifically, recent research shed light on the cavitation process of microbubbles and fluid motion during insonation of ultrasound, on the spatio-temporal interactions between microbubbles and cells or vessel walls, as well as on the temporal course of the subsequent biological effects. These findings have significant clinical implications on the development of optimal treatment strategies for effective drug delivery. In this article, current progress in the mechanistic understanding of ultrasound and microbubble mediated drug delivery and its implications for clinical translation is discussed. PMID:24372231

  4. Human Laboratory Settings for Assessing Drug Craving; Implications for the Evaluation of Treatment Efficacy

    Directory of Open Access Journals (Sweden)

    Zahra Alam Mehrjerdi

    2011-04-01

    Full Text Available Research on assessing craving in laboratory settings often involves inducing and then measuring craving in subjects. Cue-induced craving is studied in laboratory settings using the cue reactivity paradigm, in which drug-related photos, videos, evocative scripts, olfactory cues, and paraphernalia may induce craving. Cue-induced craving evoked by drug-related stimuli could be associated with relapse and recurrence of drug addiction. In this article, the authors review different methods of assessing craving in laboratory settings and explain how human laboratory settings can bridge the gap between randomized clinical trials (RCTs and animal models on pharmacological treatments for drug dependence. The brief reviewed literature provides strong evidence that laboratory-based studies of craving may improve our understanding of how subjective reports of drug craving are related to objective measures of drug abuse and laboratory settings provide an opportunity to measure the degree to which they co-vary during pharmacological interventions. This issue has important implications inclinical studies.

  5. Evaluating drug prices, availability, affordability, and price components: implications for access to drugs in Malaysia.

    Directory of Open Access Journals (Sweden)

    Zaheer Ud Din Babar

    2007-03-01

    Full Text Available BACKGROUND: Malaysia's stable health care system is facing challenges with increasing medicine costs. To investigate these issues a survey was carried out to evaluate medicine prices, availability, affordability, and the structure of price components. METHODS AND FINDINGS: The methodology developed by the World Health Organization (WHO and Health Action International (HAI was used. Price and availability data for 48 medicines was collected from 20 public sector facilities, 32 private sector retail pharmacies and 20 dispensing doctors in four geographical regions of West Malaysia. Medicine prices were compared with international reference prices (IRPs to obtain a median price ratio. The daily wage of the lowest paid unskilled government worker was used to gauge the affordability of medicines. Price component data were collected throughout the supply chain, and markups, taxes, and other distribution costs were identified. In private pharmacies, innovator brand (IB prices were 16 times higher than the IRPs, while generics were 6.6 times higher. In dispensing doctor clinics, the figures were 15 times higher for innovator brands and 7.5 for generics. Dispensing doctors applied high markups of 50%-76% for IBs, and up to 316% for generics. Retail pharmacy markups were also high-25%-38% and 100%-140% for IBs and generics, respectively. In the public sector, where medicines are free, availability was low even for medicines on the National Essential Drugs List. For a month's treatment for peptic ulcer disease and hypertension people have to pay about a week's wages in the private sector. CONCLUSIONS: The free market by definition does not control medicine prices, necessitating price monitoring and control mechanisms. Markups for generic products are greater than for IBs. Reducing the base price without controlling markups may increase profits for retailers and dispensing doctors without reducing the price paid by end users. To increase access and

  6. Evaluating Drug Prices, Availability, Affordability, and Price Components: Implications for Access to Drugs in Malaysia

    Science.gov (United States)

    Babar, Zaheer Ud Din; Ibrahim, Mohamed Izham Mohamed; Singh, Harpal; Bukahri, Nadeem Irfan; Creese, Andrew

    2007-01-01

    Background Malaysia's stable health care system is facing challenges with increasing medicine costs. To investigate these issues a survey was carried out to evaluate medicine prices, availability, affordability, and the structure of price components. Methods and Findings The methodology developed by the World Health Organization (WHO) and Health Action International (HAI) was used. Price and availability data for 48 medicines was collected from 20 public sector facilities, 32 private sector retail pharmacies and 20 dispensing doctors in four geographical regions of West Malaysia. Medicine prices were compared with international reference prices (IRPs) to obtain a median price ratio. The daily wage of the lowest paid unskilled government worker was used to gauge the affordability of medicines. Price component data were collected throughout the supply chain, and markups, taxes, and other distribution costs were identified. In private pharmacies, innovator brand (IB) prices were 16 times higher than the IRPs, while generics were 6.6 times higher. In dispensing doctor clinics, the figures were 15 times higher for innovator brands and 7.5 for generics. Dispensing doctors applied high markups of 50%–76% for IBs, and up to 316% for generics. Retail pharmacy markups were also high—25%–38% and 100%–140% for IBs and generics, respectively. In the public sector, where medicines are free, availability was low even for medicines on the National Essential Drugs List. For a month's treatment for peptic ulcer disease and hypertension people have to pay about a week's wages in the private sector. Conclusions The free market by definition does not control medicine prices, necessitating price monitoring and control mechanisms. Markups for generic products are greater than for IBs. Reducing the base price without controlling markups may increase profits for retailers and dispensing doctors without reducing the price paid by end users. To increase access and affordability

  7. Evaluating drug prices, availability, affordability, and price components: implications for access to drugs in Malaysia.

    Science.gov (United States)

    Babar, Zaheer Ud Din; Ibrahim, Mohamed Izham Mohamed; Singh, Harpal; Bukahri, Nadeem Irfan; Creese, Andrew

    2007-03-27

    Malaysia's stable health care system is facing challenges with increasing medicine costs. To investigate these issues a survey was carried out to evaluate medicine prices, availability, affordability, and the structure of price components. The methodology developed by the World Health Organization (WHO) and Health Action International (HAI) was used. Price and availability data for 48 medicines was collected from 20 public sector facilities, 32 private sector retail pharmacies and 20 dispensing doctors in four geographical regions of West Malaysia. Medicine prices were compared with international reference prices (IRPs) to obtain a median price ratio. The daily wage of the lowest paid unskilled government worker was used to gauge the affordability of medicines. Price component data were collected throughout the supply chain, and markups, taxes, and other distribution costs were identified. In private pharmacies, innovator brand (IB) prices were 16 times higher than the IRPs, while generics were 6.6 times higher. In dispensing doctor clinics, the figures were 15 times higher for innovator brands and 7.5 for generics. Dispensing doctors applied high markups of 50%-76% for IBs, and up to 316% for generics. Retail pharmacy markups were also high-25%-38% and 100%-140% for IBs and generics, respectively. In the public sector, where medicines are free, availability was low even for medicines on the National Essential Drugs List. For a month's treatment for peptic ulcer disease and hypertension people have to pay about a week's wages in the private sector. The free market by definition does not control medicine prices, necessitating price monitoring and control mechanisms. Markups for generic products are greater than for IBs. Reducing the base price without controlling markups may increase profits for retailers and dispensing doctors without reducing the price paid by end users. To increase access and affordability, promotion of generic medicines and improved availability

  8. Overview of Medicare Part D prescription drug benefit: potential implications for patients with psychotic disorders.

    Science.gov (United States)

    Rosenberg, Jack M

    2007-01-15

    Medicare Part D prescription drug benefits are reviewed. Potential implications for patients with psychotic disorders in relation to Medicare Part D are discussed. The newly created Medicare Part D provides prescription drug benefits to many individuals formerly without prescription benefits and, possibly, lower-cost benefits to those who previously relied on other benefits. Participating prescription plans use a variety of pharmacy management tools to minimize costs while providing benefit plans that meet Part D requirements for composition and coverage. Patients then have the challenge of choosing a prescription drug plan that will best satisfy their prescriptions needs. The rollout of Part D has not been without problems, and although more Medicare participants are receiving prescription drug benefits at a greater savings, there are concerns that Part D may not provide adequate coverage for all patients or for patients requiring certain types of medications, especially some psychotropic medications. Pharmacists have voiced concerns about the Medicare Part D drug plan in regard to both the degree of coverage it provides to enrollees and the difficulty in administering the benefit.

  9. The neurobiology of psychedelic drugs: implications for the treatment of mood disorders.

    Science.gov (United States)

    Vollenweider, Franz X; Kometer, Michael

    2010-09-01

    After a pause of nearly 40 years in research into the effects of psychedelic drugs, recent advances in our understanding of the neurobiology of psychedelics, such as lysergic acid diethylamide (LSD), psilocybin and ketamine have led to renewed interest in the clinical potential of psychedelics in the treatment of various psychiatric disorders. Recent behavioural and neuroimaging data show that psychedelics modulate neural circuits that have been implicated in mood and affective disorders, and can reduce the clinical symptoms of these disorders. These findings raise the possibility that research into psychedelics might identify novel therapeutic mechanisms and approaches that are based on glutamate-driven neuroplasticity.

  10. Transmission intensity and drug resistance in malaria population dynamics: implications for climate change.

    Science.gov (United States)

    Artzy-Randrup, Yael; Alonso, David; Pascual, Mercedes

    2010-10-26

    Although the spread of drug resistance and the influence of climate change on malaria are most often considered separately, these factors have the potential to interact through altered levels of transmission intensity. The influence of transmission intensity on the evolution of drug resistance has been addressed in theoretical studies from a population genetics' perspective; less is known however on how epidemiological dynamics at the population level modulates this influence. We ask from a theoretical perspective, whether population dynamics can explain non-trivial, non-monotonic, patterns of treatment failure with transmission intensity, and, if so, under what conditions. We then address the implications of warmer temperatures in an East African highland, where, as in other similar regions at the altitudinal edge of malaria's distribution, there has been a pronounced increase of cases from the 1970s to the 1990s. Our theoretical analyses, with a transmission model that includes different levels of immunity, demonstrate that an increase in transmission beyond a threshold can lead to a decrease in drug resistance, as previously shown, but that a second threshold may occur and lead to the re-establishment of drug resistance. Estimates of the increase in transmission intensity from the 1970s to the 1990s for the Kenyan time series, obtained by fitting the two-stage version of the model with an explicit representation of vector dynamics, suggest that warmer temperatures are likely to have moved the system towards the first threshold, and in so doing, to have promoted the faster spread of drug resistance. Climate change and drug resistance can interact and need not be considered as alternative explanations for trends in disease incidence in this region. Non-monotonic patterns of treatment failure with transmission intensity similar to those described as the 'valley phenomenon' for Uganda can result from epidemiological dynamics but under poorly understood assumptions.

  11. Drug: D00600 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00600 Drug Labetalol hydrochloride (JP16/USP); Normodyne (TN); Trandate (TN) C19H2...nts 214 Antihypertensives 2149 Others D00600 Labetalol hydrochloride (JP16/USP) Anatomical Therapeutic Chemi...ENTS C07AG Alpha and beta blocking agents C07AG01 Labetalol D00600 Labetalol hydrochloride (JP16/USP) USP dr...ug classification [BR:br08302] Cardiovascular Agents Beta-adrenergic Blocking Agents Labetalol D00600 Lab...Protein-coupled receptors Rhodopsin family Adrenaline alpha1-adrenergic receptor [HSA:146 147 148] [KO:K04137 K04136 K04135] Lab

  12. Drug: D00432 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00432 Drug Nadolol (JP16/USP/INN); Corgard (TN) C17H27NO4 309.194 309.4006 D00432....lar agents 212 Antiarrhythmic agents 2123 Beta blockers D00432 Nadolol (JP16/USP/INN) Anatomical Therapeutic...ING AGENTS C07AA Beta blocking agents, non-selective C07AA12 Nadolol D00432 Nadol...ol (JP16/USP/INN) USP drug classification [BR:br08302] Cardiovascular Agents Beta-adrenergic Blocking Agents Nadolol D00432...eceptors Rhodopsin family Adrenaline beta1-adrenergic receptor [HSA:153] [KO:K04141] Nadolol [ATC:C07AA12] D00432

  13. Drug: D03415 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D03415 Drug Carvedilol phosphate hydrate (JAN); Carvedilol phosphate (USAN); Coreg ...nd beta blocking agents C07AG02 Carvedilol D03415 Carvedilol phosphate hydrate (JAN); Carvedilol... phosphate (USAN) USP drug classification [BR:br08302] Cardiovascular Agents Beta-adrenergic Blocking Agents Carvedilo...l D03415 Carvedilol phosphate hydrate (JAN); Carvedilol phosphate (USAN) Target-bas...ily Adrenaline alpha1-adrenergic receptor [HSA:146 147 148] [KO:K04137 K04136 K04135] Carvedilol [ATC:C07AG02] D03415 Carvedilol

  14. Understanding the Bases of Function and Modulation of α7 Nicotinic Receptors: Implications for Drug Discovery.

    Science.gov (United States)

    Corradi, Jeremías; Bouzat, Cecilia

    2016-09-01

    The nicotinic acetylcholine receptor (nAChR) belongs to a superfamily of pentameric ligand-gated ion channels involved in many physiologic and pathologic processes. Among nAChRs, receptors comprising the α7 subunit are unique because of their high Ca(2+) permeability and fast desensitization. nAChR agonists elicit a transient ion flux response that is further sustained by the release of calcium from intracellular sources. Owing to the dual ionotropic/metabotropic nature of α7 receptors, signaling pathways are activated. The α7 subunit is highly expressed in the nervous system, mostly in regions implicated in cognition and memory and has therefore attracted attention as a novel drug target. Additionally, its dysfunction is associated with several neuropsychiatric and neurologic disorders, such as schizophrenia and Alzheimer's disease. α7 is also expressed in non-neuronal cells, particularly immune cells, where it plays a role in immunity, inflammation, and neuroprotection. Thus, α7 potentiation has emerged as a therapeutic strategy for several neurologic and inflammatory disorders. With unique activation properties, the receptor is a sensitive drug target carrying different potential binding sites for chemical modulators, particularly agonists and positive allosteric modulators. Although macroscopic and single-channel recordings have provided significant information about the underlying molecular mechanisms and binding sites of modulatory compounds, we know just the tip of the iceberg. Further concerted efforts are necessary to effectively exploit α7 as a drug target for each pathologic situation. In this article, we focus mainly on the molecular basis of activation and drug modulation of α7, key pillars for rational drug design.

  15. [Neuropsychological characterization of functional and dysfunctional impulsivity in drug addicts: clinical implications].

    Science.gov (United States)

    Pedrero-Pérez, Eduardo J; Ruiz Sánchez de León, José M; Rojo Mota, Gloria; Llanero Luque, Marcos; Puerta García, Carmen

    2012-01-01

    Impulsivity is a stable correlate throughout the course of drug addiction. However, it has always been studied as a negative condition, linked to psychopathology. Dickman (1990) proposed two subdimensions of impulsivity, dysfunctional (DI) and functional (FI). He defines the latter as the tendency for rapid, goal-oriented decision-making characterized by well calculated risks. Only a few studies have attempted to differentiate between these two subdimensions using classical neuropsychological tests. Fifty two drug addicts in treatment were tested using Dickman's Impulsivity Inventory and a battery of classical neuropsychological tests. FI shows moderate to high correlations with many classical neuropsychological test scores in relation to enhanced executive functioning, whereas DI reveals surprisingly weak and scarce correlations with indicators of impaired executive functioning. DI appears to be a trait related to some difficulties in classical neuropsychological tests, while FI emerges as a consistent and much stronger predictor of higher attention capacity, lower distractibility, better precision, fewer errors, and better maintenance of goal-oriented strategies. Thus, functional impulsivity is related to positive conditions and more efficient cognitive functioning. Implications for the treatment of drug addictions are suggested.

  16. Specific noncovalent interactions at protein-ligand interface: implications for rational drug design.

    Science.gov (United States)

    Zhou, P; Huang, J; Tian, F

    2012-01-01

    Specific noncovalent interactions that are indicative of attractive, directional intermolecular forces have always been of key interest to medicinal chemists in their search for the "glue" that holds drugs and their targets together. With the rapid increase in the number of solved biomolecular structures as well as the performance enhancement of computer hardware and software in recent years, it is now possible to give more comprehensive insight into the geometrical characteristics and energetic landscape of certain sophisticated noncovalent interactions present at the binding interface of protein receptors and small ligands based on accumulated knowledge gaining from the combination of two quite disparate but complementary approaches: crystallographic data analysis and quantum-mechanical ab initio calculation. In this perspective, we survey massive body of published works relating to structural characterization and theoretical investigation of three kinds of strong, specific, direct, enthalpy-driven intermolecular forces, including hydrogen bond, halogen bond and salt bridge, involved in the formation of protein-ligand complex architecture in order to characterize their biological functions in conferring affinity and specificity for ligand recognition by host protein. In particular, the biomedical implications of raised knowledge are discussed with respect to potential applications in rational drug design.

  17. Person Classification in Organizational Settings: A Literature Review and Discussion of its Implications for the Diagnosis of Drug Abusers

    Science.gov (United States)

    Dembo, Richard

    1978-01-01

    This paper reviews theory and research on client classification and their processing in various organizational settings, with emphasis on drug abusers. Implications are drawn in terms of developing a better model of the social psychology of institutional life, and diagnostic-screening units more serviceable to needs of clients. (Author)

  18. Drug: D07505 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07505 Mixture, Drug Latanoprost - timolol maleate mixt; Xalacom (TN) Latanoprost [DR:D00356], Tim...3] S SENSORY ORGANS S01 OPHTHALMOLOGICALS S01E ANTIGLAUCOMA PREPARATIONS AND MIOTICS S01ED Beta blocking agents S01ED51 Tim...olol, combinations D07505 Latanoprost - timolol maleate mixt PubChem: 124490298 ... ...sensory organs 13 Agents affecting sensory organs 131 Ophthalmic agents 1319 Othe...rs D07505 Latanoprost - timolol maleate mixt Anatomical Therapeutic Chemical (ATC) classification [BR:br0830

  19. Minimizing the risk of chemically reactive metabolite formation of new drug candidates: implications for preclinical drug design.

    Science.gov (United States)

    Brink, Andreas; Pähler, Axel; Funk, Christoph; Schuler, Franz; Schadt, Simone

    2016-11-27

    Many pharmaceutical companies aim to reduce reactive metabolite formation by chemical modification at early stages of drug discovery. A practice often applied is the detection of stable trapping products of electrophilic intermediates with nucleophilic trapping reagents to guide rational structure-based drug design. This contribution delineates this strategy to minimize the potential for reactive metabolite formation of clinical candidates during preclinical drug optimization, exemplified by the experience at Roche over the past decade. For the majority of research programs it was possible to proceed with compounds optimized for reduced covalent binding potential. Such optimized candidates are expected to have a higher likelihood of succeeding throughout the development processes, resulting in safer drugs.

  20. Efficacy of controlled-release isosorbide-5-mononitrate as adjunctive treatment to beta-blocking agents in patients with stable angina pectoris

    DEFF Research Database (Denmark)

    Svendsen, Jesper Hastrup; Aldershvile, J; Abildgaard, U

    1989-01-01

    to a beta blocker. In bicycle ergometer exercise tests performed 4 h after study drug intake, total exercise time and time until 1-mm ST-depression increased significantly during both regimens as compared with placebo (p less than 0.05). However, only the 60-mg once-daily regimen was significantly better...... than placebo with regard to time until angina pectoris. The results indicate that ISMN-CR 60 mg once daily is effective as adjunctive to beta-blocker treatment, and nitrate tolerance appeared to develop during the twice-daily regimen. In 10 of the patients, the effect of additional sublingual...

  1. [Clopidogrel--proton pump inhibitors drug interaction: implications to clinical practice].

    Science.gov (United States)

    Fontes-Carvalho, Ricardo; Albuquerque, Aníbal

    2010-10-01

    Recent studies have raised the concern that proton pump inhibitors (PPIs) could potentially interfere with clopidogrel antiplatelet effect. This association is frequent in clinical practice and is recommended by recent consensus guidelines in patients taking dual antiplatelet therapy to prevent gastrointestinal (GI) bleeding. Clopidogrel is a pro-drug which needs to be metabolized into its active metabolite, by cytochrome P450, especially by CYP2C19 isoenzyme. Various PPIs can inhibit CYP2C19, which could possibly decrease clopidogrel bioactivation process and, therefore, its antiplatelet effect. Various platelet function studies have shown that omeprazol can significantly decrease clopidogrel inhibitory effect on platelet P2Y12 receptor, leading to an increase in the number of patients who are "nonresponders" to clopidogrel. These pharmacokinetic studies also shown that this is not probably a class effect of PPIs, because they are metabolized to varying degrees by CYP2C19. The clinical impact of these observations remains uncertain, because various observational studies have shown conflicting results, and remains to demonstrate if PPIs can really increase the risk of cardiovascular events in patients taking clopidogrel. In this review we will discuss the pharmacokinetic basis underlying this drug interaction, the effect of different PPIs on platelet function tests and we will analyze in detail the potential clinical implications of using this association, both on cardiovascular and gastrointestinal events. Until further data is available, some clinical strategies can be recommended: (1) individual gastrointestinal risk assessment, with PPIs administration only to patients on dual anti-platelet therapy with additional GI risk factors; (2) preferential use of PPIs that have shown less interference with clopidogrel efficacy; (3) wide separation of PPI and clopidogrel dosing to minimize the risk of interaction (PPI may be given before breakfast and clopidogrel at

  2. London audit of drug-related overdose deaths: characteristics and typology, and implications for prevention and monitoring.

    Science.gov (United States)

    Hickman, Matthew; Carrivick, Sandra; Paterson, Susan; Hunt, Neil; Zador, Deborah; Cusick, Linda; Henry, John

    2007-02-01

    To describe the circumstances and draft a typology of drug-related overdose deaths. London, 2003. An audit of 148 drug overdose deaths (involving heroin, methadone, dihydrocodeine, cocaine, amphetamine or MDMA) investigated by coroners during 2003. Information extracted on toxicology, pathology and circumstances were used to identify drug(s) implicated in the death. Poly- or multiple drug use was detected in the majority of deaths with at least 69 different combinations, including 66% for heroin and 42% for cocaine. Six categories of death were identified involving an opiate (100, 68%); cocaine (14, 9%); other controlled drug (five, 3%); mixed drug overdose (18, 12%); other prescribed drug (five, 3%); and other causes (seven, 5%). A witness was present and the death was not instantaneous in 92 (61%) cases, although evidence in the coronial file suggested that in the majority of cases the overdose went unnoticed until too late to intervene. In all, 15 (one in 10) of the deceased were released from prison within 3 months of death; and 37 (one in four) were reported as in receipt of a methadone prescription. Perhaps for the first time in the United Kingdom cocaine was detected in more drug overdose deaths than methadone. However, reducing heroin use is central to the prevention of drug-related deaths. We recommend that overdose prevention encompasses strategies to encourage a 'mutual duty of care' among problem drug users, and in the United Kingdom further investigation of the relationship of methadone treatment failures on overall trends in drug-related deaths is merited.

  3. Disease control implications of India's changing multi-drug resistant tuberculosis epidemic.

    Directory of Open Access Journals (Sweden)

    Sze-Chuan Suen

    Full Text Available BACKGROUND: Multi-drug resistant tuberculosis (MDR TB is a major health challenge in India that is gaining increasing public attention, but the implications of India's evolving MDR TB epidemic are poorly understood. As India's MDR TB epidemic is transitioning from a treatment-generated to transmission-generated epidemic, we sought to evaluate the potential effectiveness of the following two disease control strategies on reducing the prevalence of MDR TB: a improving treatment of non-MDR TB; b shortening the infectious period between the activation of MDR TB and initiation of effective MDR treatment. METHODS AND FINDINGS: We developed a dynamic transmission microsimulation model of TB in India. The model followed individuals by age, sex, TB status, drug resistance status, and treatment status and was calibrated to Indian demographic and epidemiologic TB time trends. The main effectiveness measure was reduction in the average prevalence reduction of MDR TB over the ten years after control strategy implementation. We find that improving non-MDR cure rates to avoid generating new MDR cases will provide substantial non-MDR TB benefits but will become less effective in reducing MDR TB prevalence over time because more cases will occur from direct transmission--by 2015, the model estimates 42% of new MDR cases are transmission-generated and this proportion continues to rise over time, assuming equal transmissibility of MDR and drug-susceptible TB. Strategies that disrupt MDR transmission by shortening the time between MDR activation and treatment are projected to provide greater reductions in MDR prevalence compared with improving non-MDR treatment quality: implementing MDR diagnostic improvements in 2017 is expected to reduce MDR prevalence by 39%, compared with 11% reduction from improving non-MDR treatment quality. CONCLUSIONS: As transmission-generated MDR TB becomes a larger driver of the MDR TB epidemic in India, rapid and accurate MDR TB

  4. Human loci involved in drug biotransformation: worldwide genetic variation, population structure, and pharmacogenetic implications.

    Science.gov (United States)

    Maisano Delser, Pierpaolo; Fuselli, Silvia

    2013-05-01

    genes. The population structure defined by PGx loci supports the presence of six genetic clusters reflecting geographic location of samples. In particular, the results of the DAPC analyses show that 27 SNPs substantially contribute to the first three discriminant functions. Among these SNPs, some, such as the intronic rs1403527 of NR1I2 and the non-synonymous rs699 of AGT, are known to be associated with specific drug responses. Their substantial variation between different groups of populations may have important implications for PGx practical applications.

  5. High-cost generic drugs--implications for patients and policymakers.

    Science.gov (United States)

    Alpern, Jonathan D; Stauffer, William M; Kesselheim, Aaron S

    2014-11-13

    Some older generic drugs have become very expensive, owing to factors including drug shortages, supply disruptions, and consolidations in the generic-drug industry. But generics manufacturers that legally obtain a market monopoly can also unilaterally raise prices.

  6. Blood-brain barrier pathology in Alzheimer's and Parkinson's disease: implications for drug therapy.

    Science.gov (United States)

    Desai, Brinda S; Monahan, Angela J; Carvey, Paul M; Hendey, Bill

    2007-01-01

    The blood-brain barrier (BBB) is a tightly regulated barrier in the central nervous system. Though the BBB is thought to be intact during neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease (PD), recent evidence argues otherwise. Dysfunction of the BBB may be involved in disease progression, eliciting of peripheral immune response, and, most importantly, altered drug efficacy. In this review, we will give a brief overview of the BBB, its components, and their functions. We will critically evaluate the current literature in AD and PD BBB pathology resulting from insult, neuroinflammation, and neurodegeneration. Specifically, we will discuss alterations in tight junction, transport and endothelial cell surface proteins, and vascular density changes, all of which result in altered permeability. Finally, we will discuss the implications of BBB dysfunction in current and future therapeutics. Developing a better appreciation of BBB dysfunction in AD and PD may not only provide novel strategies in treatment, but will prove an interesting milestone in understanding neurodegenerative disease etiology and progression.

  7. Minireview: Signal bias, allosterism, and polymorphic variation at the GLP-1R: implications for drug discovery.

    Science.gov (United States)

    Koole, Cassandra; Savage, Emilia E; Christopoulos, Arthur; Miller, Laurence J; Sexton, Patrick M; Wootten, Denise

    2013-08-01

    The glucagon-like peptide-1 receptor (GLP-1R) controls the physiological responses to the incretin hormone glucagon-like peptide-1 and is a major therapeutic target for the treatment of type 2 diabetes, owing to the broad range of effects that are mediated upon its activation. These include the promotion of glucose-dependent insulin secretion, increased insulin biosynthesis, preservation of β-cell mass, improved peripheral insulin action, and promotion of weight loss. Regulation of GLP-1R function is complex, with multiple endogenous and exogenous peptides that interact with the receptor that result in the activation of numerous downstream signaling cascades. The current understanding of GLP-1R signaling and regulation is limited, with the desired spectrum of signaling required for the ideal therapeutic outcome still to be determined. In addition, there are several single-nucleotide polymorphisms (used in this review as defining a natural change of single nucleotide in the receptor sequence; clinically, this is viewed as a single-nucleotide polymorphism only if the frequency of the mutation occurs in 1% or more of the population) distributed within the coding sequence of the receptor protein that have the potential to produce differential responses for distinct ligands. In this review, we discuss the current understanding of GLP-1R function, in particular highlighting recent advances in the field on ligand-directed signal bias, allosteric modulation, and probe dependence and the implications of these behaviors for drug discovery and development.

  8. Structural specificity of mucosal-cell transport and metabolism of peptide drugs: implication for oral peptide drug delivery

    Science.gov (United States)

    Bai, J. P.; Amidon, G. L.

    1992-01-01

    The brush border membrane of intestinal mucosal cells contains a peptide carrier system with rather broad substrate specificity and various endo- and exopeptidase activities. Small peptide (di-/tripeptide)-type drugs with or without an N-terminal alpha-amino group, including beta-lactam antibiotics and angiotensin-converting enzyme (ACE) inhibitors, are transported by the peptide transporter. Polypeptide drugs are hydrolyzed by brush border membrane proteolytic enzymes to di-/tripeptides and amino acids. Therefore, while the intestinal brush border membrane has a carrier system facilitating the absorption of di-/tripeptide drugs, it is a major barrier limiting oral availability of polypeptide drugs. In this paper, the specificity of peptide transport and metabolism in the intestinal brush border membrane is reviewed.

  9. Structural specificity of mucosal-cell transport and metabolism of peptide drugs: implication for oral peptide drug delivery

    Science.gov (United States)

    Bai, J. P.; Amidon, G. L.

    1992-01-01

    The brush border membrane of intestinal mucosal cells contains a peptide carrier system with rather broad substrate specificity and various endo- and exopeptidase activities. Small peptide (di-/tripeptide)-type drugs with or without an N-terminal alpha-amino group, including beta-lactam antibiotics and angiotensin-converting enzyme (ACE) inhibitors, are transported by the peptide transporter. Polypeptide drugs are hydrolyzed by brush border membrane proteolytic enzymes to di-/tripeptides and amino acids. Therefore, while the intestinal brush border membrane has a carrier system facilitating the absorption of di-/tripeptide drugs, it is a major barrier limiting oral availability of polypeptide drugs. In this paper, the specificity of peptide transport and metabolism in the intestinal brush border membrane is reviewed.

  10. Acute influence of different beta-blocking agents upon left heart hemodynamics at rest and during exercise in patients with coronary artery disease.

    Science.gov (United States)

    Reale, A; Nigri, A; Gioffrè, P A; Motolese, M

    1979-02-01

    The study investigated the acute hemodynamic changes induced in patients with angiographically confirmed coronary artery disease by 3 beta-blockers: metoprolol, cardioselective without intrinsic sympathomimetic activity (ISA), group I, 11 patients; bunitrolol, noncardioselective with ISA, group II, 11 patients; oxprenolol, noncardioselective with ISA, group III, 11 patients. Hemodynamic variables were obtained at rest and during exercise, before and 45 min after 10 mg i.v. of the drug. Changes in LVEDP and cardiac indexes were such as LV function was improved in 1 patient of group I, 7 patients of group II and 5 patients of group III; impaired in 4 patients of group I and in 1 patient of group III; unchanged in the others. Contractility indexes were less influenced by bunitrolol and oxprenolol. During exercise there was a significant difference between groups for LVEDP which was lower in group II (P less than 0.01). The data seem to indicate that the choice of the beta-blocker may be of importance when it is desirable that an already compromised cardiac function be not further impaired by pharmacological intervention.

  11. Clinical implications of molecular drug resistance testing for Mycobacterium tuberculosis: a TBNET/RESIST-TB consensus statement.

    Science.gov (United States)

    Domínguez, J; Boettger, E C; Cirillo, D; Cobelens, F; Eisenach, K D; Gagneux, S; Hillemann, D; Horsburgh, R; Molina-Moya, B; Niemann, S; Tortoli, E; Whitelaw, A; Lange, C

    2016-01-01

    The emergence of drug-resistant strains of Mycobacterium tuberculosis is a challenge to global tuberculosis (TB) control. Although culture-based methods have been regarded as the gold standard for drug susceptibility testing (DST), molecular methods provide rapid information on mutations in the M. tuberculosis genome associated with resistance to anti-tuberculosis drugs. We ascertained consensus on the use of the results of molecular DST for clinical treatment decisions in TB patients. This document has been developed by TBNET and RESIST-TB groups to reach a consensus about reporting standards in the clinical use of molecular DST results. Review of the available literature and the search for evidence included hand-searching journals and searching electronic databases. The panel identified single nucleotide mutations in genomic regions of M. tuberculosis coding for katG, inhA, rpoB, embB, rrs, rpsL and gyrA that are likely related to drug resistance in vivo. Identification of any of these mutations in clinical isolates of M. tuberculosis has implications for the management of TB patients, pending the results of in vitro DST. However, false-positive and false-negative results in detecting resistance-associated mutations in drugs for which there is poor or unproven correlation between phenotypic and clinical drug resistance complicate the interpretation. Reports of molecular DST results should therefore include specific information on the mutations identified and provide guidance for clinicians on interpretation and on the choice of the appropriate initial drug regimen.

  12. Regulation of drug-metabolizing enzymes in infectious and inflammatory disease: implications for biologics-small molecule drug interactions.

    Science.gov (United States)

    Mallick, Pankajini; Taneja, Guncha; Moorthy, Bhagavatula; Ghose, Romi

    2017-06-01

    Drug-metabolizing enzymes (DMEs) are primarily down-regulated during infectious and inflammatory diseases, leading to disruption in the metabolism of small molecule drugs (smds), which are increasingly being prescribed therapeutically in combination with biologics for a number of chronic diseases. The biologics may exert pro- or anti-inflammatory effect, which may in turn affect the expression/activity of DMEs. Thus, patients with infectious/inflammatory diseases undergoing biologic/smd treatment can have complex changes in DMEs due to combined effects of the disease and treatment. Areas covered: We will discuss clinical biologics-SMD interaction and regulation of DMEs during infection and inflammatory diseases. Mechanistic studies will be discussed and consequences on biologic-small molecule combination therapy on disease outcome due to changes in drug metabolism will be highlighted. Expert opinion: The involvement of immunomodulatory mediators in biologic-SMDs is well known. Regulatory guidelines recommend appropriate in vitro or in vivo assessments for possible interactions. The role of cytokines in biologic-SMDs has been documented. However, the mechanisms of drug-drug interactions is much more complex, and is probably multi-factorial. Studies aimed at understanding the mechanism by which biologics effect the DMEs during inflammation/infection are clinically important.

  13. Self-reported risks for multiple-drug resistance among new tuberculosis cases: implications for drug susceptibility screening and treatment.

    Directory of Open Access Journals (Sweden)

    Timothy F Brewer

    Full Text Available BACKGROUND: Multiple drug-resistance in new tuberculosis (TB cases accounts for the majority of all multiple drug-resistant TB (MDR-TB worldwide. Effective control requires determining which new TB patients should be tested for MDR disease, yet the effectiveness of global screening recommendations of high-risk groups is unknown. METHODS: Sixty MDR-TB cases with no history of previous TB treatment, 80 drug-sensitive TB and 80 community-based controls were recruited in Lima, Peru between August and December, 2008 to investigate whether recommended screening practices identify individuals presenting with MDR-TB. Odd ratios (OR and 95% confidence intervals (CI were calculated using logistic regression to study the association of potential risk factors with case/control variables. RESULTS: MDR-TB cases did not differ from drug-sensitive TB and community controls in rates of human immunodeficiency virus infection, reported hospital or prison visits in the 3 years prior to diagnosis. MDR-TB cases were more likely than drug-sensitive TB controls to have had a recent MDR-TB household contact (OR 4.66, (95% CI 1.56-13.87; however, only 15 cases (28.3% reported this exposure. In multivariate modeling, recent TB household contact, but not contact with an MDR-TB case, remained predictive of MDR-TB, OR 7.47, (95% CI 1.91-29.3. Living with a partner rather than parents was associated with a lower risk of MDR-TB, OR 0.15, (95% CI 0.04-0.51. CONCLUSION: Targeted drug susceptibility testing (DST linked to reported MDR-TB contact or other high-risk exposures does not identify the majority of new TB cases with MDR disease in Lima where it is endemic. All new TB cases should be screened with DST to identify MDR patients. These findings are likely applicable to other regions with endemic MDR-TB.

  14. Managing la malilla: Exploring drug treatment experiences among injection drug users in Tijuana, Mexico, and their implications for drug law reform.

    Science.gov (United States)

    Syvertsen, Jennifer; Pollini, Robin A; Lozada, Remedios; Vera, Alicia; Rangel, Gudelia; Strathdee, Steffanie A

    2010-11-01

    In August 2009, Mexico reformed its drug laws and decriminalized small quantities of drugs for personal use; offenders caught three times will be mandated to enter drug treatment. However, little is known about the quality or effectiveness of drug treatment programs in Mexico. We examined injection drug users' (IDUs) experiences in drug treatment in Tijuana, Mexico, with the goal of informing program planning and policy. We examined qualitative and quantitative data from Proyecto El Cuete, a multi-phased research study on HIV risk among IDUs in Tijuana. Phase I consisted of 20 in-depth interviews and Phase II employed respondent-driven sampling to recruit 222 IDUs for a quantitative survey. We also reviewed national drug policy documents, surveillance data, and media reports to situate drug users' experiences within the broader sociopolitical context. Participants in the qualitative study were 50% male with a mean age of 32; most injected heroin (85.0%) and methamphetamine (60.0%). The quantitative sample was 91.4% male with a mean age of 35; 98.2% injected heroin and 83.7% injected heroin and methamphetamine together. The majority of participants reported receiving treatment: residential treatment was most common, followed by methadone; other types of services were infrequently reported. Participants' perceptions of program acceptability and effectiveness were mixed. Mistreatment emerged as a theme in the qualitative interviews and was reported by 21.6% of Phase II participants, primarily physical (72.0%) and verbal (52.0%) abuse. Our results point to the need for political, economic, and social investment in the drug treatment system before offenders are sentenced to treatment under the revised national drug law. Resources are needed to strengthen program quality and ensure accountability. The public health impact of the new legislation that attempts to bring drug treatment to the forefront of national drug policy should be systematically evaluated. Copyright

  15. Polypharmacotherapy and drug-drug interactions in patients hospitalized in an Internal Medicine department: magnitude of the problem and clinical implications

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    Luigi Lusiani

    2013-04-01

    Full Text Available BACKGROUND The use of multiple drugs is a growing problem in elderly patients: it increases the risk of drug-drug interactions and reduces the compliance to cures. The magnitude and the clinical implications of this phenomenon in patients hospitalized in Internal Medicine departments (IM remain largely unknown. AIM OF THE STUDY To evaluate how frequently polypharmacotherapy occurs in IM patients, to what extent the hospitalization affects it, and to what extent potential drug-drug interactions have to do with the treated conditions. MATERIALS AND METHODS In this observational study, the clinical records of 232 consecutive patients (median age 80 years were reviewed, and the medical prescriptions on admission to and at discharge from the hospital were analysed, with special regard to potential drugdrug interactions, using the Micromedex® Healthcare Series system (www.thomsonhc.com; the interactions were classified in terms of severity and type (clinical relevance. RESULTS The total number of prescribed drugs per-patient on admission and at discharge were 4.73 ± 2.88 vs 5.69 ± 2.78 (p < 0.01; the number of potentially harmful interactions were 0.91 ± 1.17 vs 1.39 ± 1.59 (p < 0.01; the percentage of patients at risk for any interactions (mostly moderate or severe, as a matter of fact were 53% vs 66% (p < 0.01. As for clinical relevance, most interactions were of the pharmacodymanic type (67 vs 93, p n.s., and very few patients (5 vs 5 had interactions potentially interfering with their disease status. The risk of interactions progressively increased with the number of prescribed drugs, reaching a plateau of 60% with the combination of 4 drugs. CONCLUSIONS Our data confirm that drug-drug interactions due to polypharmacotherapy are a relevant problem in patients hospitalized in IM, and that hospitalization per se adds to its magnitude. Although few patients seem to be directly threatened in their disease status, most of them are exposed to the

  16. Human Food Safety Implications of Variation in Food Animal Drug Metabolism

    OpenAIRE

    Zhoumeng Lin; Christopher I. Vahl; Riviere, Jim E.

    2016-01-01

    Violative drug residues in animal-derived foods are a global food safety concern. The use of a fixed main metabolite to parent drug (M/D) ratio determined in healthy animals to establish drug tolerances and withdrawal times in diseased animals results in frequent residue violations in food-producing animals. We created a general physiologically based pharmacokinetic model for representative drugs (ceftiofur, enrofloxacin, flunixin, and sulfamethazine) in cattle and swine based on extensive pu...

  17. Imaging of Cells and Nanoparticles : Implications for Drug Delivery to the Brain

    NARCIS (Netherlands)

    Stojanov, Katica; Zuhorn, Inge S.; Dierckx, Rudi A. J. O.; de Vries, Erik F. J.

    2012-01-01

    A major challenge in the development of central nervous system drugs is to obtain therapeutic effective drug concentrations inside the brain. Many potentially effective drugs have never reached clinical application because of poor brain penetration. Currently, devices are being developed that may im

  18. The status of doping and drug use and the implications for boxing.

    Science.gov (United States)

    Wadler, Gary I

    2009-10-01

    Boxers are not immune from the abuse of drugs. This article outlines the history of drug taking in boxing and sport in general. The current criteria that constitute doping, and prohibited substances and methods in and out of competition, according to guidelines issued by the World Anti-Doping Agency, are listed. Drugs and therapeutic exemptions are discussed.

  19. Molecular markers of anti-malarial drug resistance in Lahj Governorate, Yemen: baseline data and implications

    Directory of Open Access Journals (Sweden)

    Chance Michael L

    2011-08-01

    Full Text Available Abstract Background This is an investigation of anti-malarial molecular markers coupled with a therapeutic efficacy test of chloroquine (CQ against falciparum malaria in an area of unstable malaria in Lahj Governorate, Yemen. The study was aimed at assessment of therapeutic response to CQ and elucidation of baseline information on molecular markers for Plasmodium falciparum resistance against CQ and sulphadoxine/pyrimethamine (SP. Methods Between 2002 and 2003 the field test was conducted according to the standard WHO protocol to evaluate the therapeutic efficacy of CQ in 124 patients with falciparum malaria in an endemic area in Lahj Governorate in Yemen. Blood samples collected during this study were analysed for P. falciparum chloroquine resistance transporter gene (pfcrt-76 polymorphisms, mutation pfcrt-S163R and the antifolate resistance-associated mutations dihydrofolate reductase (dhfr-C59R and dihydropteroate synthase (dhps-K540E. Direct DNA sequencing of the pfcrt gene from three representative field samples was carried out after DNA amplification of the 13 exons of the pfcrt gene. Results Treatment failure was detected in 61% of the 122 cases that completed the 14-day follow-up. The prevalence of mutant pfcrt T76 was 98% in 112 amplified pre-treatment samples. The presence of pfcrt T76 was poorly predictive of in vivo CQ resistance (PPV = 61.8%, 95% CI = 52.7-70.9. The prevalence of dhfr Arg-59 mutation in 99 amplified samples was 5%, while the dhps Glu-540 was not detected in any of 119 amplified samples. Sequencing the pfcrt gene confirmed that Yemeni CQ resistant P. falciparum carry the old world (Asian and African CQ resistant haplotype CVIETSESI at positions 72,73,74,75,76,220,271, 326 and 371. Conclusion This is the first study to report baseline information on the characteristics and implications of anti-malarial drug resistance markers in Yemen. It is also the first report of the haplotype associated with CQR P. falciparum

  20. Beta-blocking agents and electroconvulsive therapy

    NARCIS (Netherlands)

    W.W. van den Broek (Walter); T.H.N. Groenland (Theo); P.G.H. Mulder (Paul); A. Kusuma (Ari); T.K. Birkenhäger (Tom); E.M. Pluijms (Esther); J.A. Bruijn (Jan)

    2007-01-01

    textabstractIn this review we want to summarize the results of the placebo-controlled randomized clinical trials with betablocking adrenergic agents during electroconvulsive therapy (ECT), and review the effect on seizure duration and cardiovascular variables. We searched for studies in the

  1. Beta-Blocking Agents and Electroconvulsive Therapy

    NARCIS (Netherlands)

    W.W. van den Broek (Walter); T.H.N. Groenland (Theo); A. Kusuma (Ari); T.K. Birkenhäger (Tom); E.M. Pluijms (Esther); J.A. Bruijn (Jan); P.G.H. Mulder (Paul)

    2007-01-01

    textabstractIn this review we want to summarize the results of the placebo-controlled randomized clinical trials with betablocking adrenergic agents during electroconvulsive therapy (ECT), and review the effect on seizure duration and cardiovascular variables. We searched for studies in the

  2. Beta-Blocking Agents and Electroconvulsive Therapy

    NARCIS (Netherlands)

    W.W. van den Broek (Walter); T.H.N. Groenland (Theo); A. Kusuma (Ari); T.K. Birkenhäger (Tom); E.M. Pluijms (Esther); J.A. Bruijn (Jan); P.G.H. Mulder (Paul)

    2007-01-01

    textabstractIn this review we want to summarize the results of the placebo-controlled randomized clinical trials with betablocking adrenergic agents during electroconvulsive therapy (ECT), and review the effect on seizure duration and cardiovascular variables. We searched for studies in the electron

  3. Beta-blocking agents and electroconvulsive therapy

    NARCIS (Netherlands)

    W.W. van den Broek (Walter); T.H.N. Groenland (Theo); P.G.H. Mulder (Paul); A. Kusuma (Ari); T.K. Birkenhäger (Tom); E.M. Pluijms (Esther); J.A. Bruijn (Jan)

    2007-01-01

    textabstractIn this review we want to summarize the results of the placebo-controlled randomized clinical trials with betablocking adrenergic agents during electroconvulsive therapy (ECT), and review the effect on seizure duration and cardiovascular variables. We searched for studies in the electron

  4. Human Food Safety Implications of Variation in Food Animal Drug Metabolism

    Science.gov (United States)

    Lin, Zhoumeng; Vahl, Christopher I.; Riviere, Jim E.

    2016-01-01

    Violative drug residues in animal-derived foods are a global food safety concern. The use of a fixed main metabolite to parent drug (M/D) ratio determined in healthy animals to establish drug tolerances and withdrawal times in diseased animals results in frequent residue violations in food-producing animals. We created a general physiologically based pharmacokinetic model for representative drugs (ceftiofur, enrofloxacin, flunixin, and sulfamethazine) in cattle and swine based on extensive published literature. Simulation results showed that the M/D ratio was not a fixed value, but a time-dependent range. Disease changed M/D ratios substantially and extended withdrawal times; these effects exhibited drug- and species-specificity. These results challenge the interpretation of violative residues based on the use of the M/D ratio to establish tolerances for metabolized drugs. PMID:27302389

  5. Representation of target-bound drugs by computed conformers: implications for conformational libraries

    Directory of Open Access Journals (Sweden)

    Goede Andrean

    2006-06-01

    Full Text Available Abstract Background The increasing number of known protein structures provides valuable information about pharmaceutical targets. Drug binding sites are identifiable and suitable lead compounds can be proposed. The flexibility of ligands is a critical point for the selection of potential drugs. Since computed 3D structures of millions of compounds are available, the knowledge of their binding conformations would be a great benefit for the development of efficient screening methods. Results Integration of two public databases allowed superposition of conformers for 193 approved drugs with 5507 crystallised target-bound counterparts. The generation of 9600 drug conformers using an atomic force field was carried out to obtain an optimal coverage of the conformational space. Bioactive conformations are best described by a conformational ensemble: half of all drugs exhibit multiple active states, distributed over the entire range of the reachable energy and conformational space. A number of up to 100 conformers per drug enabled us to reproduce the bound states within a similarity threshold of 1.0 Å in 70% of all cases. This fraction rises to about 90% for smaller or average sized drugs. Conclusion Single drugs adopt multiple bioactive conformations if they interact with different target proteins. Due to the structural diversity of binding sites they adopt conformations that are distributed over a broad conformational space and wide energy range. Since the majority of drugs is well represented by a predefined low number of conformers (up to 100 this procedure is a valuable method to compare compounds by three-dimensional features or for fast similarity searches starting with pharmacophores. The underlying 9600 generated drug conformers are downloadable from the Super Drug Web site 1. All superpositions are visualised at the same source. Additional conformers (110,000 of 2400 classified WHO-drugs are also available.

  6. Implications of the new Food and Drug Administration draft guidance on human factors engineering for diabetes device manufacturers.

    Science.gov (United States)

    Wilcox, Stephen B; Drucker, Daniel

    2012-03-01

    This article discusses the implications of the new Food and Drug Administration's draft guidance on human factors and usability engineering for the development of diabetes-related devices. Important considerations include the challenge of identifying users, when the user population is so dramatically broad, and the challenge of identifying use environments when the same can be said for use environments. Another important consideration is that diabetes-related devices, unlike many other medical devices, are used constantly as part of the user's lifestyle--adding complexity to the focus on human factors and ease of use emphasized by the draft guidance.

  7. Transmission Intensity and Drug Resistance in Malaria Population Dynamics : Implications for Climate Change

    NARCIS (Netherlands)

    Artzy-Randrup, Yael; Alonso, David; Pascual, Mercedes

    2010-01-01

    Although the spread of drug resistance and the influence of climate change on malaria are most often considered separately, these factors have the potential to interact through altered levels of transmission intensity. The influence of transmission intensity on the evolution of drug resistance has b

  8. 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 a

  9. Disease-modifying antirheumatic drugs in pregnancy - Current status and implications for the future

    NARCIS (Netherlands)

    Vroom, Fokaline; de Walle, Hermien E. K.; van de Laar, Mart A. J. F.; Brouwers, Jacobus R. B. J.; de Jong-van den Berg, Lolkje T. W.

    2006-01-01

    Drug use during pregnancy is sometimes unavoidable, especially in chronic inflammatory diseases such as rheumatoid arthritis (RA). The use of disease-modifying antirheumatic drugs (DMARDs) often starts in the early stage of RA; therefore, women of reproductive age are at risk for exposure to a DMARD

  10. Disease-modifying antirheumatic drugs in pregnancy - Current status and implications for the future

    NARCIS (Netherlands)

    Vroom, Fokaline; de Walle, Hermien E. K.; van de Laar, Mart A. J. F.; Brouwers, Jacobus R. B. J.; de Jong-van den Berg, Lolkje T. W.

    2006-01-01

    Drug use during pregnancy is sometimes unavoidable, especially in chronic inflammatory diseases such as rheumatoid arthritis (RA). The use of disease-modifying antirheumatic drugs (DMARDs) often starts in the early stage of RA; therefore, women of reproductive age are at risk for exposure to a DMARD

  11. Designing Novel Nanoformulations Targeting Glutamate Transporter Excitatory Amino Acid Transporter 2: Implications in Treating Drug Addiction.

    Science.gov (United States)

    Rao, Pss; Yallapu, Murali M; Sari, Youssef; Fisher, Paul B; Kumar, Santosh

    Chronic drug abuse is associated with elevated extracellular glutamate concentration in the brain reward regions. Deficit of glutamate clearance has been identified as a contributing factor that leads to enhanced glutamate concentration following extended drug abuse. Importantly, normalization of glutamate level through induction of glutamate transporter 1 (GLT1)/ excitatory amino acid transporter 2 (EAAT2) expression has been described in several in vivo studies. GLT1 upregulators including ceftriaxone, a beta-lactam antibiotic, have been effective in attenuating drug-seeking and drug-consumption behavior in rodent models. However, potential obstacles toward clinical translation of GLT1 (EAAT2) upregulators as treatment for drug addiction might include poor gastrointestinal absorption, serious peripheral adverse effects, and/or suboptimal CNS concentrations. Given the growing success of nanotechnology in targeting CNS ailments, nanoformulating known GLT1 (EAAT2) upregulators for selective uptake across the blood brain barrier presents an ideal therapeutic approach for treating drug addiction. In this review, we summarize the results obtained with promising GLT1 (EAAT2) inducing compounds in animal models recapitulating drug addiction. Additionally, the various nanoformulations that can be employed for selectively increasing the CNS bioavailability of GLT1 (EAAT2) upregulators are discussed. Finally, the applicability of GLT1 (EAAT2) induction via central delivery of drug-loaded nanoformulations is described.

  12. Young Adult Male Satisfaction with Drug & Alcohol Rehabilitation Facilities: Interior Design Implications.

    Science.gov (United States)

    Potthoff, Joy K.

    1991-01-01

    Examined young adult male patient (n=18) satisfaction with interior environments of three different in-patient drug and alcohol rehabilitation facilities: renovated Elk's Club; hospital wing; and facility built for drug and alcohol treatment. Findings indicated satisfaction declined over four-week treatment period; familiar objects were missed;…

  13. Phase 0 clinical trials: Theoretical and practical implications in oncologic drug development

    NARCIS (Netherlands)

    P.M. Coloma (Preciosa)

    2012-01-01

    textabstractDrug discovery and development has become a risky, expensive, and protracted process, with the cost of introducing a new drug to the market going as high as US$2 billion and the entire process taking at least 10-15 years. Great advances in biomedical research in recent years have not res

  14. Performance enhancing drug abuse and cardiovascular risk in athletes: implications for the clinician.

    Science.gov (United States)

    Angell, Peter J; Chester, Neil; Sculthorpe, Nick; Whyte, Greg; George, Keith; Somauroo, John

    2012-11-01

    The use of performance-enhancing and social drugs by athletes raises a number of ethical and health concerns. The World Anti-Doping Agency was constituted to address both of these issues as well as publishing a list of, and testing for, banned substances in athletes. Despite continuing methodological developments to detect drug use and associated punishments for positive dope tests, there are still many athletes who choose to use performance and image enhancing drugs. Of primary concern to this review are the health consequences of drug use by athletes. For such a large topic we must put in place delimitations. Specifically, we will address current knowledge, controversies and emerging evidence in relation to cardiovascular (CV) health of athletes taking drugs. Further, we delimit our discussion to the CV consequences of anabolic steroids and stimulant (including amphetamines and cocaine) use. These drugs are reported in the majority of adverse findings in athlete drug screenings and thus are more likely to be relevant to the healthcare professionals responsible for the well-being of athletes. In detailing CV health issues related to anabolic steroid and stimulant abuse by athletes we critique current research evidence, present exemplar case studies and suggest important avenues for on-going research. Specifically we prompt the need for awareness of clinical staff when assessing the potential CV consequences of drug use in athletes.

  15. Valuation of Drug Abuse: A Review of Current Methodologies and Implications for Policy Making

    Science.gov (United States)

    Schori, Maayan

    2011-01-01

    This article reviews the use of several valuation methods as they relate to drug abuse and places them within the context of U.S. policy. First, cost-of-illness (COI) studies are reviewed and their limitations discussed. Second, three additional economic methods of valuing drug abuse are reviewed, including cost-effectiveness analysis (CEA),…

  16. Valuation of Drug Abuse: A Review of Current Methodologies and Implications for Policy Making

    Science.gov (United States)

    Schori, Maayan

    2011-01-01

    This article reviews the use of several valuation methods as they relate to drug abuse and places them within the context of U.S. policy. First, cost-of-illness (COI) studies are reviewed and their limitations discussed. Second, three additional economic methods of valuing drug abuse are reviewed, including cost-effectiveness analysis (CEA),…

  17. Statin Drugs Markedly Inhibit Testosterone Production by Rat Leydig Cells In Vitro: Implications for Men

    Science.gov (United States)

    Statin drugs lower blood cholesterol by inhibiting hepatic 3-hydroxy-3-methylglutaryl-Coenzyme-A reductase. During drug development it was shown that statins inhibit production of cholesterol in the testis. We evaluated testosterone production in vitro, using highly purified rat ...

  18. Comparative modelling of human β tubulin isotypes and implications for drug binding

    Science.gov (United States)

    Torin Huzil, J.; Ludueña, Richard F.; Tuszynski, Jack

    2006-02-01

    The protein tubulin is a target for several anti-mitotic drugs, which affect microtubule dynamics, ultimately leading to cell cycle arrest and apoptosis. Many of these drugs, including the taxanes and Vinca alkaloids, are currently used clinically in the treatment of several types of cancer. Another tubulin binding drug, colchicine, although too toxic to be used as a chemotherapeutic agent, is commonly used for the treatment of gout. The main disadvantage that all of these drugs share is that they bind tubulin indiscriminately, leading to the death of both cancerous and healthy cells. However, the broad cellular distribution of several tubulin isotypes provides a platform upon which to construct novel chemotherapeutic drugs that could differentiate between different cell types, reducing the undesirable side effects associated with current chemotherapeutic treatments. Here, we report an analysis of ten human β tubulin isotypes and discuss differences within each of the previously characterized paclitaxel, colchicine and vinblastine binding sites.

  19. Specificity quantification of biomolecular recognition and its implication for drug discovery

    Science.gov (United States)

    Yan, Zhiqiang; Wang, Jin

    2012-03-01

    Highly efficient and specific biomolecular recognition requires both affinity and specificity. Previous quantitative descriptions of biomolecular recognition were mostly driven by improving the affinity prediction, but lack of quantification of specificity. We developed a novel method SPA (SPecificity and Affinity) based on our funneled energy landscape theory. The strategy is to simultaneously optimize the quantified specificity of the ``native'' protein-ligand complex discriminating against ``non-native'' binding modes and the affinity prediction. The benchmark testing of SPA shows the best performance against 16 other popular scoring functions in industry and academia on both prediction of binding affinity and ``native'' binding pose. For the target COX-2 of nonsteroidal anti-inflammatory drugs, SPA successfully discriminates the drugs from the diversity set, and the selective drugs from non-selective drugs. The remarkable performance demonstrates that SPA has significant potential applications in identifying lead compounds for drug discovery.

  20. Payload drug vs. nanocarrier biodegradation by myeloperoxidase- and peroxynitrite-mediated oxidations: pharmacokinetic implications

    Science.gov (United States)

    Seo, Wanji; Kapralov, Alexandr A.; Shurin, Galina V.; Shurin, Michael R.; Kagan, Valerian E.; Star, Alexander

    2015-05-01

    With the advancement of nanocarriers for drug delivery into biomedical practice, assessments of drug susceptibility to oxidative degradation by enzymatic mechanisms of inflammatory cells become important. Here, we investigate oxidative degradation of a carbon nanotube-based drug carrier loaded with Doxorubicin. We employed myeloperoxidase-catalysed and peroxynitrite-mediated oxidative conditions to mimic the respiratory burst of neutrophils and macrophages, respectively. In addition, we revealed that the cytostatic and cytotoxic effects of free Doxorubicin, but not nanotube-carried drug, on melanoma and lung carcinoma cell lines were abolished in the presence of tumor-activated myeloid regulatory cells that create unique myeloperoxidase- and peroxynitrite-induced oxidative conditions. Both ex vivo and in vitro studies demonstrate that the nanocarrier protects the drug against oxidative biodegradation.With the advancement of nanocarriers for drug delivery into biomedical practice, assessments of drug susceptibility to oxidative degradation by enzymatic mechanisms of inflammatory cells become important. Here, we investigate oxidative degradation of a carbon nanotube-based drug carrier loaded with Doxorubicin. We employed myeloperoxidase-catalysed and peroxynitrite-mediated oxidative conditions to mimic the respiratory burst of neutrophils and macrophages, respectively. In addition, we revealed that the cytostatic and cytotoxic effects of free Doxorubicin, but not nanotube-carried drug, on melanoma and lung carcinoma cell lines were abolished in the presence of tumor-activated myeloid regulatory cells that create unique myeloperoxidase- and peroxynitrite-induced oxidative conditions. Both ex vivo and in vitro studies demonstrate that the nanocarrier protects the drug against oxidative biodegradation. Electronic supplementary information (ESI) available: Experimental details and data from characterization of materials synthesis and degradation studies. See DOI: 10

  1. Mycotoxins and Antifungal Drug Interactions: Implications in the Treatment of Illnesses Due to Indoor Chronic Toxigenic Mold Exposures

    Directory of Open Access Journals (Sweden)

    Ebere C. Anyanwu

    2004-01-01

    Full Text Available Chronic exposure to toxigenic molds in water-damaged buildings is an indoor environmental health problem to which escalating health and property insurance costs are raising a statewide concern in recent times. This paper reviews the structural and functional properties of mycotoxins produced by toxigenic molds and their interactive health implications with antifungal drugs. Fundamental bases of pathophysiological, neurodevelopmental, and cellular mechanisms of mycotoxic effects are evaluated. It is most likely that the interactions of mycotoxins with antifungal drugs may, at least in part, contribute to the observable persistent illnesses, antifungal drug resistance, and allergic reactions in patients exposed to chronic toxigenic molds. Safe dose level of mycotoxin in humans is not clear. Hence, the safety regulations in place at the moment remain inconclusive, precautionary, and arbitrary. Since some of the antifungal drugs are derived from molds, and since they have structural and functional groups similar to those of mycotoxins, the knowledge of their interactions are important in enhancing preventive measures.

  2. Stress modulation of drug self-administration: implications for addiction comorbidity with post-traumatic stress disorder.

    Science.gov (United States)

    Logrip, Marian L; Zorrilla, Eric P; Koob, George F

    2012-02-01

    Drug abuse and dependence present significant health burdens for our society, affecting roughly 10% of the population. Stress likely contributes to the development and persistence of drug use; for example, rates of substance dependence are elevated among individuals diagnosed with post-traumatic stress disorder (PTSD). Thus, understanding the interaction between stress and drug use, and associated neuroadaptations, is key for developing therapies to combat substance use disorders. For this purpose, many rodent models of the effects of stress exposure on substance use have been developed; the models can be classified according to three categories of stress exposure: developmental, adult nonsocial, and adult social. The present review addresses preclinical findings on the effect of each type of trauma on responses to and self-administration of drugs of abuse by focusing on a key exemplar for each category. In addition, the potential efficacy of targeting neuropeptide systems that have been implicated in stress responses and stress system neuroadaptation in order to treat comorbid PTSD and substance abuse will be discussed. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.

  3. Drug induced increases in CNS dopamine alter monocyte, macrophage and T cell functions: implications for HAND

    Science.gov (United States)

    Gaskill, Peter J.; Calderon, Tina M.; Coley, Jacqueline S.; Berman, Joan W.

    2013-01-01

    Central nervous system (CNS) complications resulting from HIV infection remain a major public health problem as individuals live longer due to the success of combined antiretroviral therapy (cART). As many as 70% of HIV infected people have HIV associated neurocognitive disorders (HAND). Many HIV infected individuals abuse drugs, such as cocaine, heroin or methamphetamine, that may be important cofactors in the development of HIV CNS disease. Despite different mechanisms of action, all drugs of abuse increase extracellular dopamine in the CNS. The effects of dopamine on HIV neuropathogenesis are not well understood, and drug induced increases in CNS dopamine may be a common mechanism by which different types of drugs of abuse impact the development of HAND. Monocytes and macrophages are central to HIV infection of the CNS and to HAND. While T cells have not been shown to be a major factor in HIV-associated neuropathogenesis, studies indicate that T cells may play a larger role in the development of HAND in HIV infected drug abusers. Drug induced increases in CNS dopamine may dysregulate functions of, or increase HIV infection in, monocytes, macrophages and T cells in the brain. Thus, characterizing the effects of dopamine on these cells is important for understanding the mechanisms that mediate the development of HAND in drug abusers. PMID:23456305

  4. Injecting drugs of abuse and immunity: implications for HIV vaccine testing and efficacy.

    Science.gov (United States)

    Ugen, Kenneth E; Nyland, Susan B

    2006-11-01

    The recreational use of legal and illegal drugs has significant effects on immune responses and can potentially modulate susceptibility to infection by a number of pathogens. A number of agents including cannabinoids (marijuana), cocaine opiates, amphetamines, nicotine and alcohol were demonstrated to have potentially adverse effects on the susceptibility to infections, mediated most likely, by adverse effects on immunity. As such, these drugs of abuse could have significant and potentially adverse effects on the vaccination efficacy of a number of vaccines currently on the market and on potential experimental vaccines currently in the pipeline. This review will present an overview on how drugs of abuse potentially impacts immune responses and vaccination efficacy. The emphasis of this review will be the effects of opiate abuse, as exemplified by injecting/intravenous drug users (IDU), on HIV/AIDS and its potential impact on vaccine efficacy trials against this devastating infection/syndrome.

  5. Phase 0 clinical trials: theoretical and practical implications in oncologic drug development

    OpenAIRE

    Coloma PM

    2013-01-01

    Preciosa M ColomaDepartment of Medical Informatics, Erasmus MC University Medical Center, Rotterdam, The NetherlandsAbstract: Drug discovery and development has become a risky, expensive, and protracted process, with the cost of introducing a new drug to the market going as high as US$2 billion and the entire process taking at least 10–15 years. Great advances in biomedical research in recent years have not resulted in translation into medical product development, and there has been...

  6. Commercial importation of prescription drugs in the United States: short-run implications.

    Science.gov (United States)

    Danzon, Patricia M; Johnson, Scott J; Long, Genia; Furukawa, Michael F

    2011-04-01

    The option of legalizing the commercial importation of prescription drugs is of continued policy interest as a way to reduce U.S. drug spending. Using IMS data, we estimate potential savings from commercial drug importation under assumptions about percentage of drugs likely to attract imports; potential supply from foreign countries; and share of savings passed on to payers. Our base case estimate is that $1.7 billion per year, or 0.6 percent of total drug spending, would be saved by payers; sensitivity analyses range from 0.2 to 2.5 percent under plausible assumptions and up to 17.4 percent under unrealistic assumptions about unlimited foreign supply, costless trade, and zero profits for intermediaries. Estimated savings to payers are less than the average price differentials between the United States and foreign countries because proposed legislation exempts certain drugs from importation; foreign markets are small relative to the United States; regulatory and other constraints may limit the volume of exports; trade is costly; and intermediaries will retain some savings. Although savings to U.S. payers/consumers would likely be small and have minimal impact on total U.S. health care spending, costs to other countries could be significant, due to reduced access and possibly higher prices. In the long run, reduced investment in R&D could adversely affect consumers globally.

  7. Computational Identification of the Paralogs and Orthologs of Human Cytochrome P450 Superfamily and the Implication in Drug Discovery

    Directory of Open Access Journals (Sweden)

    Shu-Ting Pan

    2016-06-01

    Full Text Available The human cytochrome P450 (CYP superfamily consisting of 57 functional genes is the most important group of Phase I drug metabolizing enzymes that oxidize a large number of xenobiotics and endogenous compounds, including therapeutic drugs and environmental toxicants. The CYP superfamily has been shown to expand itself through gene duplication, and some of them become pseudogenes due to gene mutations. Orthologs and paralogs are homologous genes resulting from speciation or duplication, respectively. To explore the evolutionary and functional relationships of human CYPs, we conducted this bioinformatic study to identify their corresponding paralogs, homologs, and orthologs. The functional implications and implications in drug discovery and evolutionary biology were then discussed. GeneCards and Ensembl were used to identify the paralogs of human CYPs. We have used a panel of online databases to identify the orthologs of human CYP genes: NCBI, Ensembl Compara, GeneCards, OMA (“Orthologous MAtrix” Browser, PATHER, TreeFam, EggNOG, and Roundup. The results show that each human CYP has various numbers of paralogs and orthologs using GeneCards and Ensembl. For example, the paralogs of CYP2A6 include CYP2A7, 2A13, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 2F1, 2J2, 2R1, 2S1, 2U1, and 2W1; CYP11A1 has 6 paralogs including CYP11B1, 11B2, 24A1, 27A1, 27B1, and 27C1; CYP51A1 has only three paralogs: CYP26A1, 26B1, and 26C1; while CYP20A1 has no paralog. The majority of human CYPs are well conserved from plants, amphibians, fishes, or mammals to humans due to their important functions in physiology and xenobiotic disposition. The data from different approaches are also cross-validated and validated when experimental data are available. These findings facilitate our understanding of the evolutionary relationships and functional implications of the human CYP superfamily in drug discovery.

  8. GHB Abuse Trends and Use in Drug-Facilitated Sexual Assault: Implications for Prevention.

    Science.gov (United States)

    Hensley, Laura

    2003-01-01

    Gamma-hydroxybutyric acid (GHB) has become increasingly popular on the campuses of American colleges and universities. In this paper, the characteristics of GHB and the effects of both voluntary and involuntary abuse are described. Further, implications for prevention efforts related to involuntary GHB ingestion and GHB-facilitated rape are…

  9. Prevalence and Global Health implications of social media in direct-to-consumer drug advertising.

    Science.gov (United States)

    Liang, Bryan A; Mackey, Timothy K

    2011-08-31

    Direct-to-consumer advertising (DTCA), linked to inappropriate medication use and higher health care expenditures, is the fastest growing form of pharmaceutical marketing. DTCA is legal only in the United States and New Zealand. However, the advent of online interactive social media "Web 2.0" technologies-that is, eDTCA 2.0-may circumvent DTCA legal proscriptions. The purpose of this study was to assess the prevalence of DTCA of leading pharmaceutical company presence and drug product marketing in online interactive social media technologies (eDTCA 2.0). We conducted a descriptive study of the prevalence of eDTCA 2.0 marketing in the top 10 global pharmaceutical corporations and 10 highest grossing drugs of 2009. All pharmaceutical companies reviewed (10/10, 100%) have a presence in eDTCA 2.0 on Facebook, Twitter/Friendster, sponsored blogs, and really simple syndication (RSS) feeds. In addition, 80% (8/10) have dedicated YouTube channels, and 80% (8/10) developed health care communication-related mobile applications. For reviewed drugs, 90% (9/10) have dedicated websites, 70% (7/10) have dedicated Facebook pages, 90% (9/10) have health communications-related Twitter and Friendster traffic, and 80% (8/10) have DTCA television advertisements on YouTube. We also found 90% (9/10) of these drugs had a non-corporate eDTCA 2.0 marketing presence by illegal online drug sellers. Pharmaceutical companies use eDTCA 2.0 to market themselves and their top-selling drugs. eDTCA 2.0 is also used by illicit online drug sellers. Regulators worldwide must take into account the current eDTCA 2.0 presence when attempting to reach policy and safety goals.

  10. Prevalence and Global Health Implications of Social Media in Direct-to-Consumer Drug Advertising

    Science.gov (United States)

    Liang, Bryan A

    2011-01-01

    Background Direct-to-consumer advertising (DTCA), linked to inappropriate medication use and higher health care expenditures, is the fastest growing form of pharmaceutical marketing. DTCA is legal only in the United States and New Zealand. However, the advent of online interactive social media “Web 2.0” technologies—that is, eDTCA 2.0—may circumvent DTCA legal proscriptions. Objective The purpose of this study was to assess the prevalence of DTCA of leading pharmaceutical company presence and drug product marketing in online interactive social media technologies (eDTCA 2.0). Methods We conducted a descriptive study of the prevalence of eDTCA 2.0 marketing in the top 10 global pharmaceutical corporations and 10 highest grossing drugs of 2009. Results All pharmaceutical companies reviewed (10/10, 100%) have a presence in eDTCA 2.0 on Facebook, Twitter/Friendster, sponsored blogs, and really simple syndication (RSS) feeds. In addition, 80% (8/10) have dedicated YouTube channels, and 80% (8/10) developed health care communication-related mobile applications. For reviewed drugs, 90% (9/10) have dedicated websites, 70% (7/10) have dedicated Facebook pages, 90% (9/10) have health communications-related Twitter and Friendster traffic, and 80% (8/10) have DTCA television advertisements on YouTube. We also found 90% (9/10) of these drugs had a non-corporate eDTCA 2.0 marketing presence by illegal online drug sellers. Conclusion Pharmaceutical companies use eDTCA 2.0 to market themselves and their top-selling drugs. eDTCA 2.0 is also used by illicit online drug sellers. Regulators worldwide must take into account the current eDTCA 2.0 presence when attempting to reach policy and safety goals. PMID:21880574

  11. Genetic diversity of variants involved in drug response and metabolism in Sri Lankan populations: implications for clinical implementation of pharmacogenomics

    Science.gov (United States)

    Chan, Sze Ling; Samaranayake, Nilakshi; Ross, Colin J.D.; Toh, Meng Tiak; Carleton, Bruce; Hayden, Michael R.; Teo, Yik Ying; Dissanayake, Vajira H.W.

    2016-01-01

    Background Interpopulation differences in drug responses are well documented, and in some cases they correspond to differences in the frequency of associated genetic markers. Understanding the diversity of genetic markers associated with drug response across different global populations is essential to infer population rates of drug response or risk for adverse drug reactions, and to guide implementation of pharmacogenomic testing. Sri Lanka is a culturally and linguistically diverse nation, but little is known about the population genetics of the major Sri Lankan ethnic groups. The objective of this study was to investigate the diversity of pharmacogenomic variants in the major Sri Lankan ethnic groups. Methods We examined the allelic diversity of more than 7000 variants in genes involved in drug biotransformation and response in the three major ethnic populations of Sri Lanka (Sinhalese, Sri Lankan Tamils, and Moors), and compared them with other South Asian, South East Asian, and European populations using Wright’s Fixation Index, principal component analysis, and STRUCTURE analysis. Results We observed overall high levels of similarity within the Sri Lankan populations (median FST=0.0034), and between Sri Lankan and other South Asian populations (median FST=0.0064). Notably, we observed substantial differentiation between Sri Lankan and European populations for important pharmacogenomic variants related to warfarin (VKORC1 rs9923231) and clopidogrel (CYP2C19 rs4986893) response. Conclusion These data expand our understanding of the population structure of Sri Lanka, provide a resource for pharmacogenomic research, and have implications for the clinical use of genetic testing of pharmacogenomic variants in these populations. PMID:26444257

  12. Effects of resveratrol on drug- and carcinogen-metabolizing enzymes, implications for cancer prevention.

    Science.gov (United States)

    Guthrie, Ariane R; Chow, H-H Sherry; Martinez, Jessica A

    2017-02-01

    Resveratrol is a polyphenol found in grape skins and peanuts that has demonstrated many health benefits including protection against aging, cardiovascular and metabolic disease, neurological decline, and cancer. The anticancer properties of resveratrol have been attributed to a variety of mechanisms, including its general inhibition of phase I metabolism and induction of phase II metabolism. The effects of resveratrol on these enzymes, however, are still unclear, as in vitro evidence often contrasts with animal studies and clinical trials. Reasons for these variances could include the low bioavailability of resveratrol and the effects of resveratrol metabolites. Due to resveratrol's interactions with drug-metabolizing enzymes and drug transporters, individuals concurrently taking pharmacological doses of resveratrol with other supplements or medications could potentially experience nutrient-drug interactions. This review summarizes the known effects of resveratrol and its main metabolites on drug metabolism in order to help characterize which populations might benefit from resveratrol for the prevention of cancer, as well as those that may need to avoid supplementation due to potential drug interactions.

  13. Cannabinoid modulation of drug reward and the implications of marijuana legalization.

    Science.gov (United States)

    Covey, Dan P; Wenzel, Jennifer M; Cheer, Joseph F

    2015-12-02

    Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana's illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana's psychoactive and reinforcing properties. CB1 receptors are also part of the brain endocannabinoid (eCB) system and support numerous forms of learning and memory, including the conditioned reinforcing properties of cues predicting reward or punishment. This is accomplished via eCB-dependent alterations in mesolimbic dopamine function, which plays an obligatory role in reward learning and motivation. Presynaptic CB1 receptors control midbrain dopamine neuron activity and thereby shape phasic dopamine release in target regions, particularly the nucleus accumbens (NAc). By also regulating synaptic input to the NAc, CB1 receptors modulate NAc output onto downstream neurons of the basal ganglia motor circuit, and thereby support goal-directed behaviors. Abused drugs promote short- and long-term adaptations in eCB-regulation of mesolimbic dopamine function, and thereby hijack neural systems related to the pursuit of rewards to promote drug abuse. By pharmacologically targeting the CB1 receptors, marijuana has preferential access to this neuronal system and can potently alter eCB-dependent processing of reward-related stimuli. As marijuana legalization progresses, greater access to this drug should increase the utility of marijuana as a research tool to better understand the eCB system, which has the potential to advance cannabinoid-based treatments for drug addiction.

  14. Late Onset of Prescription Drug Abuse or Dependence Among Older Adults: Implications for Treatment

    Directory of Open Access Journals (Sweden)

    Kathy Lay

    2007-12-01

    Full Text Available Prescription drug abuse and dependence is an increasing concern for older adults. This article describes issues specific to older adults with late onset abuse or dependence on prescription sedatives and/or opiates.The older adult with late onset should not be viewed as having the same issues as individuals who have a life pat- tern of drug and alcohol abuse/dependence.A chart review of older adults in a treatment program contrasts late onset prescription dependence clients (n=12 and early onset addiction clients (n=104 and outlines differences and similarities between the two samples. Social workers need to understand the specific and changing needs of older adults as they relate to assessment and treatment of drug abuse and dependence.

  15. Cardiovascular Drugs: Implications for Dental Practice Part 1 — Cardiotonics, Diuretics, and Vasodilators

    Science.gov (United States)

    Becker, Daniel E

    2007-01-01

    Appropriate preoperative assessment of dental patients should always include analysis of their medications. Cardiovascular diseases are the most common group of medical disorders that dentists encounter, and the number of drugs prescribed for managing these conditions is staggering. This justifiably raises concern and probable confusion regarding side effects and possible drug interactions with medications the dentist may deem necessary for dental care. This continuing education article is the first in a series that will address essential pharmacology of medications commonly prescribed for chronic medical care. A reasonable understanding of these agents will allow the dentist to better appreciate the medical status of their patients and avoid adverse interactions with drugs they might administer or prescribe. PMID:18085840

  16. Scabies: molecular perspectives and therapeutic implications in the face of emerging drug resistance.

    Science.gov (United States)

    Mounsey, Kate E; Holt, Deborah C; McCarthy, James; Currie, Bart J; Walton, Shelley F

    2008-02-01

    Limited effective treatments, coupled with recent observations of emerging drug resistance to oral ivermectin and 5% permethrin, raise concerns regarding the future control of scabies, especially in severe cases and in endemic areas where repeated community treatment programs are in place. There is consequently an urgent need to define molecular mechanisms of drug resistance in scabies mites and to develop and assess alternative therapeutic options, such as tea tree oil, in the event of increasing treatment failure. Molecular studies on scabies mites have, until recently, been restricted; however, recent advances are providing new insights into scabies mite biology and genetic mechanisms underlying drug resistance. These may assist in overcoming many of the current difficulties in monitoring treatment efficacy and allow the development of more sensitive tools for monitoring emerging resistance.

  17. Implications of nanoscale based drug delivery systems in delivery and targeting tubulin binding agent, noscapine in cancer cells.

    Science.gov (United States)

    Chandra, Ramesh; Madan, Jitender; Singh, Prashant; Chandra, Ankush; Kumar, Pradeep; Tomar, Vartika; Dass, Sujata K

    2012-12-01

    Noscapine, a tubulin binding anticancer agent undergoing Phase I/II clinical trials, inhibits tumor growth in nude mice bearing human xenografts of breast, lung, ovarian, brain, and prostrate origin. The analogues of noscapine like 9-bromonoscapine (EM011) are 5 to 10-fold more active than parent compound, noscapine. Noscapinoids inhibit the proliferation of cancer cells that are resistant to paclitaxel and epothilone. Noscapine also potentiated the anticancer activity of doxorubicin in a synergistic manner against triple negative breast cancer (TNBC). However, physicochemical and pharmacokinetic (ED50˜300-600 mg/kg bodyweight) limitations of noscapine present hurdle in development of commercial anticancer formulations. Therefore, objectives of the present review are to summarize the chemotherapeutic potential of noscapine and implications of nanoscale based drug delivery systems in enhancing the therapeutic efficacy of noscapine in cancer cells. We have constructed noscapine-enveloped gelatin nanoparticles, NPs and poly (ethylene glycol) grafted gelatin NPs as well as inclusion complex of noscapine in β-cyclodextrin (β-CD) and evaluated their physicochemical characteristics. The Fe3O4 NPs were also used to incorporate noscapine in its polymeric nanomatrix system where molecular weight of the polymer governed the encapsulation efficiency of drug. The enhanced noscapine delivery using μPAR-targeted optical-MR imaging trackable NPs offer a great potential for image directed targeted delivery of noscapine. Human Serum Albumin NPs (150-300 nm) as efficient noscapine drug delivery systems have also been developed for potential use in breast cancer.

  18. Thermochemical Properties of Hydrophilic Polymers from Cashew and Khaya Exudates and Their Implications on Drug Delivery.

    Science.gov (United States)

    Olorunsola, Emmanuel O; Bhatia, Partap G; Tytler, Babajide A; Adikwu, Michael U

    2016-01-01

    Characterization of a polymer is essential for determining its suitability for a particular purpose. Thermochemical properties of cashew gum (CSG) extracted from exudates of Anacardium occidentale L. and khaya gum (KYG) extracted from exudates of Khaya senegalensis were determined and compared with those of acacia gum BP (ACG). The polymers were subjected to different thermal and chemical analyses. Exudates of CSG contained higher amount of hydrophilic polymer. The pH of 2% w/v gum dispersions was in the order KYG application of cashew gum for formulation of basic and oxidizable drugs while using khaya gum for acidic drugs.

  19. Circumstances of witnessed drug overdose in New York City: implications for intervention.

    Science.gov (United States)

    Tracy, Melissa; Piper, Tinka Markham; Ompad, Danielle; Bucciarelli, Angela; Coffin, Phillip O; Vlahov, David; Galea, Sandro

    2005-08-01

    Drug users frequently witness the nonfatal and fatal drug overdoses of their peers, but often fail to intervene effectively to reduce morbidity and mortality. We assessed the circumstances of witnessed heroin-related overdoses in New York City (NYC) among a predominantly minority population of drug users. Among 1184 heroin, crack, and cocaine users interviewed between November 2001 and February 2004, 672 (56.8%) had witnessed at least one nonfatal or fatal heroin-related overdose. Of those, 444 (67.7%) reported that they or someone else present called for medical help for the overdose victim at the last witnessed overdose. In multivariable models, the respondent never having had an overdose her/himself and the witnessed overdose occurring in a public place were associated with the likelihood of calling for medical help. Fear of police response was the most commonly cited reason for not calling or delaying before calling for help (52.2%). Attempts to revive the overdose victim through physical stimulation (e.g., applying ice, causing pain) were reported by 59.7% of respondents, while first aid measures were attempted in only 11.9% of events. Efforts to equip drug users to manage overdoses effectively, including training in first aid and the provision of naloxone, and the reduction of police involvement at overdose events may have a substantial impact on overdose-related morbidity and mortality.

  20. Brain Chemistry and Behaviour: An Update on Neuroscience Research and Its Implications for Understanding Drug Addiction

    Science.gov (United States)

    Robinson, Emma S. J.

    2011-01-01

    Psychiatric disorders such as drug addiction represent one of the biggest challenges to society. This article reviews clinical and basic science research to illustrate how developments in research methodology have enabled neuroscientists to understand more about the brain mechanisms involved in addiction biology. Treating addiction represents a…

  1. Brain Chemistry and Behaviour: An Update on Neuroscience Research and Its Implications for Understanding Drug Addiction

    Science.gov (United States)

    Robinson, Emma S. J.

    2011-01-01

    Psychiatric disorders such as drug addiction represent one of the biggest challenges to society. This article reviews clinical and basic science research to illustrate how developments in research methodology have enabled neuroscientists to understand more about the brain mechanisms involved in addiction biology. Treating addiction represents a…

  2. Desirable properties of β3-adrenoceptor agonists : implications for the selection of drug development candidates

    NARCIS (Netherlands)

    Michel, Martin C; Cernecka, Hana; Ochodnicky, Peter

    2011-01-01

    β3-adrenoceptor agonists are currently in clinical development for the treatment of overactive bladder and considered for several other indications. This Perspective discusses desirable properties of such drugs mainly based on the example of overactive bladder, but at least partly they should also b

  3. Prescription drug coverage: implications for hormonal therapy adherence in women diagnosed with breast cancer.

    Science.gov (United States)

    Bradley, Cathy J; Dahman, Bassam; Jagsi, Reshma; Katz, Steven; Hawley, Sarah

    2015-11-01

    In spite of its demonstrated benefits, many women do not initiate hormonal therapy, and among those who do, many discontinue it prematurely. We examined whether differences in hormonal therapy adherence may be at least partially explained by the availability of prescription drug coverage. Women aged 20-79 years diagnosed with stage I-III breast cancer between June 2005 and February 2007 were enrolled in the study. Women completed a mailed survey, on average 9 months after diagnosis, and again approximately 4 years later (N = 712). Adjusted logistic regression was used to predict the likelihood of initiating hormonal therapy and hormonal therapy continuation. Women who had prescription drug coverage were more likely to initiate hormonal therapy relative to women without prescription drug coverage (OR 2.91, 95 % CI 1.24-6.84). Women with prescription drug coverage were also more likely to continue hormonal therapy (OR 2.23; 95 % CI 0.99-5.05, p = 0.0543). The lowest income women were also less likely to continue hormonal therapy relative to women with annual household income that exceeded $70,000 (OR 0.55; 95 % CI 0.29-1.04) with a borderline significance of (p = 0.08). This study demonstrates the critical role of prescription drug coverage in hormonal therapy initiation and continuation, independent of health insurance coverage. These findings add to the body of literature that addresses medication adherence. Financial factors must be considered along with behavioral factors that influence adherence, which is becoming increasingly relevant to oncology as treatments are shifted to oral medications, many of which are very expensive.

  4. Attitudes toward Methadone among Out-of-Treatment Minority Injection Drug Users: Implications for Health Disparities

    Directory of Open Access Journals (Sweden)

    Nickolas D. Zaller

    2009-02-01

    Full Text Available Injection drug use (IDU continues to be a significant public health issue in the U.S. and internationally, and there is evidence to suggest that the burden of injection drug use and associatedmorbidity and mortality falls disproportionately on minority communities. IDU is responsible for a significant portion of new and existing HIV/AIDS cases in many parts of the world. In the U.S., the prevalence of HIV and hepatitis C virus is higher among populations of African-American and Latino injection drug users (IDUs than among white IDUs. Methadone maintenance therapy (MMT has been demonstrated to effectively reduce opiate use, HIV risk behaviors and transmission, general mortality and criminal behavior, but opiate-dependent minorities are less likely to access MMT than whites. A better understanding of the obstacles minority IDUs face accessing treatment is needed to engage racial and ethnic disparities in IDU as well as drug-related morbidity and mortality. In this study, we explore knowledge, attitudes and beliefs about methadone among 53 out-of-treatment Latino and African-American IDUs in Providence, RI. Our findings suggest that negative perceptions of methadone persist among racial and ethnic minority IDUs in Providence, including beliefs that methadone is detrimental to health and that people should attempt to discontinue methadone treatment. Additional potential obstacles to entering methadone therapy include cost and the difficulty of regularly attending a methadone clinic as well as the belief that an individual on MMT is not abstinent from drugs. Substance use researchers and treatment professionals should engage minority communities, particularly Latino communities, in order to better understand the treatment needs of a diverse population, develop culturally appropriate MMT programs, and raise awareness of the benefits of MMT.

  5. The clinical implication of drug dependency in children and adults with inflammatory bowel disease: a review

    DEFF Research Database (Denmark)

    Duricova, Dana; Pedersen, Natalia; Lenicek, Martin

    2011-01-01

    cessation or dose decrease. However, a quick restoration of remission and sustained response is achieved when the therapy is re-introduced or dose increased. Population-based studies have demonstrated that 22-36% of adults and 14-50% of children become corticosteroid dependent. Approximately 1......Drug dependency in adult and paediatric patients with inflammatory bowel disease (IBD) is described and the significance of this response pattern in clinical practice discussed in this review. Dependent patients maintain remission while on the treatment, but they relapse shortly after drug...... corticosteroid dependency. Infliximab dependency was described in 42-66% of children and 29% of adults with Crohn's disease. The risk of surgery 50 and 40 months after treatment start was 10% and 23% in infliximab dependent children and adults, respectively. Maintenance of infliximab in dependent patients...

  6. Transactional Sex among Noninjecting Illicit Drug Users: Implications for HIV Transmission

    Directory of Open Access Journals (Sweden)

    Rafael Alves Guimarães

    2016-01-01

    Full Text Available Noninjecting illicit drug users (NIDUs present high risk for HIV infection, due especially to transactional sex. This study aimed to estimate the prevalence and risk factors for transactional sex among NIDUs in the Southwest region of Goiás State, Central Brazil. The prevalence of self-reported transactional sex was 22.8%. Prevalence in women and men was 52.7% and 16.8%, respectively, a significant difference (p<0.001. Crack use and history of sexually transmitted infections (STI were risk factors for transactional sex in men. Homelessness, crack use, sex under the influence of drugs, and history of sexual violence were risk factors for transactional sex in women. A high prevalence of transactional sex was observed among NIDUs. This risk behavior may contribute to the high rates of HIV among this population and their social networks and in the general population.

  7. The Drug war: Diplomatic and Security Implications for Mexico and the United States

    Science.gov (United States)

    2011-06-10

    their labor from services provided by a functional state. Spillover Violence Spillover violence has the potential to become one of the most...and enjoy the fruits of their labor . As enforcement along the U.S. Southwest border improves the DTOs will continue to seek alternative methods to...August 2002), 5. 83 GLOSSARY Commission Nacional de Derechos Humanos (CNDH). Mexico’s National Commission on Human Rights. Counter-drug

  8. Pharmacogenetic implications of the eNOS polymorphisms for cardiovascular action drugs

    OpenAIRE

    Pâmela Souza Silva; Riccardo Lacchini; Valéria Aguiar Gomes; José Eduardo Tanus-Santos

    2011-01-01

    The pharmacogenetics is one of the most promising fields of medicine. The conclusion of the Genome Project allowed this field to start discovering complex factors modulating the response to drugs, and new technologies are close a great expansion of the area. The cardiovascular diseases are currently among the major causes of hospitalizations and death, and have been the target of a large part of genetic studies of complex diseases. Parallel to the susceptibility to disease markers identificat...

  9. Cannabinoid modulation of drug reward and the implications of marijuana legalization

    OpenAIRE

    Covey, Dan P.; Wenzel, Jennifer M.; Cheer, Joseph F.

    2014-01-01

    Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana’s illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana’s psychoactive and reinforcing properties. CB1 receptors are also part of the brain endocannabinoid (eCB) system and support numerous forms of learning and memory, including the conditioned reinforcing properties of cues predicting reward or punishm...

  10. COMPUTER DYNAMICS SIMULATION OF DRUG DEPENDENCE THROUGH ARTIFICIAL NEURONAL NETWORK: PEDAGOGICAL AND CLINICAL IMPLICATIONS

    Directory of Open Access Journals (Sweden)

    G. SANTOS

    2008-05-01

    Full Text Available To develop and to evaluate the efficiency of a software able to simulate a virtual patient at different stages of addition was the main goal and challenge of this work. We developed the software in Borland™ Delphi  5®  programming language. Techniques of artificial intelligence, neuronal networks and expert systems, were responsible for modeling the neurobiological structures and mechanisms of the interaction with the drugs used. Dynamical simulation and  hypermedia were designed to increase the software’s interactivity which was able to show graphical information from virtual instrumentation and from realistic functional magnetic resonance imaging display. Early, the program was designed to be used by undergraduate students to improve their neurophysiologic learn, based not only in an interaction of membrane receptors with drugs, but in such a large behavioral simulation. The experimental manipulation of the software was accomplished by: i creating a virtual patient from a normal mood to a behavioral addiction, increasing gradatively: alcohol, opiate or cocaine doses. ii designing an approach to treat the patient, to get total or partial remission of behavioral disorder by combining psychopharmacology and psychotherapy. Integration of dynamic simulation with hypermedia and artificial intelligence has been able to point out behavioral details as tolerance, sensitization and level of addiction to drugs of abuse and so on, turned into a potentially useful tool in the development of teaching activities on several ways, such as education as well clinical skills, in which it could assist patients, families and health care to improve and test their knowledge and skills about different faces supported by drugs dependency. Those features are currently under investigation.

  11. The Guns-For-Drugs Trade: Implications for U.S. Foreign Policy

    Science.gov (United States)

    1991-12-01

    example of this are the two gangs that originated 20 years ago in the Los Angeles ghettos, the Bloods and the Crips . Their operations have expanded from...ELEMENTS 32 C. TERRORISTS. GUERRILLAS AND FREEDOM FIGHTERS 37 D. MERCENARIES 40 E. DOMESTIC GANGS 46 VI. PROBLEMS IN COMBATTING THE GUNS-FOR-DRUGS TRADE 48...availability of firearms. Gangs are becoming increasingly involved in narcotics trafficking which provides them the funds necessary to purchase more guns

  12. Implications of neuroscience Psychoactive drugs and identity: between history and culture

    Directory of Open Access Journals (Sweden)

    Lydia Feito Grande

    2016-02-01

    Full Text Available Neuroscientifical advances open the possibility to modify capacities in human beings, aimed to enhance them. An example is neurodrugs. Altering memory, attention or mood can make a difference in personal identity. This question about identity is analyzed and its implications on modification of human nature. This raises again the nature/culture debate, also from the contemporary neuroscience. The conclusion is that dynamism in human narrative identity is the result of an interaction between nature and culture.

  13. In vitro susceptibility of nematophagous fungi to antiparasitic drugs: interactions and implications for biological control

    Directory of Open Access Journals (Sweden)

    J. N. Vieira

    Full Text Available Abstract The fast anthelmintic resistance development has shown a limited efficiency in the control of animal’s endoparasitosis and has promoted research using alternative control methods. The use of chemicals in animal anthelmintic treatment, in association with nematophagous fungi used for biological control, is a strategy that has proven to be effective in reducing the nematode population density in farm animals. This study aims to verify the in vitro susceptibility of the nematophagous fungi Arthrobotrys oligospora, Duddingtonia flagrans and Paecilomyces lilacinus against the antiparasitic drugs albendazole, thiabendazole, ivermectin, levamisole and closantel by using the Minimum Inhibitory Concentration (MIC. MICs ranged between 4.0 and 0.031 µg/mL for albendazole, thiabendazole and ivermectin, between 0.937 and 0.117 µg/mL for levamisole, and between 0.625 and 0.034 µg/mL for closantel. The results showed that all antiparasitic drugs had an in vitro inhibitory effect on nematophagous fungi, which could compromise their action as agents of biological control. D. flagrans was the most susceptible species to all drugs.

  14. Cardiac Arrhythmias in Patients with Chronic Kidney Disease: Implications of Renal Failure for Antiarrhythmic Drug Therapy.

    Science.gov (United States)

    Potpara, Tatjana S; Jokic, Vera; Dagres, Nikolaos; Marin, Francisco; Prostran, Milica S; Blomstrom-Lundqvist, Carina; Lip, Gregory Y H

    2016-01-01

    The kidney has numerous complex interactions with the heart, including shared risk factors (e.g., hypertension, dyslipidemia, etc.) and mutual amplification of morbidity and mortality. Both cardiovascular diseases and chronic kidney disease (CKD) may cause various alterations in cardiovascular system, metabolic homeostasis and autonomic nervous system that may facilitate the occurrence of cardiac arrhythmias. Also, pre-existent or incident cardiac arrhythmias such as atrial fibrillation (AF) may accelerate the progression of CKD. Patients with CKD may experience various cardiac rhythm disturbances including sudden cardiac death. Contemporary management of cardiac arrhythmias includes the use of antiarrhythmic drugs (AADs), catheter ablation and cardiac implantable electronic devices (CIEDs). Importantly, AADs are not used only as the principal treatment strategy, but also as an adjunct therapy in combination with CIEDs, to facilitate their effects or to minimize inappropriate device activation in selected patients. Along with their principal antiarrhythmic effect, AADs may also induce cardiac arrhythmias and the risk for such proarrhythmic effect(s) is particularly increased in patients with reduced left ventricular systolic function or in the setting of electrolyte imbalance. Moreover, CKD itself can induce profound alterations in the pharmacokinetics and pharmacodynamics of many drugs including AADs, thus facilitating the drug accumulation and increased exposure. Hence, the use of AADs in patients with CKD may be challenging. In this review article, we provide an overview of the characteristics of arrhythmogenesis in patients with CKD with special emphasis on the complexity of pharmacokinetics and risk for proarrhythmias when using AADs in patients with cardiac arrhythmias and CKD.

  15. 77 FR 9946 - Draft Guidance for Industry on Drug Interaction Studies-Study Design, Data Analysis, Implications...

    Science.gov (United States)

    2012-02-21

    ... in vivo studies of drug metabolism, drug transport, and drug-drug, or drug-therapeutic protein... metabolism and/or drug transport abruptly in individuals who previously had been receiving and tolerating a particular dose of a drug. Such an abrupt alteration in metabolism or transport can change the known safety...

  16. Characteristics of drug users who witness many overdoses: implications for overdose prevention.

    Science.gov (United States)

    Bohnert, Amy S B; Tracy, Melissa; Galea, Sandro

    2012-01-01

    Programs to improve response of drug users when witnessing an overdose can reduce overdose mortality. Characteristics of drug users may be associated with the number of overdoses ever witnessed. This information could inform overdose prevention programs. Participants in New York City, who were age 18 and older with heroin and/or cocaine use in the past two months, were administered structured interviews (n=1184). Survey topics included overdose response, drug use behavior, treatment history, and demographic information. In a multivariable negative binomial regression model, those persons who were male (IRR [Incidence Rate Ratio]=1.7, CI [95% Confidence Interval]=1.4,2.2), had experienced homelessness (IRR=1.9, CI=1.4,2.6), had used heroin (IRR=2.0, CI=1.3,3.2), had overdosed themselves (IRR=1.9, CI=1.6,2.4), or had attended Narcotics Anonymous (IRR=1.3, CI=1.1,1.6) witnessed a greater count of overdoses in their lifetime. Those persons who have witnessed more overdoses were less likely to have sought medical assistance (OR [Odds Ratio]=0.7) and more likely to report counter-productive or ineffective actions (ORs between 1.9 and 2.4) at the last overdose they witnessed compared to persons who had only ever witnessed one or two overdoses. Persons at high risk for overdose are likely to witness more overdoses. Persons who had witnessed more overdoses were more likely to report taking ineffective action at the last overdose witnessed. Individuals who have witnessed many overdoses are likely key targets of overdose response training. Published by Elsevier Ireland Ltd.

  17. Context-sensitive network-based disease genetics prediction and its implications in drug discovery.

    Science.gov (United States)

    Chen, Yang; Xu, Rong

    2017-04-01

    Disease phenotype networks play an important role in computational approaches to identifying new disease-gene associations. Current disease phenotype networks often model disease relationships based on pairwise similarities, therefore ignore the specific context on how two diseases are connected. In this study, we propose a new strategy to model disease associations using context-sensitive networks (CSNs). We developed a CSN-based phenome-driven approach for disease genetics prediction, and investigated the translational potential of the predicted genes in drug discovery. We constructed CSNs by directly connecting diseases with associated phenotypes. Here, we constructed two CSNs using different data sources; the two networks contain 26 790 and 13 822 nodes respectively. We integrated the CSNs with a genetic functional relationship network and predicted disease genes using a network-based ranking algorithm. For comparison, we built Similarity-Based disease Networks (SBN) using the same disease phenotype data. In a de novo cross validation for 3324 diseases, the CSN-based approach significantly increased the average rank from top 12.6 to top 8.8% for all tested genes comparing with the SBN-based approach ( pdisease using CSNs, and demonstrated that the top-ranked genes are highly relevant to PD pathologenesis. We pin-pointed a top-ranked drug target gene for PD, and found its association with neurodegeneration supported by literature. In summary, CSNs lead to significantly improve the disease genetics prediction comparing with SBNs and provide leads for potential drug targets. nlp.case.edu/public/data/. rxx@case.edu.

  18. Public health implications of contamination of Franc CFA (XAF) circulating in Buea (Cameroon) with drug resistant pathogens.

    Science.gov (United States)

    Akoachere, Jane-Francis Tatah Kihla; Gaelle, Nana; Dilonga, Henry Meriki; Nkuo-Akenji, Theresa K

    2014-01-08

    Studies in different parts of the world have implicated money as a vehicle for transmission of pathogens. Such information which is necessary to facilitate infection control strategies is lacking in many sub-Saharan countries including Cameroon. This study analyzed the Franc de la Communauté Financiere d'Afrique (Franc CFA), the currency used in Cameroon and other countries in the Central African sub-region, as a potential vehicle for transmission of pathogenic bacteria and fungi, particularly drug-resistant strains, to generate findings which could create awareness on currency contamination and serve as a guide when formulating health policies on currency. Two hundred and thirteen currency samples representing various denominations of notes and coins randomly collected from diverse sources in Buea, Cameroon were analyzed for bacteria and fungi. The sensitivity of bacterial isolates to antibiotics was tested using the disc diffusion method. The relationship between contamination and physical state, source or denomination of currency was assessed using the χ2 test. All statistics were discussed at 0.05 significance level. Two hundred (93.9%) samples were contaminated with notes (96.6%) showing higher contamination than coins (88.2%). Uncirculated (mint) samples showed no contamination. There was a significant difference (PCFA franc circulating in Buea could serve as a vehicle for transmission of drug resistant pathogenic or potential organisms and contamination could be due to currency usage and handling as mint notes were not contaminated. Hygiene practices during or after handling currency is greatly encouraged to prevent infection.

  19. Thermochemical Properties of Hydrophilic Polymers from Cashew and Khaya Exudates and Their Implications on Drug Delivery

    Directory of Open Access Journals (Sweden)

    Emmanuel O. Olorunsola

    2016-01-01

    Full Text Available Characterization of a polymer is essential for determining its suitability for a particular purpose. Thermochemical properties of cashew gum (CSG extracted from exudates of Anacardium occidentale L. and khaya gum (KYG extracted from exudates of Khaya senegalensis were determined and compared with those of acacia gum BP (ACG. The polymers were subjected to different thermal and chemical analyses. Exudates of CSG contained higher amount of hydrophilic polymer. The pH of 2% w/v gum dispersions was in the order KYG < CSG < ACG. Calcium was the predominant ion in CSG while potassium was predominant in KYG. The FTIR spectra of CSG and KYG were similar and slightly different from that of ACG. Acacia and khaya gums exhibited the same thermal behaviour which is different from that of CSG. X-ray diffraction revealed that the three gums are the same type of polymer, the major difference being the concentration of metal ions. This work suggests the application of cashew gum for formulation of basic and oxidizable drugs while using khaya gum for acidic drugs.

  20. Thermochemical Properties of Hydrophilic Polymers from Cashew and Khaya Exudates and Their Implications on Drug Delivery

    Science.gov (United States)

    Bhatia, Partap G.; Tytler, Babajide A.; Adikwu, Michael U.

    2016-01-01

    Characterization of a polymer is essential for determining its suitability for a particular purpose. Thermochemical properties of cashew gum (CSG) extracted from exudates of Anacardium occidentale L. and khaya gum (KYG) extracted from exudates of Khaya senegalensis were determined and compared with those of acacia gum BP (ACG). The polymers were subjected to different thermal and chemical analyses. Exudates of CSG contained higher amount of hydrophilic polymer. The pH of 2% w/v gum dispersions was in the order KYG < CSG < ACG. Calcium was the predominant ion in CSG while potassium was predominant in KYG. The FTIR spectra of CSG and KYG were similar and slightly different from that of ACG. Acacia and khaya gums exhibited the same thermal behaviour which is different from that of CSG. X-ray diffraction revealed that the three gums are the same type of polymer, the major difference being the concentration of metal ions. This work suggests the application of cashew gum for formulation of basic and oxidizable drugs while using khaya gum for acidic drugs. PMID:27990303

  1. Emerging concepts on drug resistance in bladder cancer: Implications for future strategies.

    Science.gov (United States)

    Massari, Francesco; Santoni, Matteo; Ciccarese, Chiara; Brunelli, Matteo; Conti, Alessandro; Santini, Daniele; Montironi, Rodolfo; Cascinu, Stefano; Tortora, Giampaolo

    2015-10-01

    The combination chemotherapies with methotrexate plus vinblastine, doxorubicin and cisplatin (MVAC or CMV regimens) or gemcitabine plus cisplatin represent the standard as first-line therapy for patients with metastatic urothelial cancer. In Europe, vinflunine is an option for second-line therapy for patients progressed during first-line or perioperative platinum-containing regimen. Alternative regimens containing taxanes and/or gemcitabine may be valuated case by case. Furthermore, carboplatin should be considered in patients unfit for cisplatin both in the first and second-line setting. Based on these findings, a better comprehension of the mechanisms underlying the development of drug resistance in patients with bladder cancer will represent a major step forward in optimizing patients' outcome. This article reviews the current knowledge of the mechanisms and emerging strategies to overcome resistance in patients with advanced urothelial cancer.

  2. Implications of promiscuous Pim-1 kinase fragment inhibitor hydrophobic interactions for fragment-based drug design.

    Science.gov (United States)

    Good, Andrew C; Liu, Jinyu; Hirth, Bradford; Asmussen, Gary; Xiang, Yibin; Biemann, Hans-Peter; Bishop, Kimberly A; Fremgen, Trisha; Fitzgerald, Maria; Gladysheva, Tatiana; Jain, Annuradha; Jancsics, Katherine; Metz, Markus; Papoulis, Andrew; Skerlj, Renato; Stepp, J David; Wei, Ronnie R

    2012-03-22

    We have studied the subtleties of fragment docking and binding using data generated in a Pim-1 kinase inhibitor program. Crystallographic and docking data analyses have been undertaken using inhibitor complexes derived from an in-house surface plasmon resonance (SPR) fragment screen, a virtual needle screen, and a de novo designed fragment inhibitor hybrid. These investigations highlight that fragments that do not fill their binding pocket can exhibit promiscuous hydrophobic interactions due to the lack of steric constraints imposed on them by the boundaries of said pocket. As a result, docking modes that disagree with an observed crystal structure but maintain key crystallographically observed hydrogen bonds still have potential value in ligand design and optimization. This observation runs counter to the lore in fragment-based drug design that all fragment elaboration must be based on the parent crystal structure alone.

  3. Important biology events and pathways in Brucella infection and implications for novel antibiotic drug targets.

    Science.gov (United States)

    Gao, Guangjun; Xu, Jie

    2013-01-01

    Brucellosis caused by Brucella spp. is a common zoonosis in many parts of the world. Humans are infected through contact with infected animals or their dirty products. Many mechanisms are needed for this successful infection, although the mechanisms are still unclear. Host immune response and some signaling molecules play an important role in the infection event. Bacterial pathogens operate by attacking crucial intracellular pathways or some important molecules in each of these pathways for survival in their hosts. The crucial components (molecules) of immunity or pathway play a critical role in the whole process of Brucella infection. Here we summarize the findings of the Brucella-host interactions' immune system and signaling molecular cascades involved in the TLR-initiated immune response to Brucella spp. infection. The paper serves to deepen our understanding of this complex process and to provide some clues regarding the discovery of drug targets for prevention and control.

  4. Structure and dynamics of the insulin receptor: implications for receptor activation and drug discovery.

    Science.gov (United States)

    Ye, Libin; Maji, Suvrajit; Sanghera, Narinder; Gopalasingam, Piraveen; Gorbunov, Evgeniy; Tarasov, Sergey; Epstein, Oleg; Klein-Seetharaman, Judith

    2017-07-01

    Recently, major progress has been made in uncovering the mechanisms of how insulin engages its receptor and modulates downstream signal transduction. Here, we present in detail the current structural knowledge surrounding the individual components of the complex, binding sites, and dynamics during the activation process. A novel kinase triggering mechanism, the 'bow-arrow model', is proposed based on current knowledge and computational simulations of this system, in which insulin, after its initial interaction with binding site 1, engages with site 2 between the fibronectin type III (FnIII)-1 and -2 domains, which changes the conformation of FnIII-3 and eventually translates into structural changes across the membrane. This model provides a new perspective on the process of insulin binding to its receptor and, thus, could lead to future novel drug discovery efforts. Copyright © 2017 Elsevier Ltd. All rights reserved.

  5. A systematic review of reference pricing: implications for US prescription drug spending.

    Science.gov (United States)

    Lee, Joy Li-Yueh; Fischer, Micahel A; Shrank, William H; Polinski, Jennifer M; Choudhry, Niteesh K

    2012-11-01

    Given rising pharmaceutical expenditures and the widespread use of reference pricing as a costcontainment instrument abroad, we systematically reviewed the evidence evaluating reference pricing policies. We performed a structured electronic search of peer-reviewed journals for studies published before that reported on the effects of reference pricing policies on medication use, payer and patient spending, and resource consumption. Our search yielded 16 studies describing 9 reference-pricing policies from 6 countries. Reference-pricing policies led to decreases in drug prices and increases in utilization of targeted medications, while also reducing payer and patient expenditures. In addition, these policies did not lead to increased use of medical services, such as physician office visits and hospitalization. These results suggest that reference pricing may be an attractive policy strategy for the US healthcare system.

  6. Acute severe poisoning in Spain: clinical outcome related to the implicated drugs.

    Science.gov (United States)

    Frati, M E; Marruecos, L; Porta, M; Martín, M L; Laporte, J R

    1983-10-01

    The 91 patients over the age of 10 (57 women and 32 men) with severe self-poisoning admitted to the ICU of a general hospital in Barcelona during the period 1974-1980 have been retrospectively studied. Previous suicidal attempts have been identified among 32 patients; 26 patients presented a history of personality disorders, and 19 had a neurological disease, a chronic physical illness, or a history of alcoholism. Sedative-hypnotic drugs were involved in about half the number of cases, and one fifth of total cases were due to tricyclic antidepressants and phenothiazines. Paracetamol was only involved in 2 cases, and heroin in another 2 cases. Many of the most severe morbidity manifestations were related to overdoses by intermediate-acting barbiturates. Two out of a total of 5 deaths were related to butalbitone overdose. Butalbitone had been ingested as a fixed-dose combination containing butalbitone, propyphenazone, and caffeine, which is freely dispensed as an analgesic in Spain.

  7. A Case of SAPHO Syndrome with Endodontic Implications and Treatment with Biologic Drugs.

    Science.gov (United States)

    Cotti, Elisabetta; Careddu, Roberto; Schirru, Elia; Marongiu, Silvia; Barca, Maria Pina; Manconi, Paolo Emilio; Mercuro, Giuseppe

    2015-09-01

    SAPHO syndrome (SS) is an autoinflammatory disease characterized by synovitis, acne, pustulosis, hyperostosis, and osteitis. Among the sites affected by the osteoarticular manifestations of SS are the anterior chest wall and the mandible. The etiology of SS is still unknown; theories advocate a genetic predisposition and an infectious cause in association with disorders of the immune system. We report a case of SS in which there was the involvement of the mandible with a lesion of endodontic origin. A 44-year-old white woman diagnosed with SS at the university hospital was referred to the Department of Conservative Dentistry and Endodontics for a consultation. She reported spontaneous pain localized to the periapical area of tooth #19 with a history of multiple restorative and endodontic treatments. It was diagnosed as a previously treated tooth with symptomatic apical periodontitis (AP) at the time of the endodontic evaluation. A second retreatment was then performed in 1 appointment under local anesthesia. During retreatment, a separated instrument and a ledge were found in the mesiobuccal canal, and attempts to bypass it were not successful; the canal was then obturated to the reachable length. Within the same month, the patient was also administered an anti-tumor necrosis factor alpha biologic medication in association with a disease-modifying antirheumatic drugs for the treatment of SS. Within 3 months, the overall therapy had led to a marked improvement of the systemic and mandibular symptoms, and a periapical radiograph showed almost complete healing of the lesion. Medical examinations have shown a total remission of signs and symptoms starting 6 months after the initiation of treatment. After 5 years, the disease is under control, and tooth #19 is symptom free and shows absence of AP. The endodontists need to be aware of the existence of SS and the possible effects of the use of disease-modifying antirheumatic drugs and biologic medications on the

  8. Anti-amyloid Aggregation Activity of Natural Compounds: Implications for Alzheimer's Drug Discovery.

    Science.gov (United States)

    Bu, Xian-Le; Rao, Praveen P N; Wang, Yan-Jiang

    2016-08-01

    Several plant-derived natural compounds are known to exhibit anti-amyloid aggregation activity which makes them attractive as potential therapies to treat Alzheimer's disease. The mechanisms of their anti-amyloid activity are not well known. In this regard, many natural compounds are known to exhibit direct binding to various amyloid species including oligomers and fibrils, which in turn can lead to conformational change in the beta-sheet assembly to form nontoxic aggregates. This review discusses the mechanism of anti-amyloid activity of 16 natural compounds and gives structural details on their direct binding interactions with amyloid aggregates. Our computational investigations show that the physicochemical properties of natural products do fit Lipinski's criteria and that catechol and catechol-type moieties present in natural compounds act as lysine site-specific inhibitors of amyloid aggregation. Based on these observations, we propose a structural template to design novel small molecules containing site-specific ring scaffolds, planar aromatic and nonaromatic linkers with suitably substituted hydrogen bond acceptors and donors. These studies will have significant implications in the design and development of novel amyloid aggregation inhibitors with superior metabolic stability and blood-brain barrier penetration as potential agents to treat Alzheimer's disease.

  9. Role of aromatic rings in the molecular recognition of aminoglycoside antibiotics: implications for drug design.

    Science.gov (United States)

    Vacas, Tatiana; Corzana, Francisco; Jiménez-Osés, Gonzalo; González, Carlos; Gómez, Ana M; Bastida, Agatha; Revuelta, Julia; Asensio, Juan Luis

    2010-09-01

    Aminoglycoside antibiotics participate in a large variety of binding processes involving both RNA and proteins. The description, in recent years, of several clinically relevant aminoglycoside/receptor complexes has greatly stimulated the structural-based design of new bioactive derivatives. Unfortunately, design efforts have frequently met with limited success, reflecting our incomplete understanding of the molecular determinants for the antibiotic recognition. Intriguingly, aromatic rings of the protein/RNA receptors seem to be key actors in this process. Indeed, close inspection of the structural information available reveals that they are frequently involved in CH/pi stacking interactions with sugar/aminocyclitol rings of the antibiotic. While the interaction between neutral carbohydrates and aromatic rings has been studied in detail during past decade, little is known about these contacts when they involve densely charged glycosides. Herein we report a detailed experimental and theoretical analysis of the role played by CH/pi stacking interactions in the molecular recognition of aminoglycosides. Our study aims to determine the influence that the antibiotic polycationic character has on the stability, preferred geometry, and dynamics of these particular contacts. With this purpose, different aminoglycoside/aromatic complexes have been selected as model systems. They varied from simple bimolecular interactions to the more stable intramolecular CH/pi contacts present in designed derivatives. The obtained results highlight the key role played by electrostatic forces and the desolvation of charged groups in the molecular recognition of polycationic glycosides and have clear implications for the design of improved antibiotics.

  10. Regulation of tubulin expression by micro-RNAs: implications for drug resistance.

    Science.gov (United States)

    Lobert, Sharon; Graichen, Mary E

    2013-01-01

    In this chapter, we provide an overview of methods for studying micro-RNA regulation of tubulin isotypes. In clinical studies, β-tubulin isotypes were found to be biomarkers for tumor formation. In addition, because changes in the levels of specific β-tubulin isotypes alter the stability of microtubules in mitotic spindles in vitro, it has been hypothesized that changes in microtubule protein levels could contribute to chemotherapy resistance. Over the past 15 years, micro-RNAs have been shown to target mRNAs in signaling pathways involved in tumor suppression, as well as tumorigenesis. Investigating micro-RNA regulation of tubulin isotypes will shed light on the mechanisms underlying the processes that implicate tubulin isotypes as biomarkers for aggressive tumors or chemotherapy resistance. The methods discussed in this chapter include the use of micro-RNA superarrays, next-generation sequencing, real-time PCR experiments, upregulation of micro-RNAs, and immunoprecipitation of RNA-induced silencing complex. We will show examples of data collected using these methods and how these data contribute to understanding paclitaxel resistance.

  11. Medicine possession ratio as proxy for adherence to antiepileptic drugs: prevalence, associations, and cost implications

    Directory of Open Access Journals (Sweden)

    Jacobs K

    2016-04-01

    Full Text Available Karen Jacobs,1 Marlene Julyan,2 Martie S Lubbe,1 Johanita R Burger,1 Marike Cockeran1 1Medicine Usage in South Africa, Faculty of Health Sciences, 2Clinical Pharmacy, School of Pharmacy, North-West University (Potchefstroom Campus, Potchefstroom, South Africa Objective: To determine the adherence status to antiepileptic drugs (AEDs among epilepsy patients; to observe the association between adherence status and age, sex, active ingredient prescribed, treatment period, and number of comorbidities; and to determine the effect of nonadherence on direct medicine treatment cost of AEDs. Methods: A retrospective study analyzing medicine claims data obtained from a South African pharmaceutical benefit management company was performed. Patients of all ages (N=19,168, who received more than one prescription for an AED, were observed from 2008 to 2013. The modified medicine possession ratio (MPRm was used as proxy to determine the adherence status to AED treatment. The MPRm was considered acceptable (adherent if the calculated value was ≥80%, but ≤110%, whereas an MPRm of <80% (unacceptably low or >110% (unacceptably high was considered nonadherent. Direct medicine treatment cost was calculated by summing the medical scheme contribution and patient co-payment associated with each AED prescription. Results: Only 55% of AEDs prescribed to 19,168 patients during the study period had an acceptable MPRm. MPRm categories depended on the treatment period (P>0.0001; Cramer’s V=0.208 but were independent of sex (P<0.182; Cramer’s V=0.009. Age group (P<0.0001; Cramer’s V=0.067, active ingredient (P<0.0001; Cramer’s V=0.071, and number of comorbidities (P<0.0001; Cramer’s V=0.050 were statistically but not practically significantly associated with MPRm categories. AEDs with an unacceptably high MPRm contributed to 3.74% (US$736,376.23 of the total direct cost of all AEDs included in the study, whereas those with an unacceptably low MPRm amounted to US

  12. Inhibition of carboxypeptidase A by D-penicillamine: mechanism and implications for drug design.

    Science.gov (United States)

    Chong, C R; Auld, D S

    2000-06-27

    Zinc metalloprotease inhibitors are usually designed to inactivate the enzyme by forming a stable ternary complex with the enzyme and active-site zinc. D-Cysteine inhibits carboxypeptidase, ZnCPD, by forming such a complex, with a K(i) of 2.3 microM. In contrast, the antiarthritis drug D-penicillamine, D-PEN, which differs from D-Cys only by the presence of two methyl groups on the beta-carbon, inhibits ZnCPD by promoting the release of the active-site zinc. We have given the name catalytic chelator to such inhibitors. Inhibition is a two-step process characterized by formation of a complex with the enzyme (K(i(initial)) = 1.2 mM) followed by release of the active-site zinc at rates up to 420-fold faster than the spontaneous release. The initial rate of substrate hydrolysis at completion of the second step also depends on D-PEN concentration, reflecting formation of a thermodynamic equilibrium governed by the stability constants of chelator and apocarboxypeptidase for zinc (K(i(final)) = 0.25 mM). The interaction of D-PEN and D-Cys with the active-site metal has been examined by replacing the active-site zinc by a chromophoric cobalt atom. Both inhibitors perturb the d-d transitions of CoCPD in the 500-600 nm region within milliseconds of mixing but only the CoCPD.D-Cys complex displays a strong S --> Co(II) charge-transfer band at 340 nm indicative of a metal-sulfur bond. While the D-Cys complex is stable, the CoCPD.D-PEN complex breaks down to apoenzyme and Co(D-PEN)(2) with a half-life of 0.5 s. D-PEN is the first drug found to inhibit a metalloprotease by increasing the dissociation rate constant of the active-site metal. The ability of D-PEN to catalyze metal removal from carboxypeptidase A and other zinc proteases suggests a possible mechanism of action in arthritis and Wilson's disease and may also underlie complications associated with its clinical use.

  13. Problems associated with substandard and counterfeit drugs in developing countries: a review article on global implications of counterfeit drugs in the era of antiretroviral (ARVs) drugs in a free market economy.

    Science.gov (United States)

    Nsimba, Stephen E D

    2008-12-01

    To review the global implications associated with the use of substandard and or counterfeit drugs in developing and may be developed countries. The focus of this review is particularly on antiretroviral (ARVs), antimalarials and other drugs. Review of various literatures through Pub-Med, Medline, Google and Internet search to retrieve and download published materials was done by the author of this review paper. When patients receive a counterfeit medicines, they are subjected to multiple risks. They often suffer more than just an inconvenience; as they become victims of fraud medicines and are all put at risk of adverse effects from unprescribed medicines or substandard ingredients. Additionally, patients may lose confidence in health care professionals including their physician and pharmacist, and potentially modern medicine or the pharmaceutical industry in general. Counterfeit or substandard (poor quality) drugs pose threats to society; not only to the individual in terms of the health side effects experienced, but also to the public in terms of trade relations, economic implications, and the effects on global pandemics. It is vital for suppliers, providers, and patients to be aware of current trends in counterfeiting in order to best prepare for encounters with suspicious products. Furthermore, this is an issue that needs to be continually dealt with on national and international policy levels. Developing countries should try their level best to establish good laboratories for monitoring and checking quality of all pharmaceuticals manufactured locally and those imported or donated to these countries. The Ministries of Health and all stakeholders involved in this issue must ensure that all drugs meet the set or established international standards and national standards. Failure to do so will be to misuse the hard earned forex that is normally borrowed from banks for the procurement and distribution of drugs to its people. Indeed sub-standard medications do more

  14. Developments in harmine pharmacology--implications for ayahuasca use and drug-dependence treatment.

    Science.gov (United States)

    Brierley, Daniel I; Davidson, Colin

    2012-12-03

    Ayahuasca is a hallucinogenic botanical mixture originating in the Amazon area where it is used ritually, but is now being taken globally. The 2 main constituents of ayahuasca are N,N-dimethyltryptamine (DMT), a hallucinogen, and harmine, a monoamine oxidase inhibitor (MAOI) which attenuates the breakdown of DMT, which would otherwise be broken down very quickly after oral consumption. Recent developments in ayahuasca use include the sale of these compounds on the internet and the substitution of related botanical (anahuasca) or synthetic (pharmahuasca) compounds to achieve the same desired hallucinogenic effects. One intriguing result of ayahuasca use appears to be improved mental health and a reduction in recidivism to alternate (alcohol, cocaine) drug use. In this review we discuss the pharmacology of ayahuasca, with a focus on harmine, and suggest pharmacological mechanisms for the putative reduction in recidivism to alcohol and cocaine misuse. These pharmacological mechanisms include MAOI, effects at 5-HT(2A) and imidazoline receptors and inhibition of dual-specificity tyrosine-phosphorylation regulated kinase 1A (DYRK1A) and the dopamine transporter. We also speculate on the therapeutic potential of harmine in other CNS conditions. Copyright © 2012 Elsevier Inc. All rights reserved.

  15. Impairment of Serotonergic Transmission by the Antiparkinsonian Drug L-DOPA: Mechanisms and Clinical Implications

    Directory of Open Access Journals (Sweden)

    Cristina Miguelez

    2017-09-01

    Full Text Available The link between the anti-Parkinsonian drug L-3,4-dihydroxyphenylalanine (L-DOPA and the serotonergic (5-HT system has been long established and has received increased attention during the last decade. Most studies have focused on the fact that L-DOPA can be transformed into dopamine (DA and released from 5-HT terminals, which is especially important for the management of L-DOPA-induced dyskinesia. In patients, treatment using L-DOPA also impacts 5-HT neurotransmission; however, few studies have investigated the mechanisms of this effect. The purpose of this review is to summarize the electrophysiological and neurochemical data concerning the effects of L-DOPA on 5-HT cell function. This review will argue that L-DOPA disrupts the link between the electrical activity of 5-HT neurons and 5-HT release as well as that between 5-HT release and extracellular 5-HT levels. These effects are caused by the actions of L-DOPA and DA in 5-HT neurons, which affect 5-HT neurotransmission from the biosynthesis of 5-HT to the impairment of the 5-HT transporter. The interaction between L-DOPA and 5-HT transmission is especially relevant in those Parkinson’s disease (PD patients that suffer dyskinesia, comorbid anxiety or depression, since the efficacy of antidepressants or 5-HT compounds may be affected.

  16. Prevalence of Anemia and Risk of Adverse Bleeding Effect of Drugs: Implication for Therapy

    Science.gov (United States)

    Uba Nwose, Ezekiel

    2012-01-01

    This study aimed to evaluate the progress in reduction of prevalence of anemia in rural Australia. It also investigates the prevalence of hypoviscosity in anaemia with a view to determine the fraction of anaemic patients at risk of drug-inducible exacerbation of anemia. Archived clinical pathology data (N = 130, 354) for the period of 1999 to 2008 were utilized. The prevalence of anemia and hypoviscosity was evaluated by working out (i) the number that fell within anemia definition as a percentage of the population and (ii) the number that fell within hypoviscosity definition as a percentage of anemic patients. The prevalence in anemic diabetes and dyslipidaemia was further determined. There was progressive reduction in anemia from 6.1% to 3.2% over the ten years period. Prevalence of anemia is statistically significantly higher in males than in females (P < 0.0001), but protein level is lower in anemic females than in anemic males (P < 0.01). The results further show that up to 75% of anemic patients may benefit from NSAID or salicylates. This paper highlights differences between genders. It suggests more concerted effort in men's health and speculates a new factor to investigate in women's health. PMID:22506109

  17. Recurrent Glioblastomas Reveal Molecular Subtypes Associated with Mechanistic Implications of Drug-Resistance.

    Directory of Open Access Journals (Sweden)

    So Mee Kwon

    Full Text Available Previously, transcriptomic profiling studies have shown distinct molecular subtypes of glioblastomas. It has also been suggested that the recurrence of glioblastomas could be achieved by transcriptomic reprograming of tumors, however, their characteristics are not yet fully understood. Here, to gain the mechanistic insights on the molecular phenotypes of recurrent glioblastomas, gene expression profiling was performed on the 43 cases of glioblastomas including 15 paired primary and recurrent cases. Unsupervised clustering analyses revealed two subtypes of G1 and G2, which were characterized by proliferation and neuron-like gene expression traits, respectively. While the primary tumors were classified as G1 subtype, the recurrent glioblastomas showed two distinct expression types. Compared to paired primary tumors, the recurrent tumors in G1 subtype did not show expression alteration. By contrast, the recurrent tumors in G2 subtype showed expression changes from proliferation type to neuron-like one. We also observed the expression of stemness-related genes in G1 recurrent tumors and the altered expression of DNA-repair genes (i.e., AURK, HOX, MGMT, and MSH6 in the G2 recurrent tumors, which might be responsible for the acquisition of drug resistance mechanism during tumor recurrence in a subtype-specific manner. We suggest that recurrent glioblastomas may choose two different strategies for transcriptomic reprograming to escape the chemotherapeutic treatment during tumor recurrence. Our results might be helpful to determine personalized therapeutic strategy against heterogeneous glioma recurrence.

  18. Quantitative analysis of receptor allosterism and its implication for drug discovery.

    Science.gov (United States)

    Zhang, Rumin; Kavana, Michael

    2015-07-01

    G protein-coupled receptors represent the largest class of druggable targets and are known to be modulated by both orthosteric agonists and positive/negative allosteric modulators (PAMs/NAMs). Proper experimental design and data analysis for the dose matrix between an agonist and PAM or NAM are critical to elucidate the key parameters for understanding molecular mechanism and structure-activity relationship (SAR) in drug discovery. The authors provide an overview and best practice recommendations on the quantitative analysis of receptor allosterism. The authors propose a simple classification system for receptor modulators on the basis of their efficacy and affinity modifiers. The authors also outline the optimal assay designs for both fixed dose screening and dose matrix study of receptor modulators. The authors recommend the global curve fitting approach to reliably yield system- and modulator-specific parameters for SAR ranking. Furthermore, the authors suggest that the uncertainty in maximal system response has insignificant impact on SAR ranking. The authors anticipate that systems pharmacology models integrating both binding kinetics and functional allosterism will be needed to address the inherent limitations of current allosterism models.

  19. Inactivation of indispensable bacterial proteins by early proteins of bacteriophages: implication in antibacterial drug discovery.

    Science.gov (United States)

    Sau, S; Chattoraj, P; Ganguly, T; Chanda, P K; Mandal, N C

    2008-06-01

    Bacteriophages utilize host bacterial cellular machineries for their own reproduction and completion of life cycles. The early proteins that phage synthesize immediately after the entry of their genomes into bacterial cells participate in inhibiting host macromolecular biosynthesis, initiating phage-specific replication and synthesizing late proteins. Inhibition of synthesis of host macromolecules that eventually leads to cell death is generally performed by the physical and/or chemical modification of indispensable host proteins by early proteins. Interestingly, most modified bacterial proteins were shown to take part actively in phage-specific transcription and replication. Research on phages in last nine decades has demonstrated such lethal early proteins that interact with or chemically modify indispensable host proteins. Among the host proteins inhibited by lethal phage proteins, several are not inhibited by any chemical inhibitor available today. Under the context of widespread dissemination of antibiotic-resistant strains of pathogenic bacteria in recent years, the information of lethal phage proteins and cognate host proteins could be extremely invaluable as they may lead to the identification of novel antibacterial compounds. In this review, we summarize the current knowledge about some early phage proteins, their cognate host proteins and their mechanism of action and also describe how the above interacting proteins had been exploited in antibacterial drug discovery.

  20. Rabbit Model of Human Gliomas: Implications for Intra-Arterial Drug Delivery

    Science.gov (United States)

    Qin, Huamin; Janowski, Miroslaw; Pearl, Monica S.; Malysz-Cymborska, Izabela; Li, Shen; Eberhart, Charles G.

    2017-01-01

    The prognosis for malignant brain tumors remains poor despite a combination of surgery, radiotherapy, and chemotherapy. This is partly due to the blood-brain barrier, a major obstacle that prevents therapeutic agents from effectively reaching the tumor. We have recently developed a method for precise and predictable opening of the blood-brain barrier via the intra-arterial administration of mannitol, a hyperosmolar agent, in a rabbit model, whose vascular anatomy facilitates the use of standard interventional neuroradiology techniques and devices. To date, however, no protocols are available that enable human glioma modeling in rabbits. In this article, we report on the xenotransplantation of a human glioblastoma (GBM-1) in adult New Zealand rabbits. We induced multi-drug immunosuppression (Mycophenolate Mofetil, Dexamethasone, Tacrolimus) and stereotactically implanted GBM-1 tumor cells into rabbit brains. The rabbits were followed for 42 days, monitored by MRI and body weight measurements, and underwent postmortem histopathological analysis. On MRI, brain tumors were identified on T2-weighted scans. On histopathology, tumors were detected with hematoxylin/eosin and their human origin was confirmed with immunohistochemistry against human-specific antigens. Our method for human glioma modeling in rabbits provides the foundation to test novel treatment strategies, including intra-arterial therapeutic agent delivery. PMID:28103265

  1. Substrate Binding Mode and its Implication on Drug Design for Botulinum Neurotoxin A

    Energy Technology Data Exchange (ETDEWEB)

    Kumaran, D.; Rawat, R; Ahmed, A; Swaminathan, S

    2008-01-01

    The seven antigenically distinct serotypes of Clostridium botulinum neurotoxins, the causative agents of botulism, block the neurotransmitter release by specifically cleaving one of the three SNARE proteins and induce flaccid paralysis. The Centers for Disease Control and Prevention (CDC) has declared them as Category A biowarfare agents. The most potent among them, botulinum neurotoxin type A (BoNT/A), cleaves its substrate synaptosome-associated protein of 25 kDa (SNAP-25). An efficient drug for botulism can be developed only with the knowledge of interactions between the substrate and enzyme at the active site. Here, we report the crystal structures of the catalytic domain of BoNT/A with its uncleavable SNAP-25 peptide 197QRATKM202 and its variant 197RRATKM202 to 1.5 A and 1.6 A, respectively. This is the first time the structure of an uncleavable substrate bound to an active botulinum neurotoxin is reported and it has helped in unequivocally defining S1 to S5? sites. These substrate peptides make interactions with the enzyme predominantly by the residues from 160, 200, 250 and 370 loops. Most notably, the amino nitrogen and carbonyl oxygen of P1 residue (Gln197) chelate the zinc ion and replace the nucleophilic water. The P1?-Arg198, occupies the S1? site formed by Arg363, Thr220, Asp370, Thr215, Ile161, Phe163 and Phe194. The S2? subsite is formed by Arg363, Asn368 and Asp370, while S3? subsite is formed by Tyr251, Leu256, Val258, Tyr366, Phe369 and Asn388. P4?-Lys201 makes hydrogen bond with Gln162. P5?-Met202 binds in the hydrophobic pocket formed by the residues from the 250 and 200 loop. Knowledge of interactions between the enzyme and substrate peptide from these complex structures should form the basis for design of potent inhibitors for this neurotoxin.

  2. Substrate binding mode and its implication on drug design for botulinum neurotoxin A.

    Directory of Open Access Journals (Sweden)

    Desigan Kumaran

    Full Text Available The seven antigenically distinct serotypes of Clostridium botulinum neurotoxins, the causative agents of botulism, block the neurotransmitter release by specifically cleaving one of the three SNARE proteins and induce flaccid paralysis. The Centers for Disease Control and Prevention (CDC has declared them as Category A biowarfare agents. The most potent among them, botulinum neurotoxin type A (BoNT/A, cleaves its substrate synaptosome-associated protein of 25 kDa (SNAP-25. An efficient drug for botulism can be developed only with the knowledge of interactions between the substrate and enzyme at the active site. Here, we report the crystal structures of the catalytic domain of BoNT/A with its uncleavable SNAP-25 peptide (197QRATKM(202 and its variant (197RRATKM(202 to 1.5 A and 1.6 A, respectively. This is the first time the structure of an uncleavable substrate bound to an active botulinum neurotoxin is reported and it has helped in unequivocally defining S1 to S5' sites. These substrate peptides make interactions with the enzyme predominantly by the residues from 160, 200, 250 and 370 loops. Most notably, the amino nitrogen and carbonyl oxygen of P1 residue (Gln197 chelate the zinc ion and replace the nucleophilic water. The P1'-Arg198, occupies the S1' site formed by Arg363, Thr220, Asp370, Thr215, Ile161, Phe163 and Phe194. The S2' subsite is formed by Arg363, Asn368 and Asp370, while S3' subsite is formed by Tyr251, Leu256, Val258, Tyr366, Phe369 and Asn388. P4'-Lys201 makes hydrogen bond with Gln162. P5'-Met202 binds in the hydrophobic pocket formed by the residues from the 250 and 200 loop. Knowledge of interactions between the enzyme and substrate peptide from these complex structures should form the basis for design of potent inhibitors for this neurotoxin.

  3. Inhibition of urease by bismuth(III): implications for the mechanism of action of bismuth drugs.

    Science.gov (United States)

    Zhang, Li; Mulrooney, Scott B; Leung, Andy F K; Zeng, Yibo; Ko, Ben B C; Hausinger, Robert P; Sun, Hongzhe

    2006-10-01

    Bismuth compounds are widely used for the treatment of peptic ulcers and Helicobacter pylori infections. It has been suggested that enzyme inhibition plays an important role in the antibacterial activity of bismuth towards this bacterium. Urease, an enzyme that converts urea into ammonia and carbonic acid, is crucial for colonization of the acidic environment of the stomach by H. pylori. Here, we show that three bismuth complexes exhibit distinct mechanisms of urease inhibition, with some differences dependent on the source of the enzyme. Bi(EDTA) and Bi(Cys)(3) are competitive inhibitors of jack bean urease with K(i) values of 1.74 +/- 0.14 and 1.84 +/- 0.15 mM, while the anti-ulcer drug, ranitidine bismuth citrate (RBC) is a non-competitive inhibitor with a K (i) value of 1.17 +/- 0.09 mM. A (13)C NMR study showed that Bi(Cys)(3) reacts with jack bean urease during a 30 min incubation, releasing free cysteines from the metal complex. Upon incubation with Bi(EDTA) and RBC, the number of accessible cysteine residues in the homohexameric plant enzyme decreased by 5.80 +/- 0.17 and 11.94 +/- 0.13, respectively, after 3 h of reaction with dithiobis(2-nitrobenzoic acid). Kinetic analysis showed that Bi(EDTA) is both a competitive inhibitor and a time-dependent inactivator of the recombinant Klebsiella aerogenes urease. The active C319A mutant of the bacterial enzyme displays a significantly reduced sensitivity toward inactivation by Bi(EDTA) compared with the wild-type enzyme, consistent with binding of Bi(3+) to the active site cysteine (Cys(319)) as the mechanism of enzyme inactivation.

  4. Unanticipated Effects of New Drug Availability on Antiretroviral Durability: Implications for Comparative Effectiveness Research.

    Science.gov (United States)

    Eaton, Ellen F; Tamhane, Ashutosh R; Burkholder, Greer A; Willig, James H; Saag, Michael S; Mugavero, Michael J

    2016-04-01

    Background.  Durability of antiretroviral (ARV) therapy is associated with improved human immunodeficiency virus (HIV) outcomes. Data on ARV regimen durability in recent years and clinical settings are lacking. Methods.  This retrospective follow-up study included treatment-naive HIV-infected patients initiating ARV therapy between January 2007 and December 2012 in a university-affiliated HIV clinic in the Southeastern United States. Outcome of interest was durability (time to discontinuation) of the initial regimen. Durability was evaluated using Kaplan-Meier survival analyses. Cox proportional hazard analyses was used to evaluate the association among durability and sociodemographic, clinical, and regimen-level factors. Results.  Overall, 546 patients were analyzed. Median durability of all regimens was 39.5 months (95% confidence interval, 34.1-44.4). Commonly prescribed regimens were emtricitabine and tenofovir with efavirenz (51%; median duration = 40.1 months) and with raltegravir (14%; 47.8 months). Overall, 67% of patients had an undetectable viral load at the time of regimen cessation. Discontinuation was less likely with an integrase strand transfer inhibitor (adjusted hazards ratio [aHR] = 0.35, P = .001) or protease inhibitor-based regimen (aHR = 0.45, P = .006) and more likely with a higher pill burden (aHR = 2.25, P = .003) and a later treatment era (aHR = 1.64, P new drug availability and provider preference. Medication durability must be interpreted carefully in the context of a dynamic treatment landscape.

  5. Cultural Identity Among Urban American Indian/Alaska Native Youth: Implications for Alcohol and Drug Use.

    Science.gov (United States)

    Brown, Ryan A; Dickerson, Daniel L; D'Amico, Elizabeth J

    2016-10-01

    American Indian / Alaska Native (AI/AN) youth exhibit high rates of alcohol and other drug (AOD) use, which is often linked to the social and cultural upheaval experienced by AI/ANs during the colonization of North America. Urban AI/AN youth may face unique challenges, including increased acculturative stress due to lower concentrations of AI/AN populations in urban areas. Few existing studies have explored cultural identity among urban AI/AN youth and its association with AOD use. This study used systematic qualitative methods with AI/AN communities in two urban areas within California to shed light on how urban AI/AN youth construct cultural identity and how this relates to AOD use and risk behaviors. We conducted 10 focus groups with a total of 70 youth, parents, providers, and Community Advisory Board members and used team-based structured thematic analysis in the Dedoose software platform. We identified 12 themes: intergenerational stressors, cultural disconnection, AI/AN identity as protective, pan-tribal identity, mixed racial-ethnic identity, rural vs. urban environments, the importance of AI/AN institutions, stereotypes and harassment, cultural pride, developmental trajectories, risks of being AI/AN, and mainstream culture clash. Overall, youth voiced curiosity about their AI/AN roots and expressed interest in deepening their involvement in cultural activities. Adults described the myriad ways in which involvement in cultural activities provides therapeutic benefits for AI/AN youth. Interventions that provide urban AI/AN youth with an opportunity to engage in cultural activities and connect with positive and healthy constructs in AI/AN culture may provide added impact to existing interventions.

  6. BR 04-2 CONCENTRATION-RESPONSE MODELING OF ANTIHYPERTENSIVE DRUGS - IMPLICATION IN CLINICAL DEVELOPMENT.

    Science.gov (United States)

    Yim, Dong-Seok

    2016-09-01

    In the early phase of clinical development of antihypertensive drugs, quantitative modeling to predict their dose-concentration-response relationship is important to plan future clinical development and finding optimal dosage regimen at marketing approval. Two cases of concentration-response models of antihypertensive are presented here.Case 1: Carvedilol is a α1- and nonselective β- adrenergic receptor antagonist currently used for the management of mild-to-moderate essential hypertension and congestive heart failure. The aim of this study was to perform a population pharmacokinetic-pharmacodynamic (PK-PD) model that describes PK and PD (systolic blood pressure (SBP) and diastolic blood pressure (DBP)) of both IR and SR formulations of carvedilol. For population PD modeling, the sequential PK-PD modeling approach (i.e., IPP approach) was used and the turnover model incorporating cosine functions for circadian rhythm was best described the SBP and DBP changes. In conclusion, the population PK-PD model adequately explained the observed data from two different formulations.Case 2: Fimasartan is a non-peptide angiotensin II receptor antagonist which selectively blocks the AT1 receptor. Population pharmacokinetic-pharmacodynamic (PK-PD) analysis of fimasartan was performed to evaluate the food effect on mechanistic PK-PD relationship, using data from a food interaction study in 24 healthy subjects. A two-compartment linear PK model with zero-order (fasted) or Weibull (fed with high fat diet) absorption best described the PK of fimasartan. Relative bioavailability decreased by 37% when the subjects were given high fat diet. The turnover PK-PD model combined with pre-defined cosine function for circadian rhythm described the BP changes measured within 24 hours after dosing better than the effect compartment or transduction models. To predict the influence of high fat diet on the blood pressure lowering effect of fimasartan in healthy subjects, we simulated the BP

  7. Drug histories and criminality of inmates of local jails in the United States (1978): implications for treatment and rehabilitation of the drug abuser in a jail setting.

    Science.gov (United States)

    Barton, W I

    1982-04-01

    A survey by the Department of Justice in 1978 of inmates of local jails in the United States found that 68% had ever used drugs like heroin, cocaine, marijuana, amphetamines, or barbiturates outside a treatment program, and without a doctor's prescription. Offenses for which relatively larger proportions of inmates reported drug use included robbery, burglary, auto theft, larceny, and drug offenses. During the month prior to jail, 44% of inmates reported using drugs. Some 21% of convicted inmates reported being under the influence of drugs at the time of an offense for which convicted. One-fourth of inmates reporting drug use had ever been enrolled in drug treatment. Treatment and rehabilitation of the drug abuser in a jail setting is discussed.

  8. A new proposal for drug conditioning with implications for drug addiction: the Pavlovian two-step from delay to trace conditioning.

    Science.gov (United States)

    Carey, Robert J; Carrera, Marinette Pinheiro; Damianopoulos, Ernest N

    2014-12-15

    Pavlovian conditioning of drug effects is generally acknowledged to be a critical factor in the development and persistence of drug addiction. In drug conditioning the focus has essentially been on one type of Pavlovian conditioning, namely, delay conditioning in which the CS and drug UCS overlap and are temporally contiguous. Another type of Pavlovian conditioning is trace-conditioning in which the CS terminates before the onset of the UCS. While trace conditioning has been extensively studied in conditioning studies using a punctual CS and a non-drug UCS, trace conditioning has not been considered as having a role in drug conditioning. In several recent reports we have conducted experiments in which we first established a contextual drug CS using a delay conditioning protocol and subsequently used this same CS in a trace drug conditioning protocol with the same or different drug treatment and showed that the CS could be strongly modified by trace conditioning. These observations take on importance in that it has been well established that delay and trace conditioning are mediated by different CNS systems. Delay conditioning is mediated by cerebellar mechanisms, conforming to the general idea of Pavlovian conditioning as a reflexive type of learning whereas trace conditioning involves the hippocampus and frontal cortex brain structures more commonly associated with voluntary behavior. In this proposal we suggest that the emergence of potent drug associations that motivate drug-seeking behavior and addiction are initiated by delay conditioning and subsequently amplified and linked to higher brain functions by trace conditioning.

  9. Thermodynamics of Highly Supersaturated Aqueous Solutions of Poorly Water-Soluble Drugs-Impact of a Second Drug on the Solution Phase Behavior and Implications for Combination Products.

    Science.gov (United States)

    Trasi, Niraj S; Taylor, Lynne S

    2015-08-01

    There is increasing interest in formulating combination products that contain two or more drugs. Furthermore, it is also common for different drug products to be taken simultaneously. This raises the possibility of interactions between different drugs that may impact formulation performance. For poorly water-soluble compounds, the supersaturation behavior may be a critical factor in determining the extent of oral absorption. The goal of the current study was to evaluate the maximum achievable supersaturation for several poorly water-soluble compounds alone, and in combination. Model compounds included ritonavir, lopinavir, paclitaxel, felodipine, and diclofenac. The "amorphous solubility" for the pure drugs was determined using different techniques and the change in this solubility was then measured in the presence of differing amounts of a second drug. The results showed that "amorphous solubility" of each component in aqueous solution is substantially decreased by the second component, as long as the two drugs are miscible in the amorphous state. A simple thermodynamic model could be used to predict the changes in solubility as a function of composition. This information is of great value when developing co-amorphous or other supersaturating formulations and should contribute to a broader understanding of drug-drug physicochemical interactions in in vitro assays as well as in the gastrointestinal tract.

  10. Treatment of Plasmodium chabaudi Parasites with Curcumin in Combination with Antimalarial Drugs: Drug Interactions and Implications on the Ubiquitin/Proteasome System

    Directory of Open Access Journals (Sweden)

    Zoraima Neto

    2013-01-01

    Full Text Available Antimalarial drug resistance remains a major obstacle in malaria control. Evidence from Southeast Asia shows that resistance to artemisinin combination therapy (ACT is inevitable. Ethnopharmacological studies have confirmed the efficacy of curcumin against Plasmodium spp. Drug interaction assays between curcumin/piperine/chloroquine and curcumin/piperine/artemisinin combinations and the potential of drug treatment to interfere with the ubiquitin proteasome system (UPS were analyzed. In vivo efficacy of curcumin was studied in BALB/c mice infected with Plasmodium chabaudi clones resistant to chloroquine and artemisinin, and drug interactions were analyzed by isobolograms. Subtherapeutic doses of curcumin, chloroquine, and artemisinin were administered to mice, and mRNA was collected following treatment for RT-PCR analysis of genes encoding deubiquitylating enzymes (DUBs. Curcumin was found be nontoxic in BALB/c mice. The combination of curcumin/chloroquine/piperine reduced parasitemia to 37% seven days after treatment versus the control group’s 65%, and an additive interaction was revealed. Curcumin/piperine/artemisinin combination did not show a favorable drug interaction in this murine model of malaria. Treatment of mice with subtherapeutic doses of the drugs resulted in a transient increase in genes encoding DUBs indicating UPS interference. If curcumin is to join the arsenal of available antimalarial drugs, future studies exploring suitable drug partners would be of interest.

  11. Antidepressants, antimicrobials or both? Gut microbiota dysbiosis in depression and possible implications of the antimicrobial effects of antidepressant drugs for antidepressant effectiveness.

    Science.gov (United States)

    Macedo, Danielle; Filho, Adriano José Maia Chaves; Soares de Sousa, Caren Nádia; Quevedo, João; Barichello, Tatiana; Júnior, Hélio Vitoriano Nobre; Freitas de Lucena, David

    2017-01-15

    The first drug repurposed for the treatment of depression was the tuberculostatic iproniazid. At present, drugs belonging to new classes of antidepressants still have antimicrobial effects. Dysbiosis of gut microbiota was implicated in the development or exacerbation of mental disorders, such as major depressive disorder (MDD). Based on the current interest in the gut-brain axis, the focus of this narrative review is to compile the available studies regarding the influences of gut microbiota in behavior and depression and to show the antimicrobial effect of antidepressant drugs. A discussion regarding the possible contribution of the antimicrobial effect of antidepressant drugs to its effectiveness/resistance is included. The search included relevant articles from PubMed, SciELO, LILACS, PsycINFO, and ISI Web of Knowledge. MDD is associated with changes in gut permeability and microbiota composition. In this respect, antidepressant drugs present antimicrobial effects that could also be related to the effectiveness of these drugs for MDD treatment. Conversely, some antimicrobials present antidepressant effects. Both antidepressants and antimicrobials present neuroprotective/antidepressant and antimicrobial effects. Further studies are needed to evaluate the participation of antimicrobial mechanisms of antidepressants in MDD treatment as well as to determine the contribution of this effect to antidepressant resistance. Copyright © 2016 Elsevier B.V. All rights reserved.

  12. Injection drug use and HIV/AIDS in China: Review of current situation, prevention and policy implications

    Directory of Open Access Journals (Sweden)

    Chen Huey T

    2006-02-01

    Full Text Available Abstract Illicit drug abuse and HIV/AIDS have increased rapidly in the past 10 to 20 years in China. This paper reviews drug abuse in China, the HIV/AIDS epidemic and its association with injection drug use (IDU, and Chinese policies on illicit drug abuse and prevention of HIV/AIDS based on published literature and unpublished official data. As a major drug trans-shipment country with source drugs from the "Golden Triangle" and "Gold Crescent" areas in Asia, China has also become an increasingly important drug consuming market. About half of China's 1.14 million documented drug users inject, and many share needles. IDU has contributed to 42% of cumulatively reported HIV/AIDS cases thus far. Drug trafficking is illegal in China and can lead to the death penalty. The public security departments adopt "zero tolerance" approach to drug use, which conflict with harm reduction policies of the public health departments. Past experience in China suggests that cracking down on drug smuggling and prohibiting drug use alone can not prevent or solve all illicit drug related problems in the era of globalization. In recent years, the central government has outlined a series of pragmatic policies to encourage harm reduction programs; meanwhile, some local governments have not fully mobilized to deal with drug abuse and HIV/AIDS problems seriously. Strengthening government leadership at both central and local levels; scaling up methadone substitution and needle exchange programs; making HIV voluntary counseling and testing available and affordable to both urban and rural drug users; and increasing utilization of outreach and nongovernmental organizations are offered as additional strategies to help cope with China's HIV and drug abuse problem.

  13. Optimal drug use and rational drug policy.

    Science.gov (United States)

    Miller, Geoffrey F

    2011-12-01

    The Müller & Schumann (M&S) view of drug use is courageous and compelling, with radical implications for drug policy and research. It implies that most nations prohibit most drugs that could promote happiness, social capital, and economic growth; that most individuals underuse rather than overuse drugs; and that behavioral scientists could use drugs more effectively in generating hypotheses and collaborating empathically.

  14. Nanoformulated antiretroviral drug combinations extend drug release and antiretroviral responses in HIV-1-infected macrophages: implications for neuroAIDS therapeutics.

    Science.gov (United States)

    Nowacek, Ari S; McMillan, JoEllyn; Miller, Reagan; Anderson, Alec; Rabinow, Barrett; Gendelman, Howard E

    2010-12-01

    We posit that improvements in pharmacokinetics and biodistributions of antiretroviral therapies (ART) for human immunodeficiency virus type one-infected people can be achieved through nanoformulationed drug delivery systems. To this end, we manufactured nanoparticles of atazanavir, efavirenz, and ritonavir (termed nanoART) and treated human monocyte-derived macrophages (MDM) in combination therapies to assess antiretroviral responses. This resulted in improved drug uptake, release, and antiretroviral efficacy over monotherapy. MDM rapidly, within minutes, ingested nanoART combinations, at equal or similar rates, as individual formulations. Combination nanoART ingested by MDM facilitated individual drug release from 15 to >20 days. These findings are noteworthy as a nanoART cell-mediated drug delivery provides a means to deliver therapeutics to viral sanctuaries, such as the central nervous system during progressive human immunodeficiency virus type one infection. The work brings us yet another step closer to realizing the utility of nanoART for virus-infected people.

  15. Minoxidil for severe hypertension after failure of other hypotensive drugs.

    Science.gov (United States)

    Devine, B L; Fife, R; Trust, P M

    1977-01-01

    Forty-four patients with severe hypertension who were resistant to treatment with more conventional hypotensive drugs or could not tolerate the side effects were treated with minoxidil, a potent peripheral vasodilator. A beta-blocking drug and a diuretic were used routinely to control, respectively, the tachycardia and fluid retention caused by minoxidil. During treatment the outpatient supine blood pressure fell from a mean of 221/134 mm Hg to 162/98 mm Hg. Eleven patients required additional or alternative hypotensive agents before blood pressure was adequately controlled. Side effects were minor, although the invariable hirsuties caused by minoxidil was unacceptable to three women. The possibility of cardiotoxic effects, raised by early studies in dogs, has not been excluded, and therefore this drug should be used only in patients with severe hypertension. In such patients minoxidil appears to be most effective. PMID:902045

  16. Transmission Pattern of Drug-Resistant Tuberculosis and Its Implication for Tuberculosis Control in Eastern Rural China

    OpenAIRE

    Yi Hu; Barun Mathema; Weili Jiang; Barry Kreiswirth; Weibing Wang; Biao Xu

    2011-01-01

    OBJECTIVE: Transmission patterns of drug-resistant Mycobacterium tuberculosis (MTB) may be influenced by differences in socio-demographics, local tuberculosis (TB) endemicity and efficaciousness of TB control programs. This study aimed to investigate the impact of DOTS on the transmission of drug-resistant TB in eastern rural China. METHODS: We conducted a cross-sectional study of all patients diagnosed with drug-resistant TB over a one-year period in two rural Chinese counties with varying l...

  17. A unique drug distribution process for radium Ra 223 dichloride injection and its implication for product quality, patient privacy, and delineation of professional responsibilities.

    Science.gov (United States)

    Dansereau, Raymond N

    2014-11-01

    On May 15, 2013, Bayer Healthcare Pharmaceuticals announced that it had received marketing approval for the therapeutic radioactive medication radium Ra 223 dichloride injection (Xofigo; Ra 223). The product acquisition and distribution process for hospital-based nuclear pharmacies and nuclear medicine services is unlike any other. The product is distributed as a low-risk compounded sterile preparation through a single compounding nuclear pharmacy located in Denver, Colorado, pursuant to a prescription. This model for drug distribution and delivery to the user institution has implications for product quality, patient privacy, and delineation of professional responsibilities. © The Author(s) 2014.

  18. A review of literature on drug use in Sub-Saharan Africa countries and its economic and social implications.

    Science.gov (United States)

    Affinnih, Y H

    1999-02-01

    The drug problem in Africa cannot be seen as an isolated phenomenon but rather as part of the larger narcoscape which partakes of the fluid yet disjunctive qualities of Appadurai's landscapes. In this volatile environment, the transformation of Sub-Saharan Africa (SSA) nations from transit points in an international drug network to consumer countries seems inevitable. At the same time, Africa has undergone rapid economic and social changes that have facilitate this shift. A review of the literature reveals that there is a pressing need to investigate current trends and patterns of drug use in the countries of SSA. These nations, struggling with the consequences of AIDS, famine, refugees, and political unrest, could ill afford to address the consequences of widespread drug use. It is critical, therefore, that they address the drug problem before it reaches crisis proportions. To do so, they need information describing the magnitude of the problem as well as a firm understanding of the relationships between drug use and crime, unemployment, violence, and the breakdown of family life. The more that is known about the nature and complexity of drug use in Africa, the better policymakers can formulate a sound and effective strategy to curtail the drug "epidemic."

  19. The Impact of Peers and Social Disapproval on High-Risk Cannabis Use: Gender Differences and Implications for Drug Education

    Science.gov (United States)

    Butters, Jennifer E.

    2004-01-01

    Drug education programs that rely on an abstinence based philosophy neglect, and may even contribute to, the potentially adverse consequences experienced by young people who already engage in this potentially health-compromising behaviour. A predominant focus of drug research during the initial wave of rising cannabis use by young people in the…

  20. Drugs use pattern for uncomplicated malaria in medicine retail outlets in Enugu urban, southeast Nigeria: implications for malaria treatment policy.

    Science.gov (United States)

    Ezenduka, Charles C; Ogbonna, Brian O; Ekwunife, Obinna I; Okonta, Mathew J; Esimone, Charles O

    2014-06-24

    Malaria treatment policy recommends regular monitoring of drug utilization to generate information for ensuring effective use of anti-malarial drugs in Nigeria. This information is currently limited in the retail sector which constitutes a major source of malaria treatment in Nigeria, but are characterized by significant inappropriate use of drugs. This study analyzed the use pattern of anti-malarial drugs in medicine outlets to assess the current state of compliance to policy on the use of artemisinin-based combination therapy (ACT). A prospective cross-sectional survey of randomly selected medicine outlets in Enugu urban, southeast Nigeria, was conducted between May and August 2013, to determine the types, range, prices, and use pattern of anti-malarial drugs dispensed from pharmacies and patent medicine vendors (PMVs). Data were collected and analyzed for anti-malarial drugs dispensed for self-medication to patients, treatment by retail outlets and prescription from hospitals. A total of 1,321 anti-malarial drugs prescriptions were analyzed. ACT accounted for 72.7%, while monotherapy was 27.3%. Affordable Medicines Facility-malaria (AMFm) drugs contributed 33.9% (326/961) of ACT. Artemether-lumefantrine (AL), 668 (50.6%) was the most used anti-malarial drug, followed by monotherapy sulphadoxine-pyrimethamine (SP), 248 (18.8%). Median cost of ACT at $2.91 ($0.65-7.42) per dose, is about three times the median cost of monotherapy, $0.97 ($0.19-13.55). Total cost of medication (including co-medications) with ACT averaged $3.64 (95% CI; $3.53-3.75) per prescription, about twice the mean cost of treatment with monotherapy, $1.83 (95% CI; $1.57-2.1). Highest proportion 46.5% (614), of the anti-malarial drugs was dispensed to patients for self-treatment. Treatment by retail outlets accounted for 35.8% while 17.7% of the drugs were dispensed from hospital prescriptions. Self-medication, 82%, accounted for the highest source of monotherapy and a majority of prescriptions

  1. Detection of Primary T Cell Responses to Drugs and Chemicals in HLA-Typed Volunteers: Implications for the Prediction of Drug Immunogenicity.

    Science.gov (United States)

    Faulkner, Lee; Gibson, Andrew; Sullivan, Andrew; Tailor, Arun; Usui, Toru; Alfirevic, Ana; Pirmohamed, Munir; Naisbitt, Dean J; Kevin Park, B

    2016-12-01

    A number of serious adverse drug reactions are caused by T cells. An association with HLA alleles has been identified with certain reactions, which makes it difficult to develop standardized preclinical tests to predict chemical liability. We have recently developed a T cell priming assay using the drug metabolite nitroso sulfamethoxazole (SMX-NO). We now report on reproducibility of the assay, establishment of a biobank of PBMC from 1000 HLA-typed volunteers, and generation of antigen-specific responses to a panel of compounds. Forty T cell priming assays were performed with SMX-NO; 5 gave weak responses (1.5-1.9) and 34 showed good (SI 2.0-3.9) or strong responses (SI  > 4.0) using readouts for proliferation and cytokine release. Thus, SMX-NO can be used as a model reagent for in vitro T cell activation. Good to strong responses were also generated to haptenic compounds (amoxicillin, piperacillin and Bandrowski's base) that are not associated with an HLA risk allele. Furthermore, responses were detected to carbamazepine (in HLA-B*15:02 donors), flucloxacillin (in 1 HLA-B*57:01 donor) and oxypurinol (in HLA-B*58:01 donors), which are associated with HLA-class I-restricted forms of hypersensitivity. In contrast, naïve T cell priming to ximelagatran, lumiracoxib, and lapatinib (HLA-class II-restricted forms of hypersensitivity) yielded negative results. Abacavir, which activates memory T cells in patients, did not activate naïve T cells from HLA-B*57:01 donors. This work shows that the priming assay can be used to assess primary T cell responses to drugs and to study mechanisms T cell priming for drugs that display HLA class I restriction. Additional studies are required to investigate HLA-class II-restricted reactions.

  2. Predicting tumor responses to mitomycin C on the basis of DT-diaphorase activity or drug metabolism by tumor homogenates: implications for enzyme-directed bioreductive drug development.

    Science.gov (United States)

    Phillips, R M; Burger, A M; Loadman, P M; Jarrett, C M; Swaine, D J; Fiebig, H H

    2000-11-15

    Mitomycin C (MMC) is a clinically used anticancer drug that is reduced to cytotoxic metabolites by cellular reductases via a process known as bioreductive drug activation. The identification of key enzymes responsible for drug activation has been investigated extensively with the ultimate aim of tailoring drug administration to patients whose tumors possess the biochemical machinery required for drug activation. In the case of MMC, considerable interest has been centered upon the enzyme DT-diaphorase (DTD) although conflicting reports of good and poor correlations between enzyme activity and response in vitro and in vivo have been published. The principle aim of this study was to provide a definitive answer to the question of whether tumor response to MMC could be predicted on the basis of DTD activity in a large panel of human tumor xenografts. DTD levels were measured in 45 human tumor xenografts that had been characterized previously in terms of their sensitivity to MMC in vitro and in vivo (the in vivo response profile to MMC was taken from work published previously). A poor correlation between DTD activity and antitumor activity in vitro as well as in vivo was obtained. This study also assessed the predictive value of an alternative approach based upon the ability of tumor homogenates to metabolize MMC. This approach is based on the premise that the overall rate of MMC metabolism may provide a better indicator of response than single enzyme measurements. MMC metabolism was evaluated in tumor homogenates (clarified by centrifugation at 1000 x g for 1 min) by measuring the disappearance of the parent compound by HPLC. In responsive [T/C 50%) tumors, the mean half life of MMC was 75+/-48.3 and 280+/-129.6 min, respectively. The difference between the two groups was statistically significant (P < 0.005). In conclusion, these results unequivocally demonstrate that response to MMC in vivo cannot be predicted on the basis of DTD activity. Measurement of MMC

  3. Cognitive and oculomotor performance in subjects with low and high schizotypy: implications for translational drug development studies

    OpenAIRE

    Koychev, I; D. Joyce; Barkus, E; Ettinger, U; Schmechtig, A; Dourish, C T; Dawson, G R; Craig, K J; Deakin, J.F.W.

    2016-01-01

    The development of drugs to improve cognition in patients with schizophrenia is a major unmet clinical need. A number of promising compounds failed in recent clinical trials, a pattern linked to poor translation between preclinical and clinical stages of drug development. Seeking proof of efficacy in early Phase 1 studies in surrogate patient populations (for example, high schizotypy individuals where subtle cognitive impairment is present) has been suggested as a strategy to reduce attrition...

  4. Routes of drug delivery into the nail apparatus: Implications for the efficacy of topical nail solutions in onychomycosis.

    Science.gov (United States)

    Gupta, Aditya K; Simpson, Fiona C

    2016-01-01

    The route of antifungal drug entry into the nail plate and the underlying nail bed plays an important role in determining the efficacy of therapy. Oral antifungal agents reach the nail bed and nail plate by being ingested and achieving antifungal levels in the blood stream that are well in excess of the minimum inhibitory concentration. The reticular circulation at the distal end of the digit enables the drug to reach the nail bed, the proximal matrix and the lateral nail folds. The drug then diffuses into the proximal, ventral and lateral nail plate. The primary route of drug delivery for topical lacquers is transungual, with drug applied to the dorsal aspect of the nail plate and penetrating to the underlying nail bed. The new topical agents approved in the US for the treatment of onychomycosis are solutions with lower viscosity and increased nail penetration characteristics; therefore, these agents penetrate through the transungual route, but also through the space between the nail plate and the nail bed. This subungual route is an important method of drug delivery and is able to in part circumvent the thickness of the nail plate.

  5. Circular Migration by Mexican Female Sex Workers Who are Injection Drug Users: Implications for HIV in Mexican Sending Communities

    Science.gov (United States)

    Ojeda, Victoria D.; Burgos, José Luis; Hiller, Sarah P.; Lozada, Remedios; Rangel, Gudelia; Vera, Alicia; Artamonova, Irina; Rodriguez, Carlos Magis

    2013-01-01

    Background Circular migration and injection drug use increase the risk of HIV transmission in sending communities. We describe female sex workers who are injection drug users’ (FSW-IDUs) circular migration and drug use behaviors. Methods Between 2008-2010, 258 migrant FSW-IDUs residing in Tijuana and Ciudad Juarez, Mexico responded to questionnaires. Results 24% of FSW-IDUs were circular migrants. HIV prevalence was 3.3% in circular migrants and 6.1% in non-circular migrants; 50% of circular and 82% of non-circular migrants were unaware of their HIV infection. Among circular migrants, 44% (n=27) consumed illicit drugs in their birthplace; 70% of these (n=20) injected drugs and one-half of injectors shared injection equipment in their birthplace. Women reporting active social relationships were significantly more likely to return home. Discussion Circular migrant FSW-IDUs exhibit multiple HIV risks and opportunities for bridging populations. Regular HIV testing and treatment and access to substance use services is critical for FSW-IDUs and their sexual/drug-using contacts. PMID:21833727

  6. Drug: D01512 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available vary secretion Anatomical Therapeutic Chemical (ATC) classification [BR:br08303] S SENSORY ORGANS S01 OPHTHALMOLOGICALS S01E ANTIGLAU...COMA PREPARATIONS AND MIOTICS S01ED Beta blocking agents

  7. An analytical method for assessing stage-specific drug activity in Plasmodium vivax malaria: implications for ex vivo drug susceptibility testing.

    Directory of Open Access Journals (Sweden)

    Douglas H Kerlin

    Full Text Available The emergence of highly chloroquine (CQ resistant P. vivax in Southeast Asia has created an urgent need for an improved understanding of the mechanisms of drug resistance in these parasites, the development of robust tools for defining the spread of resistance, and the discovery of new antimalarial agents. The ex vivo Schizont Maturation Test (SMT, originally developed for the study of P. falciparum, has been modified for P. vivax. We retrospectively analysed the results from 760 parasite isolates assessed by the modified SMT to investigate the relationship between parasite growth dynamics and parasite susceptibility to antimalarial drugs. Previous observations of the stage-specific activity of CQ against P. vivax were confirmed, and shown to have profound consequences for interpretation of the assay. Using a nonlinear model we show increased duration of the assay and a higher proportion of ring stages in the initial blood sample were associated with decreased effective concentration (EC(50 values of CQ, and identify a threshold where these associations no longer hold. Thus, starting composition of parasites in the SMT and duration of the assay can have a profound effect on the calculated EC(50 for CQ. Our findings indicate that EC(50 values from assays with a duration less than 34 hours do not truly reflect the sensitivity of the parasite to CQ, nor an assay where the proportion of ring stage parasites at the start of the assay does not exceed 66%. Application of this threshold modelling approach suggests that similar issues may occur for susceptibility testing of amodiaquine and mefloquine. The statistical methodology which has been developed also provides a novel means of detecting stage-specific drug activity for new antimalarials.

  8. Toward an increased understanding of the barriers to colonic drug absorption in humans: implications for early controlled release candidate assessment.

    Science.gov (United States)

    Tannergren, Christer; Bergendal, Anna; Lennernäs, Hans; Abrahamsson, Bertil

    2009-01-01

    The purpose of this study was to increase the understanding of in vivo colonic drug absorption in humans by summarizing and evaluating all regional in vivo human absorption data with focus on the interpretation of the colonic absorption data in relation to intestinal permeability and solubility. In addition, the usefulness of the Biopharmaceutics Classification System (BCS) in early assessment of the in vivo colonic absorption potential of controlled release drug candidates was investigated. Clinical regional absorption data (Cmax, Tmax, and AUC) of 42 drugs were collected from journal articles, abstracts, and internal reports, and the relative bioavailability in the colon (Frel(colon)) was obtained directly or calculated. Bioavailability, fraction dose absorbed, and information if the compounds were substrates for P-glycoprotein (P-gp) or cytochrome P450 3A (CYP3A) were also obtained. The BCS I drugs were well absorbed in the colon (Frel(colon) > 70%), although some drugs had lower values due to bacterial degradation in the colon. The low permeability drugs (BCS III/IV) had a lower degree of absorption in the colon (Frel(colon) colon), and atenolol and metoprolol may function as permeability markers for low and high colonic absorption, respectively. No obvious effect of P-gp on the colonic absorption of the drugs in this study was detected. There was insufficient data available to fully assess the impact of low solubility and slow dissolution rate. The estimated in vivo fractions dissolved of the only two compounds administered to the colon as both a solution and as solid particles were 55% and 92%, respectively. In conclusion, permeability and solubility are important barriers to colonic absorption in humans, and in vitro testing of these properties is recommended in early assessment of colonic absorption potential.

  9. Clinical implications of measuring drug and anti-drug antibodies by different assays when optimizing infliximab treatment failure in Crohn's disease

    DEFF Research Database (Denmark)

    Steenholdt, Casper; Bendtzen, Klaus; Brynskov, Jørn;

    2014-01-01

    classifications. The four different assays did not differ in terms of the ability to predict response to interventions defined by the algorithm. CONCLUSIONS: Despite variable analytical properties, common assays result in similar classifications and interventions in patients with IFX treatment failure......OBJECTIVES: Cost-effective guidance of therapeutic strategy in Crohn's disease patients with secondary infliximab (IFX) treatment failure may be achieved by serum IFX and anti-IFX antibody (Ab) measurements by radioimmunoassay (RIA). This study investigated implications of using other techniques...... on classification of underlying mechanism for treatment failure in most cases (79-94%). The majority (74-88%) failed IFX owing to pharmacodynamic problems, or had noninflammatory pathophysiology for symptoms resembling relapse. Applied threshold for therapeutic vs. subtherapeutic IFX level influenced...

  10. Transmission pattern of drug-resistant tuberculosis and its implication for tuberculosis control in eastern rural China.

    Directory of Open Access Journals (Sweden)

    Yi Hu

    Full Text Available OBJECTIVE: Transmission patterns of drug-resistant Mycobacterium tuberculosis (MTB may be influenced by differences in socio-demographics, local tuberculosis (TB endemicity and efficaciousness of TB control programs. This study aimed to investigate the impact of DOTS on the transmission of drug-resistant TB in eastern rural China. METHODS: We conducted a cross-sectional study of all patients diagnosed with drug-resistant TB over a one-year period in two rural Chinese counties with varying lengths of DOTS implementation. Counties included Deqing, with over 11 years' DOTS implementation and Guanyun, where DOTS was introduced 1 year prior to start of this study. We combined demographic, clinical and epidemiologic information with IS6110-based restricted fragment length polymorphism (RFLP and Spoligotyping analysis of MTB isolates. In addition, we conducted DNA sequencing of resistance determining regions to first-line anti-tuberculosis agents. RESULTS: Of the 223 drug-resistant isolates, 73(32.7% isolates were identified with clustered IS6110RFLP patterns. The clustering proportion among total drug-resistant TB was higher in Guanyun than Deqing (26/101.vs.47/122; p,0.04, but not significantly different among the 53 multidrug-resistant isolates (10/18.vs.24/35; p,0.35. Patients with cavitary had increased risk of clustering in both counties. In Guanyun, patients with positive smear test or previous treatment history had a higher clustering proportion. Beijing genotype and isolates resistant to isoniazid and/or rifampicin were more likely to be clustered. Of the 73 patients with clustered drug-resistant isolates, 71.2% lived in the same or neighboring villages. Epidemiological link (household and social contact was confirmed in 12.3% of the clustered isolates. CONCLUSION: Transmission of drug-resistant TB in eastern rural China is characterized by small clusters and limited geographic spread. Our observations highlight the need for supplementing DOTS

  11. Evaluating oversight of human drugs and medical devices: a case study of the FDA and implications for nanobiotechnology.

    Science.gov (United States)

    Paradise, Jordan; Tisdale, Alison W; Hall, Ralph F; Kokkoli, Efrosini

    2009-01-01

    This article evaluates the oversight of drugs and medical devices by the U.S. Food and Drug Administration (FDA) using an integration of public policy, law, and bioethics approaches and employing multiple assessment criteria, including economic, social, safety, and technological. Criteria assessment and expert elicitation are combined with existing literature, case law, and regulations in an integrative historical case studies approach. We then use our findings as a tool to explore possibilities for effective oversight and regulatory mechanisms for nanobiotechnology. Section I describes oversight mechanisms for human drugs and medical devices and presents current nanotechnology products. Section II describes the results of expert elicitation research. Section III highlights key criteria and relates them to the literature and larger debate. We conclude with broad lessons for the oversight of nanobiotechnology informed by Sections I-III in order to provide useful analysis from multiple disciplines and perspectives to guide discussions regarding appropriate FDA oversight.

  12. Exploit the Developed Countries Experiences of Primary School Education to Prevent Drug Addiction and Implications for Iran

    Science.gov (United States)

    Kheradmand, Ali; Zamani, Eshrat; Hedayati, Nassim

    2009-01-01

    Background: The purpose of this study was to evaluate various educations in primary schools to prevent drug addiction. Methods: In this qualitative study, data included the experiences of those who been students in the developed countries for some years as well as their parents. The data were collected by semi-structured and unstructured interviews as well as documents. Findings: The results showed that education for prevention of drug addiction begins in primary schools in the developed countries using various methods. These educations are not occasional but constant and infused in all curriculum subjects and grades. Students become familiar with various drugs and learn about their effects. Conclusion: Our findings showed that social problems are discussed openly in schools of the developed countries and students try to find solutions which are considered by authorities. PMID:24494082

  13. The motor way: Clinical implications of understanding and shaping actions with the motor system in autism and drug addiction.

    Science.gov (United States)

    Casartelli, Luca; Chiamulera, Cristiano

    2016-04-01

    To understand others' minds is crucial for survival; however, it is quite puzzling how access to others' minds can be--to some extent--direct and not necessarily mediated by conceptual reasoning. Recent advances in neuroscience have led to hypothesize a role for motor circuits not only in controlling the elementary physical features of movement (e.g., force, direction, and amplitude), but also in understanding and shaping human behavior. The concept of "motor cognition" refers to these aspects, and neurophysiological, neuroimaging, and behavioral studies in human and nonhuman primates support this view. From a clinical perspective, motor cognition represents a challenge in several domains. A thorough investigation of the neural mechanisms mediating motor action/intention understanding and automatized/compulsive behaviors seems to be a promising way to tackle a range of neurodevelopmental and drug-related disorders. On the one hand, anomalies in motor cognition may have cascade effects on social functioning in individuals with autism spectrum disorder (ASD); on the other, motor cognition may help explain the pathophysiology of drug-seeking and drug-taking behaviors in the most severe phase of drug addiction (i.e., see drug dependence, motor low-order cue reactivity). This may represent a promising approach that could improve the efficacy of rehabilitative interventions. The only way to shed light on multifactorial disorders such as ASD and drug addiction is through the investigation of their multiple factors. This motor way can promote new theoretical and experimental perspectives that would help bridge the gap between the basic neuroscience approach and clinical practice.

  14. Network-based discovery through mechanistic systems biology. Implications for applications--SMEs and drug discovery: where the action is.

    Science.gov (United States)

    Benson, Neil

    2015-08-01

    Phase II attrition remains the most important challenge for drug discovery. Tackling the problem requires improved understanding of the complexity of disease biology. Systems biology approaches to this problem can, in principle, deliver this. This article reviews the reports of the application of mechanistic systems models to drug discovery questions and discusses the added value. Although we are on the journey to the virtual human, the length, path and rate of learning from this remain an open question. Success will be dependent on the will to invest and make the most of the insight generated along the way.

  15. Variability in P-Glycoprotein Inhibitory Potency (IC50) Using Various in Vitro Experimental Systems: Implications for Universal Digoxin Drug-Drug Interaction Risk Assessment Decision Criteria

    Science.gov (United States)

    Bentz, Joe; O’Connor, Michael P.; Bednarczyk, Dallas; Coleman, JoAnn; Lee, Caroline; Palm, Johan; Pak, Y. Anne; Perloff, Elke S.; Reyner, Eric; Balimane, Praveen; Brännström, Marie; Chu, Xiaoyan; Funk, Christoph; Guo, Ailan; Hanna, Imad; Herédi-Szabó, Krisztina; Hillgren, Kate; Li, Libin; Hollnack-Pusch, Evelyn; Jamei, Masoud; Lin, Xuena; Mason, Andrew K.; Neuhoff, Sibylle; Patel, Aarti; Podila, Lalitha; Plise, Emile; Rajaraman, Ganesh; Salphati, Laurent; Sands, Eric; Taub, Mitchell E.; Taur, Jan-Shiang; Weitz, Dietmar; Wortelboer, Heleen M.; Xia, Cindy Q.; Xiao, Guangqing; Yabut, Jocelyn; Yamagata, Tetsuo; Zhang, Lei

    2013-01-01

    A P-glycoprotein (P-gp) IC50 working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC50 determinations. Each laboratory followed its in-house protocol to determine in vitro IC50 values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells—Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC50 values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC50 values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC50 values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC50 values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC50 values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC50 determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens et al., 2013) and recommendations

  16. Public health implications of contamination of Franc CFA (XAF) circulating in Buea (Cameroon) with drug resistant pathogens

    OpenAIRE

    Akoachere, Jane-Francis Tatah Kihla; Gaelle, Nana; Dilonga, Henry Meriki; Nkuo-Akenji, Theresa K

    2014-01-01

    Background Studies in different parts of the world have implicated money as a vehicle for transmission of pathogens. Such information which is necessary to facilitate infection control strategies is lacking in many sub-Saharan countries including Cameroon. This study analyzed the Franc de la Communauté Financiere d’Afrique (Franc CFA), the currency used in Cameroon and other countries in the Central African sub-region, as a potential vehicle for transmission of pathogenic bacteria and fungi, ...

  17. HEART-RATE-VARIABILITY IN LEFT-VENTRICULAR DYSFUNCTION AND HEART-FAILURE - EFFECTS AND IMPLICATIONS OF DRUG-TREATMENT

    NARCIS (Netherlands)

    TUININGA, YS; VANVELDHUISEN, DJ; BROUWER, J; HAAKSMA, J; CRIJNS, HJGM; MANINTVELD, AJ; LIE, KI

    1994-01-01

    Objective-To review the importance of heart rate variability analysis in left ventricular dysfunction and heart failure and to assess the effects of drug treatment. In patients with left: ventricular dysfunction or heart failure, a low heart rate variability is a strong predictor of a low probabilit

  18. The role of surface charge in the desolvation process of gelatin: implications in nanoparticle synthesis and modulation of drug release

    Science.gov (United States)

    Ahsan, Saad M; Rao, Chintalagiri Mohan

    2017-01-01

    The process of moving hydrophobic amino acids into the core of a protein by desolvation is important in protein folding. However, a rapid and forced desolvation can lead to precipitation of proteins. Desolvation of proteins under controlled conditions generates nanoparticles – homogeneous aggregates with a narrow size distribution. The protein nanoparticles, under physiological conditions, undergo surface erosion due to the action of proteases, releasing the entrapped drug/gene. The packing density of protein nanoparticles significantly influences the release kinetics. We have investigated the desolvation process of gelatin, exploring the role of pH and desolvating agent in nanoparticle synthesis. Our results show that the desolvation process, initiated by the addition of acetone, follows distinct pathways for gelatin incubated at different pH values and results in the generation of nanoparticles with varying matrix densities. The nanoparticles synthesized with varying matrix densities show variations in drug loading and protease-dependent extra- and intracellular drug release. These results will be useful in fine-tuning the synthesis of nanoparticles with desirable drug release profiles. PMID:28182126

  19. Understanding the Black Box of Gang Organization: Implications for Involvement in Violent Crime, Drug Sales, and Violent Victimization

    Science.gov (United States)

    Decker, Scott H.; Katz, Charles M.; Webb, Vincent J.

    2008-01-01

    This article examines the influence of gang organization on several behavioral measures. Using interview data from juvenile detention facilities in three Arizona sites, this article examines the relationship between gang organizational structure and involvement in violent crime, drug sales, victimization, and arrest. The gang literature suggests…

  20. Cognitive and oculomotor performance in subjects with low and high schizotypy: implications for translational drug development studies.

    Science.gov (United States)

    Koychev, I; Joyce, D; Barkus, E; Ettinger, U; Schmechtig, A; Dourish, C T; Dawson, G R; Craig, K J; Deakin, J F W

    2016-05-17

    The development of drugs to improve cognition in patients with schizophrenia is a major unmet clinical need. A number of promising compounds failed in recent clinical trials, a pattern linked to poor translation between preclinical and clinical stages of drug development. Seeking proof of efficacy in early Phase 1 studies in surrogate patient populations (for example, high schizotypy individuals where subtle cognitive impairment is present) has been suggested as a strategy to reduce attrition in the later stages of drug development. However, there is little agreement regarding the pattern of distribution of schizotypal features in the general population, creating uncertainty regarding the optimal control group that should be included in prospective trials. We aimed to address this question by comparing the performance of groups derived from the general population with low, average and high schizotypy scores over a range of cognitive and oculomotor tasks. We found that tasks dependent on frontal inhibitory mechanisms (N-Back working memory and anti-saccade oculomotor tasks), as well as a smooth-pursuit oculomotor task were sensitive to differences in the schizotypy phenotype. In these tasks the cognitive performance of 'low schizotypes' was significantly different from 'high schizotypes' with 'average schizotypes' having an intermediate performance. These results indicate that for evaluating putative cognition enhancers for treating schizophrenia in early-drug development studies the maximum schizotypy effect would be achieved using a design that compares low and high schizotypes.

  1. Risk factors for hepatitis C seropositivity among young people who inject drugs in New York City: Implications for prevention.

    Science.gov (United States)

    Eckhardt, Benjamin; Winkelstein, Emily R; Shu, Marla A; Carden, Michael R; McKnight, Courtney; Des Jarlais, Don C; Glesby, Marshall J; Marks, Kristen; Edlin, Brian R

    2017-01-01

    Hepatitis C virus (HCV) infection remains a significant problem in the United States, with people who inject drugs (PWID) disproportionately afflicted. Over the last decade rates of heroin use have more than doubled, with young persons (18-25 years) demonstrating the largest increase. We conducted a cross-sectional study in New York City from 2005 to 2012 among young people who injected illicit drugs, and were age 18 to 35 or had injected drugs for ≤5 years, to examine potentially modifiable factors associated with HCV among young adults who began injecting during the era of syringe services. Among 714 participants, the median age was 24 years; the median duration of drug injection was 5 years; 31% were women; 75% identified as white; 69% reported being homeless; and 48% [95% CI 44-52] had HCV antibodies. Factors associated with HCV included older age (adjusted odds ratio [AOR], 1.99 [1.52-2.63]; pyoung PWID in New York City remained high and constant during 2005-2012. Age and several injection behaviors conferred independent risk. Individuals were somewhat aware of their own risk. Public and outdoor injection and arrest for possession of a syringe are risk factors for HCV that can be modified through structural interventions.

  2. Variability in P-glycoprotein inhibitory potency (IC₅₀) using various in vitro experimental systems: implications for universal digoxin drug-drug interaction risk assessment decision criteria.

    Science.gov (United States)

    Bentz, Joe; O'Connor, Michael P; Bednarczyk, Dallas; Coleman, Joann; Lee, Caroline; Palm, Johan; Pak, Y Anne; Perloff, Elke S; Reyner, Eric; Balimane, Praveen; Brännström, Marie; Chu, Xiaoyan; Funk, Christoph; Guo, Ailan; Hanna, Imad; Herédi-Szabó, Krisztina; Hillgren, Kate; Li, Libin; Hollnack-Pusch, Evelyn; Jamei, Masoud; Lin, Xuena; Mason, Andrew K; Neuhoff, Sibylle; Patel, Aarti; Podila, Lalitha; Plise, Emile; Rajaraman, Ganesh; Salphati, Laurent; Sands, Eric; Taub, Mitchell E; Taur, Jan-Shiang; Weitz, Dietmar; Wortelboer, Heleen M; Xia, Cindy Q; Xiao, Guangqing; Yabut, Jocelyn; Yamagata, Tetsuo; Zhang, Lei; Ellens, Harma

    2013-07-01

    A P-glycoprotein (P-gp) IC₅₀ working group was established with 23 participating pharmaceutical and contract research laboratories and one academic institution to assess interlaboratory variability in P-gp IC₅₀ determinations. Each laboratory followed its in-house protocol to determine in vitro IC₅₀ values for 16 inhibitors using four different test systems: human colon adenocarcinoma cells (Caco-2; eleven laboratories), Madin-Darby canine kidney cells transfected with MDR1 cDNA (MDCKII-MDR1; six laboratories), and Lilly Laboratories Cells--Porcine Kidney Nr. 1 cells transfected with MDR1 cDNA (LLC-PK1-MDR1; four laboratories), and membrane vesicles containing human P-glycoprotein (P-gp; five laboratories). For cell models, various equations to calculate remaining transport activity (e.g., efflux ratio, unidirectional flux, net-secretory-flux) were also evaluated. The difference in IC₅₀ values for each of the inhibitors across all test systems and equations ranged from a minimum of 20- and 24-fold between lowest and highest IC₅₀ values for sertraline and isradipine, to a maximum of 407- and 796-fold for telmisartan and verapamil, respectively. For telmisartan and verapamil, variability was greatly influenced by data from one laboratory in each case. Excluding these two data sets brings the range in IC₅₀ values for telmisartan and verapamil down to 69- and 159-fold. The efflux ratio-based equation generally resulted in severalfold lower IC₅₀ values compared with unidirectional or net-secretory-flux equations. Statistical analysis indicated that variability in IC₅₀ values was mainly due to interlaboratory variability, rather than an implicit systematic difference between test systems. Potential reasons for variability are discussed and the simplest, most robust experimental design for P-gp IC₅₀ determination proposed. The impact of these findings on drug-drug interaction risk assessment is discussed in the companion article (Ellens

  3. Assessing the structural conservation of protein pockets to study functional and allosteric sites: implications for drug discovery

    Directory of Open Access Journals (Sweden)

    Daura Xavier

    2010-03-01

    Full Text Available Abstract Background With the classical, active-site oriented drug-development approach reaching its limits, protein ligand-binding sites in general and allosteric sites in particular are increasingly attracting the interest of medicinal chemists in the search for new types of targets and strategies to drug development. Given that allostery represents one of the most common and powerful means to regulate protein function, the traditional drug discovery approach of targeting active sites can be extended by targeting allosteric or regulatory protein pockets that may allow the discovery of not only novel drug-like inhibitors, but activators as well. The wealth of available protein structural data can be exploited to further increase our understanding of allosterism, which in turn may have therapeutic applications. A first step in this direction is to identify and characterize putative effector sites that may be present in already available structural data. Results We performed a large-scale study of protein cavities as potential allosteric and functional sites, by integrating publicly available information on protein sequences, structures and active sites for more than a thousand protein families. By identifying common pockets across different structures of the same protein family we developed a method to measure the pocket's structural conservation. The method was first parameterized using known active sites. We characterized the predicted pockets in terms of sequence and structural conservation, backbone flexibility and electrostatic potential. Although these different measures do not tend to correlate, their combination is useful in selecting functional and regulatory sites, as a detailed analysis of a handful of protein families shows. We finally estimated the numbers of potential allosteric or regulatory pockets that may be present in the data set, finding that pockets with putative functional and effector characteristics are widespread across

  4. Occurrence and environmental implications of the presence of drugs of abuse in wastewater treatment plants of Valencia (Spain)

    Science.gov (United States)

    Picó, Yolanda; Andres-Costa, M. Jesus; Andreu, Vicente

    2014-05-01

    Drugs of abuse are continuously discharged into wastewaters due to human excretion as parent compounds and/or secondary metabolites after consumption or accidental disposal into the toilets. (Boles and Wells,2010). Incomplete removal of these compounds during wastewater treatment results in their release to the environment. Pollution by illicit drug residues at very low concentrations is generalized in populated areas, with potential risks for human health and the environment. The impact of treated wastewater effluent on the quality of receiving waters can be evaluated performing an investigated performing an ecotoxicological risk assessment calculating the risk quotient (RQ) of the drugs of abuse level observed. In addition, back-calculation from the concentration of illicit drug in the influents of wastewater treatment plants (WWTPs) provides an important tool for estimating its local consumption (Daughton 2001). Sampling campaigns were in three years, 2011 (March 9th to 15th), 2012 (April 17th to May 1st) and 2013 (March 6th to 12th) in influents and effluents from 3 Wastewater Treatment Plants (WWTPs), Pinedo I, Pinedo II and Quart-Benàger, that treats most of the wastewater of Valencia City and its surrounding towns. Cocaine (COC), amphetamine (AMP), methamphetamine (MAMP), ecstasy (MDMA) and ketamine (KET), Benzoylecgonine (BE), 6-acethylmorphine (6-MAM), and 11-nor-9-carboxy-delta9-tetrahydrocannabinol (THC-COOH) were analyzed using mass spectrometry techniques such as liquid chromatography triple quadrupole mass spectrometry (LC-QqQ-MS/MS) Illicit drugs were extracted using solid phase extraction (SPE) and determined by liquid chromatography tandem mass spectrometry (LC-MS/MS) in positive ionization with an electrospray ionization source (ESI). The determination of drugs of abuse in the influent of the selected WWTP shows that all compounds were detected in 100% of influents from Pinedo I, Pinedo II and Quart-Benàger in samples analyzed during three years

  5. Lenalidomide, an anti-tumor drug, regulates retinal endothelial cell function: Implication for treating ocular neovascular disorder.

    Science.gov (United States)

    Dong, Ling-Feng; Yao, Jin; Wang, Xiao-Qun; Shan, Kun; Yang, Hong; Yan, Biao; Jiang, Qin

    2015-10-02

    Ocular angiogenesis is an important pathologic character of several ocular diseases, such as retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration (AMD). Inhibition of ocular angiogenesis has great therapeutic value for treating these dieses. Here we show that lenalidomide, an anti-tumor drug, has great anti-angiogenic potential in ocular diseases. Lenalidomide inhibits retinal endothelial cell viability in normal and pathological condition, and inhibits VEGF-induced endothelial cell migration and tube formation in vitro. Moreover, lenalidomide inhibits ocular angiogenesis in vivo through the reduction of angiogenesis- and inflammation-related protein expression. Collectively, lenalidomide is a promising drug for treating ocular angiogenesis through its anti-proliferative and anti-inflammatory property.

  6. Parallel Functional Activity Profiling Reveals Valvulopathogens Are Potent 5-Hydroxytryptamine2B Receptor Agonists: Implications for Drug Safety Assessment

    OpenAIRE

    Huang, Xi-Ping; Setola, Vincent; Yadav, Prem N; Allen, John A.; Rogan, Sarah C.; Hanson, Bonnie J.; Revankar, Chetana; Robers, Matt; Doucette, Chris; Roth, Bryan L.

    2009-01-01

    Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine2B (5-HT2B) receptor agonists. We have shown that activation of 5-HT2B receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscen...

  7. Hydration and N-acetyl-l-cysteine alter the microstructure of human nail and bovine hoof: implications for drug delivery.

    Science.gov (United States)

    Nogueiras-Nieto, L; Gómez-Amoza, J L; Delgado-Charro, M B; Otero-Espinar, F J

    2011-12-20

    This work aimed to (a) characterize the microstructure and porosity of human nail and bovine hoof by mercury intrusion porosimetry and SEM image analysis, (b) study the effects of hydration and of N-acetyl-l-cysteine treatment on the microstructure of both membranes, and (c) determine whether the microstructural modifications were associated with changes in drug penetration measured by standard diffusion studies. Bovine hoof surface is more porous than nail surface although there were no differences between the mean surface pore sizes. Hydration and N-acetyl-l-cysteine increased the roughness and apparent surface porosity, and the porosity determined by mercury intrusion porosimetry of both membranes. Pore-Cor™ was used to generate tridimensional structures having percolation characteristics comparable to nail and hooves. The modeled structures were horizontally banded having an inner less-porous area which disappeared upon treatment. Treatment increased the predicted permeability of the simulated structures. Triamcinolone permeation increased significantly for hooves treated N-acetyl-l-cysteine, i.e., the membranes for which microstructural and permeability changes were the largest. Thus, microstructural changes determined via mercury intrusion porosimetry and subsequently modeled by Pore-Cor™ were related to drug diffusion. Further refinement of the technique will allow fast screening of penetration enhancers to be used in ungual drug delivery. Copyright © 2011 Elsevier B.V. All rights reserved.

  8. Intracellular degradation of multilabeled poly(ethylene imine)-mesoporous silica-silica nanoparticles: implications for drug release.

    Science.gov (United States)

    Bergman, Lotta; Kankaanpää, Pasi; Tiitta, Silja; Duchanoy, Alain; Li, Ling; Heino, Jyrki; Lindén, Mika

    2013-05-06

    Mesoporous silica nanoparticles, MSNs, have emerged as an interesting carrier for drugs in vitro and in vivo. The particles are typically used in a surface functionalized form, where functional silanes or other covalently linked surface functions are used to provide anchoring sites for additional functionalities like targeting groups, imaging agents, and drugs. Here, we report results related to extra- and intracellular degradation of silica nanoparticles using multilabeled nonporous silica core-mesoporous silica shell-surface hyperbranched poly(ethylene imine) shell nanoparticles as model particles. Different fluorophores have been selectively covalently linked to different regions of the particles in order to study the particle degradation in detail under in vitro conditions in human SAOS-2 cells. A novel, quantitative method for nanoparticle degradation evaluation based on confocal fluorescence microscopy is applied. Our results suggest that the core-shell-shell MSNs degrade at a higher rate inside cells as compared to outside cells, which is of high importance for further application of this class of drug carriers.

  9. Public perceptions of the pharmaceutical industry and drug safety: implications for the pharmacovigilance professional and the culture of safety.

    Science.gov (United States)

    Olsen, Axel K; Whalen, Matthew D

    2009-01-01

    A survey of the US public titled 'Consumer Perceptions on Drug Safety' was conducted in October 2006. The survey was undertaken at that time because of the heightened public awareness of drug safety concerns over rofecoxib (Vioxx(R)) and pediatric antidepressant use. The survey was designed with questions related to public perception of the pharmaceutical industry, the US FDA, Congress and whether the US public perceived there to be a safety crisis. The survey consisted of 1726 US men and women aged 18 years and over. The survey results showed that the FDA, Congress and US pharmaceutical companies are perceived as having a notable amount of responsibility to ensure safety (by 75%, 41% and 70% of respondents, respectively). Additionally, 96% of the survey respondents indicated that they had some level of concern about adverse reactions to prescription drugs that are taken as directed. Seventy-six percent of the respondents were 'fairly' to 'extremely' concerned about adverse reactions, while approximately 42% of the survey respondents' opinions ranged from 'somewhat distrusting' to 'strongly distrusting' of the pharmaceutical companies that develop drugs. These findings are comparable to those in surveys conducted by the Kaiser Family Foundation in 2005 and PriceWaterhouseCoopers in 2007. These surveys suggest that about half the respondents believe there is both the need and desire for reform in drug safety by the pharmaceutical industry and the FDA. In reports from 2006 and 2007, the Institute of Medicine challenges the healthcare system and the FDA to adopt the principles of the culture of safety. While there have been steps taken to address the recommendations of the reports, as exemplified by the FDA Amendment Act of 2007 and the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium, true reform across the life sciences sector will only come through broad adoption of these principles. Thus, it is particularly important for

  10. Predicting Allosteric Effects from Orthosteric Binding in Hsp90-Ligand Interactions: Implications for Fragment-Based Drug Design.

    Directory of Open Access Journals (Sweden)

    Arun Chandramohan

    2016-06-01

    Full Text Available A key question in mapping dynamics of protein-ligand interactions is to distinguish changes at binding sites from those associated with long range conformational changes upon binding at distal sites. This assumes a greater challenge when considering the interactions of low affinity ligands (dissociation constants, KD, in the μM range or lower. Amide hydrogen deuterium Exchange mass spectrometry (HDXMS is a robust method that can provide both structural insights and dynamics information on both high affinity and transient protein-ligand interactions. In this study, an application of HDXMS for probing the dynamics of low affinity ligands to proteins is described using the N-terminal ATPase domain of Hsp90. Comparison of Hsp90 dynamics between high affinity natural inhibitors (KD ~ nM and fragment compounds reveal that HDXMS is highly sensitive in mapping the interactions of both high and low affinity ligands. HDXMS reports on changes that reflect both orthosteric effects and allosteric changes accompanying binding. Orthosteric sites can be identified by overlaying HDXMS onto structural information of protein-ligand complexes. Regions distal to orthosteric sites indicate long range conformational changes with implications for allostery. HDXMS, thus finds powerful utility as a high throughput method for compound library screening to identify binding sites and describe allostery with important implications for fragment-based ligand discovery (FBLD.

  11. Predicting Allosteric Effects from Orthosteric Binding in Hsp90-Ligand Interactions: Implications for Fragment-Based Drug Design

    Science.gov (United States)

    Larsson, Andreas; Nordlund, Paer; Jansson, Anna; Anand, Ganesh S.

    2016-01-01

    A key question in mapping dynamics of protein-ligand interactions is to distinguish changes at binding sites from those associated with long range conformational changes upon binding at distal sites. This assumes a greater challenge when considering the interactions of low affinity ligands (dissociation constants, KD, in the μM range or lower). Amide hydrogen deuterium Exchange mass spectrometry (HDXMS) is a robust method that can provide both structural insights and dynamics information on both high affinity and transient protein-ligand interactions. In this study, an application of HDXMS for probing the dynamics of low affinity ligands to proteins is described using the N-terminal ATPase domain of Hsp90. Comparison of Hsp90 dynamics between high affinity natural inhibitors (KD ~ nM) and fragment compounds reveal that HDXMS is highly sensitive in mapping the interactions of both high and low affinity ligands. HDXMS reports on changes that reflect both orthosteric effects and allosteric changes accompanying binding. Orthosteric sites can be identified by overlaying HDXMS onto structural information of protein-ligand complexes. Regions distal to orthosteric sites indicate long range conformational changes with implications for allostery. HDXMS, thus finds powerful utility as a high throughput method for compound library screening to identify binding sites and describe allostery with important implications for fragment-based ligand discovery (FBLD). PMID:27253209

  12. Permeabilization of the blood-brain barrier via mucosal engrafting: implications for drug delivery to the brain.

    Directory of Open Access Journals (Sweden)

    Benjamin S Bleier

    Full Text Available Utilization of neuropharmaceuticals for central nervous system(CNS disease is highly limited due to the blood-brain barrier(BBB which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson's disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS.

  13. Permeabilization of the blood-brain barrier via mucosal engrafting: implications for drug delivery to the brain.

    Science.gov (United States)

    Bleier, Benjamin S; Kohman, Richie E; Feldman, Rachel E; Ramanlal, Shreshtha; Han, Xue

    2013-01-01

    Utilization of neuropharmaceuticals for central nervous system(CNS) disease is highly limited due to the blood-brain barrier(BBB) which restricts molecules larger than 500Da from reaching the CNS. The development of a reliable method to bypass the BBB would represent an enormous advance in neuropharmacology enabling the use of many potential disease modifying therapies. Previous attempts such as transcranial catheter implantation have proven to be temporary and associated with multiple complications. Here we describe a novel method of creating a semipermeable window in the BBB using purely autologous tissues to allow for high molecular weight(HMW) drug delivery to the CNS. This approach is inspired by recent advances in human endoscopic transnasal skull base surgical techniques and involves engrafting semipermeable nasal mucosa within a surgical defect in the BBB. The mucosal graft thereby creates a permanent transmucosal conduit for drugs to access the CNS. The main objective of this study was to develop a murine model of this technique and use it to evaluate transmucosal permeability for the purpose of direct drug delivery to the brain. Using this model we demonstrate that mucosal grafts allow for the transport of molecules up to 500 kDa directly to the brain in both a time and molecular weight dependent fashion. Markers up to 40 kDa were found within the striatum suggesting a potential role for this technique in the treatment of Parkinson's disease. This proof of principle study demonstrates that mucosal engrafting represents the first permanent and stable method of bypassing the BBB thereby providing a pathway for HMW therapeutics directly into the CNS.

  14. Boar spermatozoa successfully predict mitochondrial modes of toxicity: implications for drug toxicity testing and the 3R principles.

    Science.gov (United States)

    Vicente-Carrillo, A; Edebert, I; Garside, H; Cotgreave, I; Rigler, R; Loitto, V; Magnusson, K E; Rodríguez-Martínez, H

    2015-04-01

    Replacement of animal testing by in vitro methods (3-R principles) requires validation of suitable cell models, preferably obtained non-invasively, defying traditional use of explants. Ejaculated spermatozoa are highly dependent on mitochondrial production and consumption of ATP for their metabolism, including motility display, thus becoming a suitable model for capturing multiple modes of action of drugs and other chemicals acting via mitochondrial disturbance. In this study, a hypothesis was tested that the boar spermatozoon is a suitable cell type for toxicity assessment, providing a protocol for 3R-replacement of animals for research and drug-testing. Boar sperm kinetics was challenged with a wide variety of known frank mito-toxic chemicals with previously shown mitochondrial effects, using a semi-automated motility analyser allied with real-time fluorescent probing of mitochondrial potential (MitoTracker & JC-1). Output of this sperm assay (obtained after 30 min) was compared to cell viability (ATP-content, data obtained after 24-48 h) of a hepatome-cell line (HepG2). Results of compound effects significantly correlated (Psperm variables and for most variables in (HepG2). Dose-dependent decreases of relative ATP content in HepG2 cells correlated to sperm speed (r=0.559) and proportions of motile (r=0.55) or progressively motile (r=0.53) spermatozoa. The significance of the study relies on the objectivity of computerized testing of sperm motility inhibition which is comparable albeit of faster output than somatic cell culture models. Sperm suspensions, easily and painlessly obtained from breeding boars, are confirmed as suitable biosensors for preclinical toxicology screening and ranking of lead compounds in the drug development processes.

  15. Interactions of mussel-inspired polymeric nanoparticles with gastric mucin: Implications for gastro-retentive drug delivery.

    Science.gov (United States)

    Sunoqrot, Suhair; Hasan, Lina; Alsadi, Aya; Hamed, Rania; Tarawneh, Ola

    2017-08-01

    Mussel-inspired polydopamine (pD) coatings have several unique characteristics such as durability, versatility, and robustness. In this study, we have designed pD-coated nanoparticles (NPs) of methoxy polyethylene glycol-b-poly(ε-caprolactone) (mPEG-PCL@pD) as prospective nanoscale mucoadhesive platforms for gastro-retentive drug delivery. Successful pD coating on the NPs was confirmed by Transmission Electron Microscopy and X-ray Photoelectron Spectroscopy. Mucoadhesion of pD-coated NPs was investigated in vitro using commercially available mucin under stomach lumen-mimetic conditions. Mucin-NP interactions were monitored by dynamic light scattering, which showed a significant change in particle size distribution of pD-coated NPs at mucin/NP ratios of 1:1, 1:2, and 1:4w/w. Turbidity measurements indicated the formation of large mucin-NP aggregates causing a significant increase in turbidity at mucin/NP ratios of 2:1 and 4:1w/w. pD-coated NPs exhibited a significantly higher mucin adsorption ability compared to uncoated NPs at mucin/NP ratios of 1:4, 1:2, and 1:1w/w. Zeta potential measurements demonstrated that mucin-pD-coated NP interactions were not electrostatic in nature. An ex vivo wash-off test conducted using excised sheep stomach revealed that 78% of pD-coated NPs remained attached to the mucosa after 8h of incubation, compared to only 33% of uncoated NPs. In vitro release of rifampicin, used as a model drug, showed a similar controlled release profile from both pD-coated and uncoated NPs. Our results serve to expand the versatility of mussel-inspired coatings to the design of mucoadhesive nanoscale vehicles for oral drug delivery. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment.

    Science.gov (United States)

    Huang, Xi-Ping; Setola, Vincent; Yadav, Prem N; Allen, John A; Rogan, Sarah C; Hanson, Bonnie J; Revankar, Chetana; Robers, Matt; Doucette, Chris; Roth, Bryan L

    2009-10-01

    Drug-induced valvular heart disease (VHD) is a serious side effect of a few medications, including some that are on the market. Pharmacological studies of VHD-associated medications (e.g., fenfluramine, pergolide, methysergide, and cabergoline) have revealed that they and/or their metabolites are potent 5-hydroxytryptamine(2B) (5-HT(2B)) receptor agonists. We have shown that activation of 5-HT(2B) receptors on human heart valve interstitial cells in vitro induces a proliferative response reminiscent of the fibrosis that typifies VHD. To identify current or future drugs that might induce VHD, we screened approximately 2200 U.S. Food and Drug Administration (FDA)-approved or investigational medications to identify 5-HT(2B) receptor agonists, using calcium-based high-throughput screening. Of these 2200 compounds, 27 were 5-HT(2B) receptor agonists (hits); 14 of these had previously been identified as 5-HT(2B) receptor agonists, including seven bona fide valvulopathogens. Six of the hits (guanfacine, quinidine, xylometazoline, oxymetazoline, fenoldopam, and ropinirole) are approved medications. Twenty-three of the hits were then "functionally profiled" (i.e., assayed in parallel for 5-HT(2B) receptor agonism using multiple readouts to test for functional selectivity). In these assays, the known valvulopathogens were efficacious at concentrations as low as 30 nM, whereas the other compounds were less so. Hierarchical clustering analysis of the pEC(50) data revealed that ropinirole (which is not associated with valvulopathy) was clearly segregated from known valvulopathogens. Taken together, our data demonstrate that patterns of 5-HT(2B) receptor functional selectivity might be useful for identifying compounds likely to induce valvular heart disease.

  17. Thiazolidinedione insulin sensitizers alter lipid bilayer properties and voltage-dependent sodium channel function: implications for drug discovery.

    Science.gov (United States)

    Rusinova, Radda; Herold, Karl F; Sanford, R Lea; Greathouse, Denise V; Hemmings, Hugh C; Andersen, Olaf S

    2011-08-01

    The thiazolidinediones (TZDs) are used in the treatment of diabetes mellitus type 2. Their canonical effects are mediated by activation of the peroxisome proliferator-activated receptor γ (PPARγ) transcription factor. In addition to effects mediated by gene activation, the TZDs cause acute, transcription-independent changes in various membrane transport processes, including glucose transport, and they alter the function of a diverse group of membrane proteins, including ion channels. The basis for these off-target effects is unknown, but the TZDs are hydrophobic/amphiphilic and adsorb to the bilayer-water interface, which will alter bilayer properties, meaning that the TZDs may alter membrane protein function by bilayer-mediated mechanisms. We therefore explored whether the TZDs alter lipid bilayer properties sufficiently to be sensed by bilayer-spanning proteins, using gramicidin A (gA) channels as probes. The TZDs altered bilayer elastic properties with potencies that did not correlate with their affinity for PPARγ. At concentrations where they altered gA channel function, they also altered the function of voltage-dependent sodium channels, producing a prepulse-dependent current inhibition and hyperpolarizing shift in the steady-state inactivation curve. The shifts in the inactivation curve produced by the TZDs and other amphiphiles can be superimposed by plotting them as a function of the changes in gA channel lifetimes. The TZDs' partition coefficients into lipid bilayers were measured using isothermal titration calorimetry. The most potent bilayer modifier, troglitazone, alters bilayer properties at clinically relevant free concentrations; the least potent bilayer modifiers, pioglitazone and rosiglitazone, do not. Unlike other TZDs tested, ciglitazone behaves like a hydrophobic anion and alters the gA monomer-dimer equilibrium by more than one mechanism. Our results provide a possible mechanism for some off-target effects of an important group of drugs, and

  18. Quantitative drug-susceptibility in patients treated for multidrug-resistant tuberculosis in Bangladesh: implications for regimen choice.

    Directory of Open Access Journals (Sweden)

    Scott K Heysell

    Full Text Available Multidrug-resistant tuberculosis (MDR-TB treatment in Bangladesh is empiric or based on qualitative drug-susceptibility testing (DST by comparative growth in culture media with and without a single drug concentration.Adult patients were enrolled throughout Bangladesh during the period of 2011-2013 at MDR-TB treatment initiation. Quantitative DST by minimum inhibitory concentration (MIC testing for 12 first and second-line anti-TB drugs was compared to pretreatment clinical characteristics and treatment outcomes. MIC values at or one dilution lower than the resistance breakpoint used for qualitative DST were categorized as borderline susceptible, and MIC values one or two dilutions greater as borderline resistant.Seventy-four patients were enrolled with a mean age of 35 ± 15 years, and 51 (69% were men. Of the rifampin isolates with MIC >1.0 μg/ml, 12 (19% were fully susceptible or borderline susceptible to rifabutin (MIC ≤ 0.5 μg/ml. Amikacin was fully susceptible in 73 isolates (99%, but kanamycin in only 54 (75% (p<0.001. Ofloxacin was borderline susceptible in 64%, and fully susceptible in only 14 (19% compared to 60 (81% of isolates fully susceptible for moxifloxacin (p<0.001. Kanamycin non-susceptibility and receipt of the WHO Category IV regimen trended with interim treatment failure: adjusted odd ratios respectively of 5.4 [95% CI 0.82-36.2] (p = 0.08 and 7.2 [0.64-80.7] (p = 0.11.Quantitative MIC testing could impact MDR-TB regimen choice in Bangladesh. Comparative trials of higher dose or later generation fluoroquinolone, within class change from kanamycin to amikacin, and inclusion of rifabutin appear warranted.

  19. An Epidemiological Study of Concomitant Use of Chinese Medicine and Antipsychotics in Schizophrenic Patients: Implication for Herb-Drug Interaction

    Science.gov (United States)

    Zhang, Zhang-Jin; Tan, Qing-Rong; Tong, Yao; Wang, Xue-Yi; Wang, Huai-Hai; Ho, Lai-Ming; Wong, Hei Kiu; Feng, Yi-Bin; Wang, Di; Ng, Roger; McAlonan, Grainne M.; Wang, Chuan-Yue; Wong, Vivian Taam

    2011-01-01

    Background Herb-drug interactions are an important issue in drug safety and clinical practice. The aim of this epidemiological study was to characterize associations of clinical outcomes with concomitant herbal and antipsychotic use in patients with schizophrenia. Methods and Findings In this retrospective, cross-sectional study, 1795 patients with schizophrenia who were randomly selected from 17 psychiatric hospitals in China were interviewed face-to-face using a structured questionnaire. Association analyses were conducted to examine correlates between Chinese medicine (CM) use and demographic, clinical variables, antipsychotic medication mode, and clinical outcomes. The prevalence of concomitant CM and antipsychotic treatment was 36.4% [95% confidence interval (95% CI) 34.2%–38.6%]. Patients using concomitant CM had a significantly greater chance of improved outcomes than non-CM use (61.1% vs. 34.3%, OR = 3.44, 95% CI 2.80–4.24). However, a small but significant number of patients treated concomitantly with CM had a greater risk of developing worse outcomes (7.2% vs. 4.4%, OR = 2.06, 95% CI 2.06–4.83). Significant predictors for concomitant CM treatment-associated outcomes were residence in urban areas, paranoid psychosis, and exceeding 3 months of CM use. Herbal medicine regimens containing Radix Bupleuri, Fructus Gardenia, Fructus Schisandrae, Radix Rehmanniae, Akebia Caulis, and Semen Plantaginis in concomitant use with quetiapine, clozapine, and olanzepine were associated with nearly 60% of the risk of adverse outcomes. Conclusions Concomitant herbal and antipsychotic treatment could produce either beneficial or adverse clinical effects in schizophrenic population. Potential herb-drug pharmacokinetic interactions need to be further evaluated. PMID:21359185

  20. An epidemiological study of concomitant use of Chinese medicine and antipsychotics in schizophrenic patients: implication for herb-drug interaction.

    Directory of Open Access Journals (Sweden)

    Zhang-Jin Zhang

    Full Text Available BACKGROUND: Herb-drug interactions are an important issue in drug safety and clinical practice. The aim of this epidemiological study was to characterize associations of clinical outcomes with concomitant herbal and antipsychotic use in patients with schizophrenia. METHODS AND FINDINGS: In this retrospective, cross-sectional study, 1795 patients with schizophrenia who were randomly selected from 17 psychiatric hospitals in China were interviewed face-to-face using a structured questionnaire. Association analyses were conducted to examine correlates between Chinese medicine (CM use and demographic, clinical variables, antipsychotic medication mode, and clinical outcomes. The prevalence of concomitant CM and antipsychotic treatment was 36.4% [95% confidence interval (95% CI 34.2%-38.6%]. Patients using concomitant CM had a significantly greater chance of improved outcomes than non-CM use (61.1% vs. 34.3%, OR = 3.44, 95% CI 2.80-4.24. However, a small but significant number of patients treated concomitantly with CM had a greater risk of developing worse outcomes (7.2% vs. 4.4%, OR = 2.06, 95% CI 2.06-4.83. Significant predictors for concomitant CM treatment-associated outcomes were residence in urban areas, paranoid psychosis, and exceeding 3 months of CM use. Herbal medicine regimens containing Radix Bupleuri, Fructus Gardenia, Fructus Schisandrae, Radix Rehmanniae, Akebia Caulis, and Semen Plantaginis in concomitant use with quetiapine, clozapine, and olanzepine were associated with nearly 60% of the risk of adverse outcomes. CONCLUSIONS: Concomitant herbal and antipsychotic treatment could produce either beneficial or adverse clinical effects in schizophrenic population. Potential herb-drug pharmacokinetic interactions need to be further evaluated.

  1. Cannabidiol, among Other Cannabinoid Drugs, Modulates Prepulse Inhibition of Startle in the SHR Animal Model: Implications for Schizophrenia Pharmacotherapy

    Science.gov (United States)

    Peres, Fernanda F.; Levin, Raquel; Almeida, Valéria; Zuardi, Antonio W.; Hallak, Jaime E.; Crippa, José A.; Abilio, Vanessa C.

    2016-01-01

    Schizophrenia is a severe psychiatric disorder that involves positive, negative and cognitive symptoms. Prepulse inhibition of startle reflex (PPI) is a paradigm that assesses the sensorimotor gating functioning and is impaired in schizophrenia patients as well as in animal models of this disorder. Recent data point to the participation of the endocannabinoid system in the pathophysiology and pharmacotherapy of schizophrenia. Here, we focus on the effects of cannabinoid drugs on the PPI deficit of animal models of schizophrenia, with greater focus on the SHR (Spontaneously Hypertensive Rats) strain, and on the future prospects resulting from these findings. PMID:27667973

  2. Cannabidiol, among other cannabinoid drugs, modulates prepulse inhibition of startle in the SHR animal model: implications for schizophrenia pharmacotherapy

    Directory of Open Access Journals (Sweden)

    Fernanda Fiel Peres

    2016-09-01

    Full Text Available Schizophrenia is a severe psychiatric disorder that involves positive, negative and cognitive symptoms. Prepulse inhibition of startle reflex (PPI is a paradigm that assesses the sensorimotor gating functioning and is impaired in schizophrenia patients as well as in animal models of this disorder. Recent data point to the participation of the endocannabinoid system in the pathophysiology and pharmacotherapy of schizophrenia. Here, we focus on the effects of cannabinoid drugs on the PPI deficit of animal models of schizophrenia, with greater focus on the SHR (Spontaneously Hypertensive Rats strain, and on the future prospects resulting from these findings.

  3. A simple assay for mammalian spermine oxidase: a polyamine catabolic enzyme implicated in drug response and disease.

    Science.gov (United States)

    Goodwin, Andrew C; Murray-Stewart, Tracy R; Casero, Robert A

    2011-01-01

    Spermine oxidase (SMO), the most recently characterized polyamine metabolic enzyme, catalyzes the direct back-conversion of spermine to spermidine in an FAD-dependent reaction that also yields the byproducts hydrogen peroxide (H(2)O(2)) and 3-aminopropanal. These metabolites, particularly H(2)O(2), have been implicated in cytotoxic cellular responses to specific antitumor polyamine analogs, as well as in the inflammation-associated generation of DNA damage. This chapter describes a rapid, sensitive, and inexpensive method for the chemiluminescent measurement of SMO (or alternatively, N (1)-acetyl polyamine oxidase, APAO) enzyme activity in cultured cell lysates, without the need for radioactive reagents or the use of high performance liquid chromatography (HPLC). Specifically, H(2)O(2) production by SMO is coupled to chemiluminescence generated by the horseradish peroxidase-catalyzed oxidation of luminol. Detailed protocols for preparation of reagents, harvesting cell lysates, generation of a standard curve, assaying of samples, and calculation of SMO enzyme activity are presented.

  4. Molecular dynamics of Mycobacterium tuberculosis KasA: implications for inhibitor and substrate binding and consequences for drug design

    Science.gov (United States)

    Schaefer, Benjamin; Kisker, Caroline; Sotriffer, Christoph A.

    2011-11-01

    Inhibition of the production of fatty acids as essential components of the mycobacterial cell wall has been an established way of fighting tuberculosis for decades. However, increasing resistances and an outdated medical treatment call for the validation of new targets involved in this crucial pathway. In this regard, the β-ketoacyl ACP synthase KasA is a promising enzyme. In this study, three molecular dynamics simulations based on the wildtype crystal structures of inhibitor bound and unbound KasA were performed in order to investigate the flexibility and conformational space of this target. We present an exhaustive analysis of the binding-site flexibility and representative pocket conformations that may serve as new starting points for structure-based drug design. We also revealed a mechanism which may account for the comparatively low binding affinity of thiolactomycin. Furthermore, we examined the behavior of water molecules within the binding pocket and provide recommendations how to handle them in the drug design process. Finally, we analyzed the dynamics of a channel that accommodates the long-chain fatty acid substrates and, thereby, propose a mechanism of substrate access to this channel and how products are most likely released.

  5. Phenotypic Screening of Small-Molecule Inhibitors: Implications for Therapeutic Discovery and Drug Target Development in Traumatic Brain Injury.

    Science.gov (United States)

    Al-Ali, Hassan; Lemmon, Vance P; Bixby, John L

    2016-01-01

    The inability of central nervous system (CNS) neurons to regenerate damaged axons and dendrites following traumatic brain injury (TBI) creates a substantial obstacle for functional recovery. Apoptotic cell death, deposition of scar tissue, and growth-repressive molecules produced by glia further complicate the problem and make it challenging for re-growing axons to extend across injury sites. To date, there are no approved drugs for the treatment of TBI, accentuating the need for relevant leads. Cell-based and organotypic bioassays can better mimic outcomes within the native CNS microenvironment than target-based screening methods and thus should speed the discovery of therapeutic agents that induce axon or dendrite regeneration. Additionally, when used to screen focused chemical libraries such as small-molecule protein kinase inhibitors, these assays can help elucidate molecular mechanisms involved in neurite outgrowth and regeneration as well as identify novel drug targets. Here, we describe a phenotypic cellular (high content) screening assay that utilizes brain-derived primary neurons for screening small-molecule chemical libraries.

  6. Implications of international law for the treatment of cancer: the Single Convention on Narcotic Drugs and the TRIPS Agreement.

    Science.gov (United States)

    Liberman, J

    2011-12-01

    The development, manufacture, trade and distribution of medicines all take place within a web of international legal obligations that states have accepted under a range of multilateral, plurilateral and bilateral agreements. International law can operate either to facilitate or hinder access, depending on how it is developed and implemented. This article examines two areas of international law that are relevant to cancer treatment: the international drug control system, which regulates opioid analgesics; and the World Trade Organization's Trade-Related Aspects of Intellectual Property Agreement. This article outlines recent developments in relation to both, including in the activities of the Vienna-based agencies that collectively oversee the implementation of the Single Convention on Narcotic Drugs, and in the negotiation of the recent United Nations General Assembly Political Declaration on Non-communicable Diseases. While underlining the importance of law, this article notes that battles over law should not distract from the importance of other essential efforts to enhance access to medicines within the context of the strengthening of health systems. Copyright © 2011 The Royal Society for Public Health. Published by Elsevier Ltd. All rights reserved.

  7. Inhibition of EGF Uptake by Nephrotoxic Antisense Drugs In Vitro and Implications for Preclinical Safety Profiling

    Directory of Open Access Journals (Sweden)

    Annie Moisan

    2017-03-01

    Full Text Available Antisense oligonucleotide (AON therapeutics offer new avenues to pursue clinically relevant targets inaccessible with other technologies. Advances in improving AON affinity and stability by incorporation of high affinity nucleotides, such as locked nucleic acids (LNA, have sometimes been stifled by safety liabilities related to their accumulation in the kidney tubule. In an attempt to predict and understand the mechanisms of LNA-AON-induced renal tubular toxicity, we established human cell models that recapitulate in vivo behavior of pre-clinically and clinically unfavorable LNA-AON drug candidates. We identified elevation of extracellular epidermal growth factor (EGF as a robust and sensitive in vitro biomarker of LNA-AON-induced cytotoxicity in human kidney tubule epithelial cells. We report the time-dependent negative regulation of EGF uptake and EGF receptor (EGFR signaling by toxic but not innocuous LNA-AONs and revealed the importance of EGFR signaling in LNA-AON-mediated decrease in cellular activity. The robust EGF-based in vitro safety profiling of LNA-AON drug candidates presented here, together with a better understanding of the underlying molecular mechanisms, constitutes a significant step toward developing safer antisense therapeutics.

  8. Phosphorylation mediated structural and functional changes in pentameric ligand-gated ion channels: implications for drug discovery.

    Science.gov (United States)

    Talwar, Sahil; Lynch, Joseph W

    2014-08-01

    Pentameric ligand-gated ion channels (pLGICs) mediate numerous physiological processes, including fast neurotransmission in the brain. They are targeted by a large number of clinically-important drugs and disruptions to their function are associated with many neurological disorders. The phosphorylation of pLGICs can result in a wide range of functional consequences. Indeed, many neurological disorders result from pLGIC phosphorylation. For example, chronic pain is caused by the protein kinase A-mediated phosphorylation of α3 glycine receptors and nicotine addiction is mediated by the phosphorylation of α4- or α7-containing nicotinic receptors. A recent study demonstrated that phosphorylation can induce a global conformational change in a pLGIC that propagates to the neurotransmitter-binding site. Here we present evidence that phosphorylation-induced global conformational changes may be a universal phenomenon in pLGICs. This raises the possibility of designing drugs to specifically treat disease-modified pLGICs. This review summarizes some of the opportunities available in this area.

  9. [European Union regulatory and quality requirements for botanical drugs and their implications for Chinese herbal medicinal products development].

    Science.gov (United States)

    Zhu, You-Ping

    2017-06-01

    This paper introduces regulatory pathways and characteristic quality requirements for marketing authorization of herbal medicinal products in the European Union(EU), and the legal status and applications of "European Union list of herbal substances, preparations and combinations" and "European Union herbal monographs". Also introduced are Chinese herbs that have been granted the EU list entry, those with EU herbal monographs, and registered EU traditional herbal medicinal products with Chinese herbs as active ingredients. Special attention is paid to the technical details of three authorized EU herbal medicinal products (Veregen, Sativex and Episalvan) in comparison with Andrographis paniculata extract HMPL-004 that failed the phase Ⅲ clinical trial for ulcerative colitis. The paper further emphasizes the importance of enriching active fractions of herbal extracts and taking regulatory and quality considerations into account in early stage of botanical drug development. Copyright© by the Chinese Pharmaceutical Association.

  10. Structure and function of cardiac troponin C (TNNC1): Implications for heart failure, cardiomyopathies, and troponin modulating drugs.

    Science.gov (United States)

    Li, Monica X; Hwang, Peter M

    2015-10-25

    In striated muscle, the protein troponin complex turns contraction on and off in a calcium-dependent manner. The calcium-sensing component of the complex is troponin C, which is expressed from the TNNC1 gene in both cardiac muscle and slow-twitch skeletal muscle (identical transcript in both tissues) and the TNNC2 gene in fast-twitch skeletal muscle. Cardiac troponin C (cTnC) is made up of two globular EF-hand domains connected by a flexible linker. The structural C-domain (cCTnC) contains two high affinity calcium-binding sites that are always occupied by Ca(2+) or Mg(2+) under physiologic conditions, stabilizing an open conformation that remains anchored to the rest of the troponin complex. In contrast, the regulatory N-domain (cNTnC) contains a single low affinity site that is largely unoccupied at resting calcium concentrations. During muscle activation, calcium binding to cNTnC favors an open conformation that binds to the switch region of troponin I, removing adjacent inhibitory regions of troponin I from actin and allowing muscle contraction to proceed. Regulation of the calcium binding affinity of cNTnC is physiologically important, because it directly impacts the calcium sensitivity of muscle contraction. Calcium sensitivity can be modified by drugs that stabilize the open form of cNTnC, post-translational modifications like phosphorylation of troponin I, or downstream thin filament protein interactions that impact the availability of the troponin I switch region. Recently, mutations in cTnC have been associated with hypertrophic or dilated cardiomyopathy. A detailed understanding of how calcium sensitivity is regulated through the troponin complex is necessary for explaining how mutations perturb its function to promote cardiomyopathy and how post-translational modifications in the thin filament affect heart function and heart failure. Troponin modulating drugs are being developed for the treatment of cardiomyopathies and heart failure.

  11. HCV subtype characterization among injection drug users: implication for a crucial role of Zhenjiang in HCV transmission in China.

    Directory of Open Access Journals (Sweden)

    Chiyu Zhang

    Full Text Available BACKGROUND: HCV transmission is closely associated with drug-trafficking routes in China. However, the transmission route of HCV in Eastern China remains unclear. Here, we investigate the role of Zhenjiang city of Jiangsu province, an important transportation hub linking Shanghai with other regions of China, in HCV transmission. METHODOLOGY/PRINCIPAL FINDINGS: A total of 141 whole blood samples were collected from injection drug users (IDUs in Zhenjiang and then tested for HCV infection. Of them, 115 HCV positive plasmas were subjected to RNA extraction, RT-PCR amplification, and sequencing. The subtype characterization and the evolutionary origin of HCV strains circulating in Zhenjiang were determined using polygenetic or phylogeographic analyses. Seven HCV subtypes 1b, 2a, 3a, 3b, 6a, 6e and 6n were detected among Zhenjiang IDUs, showing a complex HCV epidemic. The most predominant subtypes were 3a (38% and 1b (26.8%. Among these subtypes, subtypes 3b, 6n and 6e originated from Southwestern China (i.e., Yunnan and/or Guangxi, subtypes 2a and 6a from Southern China (i.e., Guangdong, subtype 1b from Central (i.e., Henan and Northwestern (i.e., Xinjiang China, and subtype 3a from Southwestern (i.e., Yunnan and Northwestern (i.e., Xinjiang China. From Zhenjiang, subtypes 1b and 2a were further spread to Eastern (i.e., Shanghai and Northern (i.e., Beijing China, respectively. CONCLUSIONS/SIGNIFICANCE: The mixing of seven HCV subtypes in Zhenjiang from all quarters of China indicates that as an important middle station, Zhenjiang plays a crucial role in HCV transmission, just as it is important in population migration between other regions of China and Eastern China.

  12. Toxicodynamics of Rigid Polystyrene Microparticles on Pulmonary Gas Exchange in Mice: Implications for Microemboli-based Drug Delivery Systems

    Science.gov (United States)

    Kutscher, HL.; Gao, D.; Li, S.; Massa, CB.; Cervelli, J.; Deshmukh, M.; Joseph, LB.; Laskin, DL.; Sinko, PJ.

    2013-01-01

    The toxicodynamic relationship between the number and size of pulmonary microemboli resulting from uniformly sized, rigid polystyrene microparticles (MPs) administered intravenously and their potential effects on pulmonary gas exchange was investigated. CD-1 male mice (6–8 wk) were intravenously administered 10, 25 and 45 μm diameter MPs. Oxygen hemoglobin saturation in the blood (SpO2) was measured non-invasively using a pulse oximeter while varying inhaled oxygen concentration (FIO2). Resulting data were fit to a physiologically based non-linear mathematical model that estimates 2 parameters: ventilation-perfusion ratio (VA/Q) and shunt (percentage of deoxygenated blood returning to systemic circulation). The number of MPs administered prior to a statistically significant reduction in normalized VA/Q was dependent on particle size. MP doses that resulted in a significant reduction in normalized VA/Q one day post-treatment were 4,000, 40,000 and 550,000 MPs/g for 45, 25 and 10 μm MPs, respectively. The model estimated VA/Q and shunt returned to baseline levels 7 days post-treatment. Measuring SpO2 alone was not sufficient to observe changes in gas exchange; however, when combined with model-derived VA/Q and shunt early reversible toxicity from pulmonary microemboli was detected suggesting that the model and physical measurements are both required for assessing toxicity. Moreover, it appears that the MP load required to alter gas exchange in a mouse prior to lethality is significantly higher than the anticipated required MP dose for effective drug delivery. Overall, the current results indicate that the microemboli-based approach for targeted pulmonary drug delivery is potentially safe and should be further explored. PMID:23142466

  13. Employee assistance program services for alcohol and other drug problems: implications for increased identification and engagement in treatment.

    Science.gov (United States)

    Jacobson, Jodi M; Sacco, Paul

    2012-01-01

    Fourteen million U.S. workers meet the diagnostic criteria for substance dependence, costing millions in lost productivity. Prior research suggests that employees who follow through with their Employee Assistance Program's (EAP) recommendations are more likely to participate and remain engaged in alcohol and other drug (AOD) treatment programs. This study identified rates of lifetime EAP service use for AOD problems and compared adults who reported using EAP services for AOD problems with those who used services other than EAP. Researchers analyzed a subset of participants from the National Epidemiologic Survey of Alcohol and Related Conditions who reported having received help for an AOD problem (NESARC, 2001-2002). Statistical analyses tested for differences in sociodemographic variables, lifetime mental health and substance abuse disorders, and health disability between EAP services users and users of other types of services. Among adults who sought services for AOD problems (n= 2,272), 7.58% (n= 166) reported using EAP services for these problems at some point during their lives. Major depressive disorder (lifetime), a drug use disorder (lifetime), and Black race/ethnicity were associated with a greater likelihood that someone would seek EAP services for help with their AOD problem. Results provide a foundation for researchers to understand who uses EAP services for AOD problems. Health and mental health professionals should increase their knowledge of EAP services to improve continuity of care for employees with AOD problems. EAPs are in a unique position to reach out to vulnerable employees in the workplace and engage them in treatment. Copyright © American Academy of Addiction Psychiatry.

  14. Proteomic profiling of patient-derived glioblastoma xenografts identifies a subset with activated EGFR: implications for drug development.

    Science.gov (United States)

    Brown, Kristine E; Chagoya, Gustavo; Kwatra, Shawn G; Yen, Timothy; Keir, Stephen T; Cooter, Mary; Hoadley, Katherine A; Rasheed, Ahmed; Lipp, Eric S; Mclendon, Roger; Ali-Osman, Francis; Bigner, Darell D; Sampson, John H; Kwatra, Madan M

    2015-06-01

    The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. To date, proteomic level validation of widely used patient-derived glioblastoma xenografts (PDGX) has not been performed. In the present study, we characterized 20 PDGX models according to subtype classification based on The Cancer Genome Atlas criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. The 20 PDGXs belonged to three of four The Cancer Genome Atlas subtypes: eight classical, eight mesenchymal, and four proneural; none neural. Amplification of EGFR gene was observed in 9 of 20 xenografts, and of these, 3 harbored the EGFRvIII mutation. We then performed proteomic profiling of PDGX, analyzing expression/activity of several proteins including EGFR. Levels of EGFR phosphorylated at Y1068 vary considerably between PDGX samples, and this pattern was also seen in primary GBM. Partitioning of 20 PDGX into high (n = 5) and low (n = 15) groups identified a panel of proteins associated with high EGFR activity. Thus, PDGX with high EGFR activity represent an excellent pre-clinical model to develop therapies for a subset of GBM patients whose tumors are characterized by high EGFR activity. Further, the proteins found to be associated with high EGFR activity can be monitored to assess the effectiveness of targeting EGFR. The development of drugs to inhibit glioblastoma (GBM) growth requires reliable pre-clinical models. We validated proteomic profiles using patient-derived glioblastoma xenografts (PDGX), characterizing 20 PDGX models according to subtype classification based on The Cancer Genome Atlas (TCGA) criteria, TP53, PTEN, IDH 1/2, and TERT promoter genetic analysis, EGFR amplification status, and examined their proteomic profiles against those of their parent tumors. Proteins found to be associated with high EGFR activity represent potential

  15. Potential to enhance the prescribing of generic drugs in patients with mental health problems in Austria; implications for the future

    Directory of Open Access Journals (Sweden)

    Brian eGodman

    2013-01-01

    Full Text Available Introduction: Scrutiny over pharmaceutical expenditure is increasing leading to multiple reforms. This includes Austria with measures to lower generic prices and enhance their utilisation. However the situation for newer antidepressants and atypical antipsychotic drugs (AAPs is different to PPIs, statins and renin-angiotensin drugs with greater tailoring of therapy and no wish to switch products in stable patients. Authorities welcome generics though given high costs particularly of patented AAPs. Objective: Assess (a changes in utilisation of venlafaxine versus other newer anti-depressants before and after availability of generics, (b utilisation of generic versus originator venlafaxine, (c price reductions of venlafaxine over time and influence on total expenditure, (d utilisation of risperidone versus other AAPs, (e suggest potential additional reforms that could be introduced if pertinent. Methodology: A quasi-experimental study design with a segmented time series and an observational study. Utilisation measured in defined daily doses (DDDs and total expenditure per DDD and over time. Results: No appreciable changes in the utilization patterns of venlafaxine and risperidone after generics. The reduction in expenditure/ DDD for venlafaxine decreased overall expenditure on antidepressants by 5% by the end of the study versus just before generics despite a 37% increase in utilization. Expenditure will further decrease if there was reduced prescribing of duloxetine. Conclusion: Depression, schizophrenia and bipolar diseases are complex diseases. As a result, specific measures are needed to encourage prescribing of generic risperidone and venlafaxine when multiple choices are appropriate, and authorities cannot rely on a ´Hawthorne´ effect between classes to enhance use of generics first line. Measures may include prescribing restrictions for duloxetine. No specific measures planned for AAPs with more generics becoming available.

  16. Cyclosporin A in Membrane Lipids Environment: Implications for Antimalarial Activity of the Drug--The Langmuir Monolayer Studies.

    Science.gov (United States)

    Dynarowicz-Łątka, Patrycja; Wnętrzak, Anita; Makyła-Juzak, Katarzyna

    2015-12-01

    Cyclosporin A (CsA), a hydrophobic cyclic peptide produced by the fungus Tolypocladium inflatum, is well known for its high efficiency as an immunosuppressor for transplanted organs and anti-inflammatory properties; however, it is also active as antiparasitic (antimalarial) drug. Antimalarial mechanism of CsA action lacks a detailed understanding at molecular level. Due to a high lipophilicity of CsA, it is able to interact with lipids of cellular membrane; however, molecular targets of this drug are still unknown. To get a deeper insight into the mode of antimalarial activity of CsA, it is of utmost importance to examine its interactions with membrane components. To reach this goal, the Langmuir monolayer technique, which serves as a very useful, easy to handle and controllable model of biomembranes, has been employed. In this work, the interactions between CsA and main membrane lipids, i.e., cholesterol (Chol), 2-oleoyl-1-palmitoyl-3-phosphocholine (POPC), and sphingomyelin (SM), have been investigated. Attractive interactions are observed only for CsA mixtures with SM, while repulsive forces occur in systems containing remaining membrane lipids. Taking into consideration mutual interactions between membrane lipids (Chol-SM; Chol-POPC and SM-POPC), the behavior of CsA in model erythrocyte membrane of normal and infected cells has been analyzed. Our results prove strong affinity of CsA to SM in membrane environment. Since normal and parasitized erythrocytes differ significantly in the level of SM, this phospholipid may be considered as a molecular target for antimalarial activity of CsA.

  17. Implications of Parkinson's disease pathophysiology for the development of cell replacement strategies and drug discovery in neurodegenerative diseases.

    Science.gov (United States)

    Pan-Montojo, Francisco; Funk, Richard H W

    2012-11-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder traditionally characterized by the loss of dopaminergic neurons in the substantia nigra (SN) at the midbrain. The potential use of adult or embryonic stem cells, induced pluriputent stem (iPS) cells and endogenous neurogenesis in cell replacement strategies has lead to numerous studies and clinical trials in this direction. It is now possible to differentiate stem cells into dopaminergic neurons in vitro and clinical trials have shown an improvement in PD-related symptoms after intra-striatal embryonic transplants and acceptable cell survival rates on the mid term. However, clinical improvement is transitory and associated with a strong placebo effect. Interestingly, recent pathological studies in PD patients who received embryonic stem cells show that in PD patients, grafted neurons show PD-related pathology. In this manuscript we review the latest findings regarding PD pathophysiology and give an outlook on the implications of these findings in how cell replacement strategies for PD treatment should be tested. These include changes in the type of animal models used, the preparation/conditioning of the cells before intracerebral injection, specially regarding backbone chronic diseases in iPS cells and determining the optimal proliferation, survival, differentiation and migration capacity of the grafted cells.

  18. Dorsal medial prefrontal cortex (MPFC) circuitry in rodent models of cocaine use: implications for drug addiction therapies.

    Science.gov (United States)

    Jasinska, Agnes J; Chen, Billy T; Bonci, Antonello; Stein, Elliot A

    2015-03-01

    Although the importance of the medial prefrontal cortex (MPFC) in cocaine addiction is well established, its precise contribution to cocaine seeking, taking and relapse remains incompletely understood. In particular, across two different models of cocaine self-administration, pharmacological or optogenetic activation of the dorsal MPFC has been reported to sometimes promote and sometimes inhibit cocaine seeking. We highlight important methodological differences between the two experimental paradigms and propose a framework to potentially reconcile the apparent discrepancy. We also draw parallels between these pre-clinical models of cocaine self-administration and human neuro-imaging studies in cocaine users, and argue that both lines of evidence point to dynamic interactions between cue-reactivity processes and control processes within the dorsal MPFC circuitry. From a translational perspective, these findings underscore the importance of interventions and therapeutics targeting not just a brain region, but a specific computational process within that brain region, and may have implications for the design and implementation of more effective treatments for human cocaine addiction. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

  19. Toxicodynamics of rigid polystyrene microparticles on pulmonary gas exchange in mice: Implications for microemboli-based drug delivery systems

    Energy Technology Data Exchange (ETDEWEB)

    Kutscher, H.L. [Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); Gao, D.; Li, S. [Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); UMDNJ-Rutgers CounterACT Research Center of Excellence, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); Massa, C.B.; Cervelli, J. [Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); Deshmukh, M. [Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); UMDNJ-Rutgers CounterACT Research Center of Excellence, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); Joseph, L.B.; Laskin, D.L. [UMDNJ-Rutgers CounterACT Research Center of Excellence, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); Sinko, P.J., E-mail: sinko@rci.rutgers.edu [Department of Pharmaceutics, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States); UMDNJ-Rutgers CounterACT Research Center of Excellence, Rutgers, The State University of New Jersey, Piscataway, NJ 08854 (United States)

    2013-01-15

    The toxicodynamic relationship between the number and size of pulmonary microemboli resulting from uniformly sized, rigid polystyrene microparticles (MPs) administered intravenously and their potential effects on pulmonary gas exchange were investigated. CD-1 male mice (6–8 weeks) were intravenously administered 10, 25 and 45 μm diameter MPs. Oxygen hemoglobin saturation in the blood (SpO{sub 2}) was measured non-invasively using a pulse oximeter while varying inhaled oxygen concentration (F{sub I}O{sub 2}). The resulting data were fit to a physiologically based non-linear mathematical model that estimates 2 parameters: ventilation–perfusion ratio (V{sub A}/Q) and shunt (percentage of deoxygenated blood returning to systemic circulation). The number of MPs administered prior to a statistically significant reduction in normalized V{sub A}/Q was dependent on particle size. MP doses that resulted in a significant reduction in normalized V{sub A}/Q one day post-treatment were 4000, 40,000 and 550,000 MPs/g for 45, 25 and 10 μm MPs, respectively. The model estimated V{sub A}/Q and shunt returned to baseline levels 7 days post-treatment. Measuring SpO{sub 2} alone was not sufficient to observe changes in gas exchange; however, when combined with model-derived V{sub A}/Q and shunt early reversible toxicity from pulmonary microemboli was detected suggesting that the model and physical measurements are both required for assessing toxicity. Moreover, it appears that the MP load required to alter gas exchange in a mouse prior to lethality is significantly higher than the anticipated required MP dose for effective drug delivery. Overall, the current results indicate that the microemboli-based approach for targeted pulmonary drug delivery is potentially safe and should be further explored. -- Highlights: ► Murine pulmonary gas exchange after microembolization was non-invasively studied. ► A physiologically based model quantified impairment of pulmonary gas exchange.

  20. Three-dimensional lung tumor microenvironment modulates therapeutic compound responsiveness in vitro--implication for drug development.

    Directory of Open Access Journals (Sweden)

    Jason E Ekert

    Full Text Available Three-dimensional (3D cell culture is gaining acceptance in response to the need for cellular models that better mimic physiologic tissues. Spheroids are one such 3D model where clusters of cells will undergo self-assembly to form viable, 3D tumor-like structures. However, to date little is known about how spheroid biology compares to that of the more traditional and widely utilized 2D monolayer cultures. Therefore, the goal of this study was to characterize the phenotypic and functional differences between lung tumor cells grown as 2D monolayer cultures, versus cells grown as 3D spheroids. Eight lung tumor cell lines, displaying varying levels of epidermal growth factor receptor (EGFR and cMET protein expression, were used to develop a 3D spheroid cell culture model using low attachment U-bottom plates. The 3D spheroids were compared with cells grown in monolayer for 1 EGFR and cMET receptor expression, as determined by flow cytometry, 2 EGFR and cMET phosphorylation by MSD assay, and 3 cell proliferation in response to epidermal growth factor (EGF and hepatocyte growth factor (HGF. In addition, drug responsiveness to EGFR and cMET inhibitors (Erlotinib, Crizotinib, Cetuximab [Erbitux] and Onartuzumab [MetMab] was evaluated by measuring the extent of cell proliferation and migration. Data showed that EGFR and cMET expression is reduced at day four of untreated spheroid culture compared to monolayer. Basal phosphorylation of EGFR and cMET was higher in spheroids compared to monolayer cultures. Spheroids showed reduced EGFR and cMET phosphorylation when stimulated with ligand compared to 2D cultures. Spheroids showed an altered cell proliferation response to HGF, as well as to EGFR and cMET inhibitors, compared to monolayer cultures. Finally, spheroid cultures showed exceptional utility in a cell migration assay. Overall, the 3D spheroid culture changed the cellular response to drugs and growth factors and may more accurately mimic the natural

  1. Three-dimensional lung tumor microenvironment modulates therapeutic compound responsiveness in vitro--implication for drug development.

    Science.gov (United States)

    Ekert, Jason E; Johnson, Kjell; Strake, Brandy; Pardinas, Jose; Jarantow, Stephen; Perkinson, Robert; Colter, David C

    2014-01-01

    Three-dimensional (3D) cell culture is gaining acceptance in response to the need for cellular models that better mimic physiologic tissues. Spheroids are one such 3D model where clusters of cells will undergo self-assembly to form viable, 3D tumor-like structures. However, to date little is known about how spheroid biology compares to that of the more traditional and widely utilized 2D monolayer cultures. Therefore, the goal of this study was to characterize the phenotypic and functional differences between lung tumor cells grown as 2D monolayer cultures, versus cells grown as 3D spheroids. Eight lung tumor cell lines, displaying varying levels of epidermal growth factor receptor (EGFR) and cMET protein expression, were used to develop a 3D spheroid cell culture model using low attachment U-bottom plates. The 3D spheroids were compared with cells grown in monolayer for 1) EGFR and cMET receptor expression, as determined by flow cytometry, 2) EGFR and cMET phosphorylation by MSD assay, and 3) cell proliferation in response to epidermal growth factor (EGF) and hepatocyte growth factor (HGF). In addition, drug responsiveness to EGFR and cMET inhibitors (Erlotinib, Crizotinib, Cetuximab [Erbitux] and Onartuzumab [MetMab]) was evaluated by measuring the extent of cell proliferation and migration. Data showed that EGFR and cMET expression is reduced at day four of untreated spheroid culture compared to monolayer. Basal phosphorylation of EGFR and cMET was higher in spheroids compared to monolayer cultures. Spheroids showed reduced EGFR and cMET phosphorylation when stimulated with ligand compared to 2D cultures. Spheroids showed an altered cell proliferation response to HGF, as well as to EGFR and cMET inhibitors, compared to monolayer cultures. Finally, spheroid cultures showed exceptional utility in a cell migration assay. Overall, the 3D spheroid culture changed the cellular response to drugs and growth factors and may more accurately mimic the natural tumor

  2. Three-Dimensional Lung Tumor Microenvironment Modulates Therapeutic Compound Responsiveness In Vitro – Implication for Drug Development

    Science.gov (United States)

    Ekert, Jason E.; Johnson, Kjell; Strake, Brandy; Pardinas, Jose; Jarantow, Stephen; Perkinson, Robert; Colter, David C.

    2014-01-01

    Three-dimensional (3D) cell culture is gaining acceptance in response to the need for cellular models that better mimic physiologic tissues. Spheroids are one such 3D model where clusters of cells will undergo self-assembly to form viable, 3D tumor-like structures. However, to date little is known about how spheroid biology compares to that of the more traditional and widely utilized 2D monolayer cultures. Therefore, the goal of this study was to characterize the phenotypic and functional differences between lung tumor cells grown as 2D monolayer cultures, versus cells grown as 3D spheroids. Eight lung tumor cell lines, displaying varying levels of epidermal growth factor receptor (EGFR) and cMET protein expression, were used to develop a 3D spheroid cell culture model using low attachment U-bottom plates. The 3D spheroids were compared with cells grown in monolayer for 1) EGFR and cMET receptor expression, as determined by flow cytometry, 2) EGFR and cMET phosphorylation by MSD assay, and 3) cell proliferation in response to epidermal growth factor (EGF) and hepatocyte growth factor (HGF). In addition, drug responsiveness to EGFR and cMET inhibitors (Erlotinib, Crizotinib, Cetuximab [Erbitux] and Onartuzumab [MetMab]) was evaluated by measuring the extent of cell proliferation and migration. Data showed that EGFR and cMET expression is reduced at day four of untreated spheroid culture compared to monolayer. Basal phosphorylation of EGFR and cMET was higher in spheroids compared to monolayer cultures. Spheroids showed reduced EGFR and cMET phosphorylation when stimulated with ligand compared to 2D cultures. Spheroids showed an altered cell proliferation response to HGF, as well as to EGFR and cMET inhibitors, compared to monolayer cultures. Finally, spheroid cultures showed exceptional utility in a cell migration assay. Overall, the 3D spheroid culture changed the cellular response to drugs and growth factors and may more accurately mimic the natural tumor

  3. Dealing food: Female drug users’ narratives about food in a prison place and implications for their health

    Science.gov (United States)

    Smoyer, Amy B.; Blankenship, Kim M.

    2015-01-01

    Background Prison is a major “place” for drug users in the US, yet remarkably little is known about the lived experience of incarceration. More information about prison life is needed to improve health outcomes for incarcerated and formerly incarcerated people. Methods Thirty (30) formerly incarcerated women were interviewed about prison food. All interviews were digitally recorded and transcribed. Qualitative data analysis software was used to code and organize the data using thematic analysis. Results As described in these participants’ narratives, prison food systems contributed to the construction of boundaries that distinguished the prison place from places and life outside the institution's walls. Participants also described boundaries within the prison that resulted in a patchwork of interior places, each with their own unique structure, meaning, and food system. These places, constructed by physical location, movement, and power, or lack thereof, included various micro-geographies that further defined women's individual prison experience. The boundaries that separated these places were not fixed: Women shifted and diminished internal and external borders by resisting food policies and reproducing their outside lives inside. Conclusion These findings call for public policy officials and prison administrators to reexamine the prison place in order to facilitate healthier eating behaviors and lay the groundwork for more positive communication between inmates and correctional staff and administration. More research is needed to measure how these types of changes to the prison food environment impact nutritional, mental health, substance abuse, and criminal justice outcomes. PMID:24412007

  4. Current Challenges to the United States’ AIDS Drug Assistance Program and Possible Implications of the Affordable Care Act

    Directory of Open Access Journals (Sweden)

    Kathleen A. McManus

    2013-01-01

    Full Text Available AIDS Drug Assistance Programs, enacted through the Ryan White Comprehensive AIDS Resources Emergency Act of 1990, are the “payer of last resort” for prescription medications for lower income, uninsured, or underinsured people living with HIV/AIDS. ADAPs face declining funding from the federal government. State funding of ADAP is discretionary, but some states increased their contributions to meet the gap in funding. The demand for ADAP support is increasing as people living with HIV are living longer; the antiretroviral therapy (ART guidelines have been changed to recommend initiation of treatment for all; the United States is increasing HIV testing goals; and the recession continues. In the setting of increased demand and limited funding, ADAPs are employing cost containment measures. Since 2010, emergency federal funds have bailed out ADAP, but these are not sustainable. In the coming years, providers and policy makers associated with HIV care will need to navigate the implementation of the Affordable Care Act (ACA. Lessons learned from the challenges associated with providing sustainable access to ART for vulnerable populations through ADAP should inform upcoming decisions about how to ensure delivery of ART during and after the implementation of the ACA.

  5. Evolutionary relationships of Aurora kinases: Implications for model organism studies and the development of anti-cancer drugs

    Directory of Open Access Journals (Sweden)

    Patrick Denis R

    2004-10-01

    Full Text Available Abstract Background As key regulators of mitotic chromosome segregation, the Aurora family of serine/threonine kinases play an important role in cell division. Abnormalities in Aurora kinases have been strongly linked with cancer, which has lead to the recent development of new classes of anti-cancer drugs that specifically target the ATP-binding domain of these kinases. From an evolutionary perspective, the species distribution of the Aurora kinase family is complex. Mammals uniquely have three Aurora kinases, Aurora-A, Aurora-B, and Aurora-C, while for other metazoans, including the frog, fruitfly and nematode, only Aurora-A and Aurora-B kinases are known. The fungi have a single Aurora-like homolog. Based on the tacit assumption of orthology to human counterparts, model organism studies have been central to the functional characterization of Aurora kinases. However, the ortholog and paralog relationships of these kinases across various species have not been rigorously examined. Here, we present comprehensive evolutionary analyses of the Aurora kinase family. Results Phylogenetic trees suggest that all three vertebrate Auroras evolved from a single urochordate ancestor. Specifically, Aurora-A is an orthologous lineage in cold-blooded vertebrates and mammals, while structurally similar Aurora-B and Aurora-C evolved more recently in mammals from a duplication of an ancestral Aurora-B/C gene found in cold-blooded vertebrates. All so-called Aurora-A and Aurora-B kinases of non-chordates are ancestral to the clade of chordate Auroras and, therefore, are not strictly orthologous to vertebrate counterparts. Comparisons of human Aurora-B and Aurora-C sequences to the resolved 3D structure of human Aurora-A lends further support to the evolutionary scenario that vertebrate Aurora-B and Aurora-C are closely related paralogs. Of the 26 residues lining the ATP-binding active site, only three were variant and all were specific to Aurora-A. Conclusions In

  6. Inhibition of CYP3A4 and CYP2C9 by podophyllotoxin: Implication for clinical drug–drug interactions

    Indian Academy of Sciences (India)

    Jin-Hui Song; Dong-Xue Sun; Bin Chen; Dai-Hong Ji; Jie Pu; Jie Xu; Feng-De Tian; Lin Guo

    2011-12-01

    Podophyllotoxin (PPT) and its derivatives exert significant anti-cancer activities, and one derivative etoposide is often utilized to treat various cancers in the clinic. The aim of the present study is to investigate the inhibitory effects of PPT on major cytochrome P450 (CYP) isoforms in human livers. Inhibition of CYP3A4, CYP2C9, CYP2C8, CYP2D6, CYP2E1 and CYP2A6 by PPT was investigated in the human liver microsomal system. Time-dependent inhibition of CYP3A4 by PPT was also evaluated. The results showed that PPT strongly exhibited inhibitory effects on CYP3A4 and CYP2C9 in a concentration-dependent manner. Half inhibition concentration (IC50) was 1.1±0.3 and 4.6±0.3 M for CYP3A4 and CYP2C9, respectively. Inhibition kinetic analysis showed that PPT exhibited competitive inhibition towards CYP3A4 and CYP2C9 with Ki of 1.6 and 2.0 M, respectively. Additionally, PPT exerted time-dependent inhibition towards CYP3A4 and the kinetic parameters were 4.4±2.1 M and 0.06±0.01 min–1 for KI and kinact, respectively. Our experimental data indicate that potential drug–drug interaction (DDI) might exist when PPT is co-administered with the substrates which mainly undergo CYP3A4- or CYP2C9-mediated metabolism.

  7. Mitophagy or how to control the Jekyll and Hyde embedded in mitochondrial metabolism: implications for melanoma progression and drug resistance.

    Science.gov (United States)

    Soengas, María S

    2012-11-01

    Proteins and pathways that control cell fate are placed under intense scrutiny. The same tight regulation applies to essential organelles that can both sustain cell survival or promote self-degradation programs. Mitochondria are perhaps the prime example of cellular machineries with split functions (personalities). As a main source of ATP, mitochondria represent the main powerhouse of eukaryotic cells. However, mitochondrial respiration has the hidden complication of the production of potentially harmful reactive oxygen species (ROS). Moreover, mitochondria holds an armamentarium of stress-response factors, which depending on the context, may lead to pro-inflammatory signals, and to various forms of cell death, ranging from apoptosis to necrosis. A main clearance mechanism to eliminate superfluous, damaged or hyperactive mitochondria is selective mitophagy. Mitophagy, in fact, is emerging as a key quality-control mechanism in cancer cells. Specifically, malignant transformation has been found to induce marked changes in mitochondrial dynamics and structure. Moreover, a key hallmark of tumor progression is metabolic reprogramming, which further deregulates ROS content and renders cells more susceptible to mitochondrial perturbations. Despite its increasing relevance in cancer biology, the field of mitophagy remains virtually unexplored in melanoma. However, given unique antioxidant mechanisms in melanocytic cells (e.g., linked to melanin) and the idiosyncratic interplay between ROS and hypoxia (both mitophagy inducers) in melanoma, this tumor type represents an ideal scenario for physiological studies of mitochondrial turnover. This perspective summarizes proof of concept for in-depth basic and translational studies of mitophagy in melanoma. Particular emphasis is dedicated to new opportunities for gene discovery and drug design in this still aggressive disease. © 2012 John Wiley & Sons A/S.

  8. Multiparameter phospho-flow analysis of lymphocytes in early rheumatoid arthritis: implications for diagnosis and monitoring drug therapy.

    Directory of Open Access Journals (Sweden)

    Carole L Galligan

    -activation of specific signaling effectors in the PB from patients with ERA. Notably, phosphorylation of these signaling effectors did not distinguish ERA from late RA, suggesting that the activation status of discrete cell populations is already established early in disease. However, when the ratio of MFI values for p-AKT and p-p38 is >1.5, there is a high likelihood of having a diagnosis of RA. Our results suggest that longitudinal sampling of patients undergoing therapy may result in phospho-signatures that are predictive of drug responsiveness.

  9. A case study using a patient satisfaction survey to improve the delivery and effectiveness of drug addiction treatment services: marketing implications and organizational impact.

    Science.gov (United States)

    Hogan, Beth; Hershey, Lewis; Ritchey, Steven

    2007-01-01

    Drug abuse and addiction continues to negatively impact many lives in this country. The United States health care system has grappled with how to best serve this vulnerable population. Since the personal and societal costs of addiction are high, all recent iterations of the United States strategic health plans (such as Healthy People 2010) have prioritized this area for improvement. At the local level, health care providers who care for those with addictions are challenged with shrinking insurance coverage for services, a difficult patient population, lack of treatment options, growing ranks of indigent patients, as well as a plethora of additional management challenges. It is known that successful treatment is integrally linked with patient satisfaction with services. The most critical factors in successful addiction treatment (from a patient's perspective) are (1) their belief that the counselor cares about them and, (2) their belief that they can recover. This paper reports a case study in the use of a patient satisfaction survey as a quality management/service refinement tool within a methadone treatment setting. Results indicate that the use of the survey itself provides patients with a tangible cue supporting the presence of the critical success factors. Further, the use of a survey provides a baseline for future measurements and trending. The paper concludes with a discussion of the marketing and organizational implications of incorporating the patient satisfaction survey into the ongoing delivery program for addiction services.

  10. Real-time study of E-cadherin and membrane dynamics in living animals: implications for disease modeling and drug development.

    Science.gov (United States)

    Serrels, Alan; Timpson, Paul; Canel, Marta; Schwarz, Juliane P; Carragher, Neil O; Frame, Margaret C; Brunton, Valerie G; Anderson, Kurt I

    2009-04-01

    The ability of tumor cells to invade and metastasize requires deregulation of interactions with adjacent cells and the extracellular matrix. A major challenge of cancer biology is to observe the dynamics of the proteins involved in this process in their functional and physiologic context. Here, for the first time, we have used photobleaching and photoactivation to compare the mobility of cell adhesion and plasma membrane probes in vitro and in tumors grown in mice (in vivo). We find differences between in vitro and in vivo recovery dynamics of two key molecules, the tumor suppressor E-cadherin and the membrane-targeting sequence of H-Ras. Our data show that E-cadherin dynamics are significantly faster in vivo compared with cultured cells, that the ratio of E-cadherin stabilized in cell-cell junctions is significantly higher in vivo, and that E-cadherin mobility correlates with cell migration. Moreover, quantitative imaging has allowed us to assess the effects of therapeutic intervention on E-cadherin dynamics using dasatinib, a clinically approved Src inhibitor, and show clear differences in the efficacy of drug treatment in vivo. Our results show for the first time the utility of photobleaching and photoactivation in the analysis of dynamic biomarkers in living animals. Furthermore, this work highlights critical differences in molecular dynamics in vitro and in vivo, which have important implications for the use of cultured disease models as surrogates for living tissue.

  11. Motivations and Implications of Community Service Provision by La Familia Michoacána / Knights Templar and other Mexican Drug Cartels

    Directory of Open Access Journals (Sweden)

    Shawn T. Flanigan

    2014-10-01

    Full Text Available Research demonstrates that service provision by violent organizations can be an effective strategy for coercing the local community to accept and conceal a group’s violent activities, and for creating loyalty to these groups. This has been most frequently explored among political organizations such as terrorist groups, with organizations like Hezbollah and Hamas very visibly engaged in providing social welfare in addition to their violent activities. Recent reports indicate that criminal organizations in Mexico also are involved in instances of public service provision in local communities. This article explores the extent to which drug cartels operating in Mexico are involved in public service provision to members of communities where they operate, and considers possible motivations and implications for public service provision by these criminal organizations, with specific attention to the organization La Familia Michoacána/ Knights Templar. The article also gives attention to the consequences to citizenship and government of service provision by violent nonstate actors, and the ways such service provision may disrupt the social contract between the citizen and the state.

  12. Probing secondary glutaminyl cyclase (QC) inhibitor interactions applying an in silico-modeling/site-directed mutagenesis approach: implications for drug development.

    Science.gov (United States)

    Koch, Birgit; Buchholz, Mirko; Wermann, Michael; Heiser, Ulrich; Schilling, Stephan; Demuth, Hans-Ulrich

    2012-12-01

    Glutaminyl cyclases (QCs) catalyze the formation of pyroglutamate-modified amyloid peptides deposited in neurodegenerative disorders such as Alzheimer's disease. Inhibitors of QC are currently in development as potential therapeutics. The crystal structures of the potent inhibitor PBD150 bound to human and murine QC (hQC, mQC) have been described recently. The binding modes of a dimethoxyphenyl moiety of the inhibitor are significantly different between the structures, which contrasts with a similar K(i) value. We show the conformation of PBD150 prone to disturbance by protein-protein interactions within the crystals. Semi-empirical calculations of the enzyme-inhibitor interaction within the crystal suggest significant differences in the dissociation constants between the binding modes. To probe for interactions in solution, a site-directed mutagenesis on hQC was performed. The replacement of F325 and I303 by alanine or asparagine resulted in a 800-fold lower activity of the inhibitor, whereas the exchange of S323 by alanine or valine led to a 20-fold higher activity of PBD150. The results provide an example of deciphering the interaction mode between a target enzyme and lead substance in solution, if co-crystallization does not mirror such interactions properly. Thus, the study might provide implications for rapid screening of binding modes also for other drug targets.

  13. Synthesis and pharmacological activity of adaprolol enantiomers: a new soft drug for treating glaucoma.

    Science.gov (United States)

    Boder, N; Elkoussi, A; Zuobi, K; Kovacs, P

    1996-01-01

    Adaprolol maleate is a new beta-adrenergic antagonist that is being developed to treat glaucoma. The soft drug was designed to minimize systemic activity through facile inactivation to an inactive metabolite. Studies with other potent beta-adrenergic antagonists indicated that tissue specific receptor differences might be more stringent for selected beta-adrenergic blocking activities and suggested that R enantiomers of traditional beta-blockers should be developed for controlling glaucoma. The present studies demonstrate that the potent ocular hypotensive effects of adaprolol are not stereoselective. In contrast, cardiac effects could be detected after intravenous S(+) adaprolol, but not R(-) adaprolol. The studies confirm that adaprolol functions as a potent beta-adrenergic antagonist. The negligible systemic beta-blocking activity detected with opthalmic administration of adaprolol is consistent with soft drug design.

  14. Scavenging of free-radical metabolites of aniline xenobiotics and drugs by amino acid derivatives: toxicological implications of radical-transfer reactions.

    Science.gov (United States)

    Michail, Karim; Baghdasarian, Argishti; Narwaley, Malyaj; Aljuhani, Naif; Siraki, Arno G

    2013-12-16

    is proposed between aminocarboxylates and arylamine free radicals via the carboxylic group-linked tertiary nitrogen of the deprotonated amino acid derivatives. These findings may have significant implications for the biological fate of arylamine xenobiotic and drug free-radical metabolites.

  15. Neurodevelopmental Animal Models Reveal the Convergent Role of Neurotransmitter Systems, Inflammation, and Oxidative Stress as Biomarkers of Schizophrenia: Implications for Novel Drug Development.

    Science.gov (United States)

    Möller, M; Swanepoel, T; Harvey, B H

    2015-07-15

    Schizophrenia is a life altering disease with a complex etiology and pathophysiology, and although antipsychotics are valuable in treating the disorder, certain symptoms and/or sufferers remain resistant to treatment. Our poor understanding of the underlying neuropathological mechanisms of schizophrenia hinders the discovery and development of improved pharmacological treatment, so that filling these gaps is of utmost importance for an improved outcome. A vast amount of clinical data has strongly implicated the role of inflammation and oxidative insults in the pathophysiology of schizophrenia. Preclinical studies using animal models are fundamental in our understanding of disease development and pathology as well as the discovery and development of novel treatment options. In particular, social isolation rearing (SIR) and pre- or postnatal inflammation (PPNI) have shown great promise in mimicking the biobehavioral manifestations of schizophrenia. Furthermore, the "dual-hit" hypothesis of schizophrenia states that a first adverse event such as genetic predisposition or a prenatal insult renders an individual susceptible to develop the disease, while a second insult (e.g., postnatal inflammation, environmental adversity, or drug abuse) may be necessary to precipitate the full-blown syndrome. Animal models that emphasize the "dual-hit" hypothesis therefore provide valuable insight into understanding disease progression. In this Review, we will discuss SIR, PPNI, as well as possible "dual-hit" animal models within the context of the redox-immune-inflammatory hypothesis of schizophrenia, correlating such changes with the recognized monoamine and behavioral alterations of schizophrenia. Finally, based on these models, we will review new therapeutic options, especially those targeting immune-inflammatory and redox pathways.

  16. Factors associated with physical and sexual violence by police among people who inject drugs in Ukraine: implications for retention on opioid agonist therapy

    Directory of Open Access Journals (Sweden)

    Oksana Kutsa

    2016-07-01

    Full Text Available Introduction: Ukraine's volatile HIV epidemic, one of the largest in Eastern Europe and Central Asia, remains concentrated in people who inject drugs (PWID. HIV prevalence is high (21.3% to 41.8% among the estimated 310,000 PWID. Opioid agonist therapy (OAT is the most cost-effective HIV prevention strategy there, yet OAT services are hampered by negative attitudes and frequent harassment of OAT clients and site personnel by law enforcement. This paper examines the various types of police violence that Ukrainian PWID experience and factors associated with the different types of violence, as well as the possible implications of police harassment on OAT retention. Methods: In 2014 to 2015, we conducted a cross-sectional survey in five Ukrainian cities with 1613 PWID currently, previously and never on OAT, using a combination of respondent-driven sampling, as well as random sampling. We analysed correlates of police violence by multiple factors, including by gender, and their effects on duration of OAT retention. Self-reported physical and sexual violence by police were the two primary outcomes, while retention on OAT was used as a secondary outcome. Results: Overall, 1033 (64.0% PWID reported being physically assaulted by police, which was positively correlated with currently or previously being on OAT (69.1% vs. 60.2%; p<0.01. HIV prevalence rates were higher in those receiving OAT than those not on OAT (47.6% vs. 36.1%; p<0.01. Police violence experiences differed by sex, with men experiencing significantly more physical violence, while women experienced more sexual violence (65.9% vs. 42.6%; p<0.01. For PWID who had successfully accessed OAT, longer OAT retention was significantly correlated both with sexual assault by police and fewer non-fatal overdoses. Conclusions: Police violence is a frequent experience among PWID in Ukraine, particularly for those accessing OAT, an evidence-based primary and secondary HIV prevention strategy. Police

  17. Drug–drug conditioning between citalopram and haloperidol or olanzapine in a conditioned avoidance response model: implications for polypharmacy in schizophrenia

    OpenAIRE

    Sparkman, Nathan L; Li, Ming

    2012-01-01

    Patients with schizophrenia often have anxiety and depression, and thus are treated with multiple psychotherapeutic medications. This practice of polypharmacy increases the possibility for drug–drug interactions. However, the pharmacological and behavioral mechanisms underlying drug–drug interactions in schizophrenia remain poorly understood. In the present study, we adopted a preclinical approach and examined a less known behavioral mechanism, drug–drug conditioning (DDC) between haloperidol...

  18. Supersaturation, nucleation, and crystal growth during single- and biphasic dissolution of amorphous solid dispersions: polymer effects and implications for oral bioavailability enhancement of poorly water soluble drugs.

    Science.gov (United States)

    Sarode, Ashish L; Wang, Peng; Obara, Sakae; Worthen, David R

    2014-04-01

    The influence of polymers on the dissolution, supersaturation, crystallization, and partitioning of poorly water soluble compounds in biphasic media was evaluated. Amorphous solid dispersions (ASDs) containing felodipine (FLD) and itraconazole (ITZ) were prepared by hot melt mixing (HMM) using various polymers. The ASDs were analyzed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), and HPLC. Amorphous drug conversion was confirmed using DSC and PXRD, and drug stability by HPLC. Single- and biphasic dissolution studies of the ASDs with concurrent dynamic light scattering (DLS) and polarized light microscopic (PLM) analysis of precipitated drugs were performed. HPLC revealed no HMM-induced drug degradation. Maximum partitioning into the organic phase was dependent upon the degree of supersaturation. Although the highest supersaturation of FLD was attained using Eudragit® EPO and AQOAT® AS-LF with better nucleation and crystal growth inhibition using the latter, higher partitioning of the drug into the organic phase was achieved using Pharmacoat® 603 and Kollidon® VA-64 by maintaining supersaturation below critical nucleation. Critical supersaturation for ITZ was surpassed using all of the polymers, and partitioning was dependent upon nucleation and crystal growth inhibition in the order of Pharmacoat® 603>Eudragit® L-100-55>AQOAT® AS-LF. HMM drug-polymer systems that prevent drug nucleation by staying below critical supersaturation are more effective for partitioning than those that achieve the highest supersaturation.

  19. Artemisinin combination therapies price disparity between government and private health sectors and its implication on antimalarial drug consumption pattern in Morogoro Urban District, Tanzania

    Directory of Open Access Journals (Sweden)

    Malisa Allen

    2012-03-01

    Full Text Available Abstract Background Universal access to effective treatments is a goal of the Roll Back Malaria Partnership. However, despite official commitments and substantial increases in financing, this objective remains elusive, as development assistance continue to be routed largely through government channels, leaving the much needed highly effective treatments inaccessible or unaffordable to those seeking services in the private sector. Methods To quantify the effect of price disparity between the government and private health systems, this study have audited 92 government and private Drug Selling Units (DSUs in Morogoro urban district in Tanzania to determine the levels, trend and consumption pattern of antimalarial drugs in the two health systems. A combination of observation, interviews and questionnaire administered to the service providers of the randomly selected DSUs were used to collect data. Results ALU was the most selling antimalarial drug in the government health system at a subsidized price of 300 TShs (0.18 US$. By contrast, ALU that was available in the private sector (coartem was being sold at a price of about 10,000 TShs (5.9 US$, the price that was by far unaffordable, prompting people to resort to cheap but failed drugs. As a result, metakelfin (the phased out drug was the most selling drug in the private health system at a price ranging from 500 to 2,000 TShs (0.29–1.18 US$. Conclusions In order for the prompt diagnosis and treatment with effective drugs intervention to have big impact on malaria in mostly low socioeconomic malaria-endemic areas of Africa, inequities in affordability and access to effective treatment must be eliminated. For this to be ensued, subsidized drugs should be made available in both government and private health sectors to promote a universal access to effective safe and affordable life saving antimalarial drugs.

  20. The decline of anti-drug antibody titres after discontinuation of anti-TNFs: implications for predicting re-induction outcome in IBD.

    Science.gov (United States)

    Ben-Horin, S; Mazor, Y; Yanai, H; Ron, Y; Kopylov, U; Yavzori, M; Picard, O; Fudim, E; Maor, Y; Lahat, A; Coscas, D; Eliakim, R; Dotan, I; Chowers, Y

    2012-03-01

    Anti-drug antibodies can be elicited by infliximab and adalimumab, but the rate of their decay after therapy is stopped is unknown. To investigate the decline of anti-drug antibody titre after anti-TNF cessation, and to evaluate the clinical utility of anti-drug antibody measurement before anti-TNF re-induction. Inflammatory bowel disease (IBD) patients who stopped anti-TNF therapy and had measurable anti-drug antibodies were prospectively followed up by serial blood measurements of antibodies levels. The clinical outcome of a second cohort of patients who received re-induction by infliximab or adalimumab after a drug holiday >4 months was determined vis-à-vis their anti-drug antibodies status before re-induction. The first cohort included 22 patients with anti-drug antibodies who were prospectively followed up after cessation of anti-TNF. Sixteen had antibodies-to-infliximab (ATI) and six had antibodies-to-adalimumab (ATA). ATI titres declined within 12 months to below detection levels in 13/16 infliximab-treated patients, whereas ATA titres became undetectable in only 2/6 adalimumab-treated patients (P = 0.04). The second cohort comprised 27 patients who resumed anti-TNFs (24 infliximab, 3 adalimumab). Of these, 3/5 patients with measurable anti-drug antibodies before re-induction experienced severe hypersensitivity reaction and/or nonresponse mandating drug-discontinuation, compared to 11/22 patients who were re-induced without measurable anti-drug antibodies (OR = 1.5, 95% CI 0.2-11, P = 0.7). Antibodies to infliximab titres decline to undetectable levels within one year of cessation of infliximab in the majority of patients, whereas antibodies to adalimumab seem to persist longer after adalimumab discontinuation. Measuring antibodies to infliximab prior to infliximab re-induction is probably of little clinical utility, especially if more than a 12-month drug-holiday has elapsed. © 2012 Blackwell Publishing Ltd.

  1. From Drug Wars to Criminal Insurgency: Mexican Cartels, Criminal Enclaves and Criminal Insurgency in Mexico and Central America. Implications for Global Security

    OpenAIRE

    Sullivan, John P.

    2011-01-01

    Transnational organized crime is a pressing global security issue. Mexico is currently embroiled in a protracted drug war. Mexican drug cartels and allied gangs (actually poly-crime organizations) are currently challenging states and sub-state polities (in Mexico, Guatemala, El Salvador and beyond) to capitalize on lucrative illicit global economic markets. As a consequence of the exploitation of these global economic flows, the cartels are waging war on each other and state institutions to g...

  2. Investigation of the motion of a viscous fluid in the vitreous cavity induced by eye rotations and implications for drug delivery

    Science.gov (United States)

    Bonfiglio, Andrea; Repetto, Rodolfo; Siggers, Jennifer H.; Stocchino, Alessandro

    2013-03-01

    Intravitreal drug delivery is a commonly used treatment for several retinal diseases. The objective of this research is to characterize and quantify the role of the vitreous humor motion, induced by saccadic movements, on drug transport processes in the vitreous chamber. A Perspex model of the human vitreous chamber was created, and filled with a purely viscous fluid, representing eyes with a liquefied vitreous humor or those containing viscous tamponade fluids. Periodic movements were applied to the model and the resulting three-dimensional (3D) flow fields were measured. Drug delivery within the vitreous chamber was investigated by calculating particle trajectories using integration over time of the experimental velocity fields. The motion of the vitreous humor generated by saccadic eye movements is intrinsically 3D. Advective mass transport largely overcomes molecular diffusive transport and is significantly anisotropic, leading to a much faster drug dispersion than in the case of stationary vitreous humor. Disregarding the effects of vitreous humor motion due to eye movements when predicting the efficiency of drug delivery treatments leads to significant underestimation of the drug transport coefficients, and this, in turn, will lead to significantly erroneous predictions of the concentration levels on the retina.

  3. Drug-drug interactions between clopidogrel and novel cardiovascular drugs.

    Science.gov (United States)

    Pelliccia, Francesco; Rollini, Fabiana; Marazzi, Giuseppe; Greco, Cesare; Gaudio, Carlo; Angiolillo, Dominick J

    2015-10-15

    The combination of aspirin and the thienopyridine clopidogrel is a cornerstone in the prevention of atherothrombotic events. These two agents act in concert to ameliorate the prothrombotic processes stimulated by plaque rupture and vessel injury complicating cardiovascular disease. Guidelines recommend the use of clopidogrel in patients with acute coronary syndromes and in those undergoing percutaneous coronary intervention, and the drug remains the most utilized P2Y12 receptor inhibitor despite the fact that newer antiplatelet agents are now available. In recent years, numerous studies have shown inconsistency in the efficacy of clopidogrel to prevent atherothrombotic events. Studies of platelet function testing have shown variability in the response to clopidogrel. One of the major reason for this phenomenon lies in the interaction between clopidogrel and other drugs that may affect clopidogrel absorption, metabolism, and ultimately its antiplatelet action. Importantly, these drug-drug interactions have prognostic implications, since patients with high on-treatment platelet reactivity associated with reduced clopidogrel metabolism have an increased risk of ischemia. Previous systematic reviews have focused on drug-drug interactions between clopidogrel and specific pharmacologic classes, such as proton pump inhibitors, calcium channel blockers, and statins. However, more recent pieces of scientific evidence show that clopidogrel may also interact with newer drugs that are now available for the treatment of cardiovascular patients. Accordingly, the aim of this review is to highlight and discuss recent data on drug-drug interactions between clopidogrel and third-generation proton pump inhibitors, pantoprazole and lansoprazole, statins, pitavastatin, and antianginal drug, ranolazine.

  4. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use Hurts Kids Drug Use Hurts Unborn Children Drug Use Hurts Your Health Drug Use Hurts ... Find Treatment/Rehab Resources Prevent Drug Use Help Children and Teens Stay Drug-Free Talking to Kids ...

  5. Drug Facts

    Medline Plus

    Full Text Available ... Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Use and Other People Drug Use and Families Drug Use and Kids Drug Use and Unborn ...

  6. Novel Non-Peptide Inhibitors against SmCL1 of Schistosoma mansoni: In Silico Elucidation, Implications and Evaluation via Knowledge Based Drug Discovery.

    Science.gov (United States)

    Zafar, Atif; Ahmad, Sabahuddin; Rizvi, Asim; Ahmad, Masood

    2015-01-01

    Schistosomiasis is a major endemic disease known for excessive mortality and morbidity in developing countries. Because praziquantel is the only drug available for its treatment, the risk of drug resistance emphasizes the need to discover new drugs for this disease. Cathepsin SmCL1 is the critical target for drug design due to its essential role in the digestion of host proteins for growth and development of Schistosoma mansoni. Inhibiting the function of SmCL1 could control the wide spread of infections caused by S. mansoni in humans. With this objective, a homology modeling approach was used to obtain theoretical three-dimensional (3D) structure of SmCL1. In order to find the potential inhibitors of SmCL1, a plethora of in silico techniques were employed to screen non-peptide inhibitors against SmCL1 via structure-based drug discovery protocol. Receiver operating characteristic (ROC) curve analysis and molecular dynamics (MD) simulation were performed on the results of docked protein-ligand complexes to identify top ranking molecules against the modelled 3D structure of SmCL1. MD simulation results suggest the phytochemical Simalikalactone-D as a potential lead against SmCL1, whose pharmacophore model may be useful for future screening of potential drug molecules. To conclude, this is the first report to discuss the virtual screening of non-peptide inhibitors against SmCL1 of S. mansoni, with significant therapeutic potential. Results presented herein provide a valuable contribution to identify the significant leads and further derivatize them to suitable drug candidates for antischistosomal therapy.

  7. Age-Related Inducibility of Carboxylesterases by the Antiepileptic Agent Phenobarbital and Implications in Drug Metabolism and Lipid Accumulation 1, 2

    Science.gov (United States)

    Xiao, Da; Chen, Yi-Tzai; Yang, Dongfang; Yan, Bingfang

    2014-01-01

    Carboxylesterases (CES) constitute a class of hydrolytic enzymes that play critical roles in drug metabolism and lipid mobilization. Previous studies with a large number of human liver samples have suggested that the inducibility of carboxylesterases is inversely related with age. To directly test this possibility, neonatal (10 days of age) and adult mice were treated with the antiepileptic agent phenobarbital. The expression and hydrolytic activity were determined on six major carboxylesterases including ces1d, the ortholog of human CES1. Without exception, all carboxylesterases tested were induced to a greater extent in neonatal than adult mice. The induction was detected at mRNA, protein and catalytic levels. Ces1d was greatly induced and found to rapidly hydrolyze the antiplatelet agent clopidogrel and support the accumulation of neutral lipids. Phenobarbital represents a large number of therapeutic agents that induce drug metabolizing enzymes and transporters in a species-conserved manner. The higher inducibility of carboxylesterases in the developmental age likely represents a general phenomenon cross species including human. Consequently, individuals in the developmental age may experience greater drug-drug interactions. The greater induction of ces1d also provides a molecular explanation to the clinical observation that children on antiepileptic drugs increase plasma lipids. PMID:22513142

  8. 药物奖赏记忆:从药物诱导的条件性位置偏爱模型中的见解%Drug reward memory:implication from drug-induced conditioned place preference model

    Institute of Scientific and Technical Information of China (English)

    刘剑锋; 李俊旭

    2016-01-01

    药物成瘾是一种慢性复发性脑疾病,其发生至少部分原因是由于异常的学习记忆所导致。大量的研究表明,成瘾性药物篡夺了正常记忆的神经环路,从而形成了长期维持的药物记忆,这可能是导致药物成瘾复吸的重要原因。本文综述了关联性药物奖赏记忆的模型之一药物诱导的条件性位置偏爱的相关研究结果,旨在阐述目前对于药物奖赏记忆的认识。药物奖赏记忆是一个动态的过程,包括习得、巩固、维持、唤起、再巩固和消退多个阶段,对这些药物奖赏记忆阶段进行药理学干预可以不同地调控药物奖赏记忆。最近,根据记忆阶段假说所发展的纯行为学模式,例如唤起-消退模式,展现出比药理学手段干预药物奖赏记忆更强的优越性。最后,本综述讨论了在药物奖赏记忆实验设计与相关实验结果解释时需要重点考虑2个方法学问题:模式和时间。目前为止,仍然不确定是否能发展一种药理学治疗方法,仅仅抹除药物奖赏记忆而不影响正常的记忆。我们提出,抑制药物奖赏记忆的方法仍不失一种有效降低复吸风险的手段。虽然目前关于药物奖赏记忆的研究对药物成瘾的治疗贡献并不大,但继续深入的研究将为降低成瘾复吸带来新的治疗方法。%Drug addiction is a chronic,relapsing brain disorder,which develops,in part,because of aberrant learning and memory. Accumulative studies during recent decades demonstrated that addictive drug hijacks the normal memory circuit in the brain to form a long-lasting drug reward memory,which determines relapse to addictive drug. In this review,we will describe what has been learned about drug reward memory,especially focused on one of the associative drug reward memory models,drug-induced conditioned place preference. Drug reward memory is a dynamic process,which consists of several stages

  9. INTERACTION BETWEEN ANTI-HYPERTENSIVE AND NON-STEROIDAL ANTI INFLAMMATORY DRUGS: IMPLICATIONS IN MANAGEMENT OF OSTEOARTHRITIS AND OPINION ON A COMPROMISE THERAPY

    Directory of Open Access Journals (Sweden)

    Mr. Adeolu O. Ajala

    2010-01-01

    Full Text Available The premise for this article is that a significant proportion of patients presenting in the clinic with osteoarthritis have hypertension as co-morbidity. A common drug of choice in managing symptoms of osteoarthritis including those affecting the knee joint is the Non-Steroidal Anti-Inflammatory Drugs (NSAIDS groups. It has been reported however that NSAIDs diminish the effects of anti-hypertensive drugs and may lead to an ineffective hypertension therapy. In order to avoid complications in the health of the patient with concomitant hypertension and osteoarthritis and who are on both antihypertensive and NSAIDs, it becomes imperative to consider using non-pharmacologic approaches such as physiotherapy in managing the symptoms of osteoarthritis in this group of patients and thereby maximizing the effects of their antihypertensive therapy. This is more so that information exists on efficacy of physiotherapy in form of therapeutic exercises and electrotherapeutic modalities in management of clinical features of osteoarthritis.

  10. Synthetic interaction between the TipN polarity factor and an AcrAB-family efflux pump implicates cell polarity in bacterial drug resistance.

    Science.gov (United States)

    Kirkpatrick, Clare L; Viollier, Patrick H

    2014-05-22

    Quinolone antibiotics are clinically important drugs that target bacterial DNA replication and chromosome segregation. Although the AcrAB-family efflux pumps generally protect bacteria from such drugs, the physiological role of these efflux systems and their interplay with other cellular events are poorly explored. Here, we report an intricate relationship between antibiotic resistance and cell polarity in the model bacterium Caulobacter crescentus. We show that a polarity landmark protein, TipN, identified by virtue of its ability to direct flagellum placement to the new cell pole, protects cells from toxic misregulation of an AcrAB efflux pump through a cis-encoded nalidixic acid-responsive transcriptional repressor. Alongside the importance of polarity in promoting the inheritance and activity of virulence functions including motility, we can now ascribe to it an additional role in drug resistance that is distinct from classical efflux mechanisms.

  11. Multiscale Modeling of Antibody-Drug Conjugates: Connecting Tissue and Cellular Distribution to Whole Animal Pharmacokinetics and Potential Implications for Efficacy.

    Science.gov (United States)

    Cilliers, Cornelius; Guo, Hans; Liao, Jianshan; Christodolu, Nikolas; Thurber, Greg M

    2016-09-01

    Antibody-drug conjugates exhibit complex pharmacokinetics due to their combination of macromolecular and small molecule properties. These issues range from systemic concerns, such as deconjugation of the small molecule drug during the long antibody circulation time or rapid clearance from nonspecific interactions, to local tumor tissue heterogeneity, cell bystander effects, and endosomal escape. Mathematical models can be used to study the impact of these processes on overall distribution in an efficient manner, and several types of models have been used to analyze varying aspects of antibody distribution including physiologically based pharmacokinetic (PBPK) models and tissue-level simulations. However, these processes are quantitative in nature and cannot be handled qualitatively in isolation. For example, free antibody from deconjugation of the small molecule will impact the distribution of conjugated antibodies within the tumor. To incorporate these effects into a unified framework, we have coupled the systemic and organ-level distribution of a PBPK model with the tissue-level detail of a distributed parameter tumor model. We used this mathematical model to analyze new experimental results on the distribution of the clinical antibody-drug conjugate Kadcyla in HER2-positive mouse xenografts. This model is able to capture the impact of the drug-antibody ratio (DAR) on tumor penetration, the net result of drug deconjugation, and the effect of using unconjugated antibody to drive ADC penetration deeper into the tumor tissue. This modeling approach will provide quantitative and mechanistic support to experimental studies trying to parse the impact of multiple mechanisms of action for these complex drugs.

  12. Gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, up-regulate tripeptidyl-peptidase 1 in brain cells via peroxisome proliferator-activated receptor α: implications for late infantile Batten disease therapy.

    Science.gov (United States)

    Ghosh, Arunava; Corbett, Grant T; Gonzalez, Frank J; Pahan, Kalipada

    2012-11-09

    The classical late infantile neuronal ceroid lipofuscinosis (LINCLs) is an autosomal recessive disease, where the defective gene is Cln2, encoding tripeptidyl-peptidase I (TPP1). At the molecular level, LINCL is caused by accumulation of autofluorescent storage materials in neurons and other cell types. Currently, there is no established treatment for this fatal disease. This study reveals a novel use of gemfibrozil and fenofibrate, Food and Drug Administration-approved lipid-lowering drugs, in up-regulating TPP1 in brain cells. Both gemfibrozil and fenofibrate up-regulated mRNA, protein, and enzymatic activity of TPP1 in primary mouse neurons and astrocytes as well as human astrocytes and neuronal cells. Because gemfibrozil and fenofibrate are known to activate peroxisome proliferator-activated receptor-α (PPARα), the role of PPARα in gemfibrozil- and fenofibrate-mediated up-regulation of TPP1 was investigated revealing that both drugs up-regulated TPP1 mRNA, protein, and enzymatic activity both in vitro and in vivo in wild type (WT) and PPARβ(-/-), but not PPARα(-/-), mice. In an attempt to delineate the mechanism of TPP1 up-regulation, it was found that the effects of the fibrate drugs were abrogated in the absence of retinoid X receptor-α (RXRα), a molecule known to form a heterodimer with PPARα. Accordingly, all-trans-retinoic acid, alone or together with gemfibrozil, up-regulated TPP1. Co-immunoprecipitation and ChIP studies revealed the formation of a PPARα/RXRα heterodimer and binding of the heterodimer to an RXR-binding site on the Cln2 promoter. Together, this study demonstrates a unique mechanism for the up-regulation of TPP1 by fibrate drugs via PPARα/RXRα pathway.

  13. Explaining human recreational use of 'pesticides': The neurotoxin regulation model of substance use vs. the hijack model and implications for age and sex differences in drug consumption

    Directory of Open Access Journals (Sweden)

    Edward H Hagen

    2013-11-01

    Full Text Available Most globally popular drugs are plant neurotoxins or their close chemical analogs. These compounds evolved to deter, not reward or reinforce, consumption. Moreover, they reliably activate virtually all toxin defense mechanisms, and are thus correctly identified by human neurophysiology as toxins. Acute drug toxicity must therefore play a more central role in drug use theory. We accordingly challenge the popular idea that the rewarding and reinforcing properties of drugs "hijack" the brain, and propose instead that the brain evolved to carefully regulate neurotoxin consumption to minimize fitness costs and maximize fitness benefits. This perspective provides a compelling explanation for the dramatic changes in substance use that occur during the transition from childhood to adulthood, and for pervasive sex differences in substance use: because nicotine and many other plant neurotoxins are teratogenic, children, and to a lesser extent women of childbearing age, evolved to avoid ingesting them. However, during the course of human evolution many adolescents and adults reaped net benefits from regulated intake of plant neurotoxins.

  14. Staff Attitudes and Services Provided by Community-Based Organizations for Alcohol and Other Drug Users in Cape Town, South Africa: Implications for Training and Education

    Science.gov (United States)

    Pasche, Sonja; Myers, Bronwyn; Louw, Johann

    2008-01-01

    Aims: The aims of this study were: (i) to describe the nature of and the extent to which community-based organizations (CBOs) in Cape Town provide services to people who have alcohol and other drug (AOD) problems; (ii) to examine the relationship between CBOs' attitudes towards individuals with AOD problems and the types of services provided; and…

  15. Medication possession ratio: implications of using fixed and variable observation periods in assessing adherence with disease-modifying drugs in patients with multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Kozma CM

    2013-06-01

    Full Text Available Chris M Kozma,1 Michael Dickson,2 Amy L Phillips,3 Dennis M Meletiche31CK Consulting Associates, LLC St Helena Island, SC, 2University of South Carolina College of Pharmacy, Columbia, SC, 3EMD Serono Inc, Rockland, MA, USABackground: The purpose of this study was to compare two methods of adherence calculation using administrative data for patients with multiple sclerosis (MS who are prescribed disease-modifying drugs.Methods: Pharmacy-billed disease-modifying drug prescription claims were selected from the 2007–2008 LifeLink™ Health Plan Claims Database. The index date was the first disease-modifying drug prescription claim. Two cohorts were created: all patients with a disease-modifying drug claim in 2007 and a subset with continuous eligibility for 12 months post-index. Adherence was calculated across all disease-modifying drugs for 12 months post-index. Medication possession ratios (MPRs with variable (start to end of therapy and fixed (365 days duration denominators were calculated. Variable MPR was calculated by summing days supply from the first to the last prescription (inclusive divided by time between the last prescription date plus days supply and the first prescription date. Variable MPR was evaluated for all patients and the continuously eligible cohort. Fixed MPR used the same numerator but divided by 365 days of follow-up and evaluated only for the continuously eligible cohort.Results: There were 3405 patients with MS and a disease-modifying drug claim in 2007 and 2145 in the continuously eligible cohort. Means for variable MPR ranged from 87.5% ± 16.6% for the continuously eligible cohort to 90.5% ± 16.0% for the 2007 cohort. The comparable value for fixed MPR was 78.0% ± 28.2% for the continuously eligible cohort. Fixed MPR gave a consistently lower rate of adherence than variable MPR at an 80% adherence threshold.Conclusion: Different adherence measures can yield different outcomes, especially when using different

  16. High prevalence of non-fatal overdose among people who inject drugs in Malaysia: Correlates of overdose and implications for overdose prevention from a cross-sectional study.

    Science.gov (United States)

    Bazazi, Alexander R; Zelenev, Alexei; Fu, Jeannia J; Yee, Ilias; Kamarulzaman, Adeeba; Altice, Frederick L

    2015-07-01

    Overdose is the leading cause of death among opioid users, but no data are available on overdose among people who inject drugs in Malaysia. We present the first estimates of the prevalence and correlates of recent non-fatal overdose among people who inject drugs in Malaysia. In 2010, 460 people who inject drugs were recruited using respondent-driven sampling (RDS) in Klang Valley to assess health outcomes associated with injection drug use. Self-reported history of non-fatal overdose in the previous 6 months was the primary outcome. Sociodemographic, behavioral and structural correlates of non-fatal overdose were assessed using multivariable logistic regression. All 460 participants used opioids and nearly all (99.1%) met criteria for opioid dependence. Most injected daily (91.3%) and were male (96.3%) and ethnically Malay (90.4%). Overall, 20% of participants had overdosed in the prior 6 months, and 43.3% had ever overdosed. The RDS-adjusted estimate of the 6-month period prevalence of overdose was 12.3% (95% confidence interval [CI] 7.9-16.6%). Having injected for more years was associated with lower odds of overdose (adjusted odds ratio [AOR] 0.6 per 5 years of injection, CI: 0.5-0.7). Rushing an injection from fear of the police nearly doubled the odds of overdose (AOR 1.9, CI: 1.9-3.6). Alcohol use was associated with recent non-fatal overdose (AOR 2.1, CI: 1.1-4.2), as was methamphetamine use (AOR 2.3, CI: 1.3-4.6). When adjusting for past-month drug use, intermittent but not daily methadone use was associated with overdose (AOR 2.8, CI: 1.5-5.9). This study reveals a large, previously undocumented burden of non-fatal overdose among people who inject drugs in Malaysia and highlights the need for interventions that might reduce the risk of overdose, such as continuous opioid substitution therapy, provision of naloxone to prevent fatal overdose, treatment of polysubstance use, and working with police to improve the risk environment. Copyright © 2014 Elsevier B

  17. Drug Facts

    Medline Plus

    Full Text Available ... Addiction? Addiction Risk Factors Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Use Hurts Other People Drug Use Hurts Families Drug Use Hurts Kids Drug Use Hurts Unborn ...

  18. Drug Facts

    Medline Plus

    Full Text Available ... Use Hurts Unborn Children Drug Use Hurts Your Health Drug Use Hurts Bodies Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug ...

  19. Drug Allergy

    Science.gov (United States)

    ... Loss of consciousness Other conditions resulting from drug allergy Less common drug allergy reactions occur days or ... you take the drug. Drugs commonly linked to allergies Although any drug can cause an allergic reaction, ...

  20. Drug Facts

    Medline Plus

    Full Text Available ... Addiction? Addiction Risk Factors Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Use Hurts Other People Drug Use Hurts Families Drug Use Hurts Kids Drug Use Hurts Unborn ...

  1. Drug Facts

    Medline Plus

    Full Text Available ... The Link Between Drug Use and HIV/AIDS Recovery & Treatment Drug Treatment Facts Does Drug Treatment Work? ... and Family Can Help Find Treatment/Rehab Resources Prevent Drug Use Help Children and Teens Stay Drug- ...

  2. Determinants of HIV-1 drug resistance in treatment-naïve patients and its clinical implications in an antiretroviral treatment program in Cameroon

    Directory of Open Access Journals (Sweden)

    Alexander Zoufaly

    2014-11-01

    Full Text Available Introduction: Facing the rapid scale-up of antiretroviral treatment (ART programs in resource-limited settings, monitoring of treatment outcome is essential in order to timely detect and tackle drawbacks [1]. Methods: In a prospective cohort study, 300 consecutive patients starting first-line ART were enrolled between 2009 and2010 in a large HIV treatment centre in rural Cameroon. Patients were followed up for 12 months. Virologic failure was defined as a VL >1000 cop/mL at month 12. Besides CD4 and viral load (VL analysis, HIV-1 drug resistance testing was performed in patients with VL>1000 copies (c/mL plasma. In those patients and controls, minority HIV-1 drug resistance mutations at baseline, and plasma drug levels were analyzed in order to identify the risk factors for virologic failure. Results: Most enrolled patients (71% were female. At baseline median CD4 cell count was 162/µL (IQR 59-259, median log10 VL was 5.4 (IQR 5.0–5.8 c/mL, and one-third of patients had World Health Organisation (WHO stage 3 or 4; 30 patients died during follow-up. Among all patients who completed follow-up 38/238 had virologic failure. These patients were younger, had lower CD4 cell counts and more often had WHO stage 3 or 4 at baseline compared to patients with VL<1000c/mL. Sixty-three percent of failing patients (24/38 had at least one mutation associated with high-level drug resistance. The M184V mutation was the most frequently detected nucleoside reverse transcriptase inhibitor (NRTI mutation (n=18 followed by TAMs (n=5 and multi-NRTI resistance mutations (n=4. The most commonly observed non-nucleoside reverse-transcriptase inhibitor (NNRTI resistance mutations were K103N (n=10, Y181C (n=7, and G190A (n=6. Drug resistance mutations at baseline were detected in 12/65 (18% patients, in 6 patients with and 6 patients without virological failure (p=0.77. Subtherapeutic NNRTI levels (OR 6.67, 95% CI 1.98–22.43, p<0.002 and poorer adherence (OR 1.54, 95% CI

  3. Recommendations on bioanalytical method stability implications of co-administered and co-formulated drugs by Global CRO Council for Bioanalysis (GCC).

    Science.gov (United States)

    Lowes, Steve; Boterman, Mark; Doig, Mira; Breda, Massimo; Jersey, Jim; Lelacheur, Richard; Shoup, Ronald; Garofolo, Fabio; Dumont, Isabelle; Martinez, Suzanne; Needham, Shane; Zimmer, Jennifer; Caturla, Maria Cruz; Couerbe, Philippe; Maltas, John; Steffen, Ray; Petrilla, James; Safavi, Afshin; Awaiye, Kayode; Bhatti, Masood; Sheldon, Curtis; Schiebl, Christine; Struwe, Petra; Turk, Douglas; Sangster, Timothy; Pattison, Colin; Fast, Douglas; Goodwin, Lee; Kamerud, John; Dinan, Andrew; Mamelak, Dan; Islam, Rafiq; Segers, Rudi; Lin, Zhongping John; Hillier, Jim; Garofolo, Wei; Folguera, Lois; Zimmer, Dieter; Zimmermann, Thomas; Pawula, Maria; Moussallie, Marc; de Souza Teixeira, Leonardo; Rocha, Thais; Allinson, John; Jardieu, Paula; Tang, Daniel; Gouty, Dominique; Wright, Laura; Truog, James; Lin, Jenny; Yamashita, Yasuhiro; Khan, Masood; Liu, Yansheng; Xu, Allan; Lundberg, Richard; Cox, Chris; Breau, Alan; Hayes, Roger; Bigogno, Chiara; Schoutsen, Dick; Dilger, Carmen; Jonker, Jianine; Bouhajib, Mohammed; Levesque, Ann; Gagnon-Carignan, Sofi; Harman, Jake; Nicholson, Robert; Jenkins, Rand; Warren, Mark; Lin, Ming Hung; Karnik, Shane; De Boer, Theo; Houghton, Richard; Green, Rachel; Demaio, William; Sable, Romuald; Smith, Kirk; Siethoff, Christoph; Cojocaru, Laura; Allen, Mike; Reuschel, Scott; Gonzalez, Pilar; Harter, Tammy; Fatmi, Saadya; Rock, Marie; Vija, Jenifer; Sayyarpour, Farhad; Malone, Michele; Nowatzke, William; Best, Stuart; Fang, Xinping

    2012-09-01

    An open letter written by the Global CRO Council for Bioanalysis (GCC) describing the GCC survey results on stability data from co-administered and co-formulated drugs was sent to multiple regulatory authorities on 14 December 2011. This letter and further discussions at different GCC meetings led to subsequent recommendations on this topic of widespread interest within the bioanalytical community over the past 2 years.

  4. Enhanced latent inhibition in dopamine receptor-deficient mice is sex-specific for the D1 but not D2 receptor subtype: implications for antipsychotic drug action.

    Science.gov (United States)

    Bay-Richter, Cecilie; O'Tuathaigh, Colm M P; O'Sullivan, Gerard; Heery, David M; Waddington, John L; Moran, Paula M

    2009-04-01

    Latent inhibition (LI) is reduced learning to a stimulus that has previously been experienced without consequence. It is an important model of abnormal allocation of salience to irrelevant information in patients with schizophrenia. In rodents LI is abolished by psychotomimetic drugs and in experimental conditions where LI is low in controls, its expression is enhanced by antipsychotic drugs with activity at dopamine (DA) receptors. It is however unclear what the independent contributions of DA receptor subtypes are to these effects. This study therefore examined LI in congenic DA D1 and D2 receptor knockout (D1 KO and D2 KO) mice. Conditioned suppression of drinking was used as the measure of learning in the LI procedure. Both male and female DA D2 KO mice showed clear enhancement of LI reproducing antipsychotic drug effects in the model. Unexpectedly, enhancement was also seen in D1 KO female mice but not in D1 KO male mice. This sex-specific pattern was not replicated in locomotor or motor coordination tasks nor in the effect of DA KOs on baseline learning in control groups indicating some specificity of the effect to LI. These data suggest that the dopaminergic mechanism underlying LI potentiation and possibly antipsychotic action may differ between the sexes, being mediated by D2 receptors in males but by both D1 and D2 receptors in females. These data suggest that the DA D1 receptor may prove an important target for understanding sex differences in the mechanisms of action of antipsychotic drugs and in the aetiology of aberrant salience allocation in schizophrenia.

  5. Reforms and initiatives in Scotland in recent years to encourage the prescribing of generic drugs, their influence and implications for other countries.

    Science.gov (United States)

    Godman, Brian; Bishop, Iain; Finlayson, Alexander E; Campbell, Stephen; Kwon, Hye-Young; Bennie, Marion

    2013-08-01

    Scotland has introduced a number of initiatives to enhance the prescribing of low-cost generic drugs versus originators and patent products in a class where these are seen as similar. The objective of this review is to appraise the influence of the various measures on subsequent utilization patterns and expenditure in high-volume classes to provide guidance. This review is principally a narrative review of published studies. The authors' found supply-side measures resulted in generic prices as low as 3% of pre-patent loss prices. Multiple demand-side measures resulted in high international non-proprietary name prescribing, and a considerable increase in prescribing efficiency for the proton pump inhibitors, statins, renin-angiotensin inhibitor drugs and selective serotonin reuptake inhibitors. There were no specific activities encouraging the prescription of losartan versus other angiotensin receptor blockers or risperidone versus other atypical antipsychotic drugs following generics and no change in their utilization patterns post generics. The authors can conclude multiple measures are needed to change physician prescribing habits. Authorities cannot rely on any 'spillover' effects to affect future prescribing, even in closely related classes.

  6. Recruiting hard-to-reach drug-using men who have sex with men into an intervention study: lessons learned and implications for applied research.

    Science.gov (United States)

    Grov, Christian; Bux, Donald; Parsons, Jeffrey T; Morgenstern, Jon

    2009-01-01

    Drug (ab)use researchers and service providers across the globe have been challenged with locating target populations and subsequently enrolling participants into their programs. This study presents data from nearly 3 years (2004-2006) of recruiting "high-risk" drug-using gay and bisexual men into a clinical research trial based in New York City. During the enrollment period, two recruitment/marketing strategies were utilized: (1) marketing of the intervention research study itself to men who were in the early stages of identifying problems with their drug use and risky sexual behavior and (2) two-stage recruitment via a lower-threshold/commitment (i.e., brief survey) and subsequent offering/enrollment into the full trial upon completion of the initial visit (i.e., a foot-in-the-door). The second approach was substantially more effective in enrolling participants into the full trial (6.3 participants/month vs. 2.5 participants/month). Furthermore, recruitment costs for the foot-in-the-door approach were substantially reduced ($356.57 per participant vs. $497.03 per participant). Compared to the marketing of interventions themselves to target populations, a two-stage recruitment strategy incorporating lower-threshold interactions may be a more effective approach to recruit for interventions.

  7. Uptake and Acceptability of Information and Communication Technology in a Community-Based Cohort of People Who Inject Drugs: Implications for Mobile Health Interventions.

    Science.gov (United States)

    Genz, Andrew; Kirk, Gregory; Piggott, Damani; Mehta, Shruti H; Linas, Beth S; Westergaard, Ryan P

    2015-06-25

    Mobile phone and Internet-based technologies are increasingly used to disseminate health information and facilitate delivery of medical care. While these strategies hold promise for reducing barriers to care for medically-underserved populations, their acceptability among marginalized populations such as people who inject drugs is not well-understood. To understand patterns of mobile phone ownership, Internet use and willingness to receive health information via mobile devices among people who inject drugs. We surveyed current and former drug injectors participating in a longitudinal cohort study in Baltimore, Maryland, USA. Respondents completed a 12-item, interviewer-administered questionnaire during a regular semi-annual study visit that assessed their use of mobile technology and preferred modalities of receiving health information. Using data from the parent study, we used logistic regression to evaluate associations among participants' demographic and clinical characteristics and their mobile phone and Internet use. The survey was completed by 845 individuals, who had a median age of 51 years. The sample was 89% African-American, 65% male, and 33% HIV-positive. Participants were generally of low education and income levels. Fewer than half of respondents (40%) indicated they had ever used the Internet. Mobile phones were used by 86% of respondents. Among mobile phone owners, 46% had used their phone for text messaging and 25% had accessed the Internet on their phone. A minority of respondents (42%) indicated they would be interested in receiving health information via phone or Internet. Of those receptive to receiving health information, a mobile phone call was the most favored modality (66%) followed by text messaging (58%) and Internet (51%). Utilization of information and communication technology among this cohort of people who inject drugs was reported at a lower level than what has been estimated for the general U.S. Our findings identify a potential

  8. Role of Electrostatic Interactions on the Transport of Druglike Molecules in Hydrogel-Based Articular Cartilage Mimics: Implications for Drug Delivery.

    Science.gov (United States)

    Ye, Fengbin; Baldursdottir, Stefania; Hvidt, Søren; Jensen, Henrik; Larsen, Susan W; Yaghmur, Anan; Larsen, Claus; Østergaard, Jesper

    2016-03-07

    In the field of drug delivery to the articular cartilage, it is advantageous to apply artificial tissue models as surrogates of cartilage for investigating drug transport and release properties. In this study, artificial cartilage models consisting of 0.5% (w/v) agarose gel containing 0.5% (w/v) chondroitin sulfate or 0.5% (w/v) hyaluronic acid were developed, and their rheological and morphological properties were characterized. UV imaging was utilized to quantify the transport properties of the following four model compounds in the agarose gel and in the developed artificial cartilage models: H-Ala-β-naphthylamide, H-Lys-Lys-β-naphthylamide, lysozyme, and α-lactalbumin. The obtained results showed that the incorporation of the polyelectrolytes chondroitin sulfate or hyaluronic acid into agarose gel induced a significant reduction in the apparent diffusivities of the cationic model compounds as compared to the pure agarose gel. The decrease in apparent diffusivity of the cationic compounds was not caused by a change in the gel structure since a similar reduction in apparent diffusivity was not observed for the net negatively charged protein α-lactalbumin. The apparent diffusivity of the cationic compounds in the negatively charged hydrogels was highly dependent on the ionic strength, pointing out the importance of electrostatic interactions between the diffusant and the polyelectrolytes. Solution based affinity studies between the model compounds and the two investigated polyelectrolytes further confirmed the electrostatic nature of their interactions. The results obtained from the UV imaging diffusion studies are important for understanding the effect of drug physicochemical properties on the transport in articular cartilage. The extracted information may be useful in the development of hydrogels for in vitro release testing having features resembling the articular cartilage.

  9. Impact of Genetic Polymorphisms of ABCB1 (MDR1, P-Glycoprotein) on Drug Disposition and Potential Clinical Implications: Update of the Literature.

    Science.gov (United States)

    Wolking, Stefan; Schaeffeler, Elke; Lerche, Holger; Schwab, Matthias; Nies, Anne T

    2015-07-01

    ATP-binding cassette transporter B1 (ABCB1; P-glycoprotein; multidrug resistance protein 1) is an adenosine triphosphate (ATP)-dependent efflux transporter located in the plasma membrane of many different cell types. Numerous structurally unrelated compounds, including drugs and environmental toxins, have been identified as substrates. ABCB1 limits the absorption of xenobiotics from the gut lumen, protects sensitive tissues (e.g. the brain, fetus and testes) from xenobiotics and is involved in biliary and renal secretion of its substrates. In recent years, a large number of polymorphisms of the ABCB1 [ATP-binding cassette, sub-family B (MDR/TAP), member 1] gene have been described. The variants 1236C>T (rs1128503, p.G412G), 2677G>T/A (rs2032582, p.A893S/T) and 3435C>T (rs1045642, p.I1145I) occur at high allele frequencies and create a common haplotype; therefore, they have been most widely studied. This review provides an overview of clinical studies published between 2002 and March 2015. In summary, the effect of ABCB1 variation on P-glycoprotein expression (messenger RNA and protein expression) and/or activity in various tissues (e.g. the liver, gut and heart) appears to be small. Although polymorphisms and haplotypes of ABCB1 have been associated with alterations in drug disposition and drug response, including adverse events with various ABCB1 substrates in different ethnic populations, the results have been majorly conflicting, with limited clinical relevance. Future research activities are warranted, considering a deep-sequencing approach, as well as well-designed clinical studies with appropriate sample sizes to elucidate the impact of rare ABCB1 variants and their potential consequences for effect sizes.

  10. The CYP4502D6 *4 and *6 alleles are the molecular genetic markers for drug response: implications in colchicine non-responder FMF patients.

    Science.gov (United States)

    Yalcıntepe, Sinem; Ozdemır, Ozturk; Sılan, Coskun; Ozen, Filiz; Uludag, Ahmet; Candan, Ferhan; Sılan, Fatma

    2016-06-01

    The cytochrome P450 2D6 (CYP2D6) is a cytochrome P450 enzyme involved in the oxidative biotransformation of the xenobiotics, carcinogens and various clinically important drugs. Patients are evaluated in three sub-groups of extensive (EM), intermediate (IM) and poor metabolizer (PM) phenotypes due to their drug-metabolising ability for the target CYP2D6 gene. Colchicine non-responsive FMF patients were prospectively genotyped for the major CYP2D6 alleles in the current study. Major CYP2D6 alleles of *1, *3, *4, *5, and *6 were genotyped for 30 responsive and 60 non-responsive FMF patients by multiplex PCR-based reverse-hybridization StripAssay and real-time PCR methods. DNA banks isolated from blood-EDTA were retrospectively used in the current patients and results were compared statistically. Increased CYP2D6 *4 and *6 allele frequencies were highly detected in the colchicine non-responsive FMF patients when compared to the responsive group. Results showed the frequencies of major CYP2D6 *1(wild), *3(2637A > delA), *4(G1934A), *5(total gene deletion) and *6(1707T del) alleles in 0.550, 0.042, 0.158, 0.025 and 0.225 for non-responder and 0.880 and 0.120 (CYP2D6*1 and *4) for the responder groups, respectively. Despite small sample size, this study suggests that there is an association between CYP2D6*4 and CYP2D6*6 alleles and drug intoxicants in colchicine non-responder FMF patients.

  11. Reports of past alcohol and drug use following participation in a motivation enhancing intervention: Implications for clinical assessment and program evaluation

    Directory of Open Access Journals (Sweden)

    Rosengren David B

    2012-05-01

    Full Text Available Abstract Background There is significant interest in the value of motivational approaches that enhance participant readiness to change, but less is known about clients’ self-reports of problematic behavior when participating in such interventions. Methods We examined whether participants in a motivationally-based intervention for DUI offenders changed their reports of substance use at postintervention (when reporting on the same 30 days that they reported on at preintervention. Specifically, Study 1 (N = 8,387 tested whether participants in PRIME For Life (PFL changed their reports about baseline substance levels when asked at postintervention versus at preintervention. Study 2 (N = 192 compared changes in self-reported baseline drinking between PFL and intervention as usual (IAU participants. Results Many participants in Study 1 did not change their reports about how much they used substances during the 30-day period before baseline. Among those who did, the most common change was an increase in reported amounts of baseline drug use, and typical and peak alcohol use. This sample also showed changes in reports of their baseline pattern of high-risk-use (consistent versus occasional. At postintervention, participants who were younger, single, or endorsing more indicators of alcohol dependence were more likely to later report greater frequency of baseline drug use, and greater peak and typical number of baseline drinks. Gender, education, and race were also associated with reporting inconsistency on some behaviors. In Study 2, PFL participants showed greater increases in reports of peak alcohol use compared to IAU, but both conditions showed similar increases for drugs and typical alcohol use. Conclusions In both research and clinical settings, a segment of participants may initially report less substance use than they do when asked later about the same baseline period. These preliminary findings suggest clinicians and researchers may

  12. Drugs and Drug Abuse.

    Science.gov (United States)

    Anastas, Robert, Comp.; And Others.

    GRADES OR AGES: Secondary grades. SUBJECT MATTER: Drugs and drug abuse. ORGANIZATION AND PHYSICAL APPEARANCE: The guide is divided into several sections, each of which is in outline or list form. It is xeroxed and spiral-bound with a paper cover. OBJECTIVES AND ACTIVITIES: No objectives are mentioned. The major portion of the guide contains a…

  13. Drug allergies

    Science.gov (United States)

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... A drug allergy involves an immune response in the body that produces an allergic reaction to a medicine. The ...

  14. Hepatitis C Virus Treatment Access Among Human Immunodeficiency Virus and Hepatitis C Virus (HCV)-Coinfected People Who Inject Drugs in Guangzhou, China: Implications for HCV Treatment Expansion.

    Science.gov (United States)

    Chu, Carissa E; Wu, Feng; He, Xi; Zhou, Kali; Cheng, Yu; Cai, Weiping; Geng, Elvin; Volberding, Paul; Tucker, Joseph D

    2016-04-01

    Background.  Hepatitis C virus (HCV) treatment access among human immunodeficiency virus (HIV)/HCV-coinfected people who inject drugs is poor, despite a high burden of disease in this population. Understanding barriers and facilitators to HCV treatment uptake is critical to the implementation of new direct-acting antivirals. Methods.  We conducted in-depth interviews with patients, physicians, and social workers at an HIV treatment facility and methadone maintenance treatment centers in Guangzhou, China to identify barriers and facilitators to HCV treatment. We included patients who were in various stages of HCV treatment and those who were not treated. We used standard qualitative methods and organized data into themes. Results.  Interview data from 29 patients, 8 physicians, and 3 social workers were analyzed. Facilitators and barriers were organized according to a modified Consolidated Framework for Implementation Research schematic. Facilitators included patient trust in physicians, hope for a cure, peer networks, and social support. Barriers included ongoing drug use, low HCV disease knowledge, fragmented reimbursement systems, HIV exceptionalism, and stigma. Conclusions.  Expanding existing harm reduction programs, HIV treatment programs, and social services may facilitate scale-up of direct-acting antivirals globally. Improving integration of ancillary social and mental health services within existing HIV care systems may facilitate HCV treatment access.

  15. Fasciola hepatica demonstrates high levels of genetic diversity, a lack of population structure and high gene flow: possible implications for drug resistance.

    Science.gov (United States)

    Beesley, Nicola J; Williams, Diana J L; Paterson, Steve; Hodgkinson, Jane

    2017-01-01

    Fasciola hepatica, the liver fluke, is a trematode parasite of considerable economic importance to the livestock industry and is a re-emerging zoonosis that poses a risk to human health in F. hepatica-endemic areas worldwide. Drug resistance is a substantial threat to the current and future control of F. hepatica, yet little is known about how the biology of the parasite influences the development and spread of resistance. Given that F. hepatica can self-fertilise and therefore inbreed, there is the potential for greater population differentiation and an increased likelihood of recessive alleles, such as drug resistance genes, coming together. This could be compounded by clonal expansion within the snail intermediate host and aggregation of parasites of the same genotype on pasture. Alternatively, widespread movement of animals that typically occurs in the UK could promote high levels of gene flow and prevent population differentiation. We identified clonal parasites with identical multilocus genotypes in 61% of hosts. Despite this, 84% of 1579 adult parasites had unique multilocus genotypes, which supports high levels of genotypic diversity within F. hepatica populations. Our analyses indicate a selfing rate no greater than 2%, suggesting that this diversity is in part due to the propensity for F. hepatica to cross-fertilise. Finally, although we identified high genetic diversity within a given host, there was little evidence for differentiation between populations from different hosts, indicating a single panmictic population. This implies that, once those emerge, anthelmintic resistance genes have the potential to spread rapidly through liver fluke populations.

  16. Hepatitis C Virus Treatment Access Among Human Immunodeficiency Virus and Hepatitis C Virus (HCV)-Coinfected People Who Inject Drugs in Guangzhou, China: Implications for HCV Treatment Expansion

    Science.gov (United States)

    Chu, Carissa E.; Wu, Feng; He, Xi; Zhou, Kali; Cheng, Yu; Cai, Weiping; Geng, Elvin; Volberding, Paul; Tucker, Joseph D.

    2016-01-01

    Background. Hepatitis C virus (HCV) treatment access among human immunodeficiency virus (HIV)/HCV-coinfected people who inject drugs is poor, despite a high burden of disease in this population. Understanding barriers and facilitators to HCV treatment uptake is critical to the implementation of new direct-acting antivirals. Methods. We conducted in-depth interviews with patients, physicians, and social workers at an HIV treatment facility and methadone maintenance treatment centers in Guangzhou, China to identify barriers and facilitators to HCV treatment. We included patients who were in various stages of HCV treatment and those who were not treated. We used standard qualitative methods and organized data into themes. Results. Interview data from 29 patients, 8 physicians, and 3 social workers were analyzed. Facilitators and barriers were organized according to a modified Consolidated Framework for Implementation Research schematic. Facilitators included patient trust in physicians, hope for a cure, peer networks, and social support. Barriers included ongoing drug use, low HCV disease knowledge, fragmented reimbursement systems, HIV exceptionalism, and stigma. Conclusions. Expanding existing harm reduction programs, HIV treatment programs, and social services may facilitate scale-up of direct-acting antivirals globally. Improving integration of ancillary social and mental health services within existing HIV care systems may facilitate HCV treatment access. PMID:27419150

  17. Passive Transfer of HIV-1 Antibodies and Drug Resistant Virus during a Health Care Worker Accident: Implications for HCW Post-Exposure Management

    Directory of Open Access Journals (Sweden)

    Carlos Fernando De Oliveira

    2008-01-01

    Full Text Available Problem statement: We studied in detail a case in which a nurse caring for an HIV-infected child suffered a deep-laceration accident with contaminated blood. Approach: The patient had been treated with zidovudine (ZDV and the nurse became infected despite prophylactic use of ZDV initiated 2 h after the accident. A reactive anti-HIV-1/2 EIA and an indeterminate western blot (gp120/160 reactivity were obtained from the nurse on the day of the accident, suggesting pre-exposure infection. However, a negative western blot and positive DNA PCR were documented 10 days after the accident and seroconversion occurred an additional two weeks later. Results: Phylogenetic analyses of HIV-1 tat and C2-C4-gp120 env regions confirmed that the nurse infected by two different HIV-1 strains present in the child. Strains present in both subjects revealed multi-nucleoside resistant HIV-1. Dilutional serological studies using 10 HIV-infected patients’ sera demonstrated that passive seroreactivity could occur with infusion of less than 1 uL of blood when highly sensitive assays are employed. Conclusion: This is the first well-documented case of passive HIV antibody detection after a percutaneous exposure. Reactive baseline serology should not be assumed to represent prior infection nor exclude prophylaxis. Transmission of drug-resistant HIV-1 corroborates the medical history and supports use of drug history and resistance testing to guide antiretroviral prophylaxis.

  18. Socio-economic implication of multi-drug resistant malaria in the community; how prepared is Nigeria for this emerging problem?

    Science.gov (United States)

    Chukwuani, C M

    1999-01-01

    The control of faciparum malaria is becoming increasingly challenging in many endemic areas of the world, including Nigeria, due to the development of resistance to chloroquine and other anti-malarial drugs. Current rising health care costs demands that any preventive medicine and/or disease control program be judged according to its economic viability. As has been previously noted, any successful control of malaria will depend on socio-economic factors that influence its prevalence and management in the community. Cost-benefit or cost-effectiveness analysis of proposed and current intervention strategic are thus justified. This paper presents a review of studies involving socio-economic evaluation of the morbidity and mortality consequences of malaria. Studies involving health facility utilization profile for malaria in Nigeria and elsewhere are also reviewed. The review finds no studies evaluating or determining an appropriate economic model/framework for malaria control in Nigeria and concludes that as enormous and challenging the problem of multi-drug resistant malaria is, it can still be contained if control and management strategies are adopted based on sound and practical socio-economic judgement.

  19. Membrane-proximal TRAIL species are incapable of inducing short circuit apoptosis signaling: Implications for drug development and basic cytokine biology.

    Science.gov (United States)

    Tatzel, Katharina; Kuroki, Lindsay; Dmitriev, Igor; Kashentseva, Elena; Curiel, David T; Goedegebuure, S Peter; Powell, Matthew A; Mutch, David G; Hawkins, William G; Spitzer, Dirk

    2016-03-03

    TRAIL continues to garner substantial interest as a recombinant cancer therapeutic while the native cytokine itself serves important tumor surveillance functions when expressed in membrane-anchored form on activated immune effector cells. We have recently developed the genetically stabilized TRAIL platform TR3 in efforts to improve the limitations associated with currently available drug variants. While in the process of characterizing mesothelin-targeted TR3 variants using a single chain antibody (scFv) delivery format (SS-TR3), we discovered that the membrane-tethered cytokine had a substantially increased activity profile compared to non-targeted TR3. However, cell death proceeded exclusively via a bystander mechanism and protected the mesothelin-positive targets from apoptosis rather than leading to their elimination. Incorporation of a spacer-into the mesothelin surface antigen or the cancer drug itself-converted SS-TR3 into a cis-acting phenotype. Further experiments with membrane-anchored TR3 variants and the native cytokine confirmed our hypothesis that membrane-proximal TRAIL species lack the capacity to physically engage their cognate receptors coexpressed on the same cell membrane. Our findings not only provide an explanation for the "peaceful" coexistence of ligand and receptor of a representative member of the TNF superfamily but give us vital clues for the design of activity-enhanced TR3-based cancer therapeutics.

  20. Differential modulation of thresholds for intracranial self-stimulation by mGlu5 positive and negative allosteric modulators: implications for effects on drug self-administration

    Directory of Open Access Journals (Sweden)

    M. Foster eOlive

    2012-01-01

    Full Text Available Pharmacological manipulation of the type 5 metabotropic glutamate (mGlu5 receptor alters various addiction related behaviors such as drug self-administration and the extinction and reinstatement of drug-seeking behavior. However, the effects of pharmacological modulation of mGlu5 receptors on brain reward function have not been widely investigated. We examined the effects of acute administration of positive and negative allosteric modulators (PAMs and NAMs, respectively on brain reward function by assessing thresholds for intracranial self-stimulation (ICSS. In addition, when acute effects were observed, we examined potential changes in altered ICSS thresholds following repeated administration. Male Sprague-Dawley rats were implanted with bipolar electrodes into the medial forebrain bundle and trained to respond for ICSS, followed by assessment of effects of mGlu5 ligands on ICSS thresholds using a discrete trials current intensity threshold determination procedure. Acute administration of the selective mGlu5 NAMs MTEP (0, 0.3, 1 or 3 mg/kg and fenobam (0, 3, 10, or 30 mg/kg dose-dependently increased ICSS thresholds (~70% at the highest dose tested, suggesting a deficit in brain reward function. Acute administration of the mGlu5 PAMs CDPPB (0, 10, 30 and 60 mg/kg or ADX47273 (0, 10, 30 and 60 mg/kg was without effect at any dose tested. When administered once daily for 5 consecutive days, the development of tolerance to the ability of threshold-elevating doses of MTEP and fenobam to increase ICSS thresholds was observed. We conclude that mGlu5 PAMs and NAMs differentially affect brain reward function, and that tolerance to the ability of mGlu5 NAMs to reduce brain reward function develops with repeated administration. These brain reward deficits should be taken into consideration when interpreting acute effects of mGlu5 NAMs on drug self-administration, and repeated administration may be an effective method to reduce these deficits.

  1. Small molecule intercalation with double stranded DNA: implications for normal gene regulation and for predicting the biological efficacy and genotoxicity of drugs and other chemicals.

    Science.gov (United States)

    Hendry, Lawrence B; Mahesh, Virendra B; Bransome, Edwin D; Ewing, Douglas E

    2007-10-01

    The binding of small molecules to double stranded DNA including intercalation between base pairs has been a topic of research for over 40 years. For the most part, however, intercalation has been of marginal interest given the prevailing notion that binding of small molecules to protein receptors is largely responsible for governing biological function. This picture is now changing with the discovery of nuclear enzymes, e.g. topoisomerases that modulate intercalation of various compounds including certain antitumor drugs and genotoxins. While intercalators are classically flat, aromatic structures that can easily insert between base pairs, our laboratories reported in 1977 that a number of biologically active compounds with greater molecular thickness, e.g. steroid hormones, could fit stereospecifically between base pairs. The hypothesis was advanced that intercalation was a salient feature of the action of gene regulatory molecules. Two parallel lines of research were pursued: (1) development of technology to employ intercalation in the design of safe and effective chemicals, e.g. pharmaceuticals, nutraceuticals, agricultural chemicals; (2) exploration of intercalation in the mode of action of nuclear receptor proteins. Computer modeling demonstrated that degree of fit of certain small molecules into DNA intercalation sites correlated with degree of biological activity but not with strength of receptor binding. These findings led to computational tools including pharmacophores and search engines to design new drug candidates by predicting desirable and undesirable activities. The specific sequences in DNA into which ligands best intercalated were later found in the consensus sequences of genes activated by nuclear receptors implying intercalation was central to their mode of action. Recently, the orientation of ligands bound to nuclear receptors was found to match closely the spatial locations of ligands derived from intercalation into unwound gene sequences

  2. Small molecule intercalation with double stranded DNA: Implications for normal gene regulation and for predicting the biological efficacy and genotoxicity of drugs and other chemicals

    Energy Technology Data Exchange (ETDEWEB)

    Hendry, Lawrence B. [Accelerated Pharmaceuticals Inc., Augusta, GA (United States)], E-mail: lhendry@comcast.net; Mahesh, Virendra B.; Bransome, Edwin D.; Ewing, Douglas E. [Accelerated Pharmaceuticals Inc., Augusta, GA (United States)

    2007-10-01

    The binding of small molecules to double stranded DNA including intercalation between base pairs has been a topic of research for over 40 years. For the most part, however, intercalation has been of marginal interest given the prevailing notion that binding of small molecules to protein receptors is largely responsible for governing biological function. This picture is now changing with the discovery of nuclear enzymes, e.g. topoisomerases that modulate intercalation of various compounds including certain antitumor drugs and genotoxins. While intercalators are classically flat, aromatic structures that can easily insert between base pairs, our laboratories reported in 1977 that a number of biologically active compounds with greater molecular thickness, e.g. steroid hormones, could fit stereospecifically between base pairs. The hypothesis was advanced that intercalation was a salient feature of the action of gene regulatory molecules. Two parallel lines of research were pursued: (1) development of technology to employ intercalation in the design of safe and effective chemicals, e.g. pharmaceuticals, nutraceuticals, agricultural chemicals; (2) exploration of intercalation in the mode of action of nuclear receptor proteins. Computer modeling demonstrated that degree of fit of certain small molecules into DNA intercalation sites correlated with degree of biological activity but not with strength of receptor binding. These findings led to computational tools including pharmacophores and search engines to design new drug candidates by predicting desirable and undesirable activities. The specific sequences in DNA into which ligands best intercalated were later found in the consensus sequences of genes activated by nuclear receptors implying intercalation was central to their mode of action. Recently, the orientation of ligands bound to nuclear receptors was found to match closely the spatial locations of ligands derived from intercalation into unwound gene sequences

  3. A Comparative Assessment of Observational Medical Outcomes Partnership and Mini-Sentinel Common Data Models and Analytics: Implications for Active Drug Safety Surveillance.

    Science.gov (United States)

    Xu, Yihua; Zhou, Xiaofeng; Suehs, Brandon T; Hartzema, Abraham G; Kahn, Michael G; Moride, Yola; Sauer, Brian C; Liu, Qing; Moll, Keran; Pasquale, Margaret K; Nair, Vinit P; Bate, Andrew

    2015-08-01

    An often key component to coordinating surveillance activities across distributed networks is the design and implementation of a common data model (CDM). The purpose of this study was to evaluate two drug safety surveillance CDMs from an ecosystem perspective to better understand how differences in CDMs and analytic tools affect usability and interpretation of results. Humana claims data from 2007 to 2012 were mapped to Observational Medical Outcomes Partnership (OMOP) and Mini-Sentinel CDMs. Data were described and compared at the patient level by source code and mapped concepts. Study cohort construction and effect estimates were also compared using two different analytical methods--one based on a new user design implementing a high-dimensional propensity score (HDPS) algorithm and the other based on univariate self-controlled case series (SCCS) design--across six established positive drug-outcome pairs to learn how differences in CDMs and analytics influence steps in the database analytic process and results. Claims data for approximately 7.7 million Humana health plan members were transformed into the two CDMs. Three health outcome cohorts and two drug cohorts showed differences in cohort size and constituency between Mini-Sentinel and OMOP CDMs, which was a result of multiple factors. Overall, the implementation of the HDPS procedure on Mini-Sentinel CDM detected more known positive associations than that on OMOP CDM. The SCCS method results were comparable on both CDMs. Differences in the implementation of the HDPS procedure between the two CDMs were identified; analytic model and risk period specification had a significant impact on the performance of the HDPS procedure on OMOP CDM. Differences were observed between OMOP and Mini-Sentinel CDMs. The analysis of both CDMs at the data model level indicated that such conceptual differences had only a slight but not significant impact on identifying known safety associations. Our results show that differences at

  4. Progress in Understanding the Genetic Information and Biosynthetic Pathways behind Amycolatopsis Antibiotics, with Implications for the Continued Discovery of Novel Drugs.

    Science.gov (United States)

    Chen, Su; Wu, Qihao; Shen, Qingqing; Wang, Hong

    2016-01-01

    Species of Amycolatopsis, well recognized as producers of both vancomycin and rifamycin, are also known for producing other secondary metabolites, with wide usage in medicine and agriculture. The molecular genetics of natural antibiotics produced by this genus have been well studied. Since the rise of antibiotic resistance, finding new drugs to fight infection has become an urgent priority. Progress in understanding the biosynthesis of metabolites greatly helps the rational manipulation of biosynthetic pathways, and thus to achieve the goal of generating novel natural antibiotics. The efforts made in exploiting Amycolatopsis genome sequences for the discovery of novel natural products and biosynthetic pathways are summarized. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Factors Influencing Uptake of Rapid HIV and Hepatitis C Screening Among Drug Misusing Adult Emergency Department Patients: Implications for Future HIV/HCV Screening Interventions.

    Science.gov (United States)

    Merchant, Roland C; DeLong, Allison K; Liu, Tao; Baird, Janette R

    2015-11-01

    In this randomized, controlled trial among 957 English- or Spanish-speaking drug misusing adult emergency department (ED) patients, we determined if a tailored brief intervention (BI) increased uptake of rapid HIV/HCV screening, and identified factors associated with greater screening uptake. Rapid HIV/HCV screening uptake was greater in the control than the BI arm (45 vs. 38 %; p Screening uptake depended on elapsed study time and which research staff member offered testing. In the control arm, uptake was lowest for those spending screening uptake generally increased over time. Tailored BI content specifically addressing participant HIV/HCV knowledge, HIV/HCV risk behaviors, or need for HIV/HCV screening was not associated with greater screening uptake. These study findings suggested factors that should be considered when designing future ED-based screening initiatives, such as elapsed study time, who offers testing, and the content of interventions.

  6. Implications of the U.S. Food and Drug Administration warning against the use of sildenafil for the treatment of pediatric pulmonary hypertension.

    Science.gov (United States)

    Abman, Steven H; Kinsella, John P; Rosenzweig, Erika B; Krishnan, Usha; Kulik, Thomas; Mullen, Mary; Wessel, David L; Steinhorn, Robin; Adatia, Ian; Hanna, Brian; Feinstein, Jeffrey; Fineman, Jeffrey; Raj, Usha; Humpl, Tilman

    2013-03-15

    Pulmonary arterial hypertension (PAH) contributes to disability and death in children with diverse cardiac, pulmonary, or systemic diseases, and therapeutic options are currently limited. Data from adult studies provide the basis for most PAH-specific therapies; however, many of these medications are commonly used in children on an off-label basis due to the life-threatening nature of PAH. Although currently approved for use in adult PAH, sildenafil is used extensively off-label for the treatment of neonates, infants, and children with PAH. Past studies have generally suggested favorable effects and outcomes in infants and young children with PAH, but these reports are generally uncontrolled observations, except for one single-center trial for persistent pulmonary hypertension of the newborn. Despite extensive clinical experience with sildenafil therapy in children and approval by the European Medicines Agency for its pediatric use in Europe, the U.S. Food and Drug Administration recently issued a warning against the use of sildenafil for pediatric PAH between 1 and 17 years of age due to an apparent increase in mortality during long-term therapy. Although these data are extremely limited, this U.S. Food and Drug Administration review challenges the pediatric PAH community to further assess the efficacy and safety of sildenafil, especially with chronic treatment. Although low doses of sildenafil are likely safe in pediatric PAH, further studies should carefully examine its role in the long-term therapy of children, especially with diverse causes of PAH. Pediatric patients with PAH require close surveillance and frequent monitoring, and persistent sildenafil monotherapy is likely insufficient with disease progression.

  7. Optical microscopy of targeted drug delivery and local distribution in skin of a topical minocycline: implications in translational research and guidance for therapeutic dose selection (Conference Presentation)

    Science.gov (United States)

    Hermsmeier, Maiko; Sawant, Tanvee; Lac, Diana; Yamamoto, Akira; Chen, Xin; Huang, Susan Y.; Nagavarapu, Usha; Evans, Conor L.; Chan, Kin Foong; Daniels, AnnaMarie

    2017-02-01

    Acne vulgaris is a chronic inflammatory skin condition commonly resulting in negative aesthetic and social impacts on those affected. Minocycline, currently available as an oral antibiotic for moderate to severe acne, has a known minimum inhibitory concentration (MIC) for the acne-causing bacterium Propionibacterium acnes (P. acnes) in vitro, with its anti-inflammatory properties also eliciting inhibitory effects on pro-inflammatory molecules. A novel topical gel composition containing solubilized minocycline (BPX-01) has been developed to directly deliver the drug to the skin. Because minocycline is a known fluorophore, fluorescence microscopy and concurrent quantitative measurements were performed on excised human facial skin dosed with different concentrations, in order to determine the spatial distribution of the drug and quantification of its local concentration in the epidermis and the pilosebaceous unit where P. acnes generally reside. Local minocycline delivery confirmed achievement of an adequate therapeutic dose to support clinical studies. Subsequently, a 4-week double-blind, randomized, vehicle controlled clinical study was performed to assess the safety and efficacy of 1% minocycline BPX-01 applied daily. No instances of cutaneous toxicity were reported, and a greater than 1 log reduction of P. acnes count was observed at week 4 with statistical significance from baseline and vehicle control. In addition, no detectable amounts of minocycline in the plasma were reported, suggesting the potential of this new formulation to diminish the known systemic adverse effects associated with oral minocycline. Follow-on clinical plans are underway to further establish the safety of BPX-01 and to evaluate its efficacy against inflammatory acne lesions in a 225 patient multi-center dose-finding study.

  8. Drug Facts

    Medline Plus

    Full Text Available ... Use and Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug ...

  9. Club Drugs

    Science.gov (United States)

    ... uses. Other uses of these drugs are abuse. Club drugs are also sometimes used as "date rape" drugs, to make someone unable to say no to or fight back against sexual assault. Abusing these drugs can ...

  10. Drug Facts

    Medline Plus

    Full Text Available ... Nicotine Facts Other Drugs of Abuse What is Addiction? Do You or a Loved One Have a Drug Use Problem? Signs of Drug Use and Addiction How Does Drug Use Become Addiction? Addiction Risk ...

  11. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & ...

  12. YouTube, "Drug Videos" and Drugs Education

    Science.gov (United States)

    Manning, Paul

    2013-01-01

    Aims: This article reports on findings to emerge from a project examining YouTube "drug videos" in the light of an emerging literature on the relationship between YouTube and health education. The aim of this article is to describe the variety of discourses circulated by the "drug videos" available on YouTube and to consider the implications of…

  13. Drug-induced lupus erythematosus

    Directory of Open Access Journals (Sweden)

    M. Carrabba

    2011-09-01

    Full Text Available Drug-induced lupus is a syndrome which share symptoms and laboratory characteristics with the idiopathic systemic lupus erythematosus (SLE. The list of medications implicated as etiologic agents in drug-induced lupus continues to grow. The terms used for this condition are lupus-like syndrome, drug-induced lupus erythematosus (DILE and drug related lupus. More than 80 drugs have been associated with DILE. The first case of DILE was reported in 1945 and associated with sulfadiazin. In 1953 it was reported that DILE was related to the use of hydralazine. Drugs responsible for the development of DILE can divided into three groups, but the list of these drugs is quite long because new drugs are included yearly in the list. The syndrome is characterised by arthralgia, myalgia, pleurisy, rash and fever in association with antinuclear antibodies in the serum. Recognition of DILE is important because it usually reverts within a few weeks after stopping the drug.

  14. Exposure to anti-malarial drugs and monitoring of adverse drug reactions using toll-free mobile phone calls in private retail sector in Sagamu, Nigeria: implications for pharmacovigilance

    Directory of Open Access Journals (Sweden)

    Ogunwande Isiaka A

    2011-08-01

    Full Text Available Abstract Background Adverse drug reactions (ADRs contribute to ill-health or life-threatening outcomes of therapy during management of infectious diseases. The exposure to anti-malarial and use of mobile phone technology to report ADRs following drug exposures were investigated in Sagamu - a peri-urban community in Southwest Nigeria. Methods Purchase of medicines was actively monitored for 28 days in three Community Pharmacies (CP and four Patent and Proprietary Medicine Stores (PPMS in the community. Information on experience of ADRs was obtained by telephone from 100 volunteers who purchased anti-malarials during the 28-day period. Results and Discussion A total of 12,093 purchases were recorded during the period. Antibiotics, analgesics, vitamins and anti-malarials were the most frequently purchased medicines. A total of 1,500 complete courses of anti-malarials were purchased (12.4% of total purchases; of this number, purchases of sulphadoxine-pyrimethamine (SP and chloroquine (CQ were highest (39.3 and 25.2% respectiuvely. Other anti-malarials purchased were artesunate monotherapy (AS - 16.1%, artemether-lumefantrine (AL 10.0%, amodiaquine (AQ - 6.6%, quinine (QNN - 1.9%, halofantrine (HF - 0.2% and proguanil (PR - 0.2%. CQ was the cheapest (USD 0.3 and halofantrine the most expensive (USD 7.7. AL was 15.6 times ($4.68 more expensive than CQ. The response to mobile phone monitoring of ADRs was 57% in the first 24 hours (day 1 after purchase and decreased to 33% by day 4. Participants in this monitoring exercise were mostly with low level of education (54%. Conclusion The findings from this study indicate that ineffective anti-malaria medicines including monotherapies remain widely available and are frequently purchased in the study area. Cost may be a factor in the continued use of ineffective monotherapies. Availability of a toll-free telephone line may facilitate pharmacovigilance and follow up of response to medicines in a resource

  15. Hypersexuality due to dopaminergic drugs.

    Science.gov (United States)

    2005-12-01

    (1) Dopamine agonists used to treat Parkinson's disease sometimes cause hypersexuality. (2) Various types of behaviour have been described, and many drugs have been implicated. (3) These disorders are dose-dependent, and subside when the dose is reduced or the drug is discontinued.

  16. [(3) H]-L685,458 binding sites are abundant in multiple peripheral organs in rats: implications for safety assessment of putative γ-secretase targeting drugs.

    Science.gov (United States)

    Yang, Zhi-Ying; Li, Jian-Ming; Xiao, Ling; Mou, Lin; Cai, Yan; Huang, He; Luo, Xue-Gang; Yan, Xiao-Xin

    2014-12-01

    γ-Secretase is a multimeric enzyme complex that carries out proteolytic processing to a variety of cellular proteins. It is currently explored as a therapeutic target for Alzheimer's disease (AD) and cancer. Mechanism-based toxicity needs to be thoroughly evaluated for γ-secretase inhibitory and/or modulatory drugs. This study comparatively assessed putative γ-secretase catalytic sites in rat peripheral tissues relative to brain and explored an effort of its pharmacological inhibition on hair regeneration. Using [(3) H]-labelled L685,458, a potent γ-secretase inhibitor, as probe, we found more abundant presence of γ-secretase binding sites in the liver, gastrointestinal tract, hair follicle, pituitary gland, ovary and testis, as compared to the brain. Local application of L658,458 delayed vibrissal regrowth following whisker removal. These results suggest that γ-secretase may execute important biological functions in many peripheral systems, as in the brain. The development of γ-secretase inhibitors/modulators for AD and cancer therapy should include close monitoring of toxicological panels for hepatic, gastrointestinal, endocrinal and reproductive functions.

  17. Nod2-Nodosome in a Cell-Free System: Implications in Pathogenesis and Drug Discovery for Blau Syndrome and Early-Onset Sarcoidosis

    Directory of Open Access Journals (Sweden)

    Tomoyuki Iwasaki

    2016-01-01

    Full Text Available Nucleotide-binding oligomerization domain-containing protein (Nod 2 is an intracellular pattern recognition receptor, which recognizes muramyl dipeptide (N-Acetylmuramyl-L-Alanyl-D-Isoglutamine: MDP, a bacterial peptidoglycan component, and makes a NF-κB-activating complex called nodosome with adaptor protein RICK (RIP2/RIPK2. Nod2 mutants are associated with the autoinflammatory diseases, Blau syndrome (BS/early-onset sarcoidosis (EOS. For drug discovery of BS/EOS, we tried to develop Nod2-nodosome in a cell-free system. FLAG-tagged RICK, biotinylated-Nod2, and BS/EOS-associated Nod2 mutants were synthesized, and proximity signals between FLAG-tagged and biotinylated proteins were detected by amplified luminescent proximity homogeneous assay (ALPHA. Upon incubation with MDP, the ALPHA signal of interaction between Nod2-WT and RICK was increased in a dose-dependent manner. The ALPHA signal of interaction between RICK and the BS/EOS-associated Nod2 mutants was more significantly increased than Nod2-WT. Notably, the ALPHA signal between Nod2-WT and RICK was increased upon incubation with MDP, but not when incubated with the same concentrations, L-alanine, D-isoglutamic acid, or the MDP-D-isoform. Thus, we successfully developed Nod2-nodosome in a cell-free system reflecting its function in vivo, and it can be useful for screening Nod2-nodosome-targeted therapeutic molecules for BS/EOS and granulomatous inflammatory diseases.

  18. Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients.

    Science.gov (United States)

    Addai, Amma B; Pandhare, Jui; Paromov, Victor; Mantri, Chinmay K; Pratap, Siddharth; Dash, Chandravanu

    2015-04-01

    Epidemiologic studies suggest that cocaine abuse worsens HIV-1 disease progression. Increased viral load has been suggested to play a key role for the accelerated HIV disease among cocaine-abusing patients. The goal of this study was to investigate whether cocaine enhances proviral DNA integration as a mechanism to increase viral load. We infected CD4(+) T cells that are the primary targets of HIV-1 in vivo and treated the cells with physiologically relevant concentrations of cocaine (1 µM-100 µM). Proviral DNA integration in the host genome was measured by nested qPCR. Our results illustrated that cocaine from 1 µM through 50 µM increased HIV-1 integration in CD4(+) T cells in a dose-dependent manner. As integration can be modulated by several early postentry steps of HIV-1 infection, we examined the direct effects of cocaine on viral integration by in vitro integration assays by use of HIV-1 PICs. Our data illustrated that cocaine directly increases viral DNA integration. Furthermore, our MS analysis showed that cocaine is able to enter CD4(+) T cells and localize to the nucleus-. In summary, our data provide strong evidence that cocaine can increase HIV-1 integration in CD4(+) T cells. Therefore, we hypothesize that increased HIV-1 integration is a novel mechanism by which cocaine enhances viral load and worsens disease progression in drug-abusing HIV-1 patients.

  19. Neighborhood differences in patterns of syringe access, use, and discard among injection drug users: implications for HIV outreach and prevention education.

    Science.gov (United States)

    Buchanan, David; Shaw, Susan; Teng, Wei; Hiser, Poppy; Singer, Merrill

    2003-09-01

    The article presents results from the Syringe Access, Use, and Discard: Context in AIDS Risk research project comparing two neighborhoods by (1) socioeconomic and demographic characteristics; (2) patterns of syringe access, use, and discard; and (3) encounters with a local human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) outreach project targeted to injection drug users (IDUs). The results show that IDUs in more economically advantaged neighborhoods were more likely to acquire syringes from a single source (rather than multiple sources), more likely to inject alone in their own residence (rather than public injection locales), and more likely to dispose of syringes in private garbage cans rather alleys or dumpsters. These results are further associated with the likelihood of encountering street outreach workers, with IDUs in more affluent neighborhoods much less likely to have any such contacts. Based on the different patterns of access, use, and discard evident in each neighborhood, the results indicate that different and more carefully tailored local outreach and prevention strategies are urgently needed.

  20. X-ray structure and inhibition of the feline infectious peritonitis virus 3C-like protease: Structural implications for drug design.

    Science.gov (United States)

    St John, Sarah E; Therkelsen, Matthew D; Nyalapatla, Prasanth R; Osswald, Heather L; Ghosh, Arun K; Mesecar, Andrew D

    2015-11-15

    Feline infectious peritonitis (FIP) is a deadly disease that effects both domestic and wild cats and is caused by a mutation in feline coronavirus (FCoV) that allows the virus to replicate in macrophages. Currently, there are no treatments or vaccines available for the treatment of FIP even though it kills approximately 5% of cats in multi-cat households per year. In an effort to develop small molecule drugs targeting FIP for the treatment of cats, we screened a small set of designed peptidomimetic inhibitors for inhibition of FIPV-3CL(pro), identifying two compounds with low to sub-micromolar inhibition, compound 6 (IC50=0.59±0.06 μM) and compound 7 (IC50=1.3±0.1 μM). We determined the first X-ray crystal structure of FIPV-3CL(pro) in complex with the best inhibitor identified, compound 6, to a resolution of 2.10 Å to better understand the structural basis for inhibitor specificity. Our study provides important insights into the structural requirements for the inhibition of FIPV-3CL(pro) by peptidomimetic inhibitors and expands the current structural knowledge of coronaviral 3CL(pro) architecture.

  1. Strength of C-H Bonds at Nitrogen a-Position: Implication for Metabolic Stability of Nitrogen-containing Drug Molecules

    Institute of Scientific and Technical Information of China (English)

    MENG Xiang-Ming; ZOU Lu-Feng; XIE Miao; FU Yao

    2008-01-01

    The available experimental αC-H BDEs of a variety of amine-containing molecules were examined by using the G3B3 and CBS-Q methods. The verified values were employed to benchmark and calibrate the density functional theory methods. It was found that the (U)BHandH/6-311++G(2df, 2p)//(U)B3LYP/6-31G(d) method was a fast and accurate method for calculating C-H BDEs at nitrogen a-positions. By using the newly benchmarked BHandH method, the aC-H BDEs in a number of nitrogen-containing drug molecules were calculated, where a dramatic variation of the αC-H BDEs was discovered. To understand this variation, the effects of mono- and double-substitution at both carbon and nitrogen atoms on the aC-H BDEs were systematically studied. The origin of the substitution effects was thoroughly discussed in terms of four categories of substituents.

  2. Drug-induced hair loss.

    Science.gov (United States)

    2016-05-01

    Hair loss can have major psychological consequences. It can be due to a wide variety of causes, including hormonal disorders, dietary factors, infections, inflammation, trauma, emotional factors, and cancer. Drugs can also induce hair loss, by interacting with the hair growth cycle. Drug-induced hair loss may be immediate or delayed, sudden or gradual, and diffuse or localised. It is usually reversible after drug discontinuation. The drugs most often implicated in hair loss are anticancer agents, interferon, azole antifungals, lithium, immunosuppressants, and many other drugs belonging to a variety of pharmacological classes.

  3. Resistance to the macrocyclic lactone moxidectin is mediated in part by membrane transporter P-glycoproteins: Implications for control of drug resistant parasitic nematodes.

    Science.gov (United States)

    Bygarski, Elizabeth E; Prichard, Roger K; Ardelli, Bernadette F

    2014-12-01

    Our objective was to determine if the resistance mechanism to moxidectin (MOX) is similar of that to ivermectin (IVM) and involves P-glycoproteins (PGPs). Several Caenorhabditis elegans strains were used: an IVM and MOX sensitive strain, 13 PGP deletion strains and the IVM-R strain which shows synthetic resistance to IVM (by creation of three point mutations in genes coding for α-subunits of glutamate gated chloride channels [GluCls]) and cross-resistance to MOX. These strains were used to compare expression of PGP genes, measure motility and pharyngeal pumping phenotypes and evaluate the ability of compounds that inhibit PGP function to potentiate sensitivity or reverse resistance to MOX. The results suggest that C. elegans may use regulation of PGPs as a response mechanism to MOX. This was indicated by the over-expression of several PGPs in both drug sensitive and IVM-R strains and the significant changes in phenotype in the IVM-R strain in the presence of PGP inhibitors. However, as the inhibitors did not completely disrupt expression of the phenotypic traits in the IVM-R strain, this suggests that there likely are multiple avenues for MOX action that may include receptors other than GluCls. If MOX resistance was mediated solely by GluCls then exposure of the IVM-R strain to PGP inhibitors should not have affected sensitivity to MOX. Targeted gene deletions showed that protection of C. elegans against MOX involves complex mechanisms and depends on the PGP gene family, particularly PGP-6. While the results presented are similar to others using IVM, there were some important differences observed with respect to PGPs which may play a role in the disparities seen in the characteristics of resistance to IVM and MOX. The similarities are of concern as parasites resistant to IVM show some degree but not complete cross-resistance to MOX; this could impact nematodes that are resistant to IVM.

  4. Resistance to the macrocyclic lactone moxidectin is mediated in part by membrane transporter P-glycoproteins: Implications for control of drug resistant parasitic nematodes

    Directory of Open Access Journals (Sweden)

    Elizabeth E. Bygarski

    2014-12-01

    Full Text Available Our objective was to determine if the resistance mechanism to moxidectin (MOX is similar of that to ivermectin (IVM and involves P-glycoproteins (PGPs. Several Caenorhabditis elegans strains were used: an IVM and MOX sensitive strain, 13 PGP deletion strains and the IVM-R strain which shows synthetic resistance to IVM (by creation of three point mutations in genes coding for α-subunits of glutamate gated chloride channels [GluCls] and cross-resistance to MOX. These strains were used to compare expression of PGP genes, measure motility and pharyngeal pumping phenotypes and evaluate the ability of compounds that inhibit PGP function to potentiate sensitivity or reverse resistance to MOX. The results suggest that C. elegans may use regulation of PGPs as a response mechanism to MOX. This was indicated by the over-expression of several PGPs in both drug sensitive and IVM-R strains and the significant changes in phenotype in the IVM-R strain in the presence of PGP inhibitors. However, as the inhibitors did not completely disrupt expression of the phenotypic traits in the IVM-R strain, this suggests that there likely are multiple avenues for MOX action that may include receptors other than GluCls. If MOX resistance was mediated solely by GluCls then exposure of the IVM-R strain to PGP inhibitors should not have affected sensitivity to MOX. Targeted gene deletions showed that protection of C. elegans against MOX involves complex mechanisms and depends on the PGP gene family, particularly PGP-6. While the results presented are similar to others using IVM, there were some important differences observed with respect to PGPs which may play a role in the disparities seen in the characteristics of resistance to IVM and MOX. The similarities are of concern as parasites resistant to IVM show some degree but not complete cross-resistance to MOX; this could impact nematodes that are resistant to IVM.

  5. NMR investigations of structural and dynamics features of natively unstructured drug peptide - salmon calcitonin: implication to rational design of potent sCT analogs.

    Science.gov (United States)

    Rawat, Atul; Kumar, Dinesh

    2013-01-01

    Backbone dynamics and conformational properties of drug peptide salmon calcitonin have been studied in aqueous solution using nuclear magnetic resonance (NMR). Although salmon calcitonin (sCT) is largely unfolded in solution (as has been reported in several circular dichroism studies), the secondary H(α) chemical shifts and three bond H(N) -H(α) coupling constants indicated that most of the residues of the peptide are populating the α-helical region of the Ramachandran (ϕ, ψ) map. Further, the peptide in solution has been found to exhibit multiple conformational states exchanging slowly on the NMR timescale (10(2) -10(3)  s(-1) ), inferred by the multiple chemical shift assignments in the region Leu4-Leu12 and around Pro23 (for residues Gln20-Tyr22 and Arg24). Possibly, these slowly exchanging multiple conformational states might inhibit symmetric self-association of the peptide and, in part, may account for its reduced aggregation propensity compared with human calcitonin (which lacks this property). The (15) N NMR-relaxation data revealed (i) the presence of slow (microsecond-to-millisecond) timescale dynamics in the N-terminal region (Cys1-Ser5) and core residues His17 and Asn26 and (ii) the presence of high frequency (nanosecond-to-picosecond) motions in the C-terminal arm. Put together, the various results suggested that (i) the flexible C-terminal of sCT (from Thr25-Thr31) is involved in identification of specific target receptors, (ii) whereas the N-terminal of sCT (from Cys1-Gln20) in solution - exhibiting significant amount of conformational plasticity and strong bias towards biologically active α-helical structure - facilitates favorable conformational adaptations while interacting with the intermembrane domains of these target receptors. Thus, we believe that the structural and dynamics features of sCT presented here will be useful guiding attributes for the rational design of biologically active sCT analogs.

  6. Health implications of water quality: drugs residues in water Repercusiones sanitarias de la calidad del agua: los residuos de medicamentos en el agua

    Directory of Open Access Journals (Sweden)

    Damià Barceló Culleres

    2011-12-01

    Full Text Available This manuscript summarizes the main results obtained in various monitoring studies conducted in the Llobregat and the Ebro River basins to evaluate the occurrence of pharmaceuticals and drugs of abuse in their aquatic environments and the potentially derived risks for environmental and human health. The occurrence of these compounds in surface waters, located downstream the point of discharge of sewage treatment plants (STP, points out STPs effluents as the main source of these substances in the aquatic environment. Both river basins had similar pharmaceutical contamination patterns. However, hazard quotients (HQ calculated for three different trophic levels (algae, daphnia and fish pointed out sulfamethoxazol (sulfamide antibiotic for algae, gemfibrozil (lipid regulator for algae and fish, clofibric acid (lipid regulator and erythromycine (macrolide antibiotic for daphnia, and ibuprofen (analgesic anti-inflammatory for all investigated tropic levels, as the compounds with the highest ecotoxicological risk in the Llobregat. In the Ebro River, the most problematic pharmaceuticals were sulfamethoxazol for algae, and erythromycine, clofibric acid and fluoxetine (anti-depressive for daphnids. Levels of drugs of abuse measured in surface waters of the Ebro River were one and two orders of magnitude lower than those observed in effluent and influent sewage waters, respectively. Lack of data about their ecotoxicity does not allow calculation of HQ for these compounds. The presence of pharmaceuticals and drugs of abuse in surface and drinking waters is not subjected to regulation; hence, they are not considered priority pollutants to be included in monitoring programs. However, due to their possible harmful outcomes in wildlife, research on their potential effects in human health is indispensable.Este trabajo resume varios estudios de monitorización de fármacos y drogas de abuso llevados a cabo en el medio ambiente acuático de las cuencas de los r

  7. Alteraciones de la Personalidad Asociadas a las Conductas Adictivas: Influencia de la Duración del Consumo y sus Implicaciones Personality Disorders Associated With Addictive Behaviour: Examining the Influence of the Drug Addiction Course and its Implications

    Directory of Open Access Journals (Sweden)

    Jesús Herrero

    2004-05-01

    Full Text Available El fenómeno de la comorbilidad es un aspecto cada vez más estudiado dentro del ámbito psicopatológico. En el campo de las toxicomanías, diferentes estudios señalan una alta prevalencia de distintos trastornos de personalidad en esta población. El objetivo de la presente investigación se centró en analizar la relación existente entre distintos trastornos de personalidad y la duración de consumo de tóxicos. La muestra de sujetos consistió en 1094 toxicómanos que fueron evaluados en una unidad de rehabilitación y tratamiento (Comunidad Terapéutica de Proyecto Hombre. A todos los participantes se les administró individualmente la versión española del Inventario Clínico Multiaxial de Millon (MCMI-II. Se presentan las dificultades del estudio de la relación entre duración de la adicción y personalidad, y se discute las implicaciones clínicas de este trabajo.Comorbidity is a central aspect in current psychopathology. In the field of drug addictions, different studies have shown a high prevalence of personality disorders in this population. The goal of the present investigation was centered on analyzing the relation between different personality disorders and the consumption duration. The subjects were 1094 drug addicts that were evaluated in a rehabilitation and treatment unit (Proyecto Hombre's Therapeutic Community. Personality disorders were ascertained using the Millon Clinical Multiaxial Inventory II Spanish version (MCMI-II. The difficulties of studying the relation among duration of addiction and personality are presented, and clinical implications of study findings are discussed.

  8. Assessment of gastrointestinal pH, fluid and lymphoid tissue in the guinea pig, rabbit and pig, and implications for their use in drug development.

    Science.gov (United States)

    Merchant, Hamid A; McConnell, Emma L; Liu, Fang; Ramaswamy, Chandrasekaran; Kulkarni, Rucha P; Basit, Abdul W; Murdan, Sudaxshina

    2011-01-18

    Laboratory animals are often used in drug delivery and research. However, basic information about their gastrointestinal pH, fluid volume, and lymphoid tissue is not completely known. We have investigated these post-mortem in healthy guinea pigs, rabbits and pigs, to assess their suitability for pre-clinical studies by comparing the results with reported human literature. The mean gastric pH (fed ad libitum) was 2.9 and 4.4 in guinea pig and pig, respectively. In contrast, a very low pH (1.6) was recorded in the rabbits. The small intestinal pH was found in the range of 6.4-7.4 in the guinea pigs and rabbits, whereas lower pH (6.1-6.7) was recorded in the pig, which may have consequences for ionisable or pH responsive systems when tested in pig. A relatively lower pH than in the small intestine was found in the caecum (6.0-6.4) and colon (6.1-6.6) of the guinea pig, rabbit and the pig. The water content in the gastrointestinal tract of guinea pig, rabbit and pig was 51g, 153g and 1546g, respectively. When normalized to the body weight, the guinea pig, had larger amounts of water compared to the rabbit and the pig (guinea pig>rabbit>pig); in contrast, a reverse order was found when normalized to per unit length of the gut (guinea pigpig). The lymphoid tissue distribution (lymphoid follicles, Peyer's patches and long strips) along the length of the gut in these animals is presented; in particular, an abundance of lymphoid tissue was found in pig's stomach, small intestine and caecum, and rabbit's appendix. Their ample presence indicated the potential utility of these animal species in oral and colonic vaccination. These differences in the gastrointestinal parameters of the guinea pig, rabbit and pig reiterates the crucial importance of correctly selecting animal models for pre-clinical studies.

  9. Differential expression and function of PDE8 and PDE4 in effector T cells: Implications for PDE8 as a drug target in inflammation.

    Directory of Open Access Journals (Sweden)

    Amanda G. Vang

    2016-08-01

    Full Text Available Abolishing the inhibitory signal of intracellular cAMP is a prerequisite for effector T (Teff cell function. The regulation of cAMP within leukocytes critically depends on its degradation by cyclic nucleotide phosphodiesterases (PDEs. We have previously shown that PDE8A, a PDE isoform with 40-100-fold greater affinity for cAMP than PDE4, is selectively expressed in Teff versus regulatory T (Treg cells and controls CD4+ Teff cell adhesion and chemotaxis. Here, we determined PDE8A expression and function in CD4+ Teff cell populations in vivo. Using magnetic bead separation to purify leukocyte populations from the lung draining hilar lymph node (HLN in a mouse model of ovalbumin-induced allergic airway disease (AAD, we found by Western immunoblot and quantitative (qRT-PCR that PDE8A protein and gene expression are enhanced in the CD4+ T cell fraction over the course of the acute inflammatory disease and recede at the late tolerant non-inflammatory stage. To evaluate PDE8A as a potential drug target, we compared the selective and combined effects of the recently characterized highly potent PDE8-selective inhibitor PF-04957325 with the PDE4-selective inhibitor piclamilast (PICL. As previously shown, PF-04957325 suppresses T cell adhesion to endothelial cells. In contrast, we found that PICL alone increased firm T cell adhesion to endothelial cells by approximately 20% and significantly abrogated the inhibitory effect of PF-04957325 on T cell adhesion by over 50% when cells were co-exposed to PICL and PF-04957325. Despite its robust effect on T cell adhesion, PF-04957325 was over two orders of magnitude less efficient than PICL in suppressing polyclonal Teff cell proliferation, and showed no effect on cytokine gene expression in these cells. More importantly, PDE8 inhibition did not suppress proliferation and cytokine production of myelin-antigen reactive proinflammatory Teff cells in vivo and in vitro. Thus, targeting PDE8 through PF-04957325

  10. Molecular monitoring of plasmodium falciparum drug susceptibility at the time of the introduction of artemisinin-based combination therapy in Yaoundé, Cameroon: Implications for the future

    Directory of Open Access Journals (Sweden)

    Menard Sandie

    2012-04-01

    Full Text Available Abstract Background Regular monitoring of the levels of anti-malarial resistance of Plasmodium falciparum is an essential policy to adapt therapy and improve malaria control. This monitoring can be facilitated by using molecular tools, which are easier to implement than the classical determination of the resistance phenotype. In Cameroon, chloroquine (CQ, previously the first-line therapy for uncomplicated malaria was officially withdrawn in 2002 and replaced initially by amodiaquine (AQ monotherapy. Then, artemisinin-based combination therapy (ACT, notably artesunate-amodiaquine (AS-AQ or artemether-lumefantrine (AL, was gradually introduced in 2004. This situation raised the question of the evolution of P. falciparum resistance molecular markers in Yaoundé, a highly urbanized Cameroonian city. Methods The genotype of pfcrt 72 and 76 and pfmdr1 86 alleles and pfmdr1 copy number were determined using real-time PCR in 447 P. falciparum samples collected between 2005 and 2009. Results This study showed a high prevalence of parasites with mutant pfcrt 76 (83% and pfmdr1 86 (93% codons. On the contrary, no mutations in the pfcrt 72 codon and no samples with duplication of the pfmdr1 gene were observed. Conclusion The high prevalence of mutant pfcrt 76T and pfmdr1 86Y alleles might be due to the choice of alternative drugs (AQ and AS-AQ known to select such genotypes. Mutant pfcrt 72 codon was not detected despite the prolonged use of AQ either as monotherapy or combined with artesunate. The absence of pfmdr1 multicopies suggests that AL would still remain efficient. The limited use of mefloquine or the predominance of mutant pfmdr1 86Y codon could explain the lack of pfmdr1 amplification. Indeed, this mutant codon is rarely associated with duplication of pfmdr1 gene. In Cameroon, the changes of therapeutic strategies and the simultaneous use of several formulations of ACT or other anti-malarials that are not officially recommended result in a

  11. Expanding access to parasite-based malaria diagnosis through retail drug shops in Tanzania: evidence from a randomized trial and implications for treatment.

    Science.gov (United States)

    Maloney, Kathleen; Ward, Abigail; Krenz, Bonnie; Petty, Nora; Bryson, Lindsay; Dolkart, Caitlin; Visser, Theodoor; Le Menach, Arnaud; Scott, Valerie K; Cohen, Justin M; Mtumbuka, Esther; Mkude, Sigsbert

    2017-01-03

    Tanzania has seen a reduction in the fraction of fevers caused by malaria, likely due in part to scale-up of control measures. While national guidelines require parasite-based diagnosis prior to treatment, it is estimated that more than half of suspected malaria treatment-seeking in Tanzania initiates in the private retail sector, where diagnosis by malaria rapid diagnostic test (RDT) or microscopy is illegal. This pilot study investigated whether the introduction of RDTs into Accredited Drug Dispensing Outlets (ADDOs) under realistic market conditions would improve case management practices. Dispensers from ADDOs in two intervention districts in Tanzania were trained to stock and perform RDTs and monitored quarterly. Each district was assigned a different recommended retail price to evaluate the need for a subsidy. Malaria RDT and artemisinin-based combination therapy (ACT) uptake and availability were measured pre-intervention and 1 year post-intervention through structured surveys of ADDO owners and exiting customers in both intervention districts and one contiguous control district. Descriptive analysis and logistic regression were used to compare the three districts and identify predictive variables for testing. A total of 310 dispensers from 262 ADDOs were trained to stock and perform RDTs. RDT availability in intervention ADDOs increased from 1% (n = 172) to 73% (n = 163) during the study; ACT medicines were available in 75% of 260 pre-intervention and 68% of 254 post-intervention ADDOs. Pre-treatment testing performed within the ADDO increased from 0 to 65% of suspected malaria patients who visited a shop (95% CI 60.8-69.6%) with no difference between intervention districts. Overall parasite-based diagnosis increased from 19 to 74% in intervention districts and from 3 to 18% in the control district. Prior knowledge of RDT availability (aOR = 1.9, p = 0.03) and RDT experience (aOR = 1.9, p = 0.01) were predictors for testing. Adherence data

  12. Characterization of the P140K, PVP(138-140)MLK, and G156A O6-methylguanine-DNA methyltransferase mutants: implications for drug resistance gene therapy.

    Science.gov (United States)

    Davis, B M; Roth, J C; Liu, L; Xu-Welliver, M; Pegg, A E; Gerson, S L

    1999-11-20

    The G156A O6-alkylguanine-DNA alkyltransferase (AGT) mutant protein, encoded by the G156A O6-methylguanine-DNA methyltransferase gene (MGMT), is resistant to O6-benzylguanine (BG) inactivation and, after transduction into hematopoietic progenitors, transmits remarkable resistance to BG and BCNU. As a result, a clinical trial, in which the MGMT gene is transduced into CD34+ cells of patients with cancer, has been approved. A newly identified AGT mutation, P140K, generates dramatically increased BG resistance relative to G156A, and suggests that gene transfer of P140K may confer improved hematopoietic cell protection. To address this hypothesis, we measured BG + BCNU and BG + TMZ resistance in G156A, P140K, or P138M/V139L/P140K (MLK) MGMT-transduced K562 cells. In addition, we performed a detailed characterization of individual properties including BG resistance, activity, and protein stability of these mutants in human hematopoetic K562 cells and E86 retroviral producer cells. In K562 cell extracts, the MLK and P140K mutants retained full activity at doses up to 1 mM BG, while G156A had a BG ED50 of 15 microM, compared with 0.1 microM for wtAGT. In the absence of BG, the G156A protein possessed a 56% reduction in specific O6-methyltransferase activity compared with wtAGT. MLK, P140K, and wtAGT all possessed similar specific activities, although the O6-methyl repair rate of all mutants was reduced 4- to 13-fold relative to wtAGT. The wtAGT, MLK, and P140K proteins were stable, with half-lives of greater than 18 hr. In contrast, only 20% of the G156A protein was stable after 12 hr in cycloheximide and, interestingly, the remaining protein appeared to retain most of the activity present in non-cycloheximide-treated cells. Differences in BG resistance, activity, and stability between P140K, MLK, and G156A suggest that P140K may be the optimal mutant for drug resistance gene transfer. However, hematopoietic K562 cells transduced with MFG-G156A, P140K, or MLK had similar

  13. Electrophysiological changes in laterodorsal tegmental neurons associated with prenatal nicotine exposure: implications for heightened susceptibility to addict to drugs of abuse.

    Science.gov (United States)

    Christensen, M H; Nielsen, M L; Kohlmeier, K A

    2015-06-01

    Prenatal nicotine exposure (PNE) is a risk factor for developing an addiction to nicotine at a later stage in life. Understanding the neurobiological changes in reward related circuitry induced by exposure to nicotine prenatally is vital if we are to combat the heightened addiction liability in these vulnerable individuals. The laterodorsal tegmental nucleus (LDT), which is comprised of cholinergic, GABAergic and glutamatergic neurons, is importantly involved in reward mediation via demonstrated excitatory projections to dopamine-containing ventral tegmental neurons. PNE could lead to alterations in LDT neurons that would be expected to alter responses to later-life nicotine exposure. To examine this issue, we monitored nicotine-induced responses of LDT neurons in brain slices of PNE and drug naive mice using calcium imaging and whole-cell patch clamping. Nicotine was found to induce rises in calcium in a smaller proportion of LDT cells in PNE mice aged 7-15 days and smaller rises in calcium in PNE animals from postnatal ages 11-21 days when compared with age-matched control animals. While inward currents induced by nicotine were not found to be different, nicotine did induce larger amplitude excitatory postsynaptic currents in PNE animals in the oldest age group when compared with amplitudes induced in similar-aged control animals. Immunohistochemically identified cholinergic LDT cells from PNE animals exhibited slower spike rise and decay slopes, which likely contributed to the wider action potential observed. Further, PNE was associated with a more negative action potential afterhyperpolarization in cholinergic cells. Interestingly, the changes found in these parameters in animals exposed prenatally to nicotine were age related, in that they were not apparent in animals from the oldest age group examined. Taken together, our data suggest that PNE induces changes in cholinergic LDT cells that would be expected to alter cellular excitability. As the changes are

  14. Drug-induced diarrhoea.

    Science.gov (United States)

    Chassany, O; Michaux, A; Bergmann, J F

    2000-01-01

    Diarrhoea is a relatively frequent adverse event, accounting for about 7% of all drug adverse effects. More than 700 drugs have been implicated in causing diarrhoea; those most frequently involved are antimicrobials, laxatives, magnesium-containing antacids, lactose- or sorbitol-containing products, nonsteroidal anti-inflammatory drugs, prostaglandins, colchicine, antineoplastics, antiarrhythmic drugs and cholinergic agents. Certain new drugs are likely to induce diarrhoea because of their pharmacodynamic properties; examples include anthraquinone-related agents, alpha-glucosidase inhibitors, lipase inhibitors and cholinesterase inhibitors. Antimicrobials are responsible for 25% of drug-induced diarrhoea. The disease spectrum of antimicrobial-associated diarrhoea ranges from benign diarrhoea to pseudomembranous colitis. Several pathophysiological mechanisms are involved in drug-induced diarrhoea: osmotic diarrhoea, secretory diarrhoea, shortened transit time, exudative diarrhoea and protein-losing enteropathy, and malabsorption or maldigestion of fat and carbohydrates. Often 2 or more mechanisms are present simultaneously. In clinical practice, 2 major types of diarrhoea are seen: acute diarrhoea, which usually appears during the first few days of treatment, and chronic diarrhoea, lasting more than 3 or 4 weeks and which can appear a long time after the start of drug therapy. Both can be severe and poorly tolerated. In a patient presenting with diarrhoea, the medical history is very important, especially the drug history, as it can suggest a diagnosis of drug-induced diarrhoea and thereby avoid multiple diagnostic tests. The clinical examination should cover severity criteria such as fever, rectal emission of blood and mucus, dehydration and bodyweight loss. Establishing a relationship between drug consumption and diarrhoea or colitis can be difficult when the time elapsed between the start of the drug and the onset of symptoms is long, sometimes up to several

  15. 美国集团采购组织分析及对我国药品采购的启示%Analysis on the group purchasing organizations in the United States and its implications for Chinese drug procurement

    Institute of Scientific and Technical Information of China (English)

    邵蓉; 谢金平; 蒋蓉

    2014-01-01

    本文采用文献研究法,详细地分析了美国集团采购组织的基本特质及其对医疗卫生体制的影响。主要内容包括集团采购组织在美国的发展历程、组织类型、基本职能、采购药品的流程及其主要费用来源,集团采购组织的特点及对医院、供应商、监管机构产生的影响。研究认为,集团采购组织为美国医疗保健提供方节约了大量成本,在医疗供应链中发挥着重要作用。建议创新与完善我国药品采购制度应更大范围、更深程度地引入市场机制,妥善协调政府与市场在药品采购中的作用;并科学设置评标方法,兼顾药品质量与价格要素,注重采购的经济实用性。%In this paper, basic characteristics of group purchasing organizations ( GPOs) and its implications for US health care system are analyzed using a literature research method. The main contents include the development process, type, basic functions, drug procurement processes, fee sources, characteristics and influence for the hospi-tals, supplies, regulators of GPOs. We suggest that GPOs have helped US health care providers save a lot of money and played an important role in the healthcare supply chain. We also suggest that market mechanisms should be intro-duced widely concerning the model innovation and improvement of domestic drug procurement. At the same time, government and the market should be coordinated properly. Moreover, scientific evaluation methods should be set in consideration of drug quality, prices and its economic practicality.

  16. Drug Facts

    Medline Plus

    Full Text Available ... and Nicotine Facts Other Drugs of Abuse What is Addiction? What are some signs and symptoms of ... to Drugs? Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? Effects of ...

  17. Drug Reactions

    Science.gov (United States)

    ... problem is interactions, which may occur between Two drugs, such as aspirin and blood thinners Drugs and food, such as statins and grapefruit Drugs and supplements, such as ginkgo and blood thinners ...

  18. Drug Resistance

    Science.gov (United States)

    HIV Treatment Drug Resistance (Last updated 3/2/2017; last reviewed 3/2/2017) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...

  19. 灰兔眼巩膜厚度测量%Scleral thickness topography of the adult Chinchilla pigmented rabbit with implications for transscleral drug delivery research

    Institute of Scientific and Technical Information of China (English)

    李杰; 兰碧菲; 赵春晖; 程凌云

    2013-01-01

    Objective To measure the scleral thickness of the rabbit eye at different locations in the globe,providing a theoretical basis for advanced research in transscleral drug delivery.Methods In this experimental study,98 eyes of 49 adult pigmented rabbits were sacrificed after deep anesthesia and the eyeballs were enucleated and fixed in 1% buffered formaldehyde and 1.25% glutaraldehyde for a minimum of 36 hours.The eyes were processed for routine paraffin embedding and sectioning.The sagittal sections at the optic nerve level were collected and used for scleral thickness study.The images were acquired at serial locations between the limbus and optic nerve and the thickness was measured with SPOT image software.The data were analyzed with generalized estimating equations (GEE) and Tukey's HSD Post Hoc Test.Results In general,the mean scleral thickness of the inferior eye globe was significantly thinner than that of the superior globe (342.9±91.3 μm versus 400.4±67.6 μm,x2=43.57,P<0.01,GEE).There were no significant differences in the scleral thickness from the pre-equator vicinity to the posterior pole,with a mean thickness of 366.8±56.3 μm at the superior globe.For the inferior globe,the mean scleral thickness at the pre-equator vicinity and at the equator was similar,340.9±72.5 μm and 340.8±76.3 μm.However,scleral thickness decreased to 293.9±57.4 μm at the post-equator vicinity and to 209.0±51.8 μm at the posterior pole.The thinnest sclera was located immediately around the optic nerve,273.5±90.5 μm for the superior and 187.7±60.1 μm for the inferior,compared to the other locations (P<0.05,Tukey's HSD Post Hoc Test).Conclusion Rabbit sclera is thinner than human sclera.In the rabbit eye globe,the superior sclera is significantly thicker than the inferior sclera and superior sclera is shorter and more uniform in thickness between the equator and the posterior pole.Scleral thickness has larger variations between the limbus and equator than

  20. GPCR Conformations: Implications for Rational Drug Design

    OpenAIRE

    Parrill, Abby L.; Bautista, Debra L.

    2010-01-01

    G protein-coupled receptors (GPCRs) comprise a large class of transmembrane proteins that play critical roles in both normal physiology and pathophysiology. These critical roles offer targets for therapeutic intervention, as exemplified by the substantial fraction of current pharmaceutical agents that target members of this family. Tremendous contributions to our understanding of GPCR structure and dynamics have come from both indirect and direct structural characterization techniques. Key fe...

  1. PXR antagonists and implication in drug metabolism

    OpenAIRE

    Mani, Sridhar; Dou, Wei; Redinbo, Matthew R.

    2013-01-01

    Adopted orphan nuclear receptor (NR), pregnane X receptor (PXR), plays a central role in the regulation of xeno- and endobiotic metabolism. Since the discovery of the functional role of PXR in 1998, there is evolving evidence for the role of PXR agonists in abrogating metabolic pathophysiology (e.g., cholestasis, hypercholesterolemia, and inflammation). However, more recently, it is clear that PXR is also an important mediator of adverse xeno- (e.g., enhances acetaminophen toxicity) and endob...

  2. Performance-Enhancing Drugs in Sport: A Different Form of Drug Abuse.

    Science.gov (United States)

    Fuller, John R.; LaFountain, Marc J.

    1987-01-01

    Addresses an often overlooked area of drug abuse: performance-enhancing drugs in sport, used for different reasons than for recreation. Examines the seriousness and prevalence of performance-enhancing drugs and presents the results of a series of interviews with steroid users to determine their attitudes. Discusses the implications of the…

  3. Effect of selected ABC-drug transporters and anticancer drug disposition in vitro and in vivo

    NARCIS (Netherlands)

    Marchetti, S.

    2013-01-01

    Studies described in the thesis that is lying in front of you aim to address the possible implications of selected ABC-drug transporters on the disposition of a number of important anticancer drugs. Although variability in drug disposition has been known for as long as pharmacological studies

  4. Aptamers as Both Drugs and Drug-Carriers

    Directory of Open Access Journals (Sweden)

    Md. Ashrafuzzaman

    2014-01-01

    Full Text Available Aptamers are short nucleic acid oligos. They may serve as both drugs and drug-carriers. Their use as diagnostic tools is also evident. They can be generated using various experimental, theoretical, and computational techniques. The systematic evolution of ligands by exponential enrichment which uses iterative screening of nucleic acid libraries is a popular experimental technique. Theory inspired methodology entropy-based seed-and-grow strategy that designs aptamer templates to bind specifically to targets is another one. Aptamers are predicted to be highly useful in producing general drugs and theranostic drugs occasionally for certain diseases like cancer, Alzheimer’s disease, and so on. They bind to various targets like lipids, nucleic acids, proteins, small organic compounds, and even entire organisms. Aptamers may also serve as drug-carriers or nanoparticles helping drugs to get released in specific target regions. Due to better target specific physical binding properties aptamers cause less off-target toxicity effects. Therefore, search for aptamer based drugs, drug-carriers, and even diagnostic tools is expanding fast. The biophysical properties in relation to the target specific binding phenomena of aptamers, energetics behind the aptamer transport of drugs, and the consequent biological implications will be discussed. This review will open up avenues leading to novel drug discovery and drug delivery.

  5. Drugs affecting the eye.

    Science.gov (United States)

    Taylor, F

    1985-08-01

    This discussion reviews drugs that affect the eye, including antihyperglycemic agents; corticosteroids; antirheumatic drugs (quinolines, indomethacin, and allopurinol); psychiatric drugs (phenothiazine, thioridazine, and chlorpromazine); drugs used in cardiology (practolol, amiodarone, and digitalis gylcosides); drugs implicated in optic neuritis and atrophy, drugs with an anticholinergic action; oral contraceptives (OCs); and topical drugs and systemic effects. Refractive changes, either myopic or hypermetropic, can occur as a result of hyperglycemia, and variation in vision is sometimes a presenting symptom in diabetes mellitus. If it causes a change in the refraction, treatment of hyperglycemia almost always produces a temporary hypermetropia. A return to the original refractive state often takes weeks, sometimes months. There is some evidence that patients adequately treated with insulin improve more rapidly than those taking oral medication. Such patients always should be referred for opthalmological evaluation as other factors might be responsible, but it might not be possible to order the appropriate spectacle correction for some time. The most important ocular side effect of the systemic adiministration of corticosteroids is the formation of a posterior subcapsular cataract. Glaucoma also can result from corticosteroids, most often when they are applied topically. Corticosteroids have been implicated in the production of benign intracranial hypertension, which is paradoxical because they also are used in its treatment. The most important side effect of drugs such as chloroquine and hydroxychloroquine is an almost always irreversible maculopathy with resultant loss of central vision. Corneal and retinal changes similar to those caused by the quinolines have been reported with indomethacin, but there is some question about a cause and effect relationship. The National Registry of Drug Induced Ocular Side Effects in the US published 30 case histories of

  6. Drug Facts

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    Full Text Available ... Marijuana (Weed, Pot) Facts MDMA (Ecstasy, Molly) Facts Meth (Crank, Ice) Facts Pain Medicine (Oxy, Vike) Facts ... Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs ...

  7. Drugged Driving

    Science.gov (United States)

    ... Parents & Educators Children & Teens Search Connect with NIDA : Google Plus Facebook LinkedIn Twitter YouTube Flickr RSS Menu ... misuse of prescription drugs can make driving a car unsafe—just like driving after drinking alcohol. Drugged ...

  8. Drug Facts

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    Full Text Available ... abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth ... 662-HELP (4357) at any time to find drug treatment centers near you. I want my daughter ...

  9. Drug Facts

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    Full Text Available ... Nicotine Facts Other Drugs of Abuse What is Addiction? What are some signs and symptoms of someone ... use problem? How Does Drug Use Become an Addiction? What Makes Someone More Likely to Get Addicted ...

  10. Drug Facts

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    Full Text Available ... Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) ... treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice ( ...

  11. Study Drugs

    Science.gov (United States)

    ... study drugs: amphetamines like Adderall, Dexedrine, or Vyvanse methylphenidates like Ritalin or Concerta Most people get study ... How Much Sleep Do I Need? Prescription Drug Abuse How to Make Homework Less Work Organizing Schoolwork & ...

  12. Drug Facts

    Medline Plus

    Full Text Available ... abuse, addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth ... 662-HELP (4357) at any time to find drug treatment centers near you. I want my daughter ...

  13. Drug Facts

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    Full Text Available ... form Search Menu Home Drugs That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts ... addiction, and treatment. Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain ...

  14. Drugs (image)

    Science.gov (United States)

    ... Drugs for fever, cough, stuffy nose, runny nose, diarrhea, and allergies are common drugs which are especially helpful during times of illness. All medications should be kept out of the reach of children.

  15. Drug Facts

    Science.gov (United States)

    ... drug. "Max" was addicted to prescription drugs. The addiction slowly took over his life. I need different people around me. To stop using marijuana, "Cristina" is making positive changes in her life. She finds support from ...

  16. Drug Facts

    Medline Plus

    Full Text Available ... Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can call 1-800-662-HELP (4357) at any time to find drug treatment centers near you. I want my daughter to ...

  17. Drug allergy

    Directory of Open Access Journals (Sweden)

    Warrington Richard

    2011-11-01

    Full Text Available Abstract Drug allergy encompasses a spectrum of immunologically-mediated hypersensitivity reactions with varying mechanisms and clinical presentations. This type of adverse drug reaction (ADR not only affects patient quality of life, but may also lead to delayed treatment, unnecessary investigations, and even mortality. Given the myriad of symptoms associated with the condition, diagnosis is often challenging. Therefore, referral to an allergist experienced in the identification, diagnosis and management of drug allergy is recommended if a drug-induced allergic reaction is suspected. Diagnosis relies on a careful history and physical examination. In some instances, skin testing, graded challenges and induction of drug tolerance procedures may be required. The most effective strategy for the management of drug allergy is avoidance or discontinuation of the offending drug. When available, alternative medications with unrelated chemical structures should be substituted. Cross-reactivity among drugs should be taken into consideration when choosing alternative agents. Additional therapy for drug hypersensitivity reactions is largely supportive and may include topical corticosteroids, oral antihistamines and, in severe cases, systemic corticosteroids. In the event of anaphylaxis, the treatment of choice is injectable epinephrine. If a particular drug to which the patient is allergic is indicated and there is no suitable alternative, induction of drug tolerance procedures may be considered to induce temporary tolerance to the drug. This article provides a backgrounder on drug allergy and strategies for the diagnosis and management of some of the most common drug-induced allergic reactions, such allergies to penicillin, sulfonamides, cephalosporins, radiocontrast media, local anesthetics, general anesthetics, acetylsalicylic acid (ASA and non-steroidal anti-inflammatory drugs.

  18. Pharmacogenomics and migraine: possible implications

    DEFF Research Database (Denmark)

    Tfelt-Hansen, P.; Brosen, K.

    2008-01-01

    cases pharmacodynamic variability we mention possible implications for the acute and preventive treatment of migraine. Pharmacogenomics will most likely in the future be one part of our therapeutic armamentarium and will provide a stronger scientific basis for optimizing drug therapy on the basis...

  19. Orphan drugs

    Directory of Open Access Journals (Sweden)

    Goločorbin-Kon Svetlana

    2013-01-01

    Full Text Available Introduction. Drugs used for treatment of rare diseases are known worldwide under the term of orphan drugs because pharmaceutical companies have not been interested in ”adopting” them, that is in investing in research, developing and producing these drugs. This kind of policy has been justified by the fact that these drugs are targeted for small markets, that only a small number of patients is available for clinical trials, and that large investments are required for the development of drugs meant to treat diseases whose pathogenesis has not yet been clarified in majority of cases. The aim of this paper is to present previous and present status of orphan drugs in Serbia and other countries. The beginning of orphan drugs development. This problem was first recognized by Congress of the United States of America in January 1983, and when the ”Orphan Drug Act” was passed, it was a turning point in the development of orphan drugs. This law provides pharmaceutical companies with a series of reliefs, both financial ones that allow them to regain funds invested into the research and development and regulatory ones. Seven years of marketing exclusivity, as a type of patent monopoly, is the most important relief that enables companies to make large profits. Conclusion. There are no sufficient funds and institutions to give financial support to the patients. It is therefore necessary to make health professionals much more aware of rare diseases in order to avoid time loss in making the right diagnosis and thus to gain more time to treat rare diseases. The importance of discovery, development and production of orphan drugs lies in the number of patients whose life quality can be improved significantly by administration of these drugs as well as in the number of potential survivals resulting from the treatment with these drugs. [Projekat Ministarstva nauke Republike Srbije, br. III 41012

  20. Club Drugs

    Science.gov (United States)

    ... Anabolic) Synthetic Cannabinoids (K2/Spice) Synthetic Cathinones (Bath Salts) Tobacco/Nicotine Other Drugs Related Topics Addiction Science Adolescent Brain Comorbidity College-Age & Young Adults ...

  1. How Strong Is the Evidence that Illicit Drug Use by Young People Is an Important Cause of Psychological or Social Harm? Methodological and Policy Implications of a Systematic Review of Longitudinal, General Population Studies

    Science.gov (United States)

    MacLeod, John; Oakes, Rachel; Oppenkowski, Thomas; Stokes-Lampard, Helen; Copello, Alex; Crome, Ilana; Davey Smith, George; Egger, Matthias; Hickman, Mathew; Judd, Ali

    2004-01-01

    Recreational use of illicit drugs (i.e. use not associated with a diagnosed drug problem) may cause psychological and social harm. A recent systematic review found that evidence for this was equivocal. Extensive evidence was only available in relation to cannabis use. This was relatively consistently associated with lower educational attainment…

  2. Drug addiction, love, and the higher power.

    Science.gov (United States)

    Sussman, Steve; Reynaud, Michel; Aubin, Henri-Jean; Leventhal, Adam M

    2011-09-01

    This discussion piece suggests that reliance on a Higher Power in drug abuse recovery programs is entertained among some addicts for its psychobiological effects. Prayer, meditation, early romantic love, and drug abuse may have in common activation of mesolimbic dopaminergic pathways of the brain and the generation of intense emotional states. In this sense, reliance on a Higher Power may operate as a substitute addiction, which replaces the psychobiological functions formerly served by drug use. Implications of this perspective are discussed.

  3. Herbal drugs and drug interactions

    OpenAIRE

    Gül Dülger

    2014-01-01

    Herbal drugs are defined as any form of a plant or plant product that contains a single herb or combinations of herbs that are believed to have complementary effects. Although they are considered to be safe, because they are natural, they may have various adverse effects, and may interact with other herbal products or conventional drugs. These interactions are especially important for drugs with narrow therapeutic indices.In the present study, pharmacokinetic and pharmacodynamic interactions ...

  4. Drugged Driving

    Science.gov (United States)

    ... Age Adults in 2015 Teens and E-cigarettes Abuse of Prescription (Rx) Drugs Affects Young Adults Most Substance Use in Women and Men View All NIDA's Publication Series Brain Power DrugFacts Mind Over Matter Research Reports NIDA Home ...

  5. Drug treatment

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    2010263 Drug resistance mechanism of non-small cell lung cancer PC9/AB2 cell line with acquired drug resistance to gefitinib.JU Lixia(鞠立霞),et al. Dept Oncol,Shanghai Pulm Hosp,Tongji Univ,Shanghai 200433. Chin J Tuberc Respir Dis 2010;33(5):354-358. Objective To

  6. Drug Education.

    Science.gov (United States)

    Sardana, Raj K.

    This autoinstructional lesson deals with the study of such drugs as marijuana and LSD, with emphasis on drug abuse. It is suggested that it can be used in science classes at the middle level of school. No prerequisites are suggested. The teacher's guide lists the behavioral objectives, the equipment needed to complete the experience and suggests…

  7. Selective fixed drug eruption to amoxycillin.

    Science.gov (United States)

    Arias, J; Férnandez-Rivas, M; Panadero, P

    1995-07-01

    A selective fixed drug eruption to amoxycillin but not other betalactam drugs is reported. Penicillins are the drugs most frequently implicated in immunological adverse reactions. The most important of these are allergic reactions where an IgE-mediated mechanism is well established. Other immunological mechanisms have been described in reactions, such as haemolytic anaemia, serum sickness, drug-induced nephritis, drug fever and contact dermatitis. Fixed drug eruption (FDE) is a type of drug-induced dermatosis, the immunopathogenesis of which remains unknown. FDE is an uncommon reaction to penicillin derivatives, and very few cases have been reported. We present a case of a selective FDE to amoxycillin (AX), with no reaction to other betalactam drugs. Although one similar case has been reported, the reactivity to other penicillin derivatives was not assessed.

  8. [Medical drug abuse and aging].

    Science.gov (United States)

    Nubukpo, Philippe; Clément, Jean-Pierre

    2013-09-01

    Drug addiction is often underestimated among the aged. Opiate drugs (mostly pain killers) are the most frequently implicated in drug addiction after benzodiazepines (BZD) in the aged. The subjects aged of 65 years or more are the most represented among the BZD users in France. Frequency of BZD use varies according to various studies from 39 to 55% in this age group. Leading a lonely life is associated with the use of psychotropic drugs among retired people (OR=1.7). Vulnerability at this age must take into account not only polypathology, but also the faster aging of a minority of the population under opiate drugs substitution treatment (OST), more subjects to drugs interaction. Drug addiction among elderly often reflects the drift of "lawful" doctor's instructions that leads to an increase in drugs use. The difficulty has to do with a lack of specificity of diagnosis of addiction at this age, but perhaps also with physicans'instructions in the aged. Some authors suggest that continued and prolonged use should be considered the main criterion for BZD addiction at this age, with or without increase in doses and failed attempt at cessation. Besides, the prescription of BZD increases after retirement and loneliness.

  9. Drug Facts

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    Full Text Available ... Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts MDMA (Ecstasy, Molly) Facts Meth (Crank, ... Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine ...

  10. Drug Facts

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    Full Text Available ... Link Between Drug Use and HIV/AIDS Treatment & Recovery What is Treatment? Why Does a Person Need ... Work? What Are the Treatment Options? What Is Recovery? What Is a Relapse? How Can Friends and ...

  11. Drug Facts

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    Full Text Available ... That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana ( ... Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) ...

  12. Drug Facts

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    Full Text Available ... MDMA (Ecstasy, Molly) Facts Meth (Crank, Ice) Facts Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco ... Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You ...

  13. Drug Facts

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    Full Text Available ... Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts MDMA ( ... Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/ ...

  14. Drug Addiction

    Science.gov (United States)

    ... stimulants Stimulants include amphetamines, meth (methamphetamine), cocaine and methylphenidate (Ritalin). They are often used and abused in ... a medication, talk to your doctor. Preventing drug abuse in children and teenagers Take these steps to ...

  15. Antiretroviral drugs.

    Science.gov (United States)

    De Clercq, Erik

    2010-10-01

    In October 2010, it will be exactly 25 years ago that the first antiretroviral drug, AZT (zidovudine, 3'-azido-2',3'-dideoxythymidine), was described. It was the first of 25 antiretroviral drugs that in the past 25 years have been formally licensed for clinical use. These antiretroviral drugs fall into seven categories [nucleoside reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), fusion inhibitors (FIs), co-receptor inhibitors (CRIs) and integrase inhibitors (INIs). The INIs (i.e. raltegravir) represent the most recent advance in the search for effective and selective anti-HIV agents. Combination of several anti-HIV drugs [often referred to as highly active antiretroviral therapy (HAART)] has drastically altered AIDS from an almost uniformly fatal disease to a chronic manageable one.

  16. Drug Facts

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    Full Text Available ... That People Abuse Alcohol Facts Bath Salts Facts Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana ( ... Watch Videos Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) ...

  17. Drug Facts

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    Full Text Available ... Ecstasy, Molly) Facts Meth (Crank, Ice) Facts Pain Medicine (Oxy, Vike) Facts Spice (K2) Facts Tobacco and ... Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine Other Drugs You can ...

  18. Prescription Drugs

    Science.gov (United States)

    ... Jackets, Yellows, and Zombie Pills Stimulants: Bennies, Black Beauties, Hearts, Roses, Skippy, The Smart Drug, Speed, and ... used to relieve anxiety or help a person sleep, such as Valium or Xanax Stimulants — used for ...

  19. Drug Facts

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    Full Text Available ... Cocaine (Coke, Crack) Facts Heroin (Smack, Junk) Facts Marijuana (Weed, Pot) Facts MDMA (Ecstasy, Molly) Facts Meth ( ... Information About Drugs Alcohol Bath Salts Cocaine Heroin Marijuana MDMA Meth Pain Medicines Spice (K2) Tobacco/Nicotine ...

  20. Proposed Policy: Drug Testing of Hawaii's Public School Teachers

    Science.gov (United States)

    Davis, Bebi

    2007-01-01

    Because of a proposed policy, public school teachers in Hawaii are facing the possibility of being randomly tested for illegal drugs. Random drug testing has many implications and its impact is questionable. In this article, the author scrutinizes the controversial drug-testing policy for both troubling and promising aspects and how educators may…

  1. Drug-drug interactions: antiretroviral drugs and recreational drugs.

    Science.gov (United States)

    Staltari, Orietta; Leporini, Christian; Caroleo, Benedetto; Russo, Emilio; Siniscalchi, Antonio; De Sarro, Giovambattista; Gallelli, Luca

    2014-01-01

    With the advances in antiretroviral (ARV) therapy, patients with Human Immunodeficiency Virus (HIV) infection are living longer, however, some patients encounter co- morbidities which sometimes require treatment. Therefore, during the treatment with ARV drugs these patients could take several recreational drugs (e.g. amphetamines, hallucinogenes, opiates, or alcohol) with a possible development of drug-drug interactions (DDIs). In particular, Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) are mainly excreted through the kidney and are not substrates of the cytochrome P450 or P-glycoprotein, therefore the DDIs during this treatment are minimal. In contrast, the other ARV drugs (i.e. non-nucleoside reversetranscriptase inhibitors, Protease inhibitors, Integrase inhibitors, chemokine receptor 5 antagonists and HIV-fusion inhibitors) are an important class of antiretroviral medications that are frequent components of HAART regimens but show several DDIs related to interaction with the cytochrome P450 or P-glycoprotein. In this paper we will review data concerning the possibility of DDI in HIV patients treated with ARV and taking recreational drugs.

  2. Incentive mechanism and implications of orphan drug market in the United States%美国罕用药市场的激励机制及其启示

    Institute of Scientific and Technical Information of China (English)

    张奇林; 宋心璐

    2016-01-01

    Serious market failure, as a result of insufficient incentive, exists in the orphan drugs market. Through legislation, the United States designed and established its owns systematic and linked orphan drugs incentive mechanism, which direct sat research, definition, clinical trials and approval of orphan drugs, so as to change the supply and demand status of orphan drugs. Such incentive mechanism erables the United States possess the most ap-proved orphan drugs in the world, and effectively relieves the problem of market failure of the orphan drugs. The ex-perience of the United States provides beneficial reference for the establishment and positive development of orphan drugs incentive mechanism in China.%罕用药市场因为激励不足存在严重失灵的问题。美国通过立法,针对罕用药的研发、认定、临床试验直至上市等各个环节,设计和建立了自成体系。联动共进的罕用药激励机制,改变了罕用药的供给和需求状况,使美国成为世界上罕用药上市最多的国家,有效缓解了罕用药市场失灵的问题。美国的经验为我国罕用药市场激励机制的建立和良性发展提供了有益的借鉴。

  3. COPD - control drugs

    Science.gov (United States)

    Chronic obstructive pulmonary disease - control drugs; Bronchodilators - COPD - control drugs; Beta agonist inhaler - COPD - control drugs; Anticholinergic inhaler - COPD - control drugs; Long-acting inhaler - COPD - ...

  4. Drug Supervision in Germany and Britain and Their Implications to China%德国和英国药品监督管理工作概况及对我国的启示∗

    Institute of Scientific and Technical Information of China (English)

    陈相龙

    2016-01-01

    该文通过检索德国和英国药政管理部门公开的法规文献和数据库,整理德国和英国药品产业及监管工作的基本情况,分析德国和英国监管工作的主要特点,总结其药品监管工作的经验。德国和英国作为发达西欧国家代表,已构建健全的监管体系和成熟的监管模式,并在实践中不断发展完善。德国和英国的药品监管经验,对完善和促进我国药品监管工作提供有益借鉴。%Through searching literature and analyzing documents, the system of drug supervision in Germany and British was analyzed, and the conspicuous features in drug supervision were obtained. Experiences of drug supervision were summarized.Germany and Britain, as representatives of developed western countries, have established wholesome supervision system and mature supervision pattern, which are continuously developed and improved in practice. Drug administration experiences of Germany and Britain provide beneficial reference to drug supervision in China.

  5. The influences of Taiwan's generic grouping price policy on drug prices and expenditures: evidence from analysing the consumption of the three most-used classes of cardiovascular drugs.

    Science.gov (United States)

    Chen, Chi-Liang; Chen, Likwang; Yang, Wei-Chih

    2008-04-12

    Controlling the growth of pharmaceutical expenditures is a major global challenge. Promotion of generic drug prescriptions or use is gaining increased support. There are substantial contextual differences in international experiences of implementing pharmaceutical policies related to generic drugs. Reporting these experiences from varied perspectives can inform future policy making. This study describes an experience of Taiwan, where patients with chronic (long-term) conditions are usually managed in hospitals and drugs are provided in this setting with costs reimbursed through the National Health Insurance (NHI). It investigates the effects of Taiwan's reimbursement rate adjustment based on chemical generic grouping in 2001. This research also demonstrates the use of micro-level longitudinal data to generate policy-relevant information. The research can be used to improve efficiency of health care resource use. We chose the three most-used classes of cardiovascular drugs for this investigation: beta blocking agents, calcium channel blockers mainly with vascular effects, and plain ACE inhibitors. For each drug class, we investigated changes in daily expense, consumption volume, and total expenditures from a pre-action period to a corresponding post-action period. We compared an exposure or "intervention" group of patients targeted by the action with a comparisonor "control" group of patients not targeted by the action. The data sources are a longitudinal database for 200,000 NHI enrolees, corresponding NHI registration data of health care facilities, and an archive recording all historical data on the reimbursement rates of drugs covered by the NHI. We adopted a fixed effects linear regression model to control for unobserved heterogeneity among patient-hospital groups. Additional descriptive statistics were applied to examine whether any inappropriate consumption of drugs in the three classes existed. The daily drug expense significantly decreased from the pre

  6. The influences of Taiwan's generic grouping price policy on drug prices and expenditures: Evidence from analysing the consumption of the three most-used classes of cardiovascular drugs

    Directory of Open Access Journals (Sweden)

    Chen Likwang

    2008-04-01

    Full Text Available Abstract Background Controlling the growth of pharmaceutical expenditures is a major global challenge. Promotion of generic drug prescriptions or use is gaining increased support. There are substantial contextual differences in international experiences of implementing pharmaceutical policies related to generic drugs. Reporting these experiences from varied perspectives can inform future policy making. This study describes an experience of Taiwan, where patients with chronic (long-term conditions are usually managed in hospitals and drugs are provided in this setting with costs reimbursed through the National Health Insurance (NHI. It investigates the effects of Taiwan's reimbursement rate adjustment based on chemical generic grouping in 2001. This research also demonstrates the use of micro-level longitudinal data to generate policy-relevant information. The research can be used to improve efficiency of health care resource use. Methods We chose the three most-used classes of cardiovascular drugs for this investigation: beta blocking agents, calcium channel blockers mainly with vascular effects, and plain ACE inhibitors. For each drug class, we investigated changes in daily expense, consumption volume, and total expenditures from a pre-action period to a corresponding post-action period. We compared an exposure or "intervention" group of patients targeted by the action with a comparisonor "control" group of patients not targeted by the action. The data sources are a longitudinal database for 200,000 NHI enrolees, corresponding NHI registration data of health care facilities, and an archive recording all historical data on the reimbursement rates of drugs covered by the NHI. We adopted a fixed effects linear regression model to control for unobserved heterogeneity among patient-hospital groups. Additional descriptive statistics were applied to examine whether any inappropriate consumption of drugs in the three classes existed. Results The daily

  7. Herbal drugs and drug interactions

    Directory of Open Access Journals (Sweden)

    Gül Dülger

    2012-01-01

    Full Text Available Herbal drugs are defined as any form of a plant or plant product that contains a single herb or combinations of herbs that are believed to have complementary effects. Although they are considered to be safe, because they are natural, they may have various adverse effects, and may interact with other herbal products or conventional drugs. These interactions are especially important for drugs with narrow therapeutic indices.In the present study, pharmacokinetic and pharmacodynamic interactions of some most commanly used herbals (St John's wort, ginkgo biloba, ginseng, ginger, garlic, echinacea, ephedra and valerian with the conventional drugs were reviewed. Pharmacokinetic interactions involve mainly induction or inhibition of the cytochrome P450 isozymes and p-glycoproteins by the herbal medicine, thus changing the absorption and/or elimination rate and consequently the efficacy of the concommitantly used drugs. St John's wort, a well known enzyme inducer, decreases the efficacy of most of the other drugs that are known to be the substrates of these enzymes.Pharmacodynamic interactions may be due to additive or synergistic effects which results in enhanced effect or toxicity, or herbal medicines with antagonistic properties reduce drug efficacy and result in therapeutic failure. For exampla, St John's wort may have synergistic effects with other antidepressant drugs used by the patient, resulting in increased CNS effects.Herbals like ginseng, ginkgo, garlic, ginger were reported to increase bleeding time, thus potentiating the effect of anticoagulant and antithrombotic agents. In conclusion, patients should be warned against the interaction between the herbal products and conventional medicines.

  8. Exploring the strength, mode, dynamics, and kinetics of binding interaction of a cationic biological photosensitizer with DNA: implication on dissociation of the drug-DNA complex via detergent sequestration.

    Science.gov (United States)

    Paul, Bijan Kumar; Guchhait, Nikhil

    2011-10-20

    The present study aims at exploring a detailed characterization of the binding interaction of a promising cancer cell photosensitizer, harmane (HM), with DNA extracted from herring sperm. The polarity-sensitive prototropic transformation of HM, a naturally occurring, fluorescent, drug-binding alkaloid, β-carboline, is remarkably modified upon interaction with DNA and is manifested through significant modulations on the absorption and emission profiles of HM. From the series of studies undertaken in the present program, for example, absorption; steady-state emission; the effect of chaotrope (urea); iodide ion-induced steady-state fluorescence quenching; circular dichroism (CD); and helix melting from absorption spectroscopy; the mode of binding of HM into the DNA helix has been substantiated to be principally intercalative. Concomitantly, a discernible dependence of the photophysics of the DNA-bound drug on the medium ionic strength indicates that electrostatic attraction should not be ignored in the interaction. Efforts have also been delivered to delineate the dynamical aspects of the interaction, such as modulation in time-resolved fluorescence decay and rotational relaxation dynamics of the drug within the DNA environment. In view of the prospective biological applications of HM, the issue of facile dissociation of intercalated HM from the DNA helix also comprises a crucial prerequisite for the functioning as an effective therapeutic agent. In this context, our results imply that the concept of detergent-sequestered dissociation of the drug from the drug-DNA complex can be a prospective strategy through an appropriate choice of the detergent molecule. The utility of the present work resides in exploring the potential applicability of the fluorescence property of HM for studying its interactions with a relevant biological target, for example, DNA. In addition, the methods and techniques used in the present work can also be exploited to study the interaction of

  9. 欧盟罕用药管理的成就与经验及其对中国的启示%Achievements and Experience of EU Orphan Drug Administration and Its Implications for China

    Institute of Scientific and Technical Information of China (English)

    林禹鸿; 吴晓明

    2012-01-01

    OBJECTIVE To put forward suggestions for orphan drug administration in China. METHODS System comparison was used. RESULTS According to issued "Orphan Drug Act" for promoting orphan drug R&D, manufacturing and marketing, European Union achieved quite significant results. It was benefited from that EU taking various effective policy measures to manage orphan drug of this field, mainly in consolidating the key legislative basis and enhancing system operability, improving special approval procedures and financial support to R&D investment, etc.. These measures would confidently benefit China of orphan drug development and improving policies management in the future by providing abundant and valuable experience. CONCLUSION We should better build the orphan drug management in China, complete the orphan drug approval system, promote transformation from the achievement of basic research for orphan drug to application area.%目的 提出我国罕用药制度的建议.方法 制度比较分析.结果 欧盟通过颁布《罕用药管理规定》以促进军用药的研发、投产和上市,取得了较为显著的成绩.这得益于欧盟在管理罕用药领域内采取各项行之有效的政策措施,主要体现在夯实主要立法基础、增强制度可操作性、完善特别审批程序以及大力资助研发投入等方面.这些举措给中国未来罕用药管理政策的制定和完善提供了丰富而又宝贵的经验.结论 我国需要建立罕用药管理制度、完善特殊审批制度、促进罕用药基础研究的成果向应用领域转化.

  10. The symbolic economy of drugs.

    Science.gov (United States)

    Lentacker, Antoine

    2016-02-01

    This essay reviews four recent studies representing a new direction in the history of pharmaceuticals and pharmaceutical science. To this end, it introduces the notion of a symbolic economy of drugs, defined as the production, circulation, and reception of signs that convey information about drugs and establish trust in them. Each of the studies under review focuses on one key signifier in this symbolic economy, namely the brand, the patent, the clinical trial, and the drug itself. Drawing on Pierre Bourdieu's theory of the economy of symbolic goods, I conceptualize these signifiers as symbolic assets, that is, as instruments of communication and credit, delivering knowledge, carrying value, and producing authority. The notion of a symbolic economy is offered with a threefold intention. First, I introduce it in order to highlight the implications of historical and anthropological work for a broader theory of the economy of drugs, thus suggesting a language for interdisciplinary conversations in the study of pharmaceuticals. Second, I deploy it in an attempt to emphasize the contributions of the recent scholarship on drugs to a critical understanding of our own contemporary ways of organizing access to drugs and information about drugs. Finally, I suggest ways in which it might be of use to scholars of other commodities and technologies.

  11. In vitro evaluation of the effects of anti-fungals, benzodiazepines and non-steroidal anti-inflammatory drugs on the glucuronidation of 19-norandrosterone: implications on doping control analysis.

    Science.gov (United States)

    Palermo, Amelia; Alessi, Beatrice; Botrè, Francesco; de la Torre, Xavier; Fiacco, Ilaria; Mazzarino, Monica

    2016-09-01

    We have studied whether the phase II metabolism of 19-norandrosterone, the most representative metabolite of 19-nortestosterone (nandrolone), can be altered in the presence of other drugs that are not presently included on the Prohibited List of the World Anti-Doping Agency. In detail, we have evaluated the effect of non-prohibited drugs belonging to the classes of anti-fungals, benzodiazepines, and non-steroidal anti-inflammatory drugs on the glucuronidation of 19-norandrosterone. In vitro assays based on the use of either pooled human liver microsomes or specific recombinant isoforms of uridine diphosphoglucuronosyl-transferase were designed and performed to monitor the formation of 19-norandrosterone glucuronide from 19-norandrosterone. Determination of 19-norandrosterone (free and conjugated fraction) was performed by gas chromatography - mass spectrometry after sample pretreatment consisting of an enzymatic hydrolysis (performed only for the conjugated fraction), liquid/liquid extraction with tert-butylmethyl ether, and derivatization to form the trimethylsilyl derivative. In parallel, a method based on reversed-phase liquid chromatography coupled to tandem mass spectrometry in positive electrospray ionization with acquisition in selected reaction monitoring mode was also developed to identify the non-prohibited drugs considered in this study. Incubation experiments have preliminarily shown that the glucuronidation of 19-norandrosterone is principally carried out by UGT2B7 (39%) and UGT2B17 (31%). Inhibition studies have shown that the yield of the glucuronidation reaction is reduced in the presence of the anti-fungals itraconazole, ketoconazole, and miconazole, of the benzodiazepine triazolam and of the non-steroidal anti-inflammatory drugs diclofenac and ibuprofen, while no alteration was recorded in the presence of all other compounds considered in this study. Copyright © 2015 John Wiley & Sons, Ltd.

  12. Policies on Orphan Drug Development in USA and European Union and their Implications to China%美国与欧盟孤儿药研发上市管理制度及对我国的启示

    Institute of Scientific and Technical Information of China (English)

    李认书; 李鸿彬

    2014-01-01

    目的:通过对美国与欧盟对孤儿药研发上市相关管理政策的分析,为我国孤儿药研发上市管理提供借鉴。方法分析美国和欧盟药政管理部门公开的法规文献和数据库检索数据,总结其对孤儿药的激励政策,分析获得孤儿药资格认定和批准上市的药物特点。结果美国和欧盟对孤儿药研发均颁布实施了诸如市场独占期、政府资助、审评专家对研究方案的指导等相应的激励政策。研发机构应采取及早申请孤儿药认定、多途径发现孤儿药及孤儿药的再开发等研发策略。结论美国和欧盟对孤儿药的研发与上市激励政策,刺激了制药企业对罕见病治疗药物的研发热情,有效缓解了罕见病无药可治的现状,对我国制定相关孤儿药政策提供了有益的借鉴。国内创新型制药企业应尽早布局孤儿药的研发,应重点关注国内已经被大众接受的罕见病和治疗,以及超说明书使用的问题;重点关注生物仿制药如单克隆抗体的研发动态;重点关注国际孤儿药专业公司的研发动态,使孤儿药在国内相关法律法规建立健全后,立即有所响应,尽早抢占孤儿药研发的领先地位和市场地位。%Objective To help China develop some encouraging policies on orphan drug development by analyzing the policies of orphan drug development of USA and European Union.Methods Relative orphan drug policies of US Food and Drug Administration and European Medicines Agency were searched, as well as orphan drug designations and approvals by FDA and EMA,and the encouraging policies were summarized and the characteristics of orphan drugs for qualification and marketing approval were analyzed. Results FDA and EMA have issued some policies to encourage orphan drug development such as market exclusivity,government funds,FDAs advising and so on.For drug researchers,some measures should be taken to promote research productivity

  13. Antineoplastic Drugs.

    Science.gov (United States)

    Morris, Sara; Michael, Nancy, Ed.

    This module on antineoplastic drugs is intended for use in inservice or continuing education programs for persons who administer medications in long-term care facilities. Instructor information, including teaching suggestions, and a listing of recommended audiovisual materials and their sources appear first. The module goal and objectives are then…

  14. Drug Facts

    Medline Plus

    Full Text Available ... Phone Numbers and Websites Search Share Listen English Español Information about this page Click on the button ... sobre el abuso de drogas, y adicción. English Español About the National Institute on Drug Abuse (NIDA) | ...

  15. Mucoactive drugs

    Directory of Open Access Journals (Sweden)

    R. Balsamo

    2010-06-01

    Full Text Available Mucus hypersecretion is a clinical feature of severe respiratory diseases such as asthma, cystic fibrosis and chronic obstructive pulmonary disease. Airway mucosal infection and/or inflammation associated with these diseases often gives rise to inflammatory products, including neutrophil-derived DNA and filamentous actin, in addition to bacteria, apoptotic cells and cellular debris, that may collectively increase mucus production and viscosity. Mucoactive agents have been the medication of choice for the treatment of respiratory diseases in which mucus hypersecretion is a clinical complication. The main purpose of mucoactive drugs is to increase the ability to expectorate sputum and/or decrease mucus hypersecretion. Many mucoactive drugs are currently available and can be classified according to their putative mechanism of action. Mucoactive medications include expectorants, mucoregulators, mucolytics and mucokinetics. By developing our understanding of the specific effects of mucoactive agents, we may result in improved therapeutic use of these drugs. The present review provides a summary of the most clinically relevant mucoactive drugs in addition to their potential mechanism of action.

  16. Drug Facts

    Medline Plus

    Full Text Available ... Prevention Phone Numbers and Websites Search Share Listen English Español Information about this page Click on the ... información sobre el abuso de drogas, y adicción. English Español About the National Institute on Drug Abuse ( ...

  17. Drug resistance

    NARCIS (Netherlands)

    Gorter, J.A.; Potschka, H.; Noebels, J.L.; Avoli, M.; Rogawski, M.A.; Olsen, R.W.; Delgado-Escueta, A.V.

    2012-01-01

    Drug resistance remains to be one of the major challenges in epilepsy therapy. Identification of factors that contribute to therapeutic failure is crucial for future development of novel therapeutic strategies for difficult-to-treat epilepsies. Several clinical studies have shown that high seizure f

  18. High affinity capture and concentration of quinacrine in polymorphonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs

    Energy Technology Data Exchange (ETDEWEB)

    Roy, Caroline; Gagné, Valérie; Fernandes, Maria J.G.; Marceau, François, E-mail: francois.marceau@crchul.ulaval.ca

    2013-07-15

    Many cationic drugs are concentrated in acidic cell compartments due to low retro-diffusion of the protonated molecule (ion trapping), with an ensuing vacuolar and autophagic cytopathology. In solid tissues, there is evidence that phagocytic cells, e.g., histiocytes, preferentially concentrate cationic drugs. We hypothesized that peripheral blood leukocytes could differentially take up a fluorescent model cation, quinacrine, depending on their phagocytic competence. Quinacrine transport parameters were determined in purified or total leukocyte suspensions at 37 °C. Purified polymorphonuclear leukocytes (PMNLs, essentially neutrophils) exhibited a quinacrine uptake velocity inferior to that of lymphocytes, but a consistently higher affinity (apparent K{sub M} 1.1 vs. 6.3 μM, respectively). However, the vacuolar (V)-ATPase inhibitor bafilomycin A1 prevented quinacrine transport or initiated its release in either cell type. PMNLs capture most of the quinacrine added at low concentrations to fresh peripheral blood leukocytes compared with lymphocytes and monocytes (cytofluorometry). Accumulation of the autophagy marker LC3-II occurred rapidly and at low drug concentrations in quinacrine-treated PMNLs (significant at ≥ 2.5 μM, ≥ 2 h). Lymphocytes contained more LAMP1 than PMNLs, suggesting that the mass of lysosomes and late endosomes is a determinant of quinacrine uptake V{sub max}. PMNLs, however, exhibited the highest capacity for pinocytosis (uptake of fluorescent dextran into endosomes). The selectivity of quinacrine distribution in peripheral blood leukocytes may be determined by the collaboration of a non-concentrating plasma membrane transport mechanism, tentatively identified as pinocytosis in PMNLs, with V-ATPase-mediated concentration. Intracellular reservoirs of cationic drugs are a potential source of toxicity (e.g., loss of lysosomal function in phagocytes). - Highlights: • Quinacrine is concentrated in acidic organelles via V-ATPase-mediated ion

  19. [Drug trafficking and international law].

    Science.gov (United States)

    Marini, Luca

    2002-01-01

    The production, the commerce and the use of drugs and other substances are ruled by several conventions of international law, that, at first, have had as object the production and the commerce of drugs for lawful purposes, and the measures required to prevent and to repress, at certain conditions, abuses and unlawful traffics. Just more recently, following some solicitations noticed by the International Community, and according to the concept of "well-balanced approach" described in the text, the measures introduced in this way were supported by a more incisive international movement, fit for the repression of unlawful traffics of drugs and to the adoption of suitable measures of prevention, also to avoid, at national level, sanitary, social and economical implications of the criminal phenomenon.

  20. Understanding drug resistance in human intestinal protozoa.

    Science.gov (United States)

    El-Taweel, Hend Aly

    2015-05-01

    Infections with intestinal protozoa continue to be a major health problem in many areas of the world. The widespread use of a limited number of therapeutic agents for their management and control raises concerns about development of drug resistance. Generally, the use of any antimicrobial agent should be accompanied by meticulous monitoring of its efficacy and measures to minimize resistance formation. Evidence for the occurrence of drug resistance in different intestinal protozoa comes from case studies and clinical trials, sometimes with a limited number of patients. Large-scale field-based assessment of drug resistance and drug sensitivity testing of clinical isolates are needed. Furthermore, the association of drug resistance with certain geographic isolates or genotypes deserves consideration. Drug resistance has been triggered in vitro and has been linked to modification of pyruvate:ferredoxin oxidoreductase, nitroreductases, antioxidant defense, or cytoskeletal system. Further mechanistic studies will have important implications in the development of second generation therapeutic agents.

  1. Regulatory and Economic Considerations of Retinal Drugs.

    Science.gov (United States)

    Shah, Ankoor R; Williams, George A

    2016-01-01

    The advent of anti-VEGF therapy for neovascular age-related macular degeneration and macular edema secondary to retinal vein occlusion and diabetes mellitus has prevented blindness in tens of thousands of people. However, the costs of these drugs are without precedent in ophthalmic drug therapeutics. An analysis of the financial implications of retinal drugs and the impact of the Food and Drug Administration on treatment of retinal disease must include not only an evaluation of the direct costs of the drugs and the costs associated with their administration, but also the cost savings which accrue from their clinical benefit. This chapter will discuss the financial and regulatory issues associated with retinal drugs.

  2. Modulation of anticancer drug toxicity by solcoseryl.

    Science.gov (United States)

    Sołtysiak-Pawluczuk, D; Jedrych, A; Jastrzebski, Z; Czyzewska-Szafran, H; Danysz, A

    1991-01-01

    The studies of the effect of solcoseryl on toxicity of selected anticancer drugs were performed in mice. The observed differential influence of solcoseryl was dependent on the type of anticancer drug as well as on the schedule of solcoseryl administration. The protective effect of the biostimulator was noticed exclusively against 5-FU toxicity. The results of our studies could provide possible implications for therapeutic approach.

  3. Atomoxetine effects on attentional bias to drug-related cues in cocaine dependent individuals

    NARCIS (Netherlands)

    Passamonti, L.; Luijten, M.; Ziauddeen, H.; Coyle-Gilchrist, I.T.S.; Rittman, T.; Brain, S.A.E.; Regenthal, R.; Franken, I.H.A.; Sahakian, B.J.; Bullmore, E.T.; Robbins, T.W.; Ersche, K.D.

    2017-01-01

    Rationale: Biased attention towards drug-related cues and reduced inhibitory control over the regulation of drug-intake characterize drug addiction. The noradrenaline system has been critically implicated in both attentional and response inhibitory processes and is directly affected by drugs such as

  4. Orexin Receptor Targets for Anti-Relapse Medication Development in Drug Addiction

    OpenAIRE

    See, Ronald E.; Luyi Zhou; Wei-Lun Sun

    2011-01-01

    Drug addiction is a chronic illness characterized by high rates of relapse. Relapse to drug use can be triggered by re-exposure to drug-associated cues, stressful events, or the drug itself after a period of abstinence. Pharmacological intervention to reduce the impact of relapse-instigating factors offers a promising target for addiction treatment. Growing evidence has implicated an important role of the orexin/hypocretin system in drug reward and drug-seeking, including animal models of rel...

  5. Permissive Attitude Towards Drug Use, Life Satisfaction, and Continuous Drug Use Among Psychoactive Drug Users in Hong Kong.

    Science.gov (United States)

    Cheung, N Wt; Cheung, Y W; Chen, X

    2016-06-01

    To examine the effects of a permissive attitude towards regular and occasional drug use, life satisfaction, self-esteem, depression, and other psychosocial variables in the drug use of psychoactive drug users. Psychosocial factors that might affect a permissive attitude towards regular / occasional drug use and life satisfaction were further explored. We analysed data of a sample of psychoactive drug users from a longitudinal survey of psychoactive drug abusers in Hong Kong who were interviewed at 6 time points at 6-month intervals between January 2009 and December 2011. Data of the second to the sixth time points were stacked into an individual time point structure. Random-effects probit regression analysis was performed to estimate the relative contribution of the independent variables to the binary dependent variable of drug use in the last 30 days. A permissive attitude towards drug use, life satisfaction, and depression at the concurrent time point, and self-esteem at the previous time point had direct effects on drug use in the last 30 days. Interestingly, permissiveness to occasional drug use was a stronger predictor of drug use than permissiveness to regular drug use. These 2 permissive attitude variables were affected by the belief that doing extreme things shows the vitality of young people (at concurrent time point), life satisfaction (at concurrent time point), and self-esteem (at concurrent and previous time points). Life satisfaction was affected by sense of uncertainty about the future (at concurrent time point), self-esteem (at concurrent time point), depression (at both concurrent and previous time points), and being stricken by stressful events (at previous time point). A number of psychosocial factors could affect the continuation or discontinuation of drug use, as well as the permissive attitude towards regular and occasional drug use, and life satisfaction. Implications of the findings for prevention and intervention work targeted at

  6. A implicação da família no uso abusivo de drogas: uma revisão crítica The family implication on the drug abusive use: a critical review

    Directory of Open Access Journals (Sweden)

    Miriam Schenker

    2003-01-01

    Full Text Available Este artigo apresenta uma revisão crítica da literatura sobre a relação entre adolescência, família e uso abusivo de drogas. Discorre sobre a importância da inserção do sintoma drogadicção no contexto familiar e sociocultural para o entendimento de sua complexidade. A família é vista como uma das fontes de socialização primária do adolescente, juntamente com a escola e o grupo de amigos. As práticas educativas e os estilos de criação da família, com seus três diferentes tipos de controle parental, são ressaltados porque podem facilitar, ou não, o uso abusivo de drogas. Os resultados das pesquisas apontam para a importância de se engajar a família no tratamento do adicto e alguns estudos ampliam o foco para engajar contextos sociais múltiplos - família, amigos, escola, comunidade e sistema legal - no tratamento do adolescente que faz uso abusivo de drogas.This article presents a critical review of the litterature about the relationship between adolescence, family and drug abusive use. Discusses the importance of inserting the drugaddiction symptom in the familiar and sociocultural context for the understanding of its complexity. Family, school and peers are seen as the adolescent primary socialization sources. Family educational practices and parenting styles, with its three different types of parental control, are emphasized because they can either facilitate, or not, drug abusive use. The researches results point to the importance of engaging the family in the addict treatment and some studies enlarge the focus to engage multiple social contexts - family, friends, school, community and legal system - in the drug abusive adolescent treatment. The results of the researchs point to the family educational practices and parenting styles that either facilitates, or not, drug abusive use, emphasizing the need to engage the family in the addict treatment.

  7. Insights into the Interaction Mechanism of Ligands with Aβ42 Based on Molecular Dynamics Simulations and Mechanics: Implications of Role of Common Binding Site in Drug Design for Alzheimer's Disease.

    Science.gov (United States)

    Kundaikar, Harish S; Degani, Mariam S

    2015-10-01

    Aggregation of β-amyloid (Aβ) into oligomers and further into fibrils is hypothesized to be a key factor in pathology of Alzheimer's disease (AD). In this study, mapping and docking were used to study the binding of ligands to protofibrils. It was followed by molecular simulations to understand the differences in interactions of known therapeutic agents such as curcumin, fluorescence-based amyloid staining agents such as thioflavin T, and diagnostic agents such as florbetapir (AV45), with Aβ protofibrils. We show that therapeutic agents bind to and distort the protofibrils, thus causing destabilization or prevention of oligomerization, in contrast to diagnostic agents which bind to but do not distort such structures. This has implications in the rational design of ligands, both for diagnostics and therapeutics of AD.

  8. [Emergent drugs (I): smart drugs].

    Science.gov (United States)

    Burillo-Putze, G; Díaz, B Climent; Pazos, J L Echarte; Mas, P Munné; Miró, O; Puiguriguer, J; Dargan, P

    2011-01-01

    In recent years, a series of new drugs, known as smart drugs or legal highs, have gaining in popularity. They are easily obtainable through online shops. This is happening amongst younger segments of the population and is associated with recreational consumption, at weekends. In general, they are synthetic derivatives of natural products. There has been hardly any clinical research into them and they are not detectable in hospital laboratories. Three of these products, BZP (1- benzylpiperazine), mefedrone (4-methylmethcathinone) and Spice are probably the most widely used in Europe. The first two are consumed as an alternative to ecstasy and cocaine and are characterized by their producing a clinical profile of a sympathetic mimetic type; on occasion, they have serious consequences, with convulsions and even death. Spice (a mixture of herbs with synthetic cannabinoids such as JWH-018, JWH-073 and CP 47497-C8) is giving rise to profiles of dependence and schizophrenia. Although the emergent drugs have an aura of safety, there is an increasing amount of experience on their secondary effects.

  9. Drug resistance and antiretroviral drug development

    OpenAIRE

    Shafer, Robert W.; Jonathan M Schapiro

    2005-01-01

    As more drugs for treating HIV have become available, drug resistance profiles within antiretroviral drug classes have become increasingly important for researchers developing new drugs and for clinicians integrating new drugs into their clinical practice. In vitro passage experiments and comprehensive phenotypic susceptibility testing are used for the pre-clinical evaluation of drug resistance. Clinical studies are required, however, to delineate the full spectrum of mutations responsible fo...

  10. Ritalin Update: Implications for Reading Teachers.

    Science.gov (United States)

    Cotter, Robert B., Jr.; Werner, Patrice Holden

    1987-01-01

    Investigates how Ritalin, a powerful stimulant drug frequently prescribed for children exhibiting hyperactive behavior, poor attention span, and/or distractibility, is prescribed for children in educational settings, what doses seem appropriate, and what effect Ritalin has on reading achievement. Discusses the implications of Ritalin research for…

  11. Recurrent fixed drug eruption caused by citiolone.

    Science.gov (United States)

    de Barrio, M; Tornero, P; Prieto, A; Sainza, T; Zubeldia, J M; Herrero, T

    1997-01-01

    Citiolone (N-acetylhomocysteinethiolactone) is a thiolic-derived medication frequently used in Spain and in other countries as a mucolytic agent for the treatment of certain hepatic disorders. Mucolytic drugs have rarely been implicated in the fixed drug eruption etiology. We report on a patient who presented several episodes of fixed exanthema related to citiolone intake. The patch test with citiolone (10% in dimethyl sulfoxide) was negative. The diagnosis was confirmed by a positive controlled oral challenge test. Other mucolytic thiolic-derivatives (N-acetylcysteine) were tolerated by the patient, thus crossreactivity between these drugs seems to be unlikely.

  12. Drug-induced subacute cutaneous lupus erythematosus.

    Science.gov (United States)

    Callen, J P

    2010-08-01

    Subacute cutaneous lupus erythematosus (SCLE) is a subset of cutaneous lupus erythematosus with unique immunologic and clinical features. The first description dates back to 1985 when a series of five patients were found to have hydrochlorothiazide-induced SCLE. Since that time, at least 40 other drugs have been implicated in the induction of SCLE.

  13. Horizonte de racionalidade acerca da dependência de drogas nos serviços de saúde: implicações para o tratamento The horizon of rationality about drug dependency in health services: implications to the treatments

    Directory of Open Access Journals (Sweden)

    Daniela Ribeiro Schneider

    2010-05-01

    Full Text Available O artigo refere-se à discussão de pesquisa baseada em metodologia de análise de conteúdo, cuja meta é explicitar o horizonte de racionalidade dos serviços de atenção aos usuários de álcool e outras drogas na Região da Grande Florianópolis, objetivando contribuir no estabelecimento de parâmetros qualitativos na avaliação de serviços de saúde. Verificou-se a existência de concepção hegemônica acerca do fenômeno da dependência de drogas e do modo de intervenção no fenômeno, síntese de racionalidades diversas e, algumas vezes, contraditórias entre si. Tal concepção centra seu modelo na noção de doença, na meta da abstinência, no busca do controle sobre a adição, operando dispositivos médico-terapêuticos e morais. Nas raízes desta concepção, encontra-se uma perspectiva subjetivista, moralista e psicopatologizante, constituindo-se em visão ahistórica e pouco crítica da produção social em torno do uso de drogas, pautada numa racionalidade de predomínio metafísico, ainda que mesclado com outras racionalidades como a científica. Discute-se a importância de correlacionar o "horizonte de racionalidade" dos serviços de saúde com a problemática da eficácia e eficiência dos tratamentos na área da dependência de drogas.This article refers to the research discussion based on methodology of content analysis, which aims at making explicit the horizon of rationality of the services provided for alcohol users and other drugs in the Great Florianópolis region, to contribute to the establishment of qualitative parameters in the evaluation of health services. It was verified that there is a hegemonic conception about the drugs dependence phenomenon as well as the way to intervene in this phenomenon, synthesis of different and, sometimes, contradictory rationalities. The model of this conception is based on the notion of disease, on the pursue for abstinence, on the struggle to control de addiction, operating

  14. Drug Coverage (Part D)

    Science.gov (United States)

    ... insurance Find health & drug plans Drug coverage (Part D) How to get drug coverage Get Medicare prescription drug coverage either from a Part D plan or a Medicare Advantage Plan offering Medicare ...

  15. National Drug Code Directory

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Drug Listing Act of 1972 requires registered drug establishments to provide the Food and Drug Administration (FDA) with a current list of all drugs...

  16. National Drug Code Directory

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Drug Listing Act of 1972 requires registered drug establishments to provide the Food and Drug Administration (FDA) with a current list of all drugs manufactured,...

  17. Prescription Drug Abuse

    Science.gov (United States)

    ... over-the-counter medications. National Institute on Drug Abuse. http://www.drugabuse.gov/publications/drugfacts/prescription-over-counter- ... 2015. Prescription drug abuse. National Institute on Drug Abuse. http://www.drugabuse.gov/publications/research-reports/prescription-drugs/ ...

  18. Drugs Approved for Leukemia

    Science.gov (United States)

    This page lists cancer drugs approved by the FDA for use in leukemia. The drug names link to NCI's Cancer Drug Information summaries. The list includes generic names, brand names, and common drug combinations, which are shown in capital letters.

  19. Drugs Approved for Retinoblastoma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for retinoblastoma. The list includes generic names and brand names. The drug names link to NCI’s Cancer Drug Information summaries.

  20. Drugs Approved for Neuroblastoma

    Science.gov (United States)

    This page lists cancer drugs approved by the Food and Drug Administration (FDA) for neuroblastoma. The list includes generic names and brand names. The drug names link to NCI's Cancer Drug Information summaries.

  1. Urine drug screen

    Science.gov (United States)

    Drug screen -- urine ... detect the presence of illegal and some prescription drugs in your urine. Their presence indicates that you recently used these drugs. Some drugs may remain in your system for ...

  2. Medication/Drug Allergy

    Science.gov (United States)

    ... Science Education & Training Home Conditions Medication/Drug Allergy Medication/Drug Allergy Make an Appointment Find a Doctor ... immediate or delayed. What Is an Allergy to Medication/Drugs? Allergies to drugs/medications are complicated, because ...

  3. Outcome Trajectories in Drug Court: Do All Participants Have Drug Problems?

    Science.gov (United States)

    Dematteo, David; Marlowe, Douglas B; Festinger, David S; Arabia, Patricia L

    2009-04-01

    Graduation rates in drug courts average 50% to 70%, but it is unclear what proportion of graduates responded to the drug court services and what proportion might not have had serious drug problems upon entry. This study cluster-analyzed urine drug screen results during the first 14 weeks of treatment on 284 participants from three misdemeanor drug courts. A four-cluster solution (R(2) > .75) produced distinct subgroups characterized by (1) consistently drug-negative urine specimens (34% of the sample), (2) consistently drug-positive specimens (21%), (3) consistently missed urine specimens (26%), and (4) urine specimens that began as drug-positive but became progressively drug-negative over time (19%). These data suggest that approximately one-third of the participants might not have had serious drug problems upon entry. Approximately one-fifth appeared to respond to drug court services, and nearly one-half continued to exhibit problems after 14 weeks. Implications for adaptive programming in drug courts are discussed.

  4. DrugCentral: online drug compendium.

    Science.gov (United States)

    Ursu, Oleg; Holmes, Jayme; Knockel, Jeffrey; Bologa, Cristian G; Yang, Jeremy J; Mathias, Stephen L; Nelson, Stuart J; Oprea, Tudor I

    2017-01-04

    DrugCentral (http://drugcentral.org) is an open-access online drug compendium. DrugCentral integrates structure, bioactivity, regulatory, pharmacologic actions and indications for active pharmaceutical ingredients approved by FDA and other regulatory agencies. Monitoring of regulatory agencies for new drugs approvals ensures the resource is up-to-date. DrugCentral integrates content for active ingredients with pharmaceutical formulations, indexing drugs and drug label annotations, complementing similar resources available online. Its complementarity with other online resources is facilitated by cross referencing to external resources. At the molecular level, DrugCentral bridges drug-target interactions with pharmacological action and indications. The integration with FDA drug labels enables text mining applications for drug adverse events and clinical trial information. Chemical structure overlap between DrugCentral and five online drug resources, and the overlap between DrugCentral FDA-approved drugs and their presence in four different chemical collections, are discussed. DrugCentral can be accessed via the web application or downloaded in relational database format. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

  5. Drug Preferences of Multiple Drug Abusers.

    Science.gov (United States)

    Harford, Robert J.

    1978-01-01

    Examined drug preferences of a group of active multiple drug abusers referred for treatment. Nearly half the respondents preferred drugs other than type they most frequently used. Preferences were related to method of administration. Results suggest preference is one among several determinants of drug use. (Author/BEF)

  6. Low prosocial attachment, involvement with drug-using peers, and adolescent drug use: a longitudinal examination of mediational mechanisms.

    Science.gov (United States)

    Henry, Kimberly L

    2008-06-01

    The process of disengagement from prosocial entities (e.g., family and school) and either simultaneous or subsequent engagement with antisocial entities (e.g., friends who use drugs) is a critical contributor to adolescent drug use and delinquency. This study provides a series of formal mediation tests to demonstrate the relationship between poor family attachment, poor school attachment, involvement with friends who use drugs, and a student's own use of drugs. Results indicate that poor family attachment exerts its effect on drug use through poor school attachment and involvement with friends who use drugs. In addition, poor school attachment exerts its effect on drug use through involvement with friends who use drugs. The results of this study corroborate theories that suggest disengagement from prosocial entities is associated with involvement with antisocial entities and eventual involvement in drug use. Implications for prevention strategies are discussed.

  7. Myths Versus Data on American Indian Drug Abuse

    Science.gov (United States)

    Streit, Fred; Nicolich, Mark J.

    1977-01-01

    A drug and alcohol use prevalence study was conducted among Montana Indians by Montana Indians. The results raise questions about culture transmission as a drug prevention strategy. Also, there is evidence of a high proportion of youth with deceased fathers. Implications for further prevention needs are presented. (Author)

  8. Campuses and the Club Drug Ecstasy. Infofacts/Resources

    Science.gov (United States)

    Powell, Amy

    2008-01-01

    Although alcohol is the drug that college students use most frequently and in greatest quantity, the designer drug ecstasy has generated both curiosity and concern in recent years. This Fact Sheet offers an overview of ecstasy, possible effects of its use, and implications for institutions of higher education. Although the number of students…

  9. Drug offers as a context for violence perpetration and victimization.

    Science.gov (United States)

    Helm, Susana; Okamoto, Scott; Kaliades, Alexis; Giroux, Danielle

    2014-01-01

    Drug use has been linked empirically with and aggression and violence among youth in national and State of Hawai'i samples. However, the nature of this link and its implications for prevention are unclear. Therefore, this article explores the intersection of drugs with aggression and violence by using the drug offer context as the unit of analysis. Native Hawaiian youth are sampled because substance use rates tend to be higher and onset tends to be earlier for them than for their non-Hawaiian peers. Fourteen sex-specific focus group discussions were held with rural Native Hawaiian middle school students (N = 64). Students discussed what they think they would do in terms of drug refusal strategies in a variety of drug offer contexts. Although aggression and violence were perceived to be socially inappropriate, students nonetheless felt drug use would be less socially competent. Narrative analyses indicated that aggression and violence were thought to function as potential drug refusal strategies. As proximal drug resistance, aggression and violence perpetration served as an immediate deterrent to the drug offerer and thus drug use. As distal drug resistance, victimization served as a rationale for avoiding drug using contexts. Implications are discussed in terms of prevention policy and practice, specifically in terms of a school-based prevention curriculum. Future research in Hawaiian epistemology and gendered approaches are warranted.

  10. Antiresorptive drug-related osteonecrosis of the jaw.

    Science.gov (United States)

    Uyanne, Jettie; Calhoun, Colonya C; Le, Anh D

    2014-04-01

    Nitrogen-containing and non-nitrogen-containing bisphosphonates have been implicated in the development of osteonecrosis of the jaw (ONJ), a condition termed bisphosphonate-related OHJ. Other antiresorptive drugs have been implicated in the development of OHJ, hence the new term antiresorptive drug-related ONJ. The underlying pathogenesis remains unclear, and no definite diagnosis or cure has been established for this debilitating condition. This article reviews some of the most common antiresorptive drugs with their associated risks of ONJ and the current understanding of the pathogenesis ONJ, and summarizes current clinical guidelines.

  11. Personality, Drug Preference, Drug Use, and Drug Availability

    Science.gov (United States)

    Feldman, Marc; Boyer, Bret; Kumar, V. K.; Prout, Maurice

    2011-01-01

    This study examined the relationship between drug preference, drug use, drug availability, and personality among individuals (n = 100) in treatment for substance abuse in an effort to replicate the results of an earlier study (Feldman, Kumar, Angelini, Pekala, & Porter, 2007) designed to test prediction derived from Eysenck's (1957, 1967)…

  12. Personality, Drug Preference, Drug Use, and Drug Availability

    Science.gov (United States)

    Feldman, Marc; Boyer, Bret; Kumar, V. K.; Prout, Maurice

    2011-01-01

    This study examined the relationship between drug preference, drug use, drug availability, and personality among individuals (n = 100) in treatment for substance abuse in an effort to replicate the results of an earlier study (Feldman, Kumar, Angelini, Pekala, & Porter, 2007) designed to test prediction derived from Eysenck's (1957, 1967)…

  13. Expression of the human UGT1 locus in transgenic mice by 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (WY-14643) and implications on drug metabolism through peroxisome proliferator-activated receptor alpha activation.

    Science.gov (United States)

    Senekeo-Effenberger, Kathy; Chen, Shujuan; Brace-Sinnokrak, Erin; Bonzo, Jessica A; Yueh, Mei-Fei; Argikar, Upendra; Kaeding, Jenny; Trottier, Jocelyn; Remmel, Rory P; Ritter, Joseph K; Barbier, Olivier; Tukey, Robert H

    2007-03-01

    The UDP-glucuronosyltransferase (UGT) 1A genes in humans have been shown to be differentially regulated in a tissue-specific fashion. Transgenic mice carrying the human UGT1 locus (Tg-UGT1) were recently created, demonstrating that expression of the nine UGT1A genes closely resembles the patterns of expression observed in human tissues. In the present study, UGT1A1, UGT1A3, UGT1A4, and UGT1A6 have been identified as targets of the peroxisome proliferator-activated receptor (PPAR) alpha in human hepatocytes and Tg-UGT1 mice. Oral administration of the PPARalpha agonist 4-chloro-6-(2,3-xylidino)-2-pyrimidinylthioacetic acid (pirinixic acid, WY-14643) to Tg-UGT1 mice led to induction of these proteins in either the liver, gastrointestinal tract, or kidney. The levels of induced UGT1A3 gene transcripts in liver and UGT1A4 protein in small intestine correlated with induced lamotrigine glucuronidation activity in these tissues. With UGT1A3 previously identified as the major human enzyme involved in human C24-glucuronidation of lithocholic acid (LCA), the dramatic induction of liver UGT1A3 RNA in Tg-UGT1 mice was consistent with the formation of LCA-24G in plasma. Furthermore, PPAR-responsive elements (PPREs) were identified flanking the UGT1A1, UGT1A3, and UGT1A6 genes by a combination of site-directed mutagenesis, specific binding to PPARalpha and retinoic acid X receptor alpha, and functional response of the concatenated PPREs in HepG2 cells overexpressing PPARalpha. In conclusion, these results suggest that oral fibrate treatment in humans will induce the UGT1A family of proteins in the gastrointestinal tract and liver, influencing bile acid glucuronidation and first-pass metabolism of other drugs that are taken concurrently with hypolipidemic therapy.

  14. Identification of a novel polyfluorinated compound as a lead to inhibit the human enzymes aldose reductase and AKR1B10: structure determination of both ternary complexes and implications for drug design.

    Science.gov (United States)

    Cousido-Siah, Alexandra; Ruiz, Francesc X; Mitschler, André; Porté, Sergio; de Lera, Ángel R; Martín, María J; Manzanaro, Sonia; de la Fuente, Jesús A; Terwesten, Felix; Betz, Michael; Klebe, Gerhard; Farrés, Jaume; Parés, Xavier; Podjarny, Alberto

    2014-03-01

    Aldo-keto reductases (AKRs) are mostly monomeric enzymes which fold into a highly conserved (α/β)8 barrel, while their substrate specificity and inhibitor selectivity are determined by interaction with residues located in three highly variable external loops. The closely related human enzymes aldose reductase (AR or AKR1B1) and AKR1B10 are of biomedical interest because of their involvement in secondary diabetic complications (AR) and in cancer, e.g. hepatocellular carcinoma and smoking-related lung cancer (AKR1B10). After characterization of the IC50 values of both AKRs with a series of polyhalogenated compounds, 2,2',3,3',5,5',6,6'-octafluoro-4,4'-biphenyldiol (JF0064) was identified as a lead inhibitor of both enzymes with a new scaffold (a 1,1'-biphenyl-4,4'-diol). An ultrahigh-resolution X-ray structure of the AR-NADP(+)-JF0064 complex has been determined at 0.85 Å resolution, allowing it to be observed that JF0064 interacts with the catalytic residue Tyr48 through a negatively charged hydroxyl group (i.e. the acidic phenol). The non-competitive inhibition pattern observed for JF0064 with both enzymes suggests that this acidic hydroxyl group is also present in the case of AKR1B10. Moreover, the combination of surface lysine methylation and the introduction of K125R and V301L mutations enabled the determination of the X-ray crystallographic structure of the corresponding AKR1B10-NADP(+)-JF0064 complex. Comparison of the two structures has unveiled some important hints for subsequent structure-based drug-design efforts.

  15. Pharmacogenomics of oral antiplatelet drugs.

    Science.gov (United States)

    Yasmina, Alfi; de Boer, Anthonius; Klungel, Olaf H; Deneer, Vera H M

    2014-03-01

    Pharmacogenomics has been implicated in the response variability of antiplatelet drugs in coronary artery disease (CAD), particularly for aspirin and clopidogrel. A large number of studies and several meta-analyses have been published on this topic, but until recently, there have been no clear conclusions and no definite guidelines on the clinical use of pharmacogenetic testing before prescribing antiplatelet drugs for CAD. In this review, the available evidence is summarized. The most consistent results are on clopidogrel, where CYP2C19 loss-of-function alleles are associated with stent thrombosis events. We recommend to genotype for CYP2C19 loss-of-function alleles in patients with CAD who are to undergo percutaneous coronary intervention and stenting, and to adjust the antiplatelet treatment based on the genotyping results.

  16. Medicines and Drugs from Plants

    Science.gov (United States)

    Agosta, William C.

    1997-07-01

    Natural preparations have been used for thousands of ages for a variety of purposes including as medicines, poisons, and psychotropic drugs. The largest grouped of preparations from living organisms are medicines, and historically these have come from plants. Quinine and aspirin are two examples of medicines which were extracted originally from plants. Mind-altering, or psychotropic, drugs come mostly from plants or fungi. In many traditional cultures, sickness and death are attributed to maligned spirits so that medicine and religion become inseparable. Uses of cohohba, snakeplant, coca, and peyote are discussed. The process by which new pharmaceuticals are discovered from natural products is described. The implications of an agreement between a major pharmaceutical company and a country in the tropics are discussed.

  17. Advances in Smoothened-targeting therapies for pancreatic cancer: implication for drug discovery from herbal medicines%胰腺癌SMO靶标治疗研究启示:从中药中发现新药

    Institute of Scientific and Technical Information of China (English)

    韩尽斌; 花永强; 陈联誉; 刘鲁明

    2012-01-01

    跨膜蛋白Smoothened(SMO)是音猬因子(sonic hedgehog homology,SHH)信号转导通路的主要成员,在SHH通信过程里发挥桥梁作用.在多种肿瘤组织中均可以检测到SHH的异常表达,胰腺癌干细胞SHH信号的表达明显高于普通胰腺癌细胞.SHH信号与肿瘤干细胞的自我复制,肿瘤血管和基质形成密切相关.使用以环巴胺、GDC-0449等SMO拮抗剂可以抑制SHH信号的异常转导,有效阻止肿瘤的生长和转移.目前已有多种SMO拮抗剂作为抗肿瘤药物进入Ⅰ期或Ⅱ期临床试验,已经有以SMO拮抗剂治疗胰腺癌的Ⅰ期临床试验.作为经典的SMO拮抗剂,环巴胺是从传统药用植物中提取出来的生物碱,这可能为中医药研究者提供思路,从中药中研发更加有效的SMO拮抗剂.%Smoothened (SMO) is a member of sonic hedgehog homology (SHH) signaling pathway.It plays a key role as a bridge between patched-1 (PTCH-1) and Gli.Aberrant SHH expression can be detected in various malignant tissues,and the expression in pancreatic cancer stem cells is higher apparently.SHH signals are closely associated with self-duplication of cancer stem cells,formation of tumor vessels as well as matrixes.SMO antagonists such as cyclopamine,GDC-0449 and so on show potential to inhibit activity of SHH signaling,and arrest the growth as well as metastases of tumors.Recently,a few of SMO antagonists have been studied in phase Ⅰ clinical trials and some are in phase Ⅱ,meanwhile,phase Ⅰ or Ⅱ trials of SMO antagonists to treat pancreatic cancer are performed currently.As the classical SMO antagonist,cyclopamine is extracted from a medicinal plant.Perhaps researchers may be able to determine more effective SMO-targeting drugs from herbal medicines in the future.

  18. AIDSinfo Drug Database

    Science.gov (United States)

    ... U V W X Y Z All Drugs Drug News Thursday, February 2, 2017 Sustiva Drug Label Updated ... Drug Label Updated Tuesday, January 31, 2017 Stribild Drug Label Updated More News Mobile Apps iPhone/iPad App Android App Back ...

  19. Schools and Drug Markets: Examining the Relationship between Schools and Neighborhood Drug Crime

    Science.gov (United States)

    Willits, Dale; Broidy, Lisa M.; Denman, Kristine

    2015-01-01

    Research on drug markets indicates that they are not randomly distributed. Instead they are concentrated around specific types of places. Theoretical and empirical literature implicates routine activities and social disorganization processes in this distribution. In the current study, we examine whether, consistent with these theories, drug…

  20. KEGG DRUG / Acutect (TN) [KEGG DRUG

    Lifescience Database Archive (English)

    Full Text Available DRUG: D06027 Entry D06027Drug Name Technetium Tc 99m apcitide (USP); Acutect (TN) F... 1 838085 1 848586 1 857781 1 868182 1 878280 1 888687 1 898288 2 908689 2 918390 1 929091 2 939092 1 949495 2 KEGG DRUG / Acutect (TN) ...

  1. Attitudes towards drug legalization among drug users.

    Science.gov (United States)

    Trevino, Roberto A; Richard, Alan J

    2002-01-01

    Research shows that support for legalization of drugs varies significantly among different sociodemographic and political groups. Yet there is little research examining the degree of support for legalization of drugs among drug users. This paper examines how frequency and type of drug use affect the support for legalization of drugs after adjusting for the effects of political affiliation and sociodemographic characteristics. A sample of 188 drug users and non-drug users were asked whether they would support the legalization of marijuana, cocaine, and heroin. Respondents reported their use of marijuana, crack, cocaine, heroin, speedball, and/or methamphetamines during the previous 30 days. Support for legalization of drugs was analyzed by estimating three separate logistic regressions. The results showed that the support for the legalization of drugs depended on the definition of "drug user" and the type of drug. In general, however, the results showed that marijuana users were more likely to support legalizing marijuana, but they were less likely to support the legalization of cocaine and heroin. On the other hand, users of crack, cocaine, heroin, speedball, and/or methamphetamines were more likely to support legalizing all drugs including cocaine and heroin.

  2. Drug Retention Times

    Energy Technology Data Exchange (ETDEWEB)

    Center for Human Reliability Studies

    2007-05-01

    The purpose of this monograph is to provide information on drug retention times in the human body. The information provided is based on plausible illegal drug use activities that might be engaged in by a recreational drug user.

  3. Drug Interaction API

    Data.gov (United States)

    U.S. Department of Health & Human Services — The Interaction API is a web service for accessing drug-drug interactions. No license is needed to use the Interaction API. Currently, the API uses DrugBank for its...

  4. Drug Plan Coverage Rules

    Science.gov (United States)

    ... get about Medicare Lost/incorrect Medicare card Report fraud & abuse File a complaint Identity theft: protect yourself ... drug plan How Part D works with other insurance Find health & drug plans Drug plan coverage rules ...

  5. Drugs: Shatter the Myths

    Science.gov (United States)

    ... ML. Tobacco, alcohol, and other risk behaviors in film: how well do MPAA ratings distinguish content? J ... about drugs and drug abuse. NDFW includes local school and community events and Drug Facts Chat Day, ...

  6. Drug-induced hepatitis

    Science.gov (United States)

    Toxic hepatitis ... to get liver damage. Some drugs can cause hepatitis with small doses, even if the liver breakdown ... liver. Many different drugs can cause drug-induced hepatitis. Painkillers and fever reducers that contain acetaminophen are ...

  7. Drugs Approved for Melanoma

    Science.gov (United States)

    ... Ask about Your Treatment Research Drugs Approved for Melanoma This page lists cancer drugs approved by the ... that are not listed here. Drugs Approved for Melanoma Aldesleukin Cobimetinib Cotellic (Cobimetinib) Dabrafenib Dacarbazine DTIC-Dome ( ...

  8. Drug Retention Times

    Energy Technology Data Exchange (ETDEWEB)

    Center for Human Reliability Studies

    2007-05-01

    The purpose of this monograph is to provide information on drug retention times in the human body. The information provided is based on plausible illegal drug use activities that might be engaged in by a recreational drug user

  9. Prescription Drug Abuse

    Science.gov (United States)

    ... Whether they're using street drugs or medications, drug abusers often have trouble at school, at home, with ... a short period of time may make a drug abuser aggressive or paranoid. Although stimulant abuse might not ...

  10. Drug Development Process

    Science.gov (United States)

    ... Device Approvals The Drug Development Process The Drug Development Process Share Tweet Linkedin Pin it More sharing ... Pin it Email Print Step 1 Discovery and Development Discovery and Development Research for a new drug ...

  11. A Comparison of Drug Use between Prostitutes and Other Female Arrestees.

    Science.gov (United States)

    Yacoubian, George S., Jr.; Urbach, Blake J.; Larsen, Kristine L.; Johnson, Regina J.; Peters, Ronald J., Jr.

    2000-01-01

    In this study, drug use data were collected from 3,587 female arrestees surveyed through Houston's Arrestee Drug Abuse Monitoring (ADAM) Program. Chi-square statistics indicated females arrested for prostitution were significantly more likely to test positive for cocaine than the non-prostitutes. Implications for drug treatment and public health…

  12. Atomoxetine effects on attentional bias to drug-related cues in cocaine dependent individuals

    NARCIS (Netherlands)

    Passamonti, L. (Luca); M. Luijten (Maartje); Ziauddeen, H.; I. Coyle-Gilchrist (Ian); Rittman, T.; Brain, S.A.E.; Regenthal, R.; I.H.A. Franken (Ingmar); Sahakian, B.J.; Bullmore, E.T.; Robbins, T.W.; Ersche, K.D.

    2017-01-01

    textabstractRationale: Biased attention towards drug-related cues and reduced inhibitory control over the regulation of drug-intake characterize drug addiction. The noradrenaline system has been critically implicated in both attentional and response inhibitory processes and is directly affected by

  13. Drug: D06912 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available nese Medicine in Japan [BR:br08304] Crude Drugs Drugs for blood Drugs for removing blood stasis D06912 *Quercus cortex; Bokusoku Drug...s for external use Drugs for external use D06912 *Quercu

  14. Nuclear Receptors in Drug Metabolism, Drug Response and Drug Interactions

    Directory of Open Access Journals (Sweden)

    Chandra Prakash

    2015-12-01

    Full Text Available Orally delivered small-molecule therapeutics are metabolized in the liver and intestine by phase I and phase II drug-metabolizing enzymes (DMEs, and transport proteins coordinate drug influx (phase 0 and drug/drug-metabolite efflux (phase III. Genes involved in drug metabolism and disposition are induced by xenobiotic-activated nuclear receptors (NRs, i.e. PXR (pregnane X receptor and CAR (constitutive androstane receptor, and by the 1α, 25-dihydroxy vitamin D3-activated vitamin D receptor (VDR, due to transactivation of xenobiotic-response elements (XREs present in phase 0-III genes. Additional NRs, like HNF4-α, FXR, LXR-α play important roles in drug metabolism in certain settings, such as in relation to cholesterol and bile acid metabolism. The phase I enzymes CYP3A4/A5, CYP2D6, CYP2B6, CYP2C9, CYP2C19, CYP1A2, CYP2C8, CYP2A6, CYP2J2, and CYP2E1 metabolize >90% of all prescription drugs, and phase II conjugation of hydrophilic functional groups (with/without phase I modification facilitates drug clearance. The conjugation step is mediated by broad-specificity transferases like UGTs, SULTs, GSTs. This review delves into our current understanding of PXR/CAR/VDR-mediated regulation of DME and transporter expression, as well as effects of single nucleotide polymorphism (SNP and epigenome (specified by promoter methylation, histone modification, microRNAs, long non coding RNAs on the expression of PXR/CAR/VDR and phase 0-III mediators, and their impacts on variable drug response. Therapeutic agents that target epigenetic regulation and the molecular basis and consequences (overdosing, underdosing, or beneficial outcome of drug-drug/drug-food/drug-herb interactions are also discussed. Precision medicine requires understanding of a drug's impact on DME and transporter activity and their NR-regulated expression in order to achieve optimal drug efficacy without adverse drug reactions. In future drug screening, new tools such as humanized mouse

  15. Stevens Johnson syndrome, toxic epidermal necrolysis and SJS-TEN overlap: A retrospective study of causative drugs and clinical outcome

    Directory of Open Access Journals (Sweden)

    Sharma Vinod

    2008-01-01

    Full Text Available Background and Aims: Stevens Johnson syndrome (SJS, toxic epidermal necrolysis (TEN and SJS-TEN overlap are serious adverse cutaneous drug reactions. Drugs are often implicated in these reactions. Methods: A retrospective analysis of inpatients′ data with these dermatological diagnoses were carried out for three years, to study the causative drugs, clinical outcome, and mortality in these conditions. Results: Thirty patients (15 TEN, nine SJS-TEN overlap, and six SJS were admitted. In 21 cases, multiple drugs were implicated whereas single drugs were responsible in nine. Anticonvulsants (35.08% were the most commonly implicated drugs followed by antibiotics (33.33% and NSAIDS (24.56%. Twenty-five patients recovered whereas five died (four TEN, one SJS-TEN overlap. Conclusion: Anticonvulsants, antibiotics and NSAIDs were the most frequently implicated drugs. TEN causes higher mortality than both SJS and SJS-TEN overlap.

  16. [Are there any sex/gender differences in drug use and drug addiction?].

    Science.gov (United States)

    Mendrek, Adrianna

    2014-01-01

    Drug use and drug addiction have been traditionally considered to be a male problem, however the gender gap has been decreasing over the past few decades. Thus, while the prevalence of alcohol, cannabis and nicotine dependence is still overall greater among men than among women, sex/gender differences in the abuse of stimulants and opiates seem to have disappeared. Moreover, women appear to be more prone to develop drug dependence, suffer more severe physical and psychological consequences of drug abuse, and have more difficulties quitting the habit. Numerous psychological, socio-cultural and biological factors have been implicated in these changing statistics. For example, while a large proportion of men initiate drug use to induce feelings of elation, energy or focus, women frequently start taking drugs to alleviate pre-existing mental health problems, including high levels of stress, feelings of alienation, depression, anxiety, or post-traumatic stress disorder. This maladaptive self-medication strategy often results in a faster transition to a habitual drug use and eventually a more severe dependence. In addition, the socio-cultural norms (particularly in the Western society) have changed dramatically over the past few decades. Thus, while there is still a more severe stigma and prejudice against women who use drugs (especially if they are pregnant of have children), overall there is much greater acceptance of women's drug use than it was several decades ago. Moreover, women have much greater access to various drugs of abuse than they used to have. Finally, over the past couple of decades new research started emerging pointing to some neurobiological factors that could also contribute to sex differences in drug addiction. Thus, there is now evidence that dopamine system, which for decades has been strongly implicated in drug reinforcement, is sexually dimorphic. The number of dopaminergic neurons, the density of the dopaminergic terminals, as well as

  17. War on Drugs Policing and Police Brutality.

    Science.gov (United States)

    Cooper, Hannah L F

    2015-01-01

    War on Drugs policing has failed to reduce domestic street-level drug activity: the cost of drugs remains low and drugs remain widely available. In light of growing attention to police brutality in the United States, this paper explores interconnections between specific War on Drugs policing strategies and police-related violence against Black adolescents and adults in the United States. This paper reviews literature about (1) historical connections between race/ethnicity and policing in the United States; (2) the ways that the War on Drugs eroded specific legal protections originally designed to curtail police powers; and (3) the implications of these erosions for police brutality targeting Black communities. Policing and racism have been mutually constitutive in the United States. Erosions to the 4th Amendment to the Constitution and to the Posse Comitatus Act set the foundations for two War on Drugs policing strategies: stop and frisk and Special Weapons and Tactics (SWAT) teams. These strategies have created specific conditions conducive to police brutality targeting Black communities. Conclusions/Importance: War on Drugs policing strategies appear to increase police brutality targeting Black communities, even as they make little progress in reducing street-level drug activity. Several jurisdictions are retreating from the War on Drugs; this retreat should include restoring rights originally protected by the 4th Amendment and Posse Comitatus. While these legal changes occur, police chiefs should discontinue the use of SWAT teams to deal with low-level nonviolent drug offenses and should direct officers to cease engaging in stop and frisk.

  18. Drug: D06722 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ranthes bidentata root Major component: Ecdysterone [CPD:C02633] Therapeutic category of drugs in Japan [BR:br08301] 5 Crude drugs... and Chinese medicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs D06...ude Drugs Drugs for blood Drugs for removing blood stasis D06722 Achyranthes root; Achyranthese root Crude drugs

  19. Drug: D06697 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ceae (buckwheat family) Polygonum tuber Major component: Chrysophanol [CPD:C10315] Therapeutic category of drugs... in Japan [BR:br08301] 5 Crude drugs and Chinese medicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs... [BR:br08304] Crude Drugs Drugs for blood Drugs for replenishing blood D06697 Polygonum root Crude drugs [BR

  20. The role of anticipation in drug addiction and reward

    Directory of Open Access Journals (Sweden)

    Jędras P

    2013-12-01

    Full Text Available Paweł Jędras, Andrew Jones, Matt FieldDepartment of Psychological Sciences, University of Liverpool, Liverpool, UKAbstract: Addiction is a chronically relapsing disorder, and substance users frequently relapse when they encounter opportunities to use drugs. In this paper, we review evidence regarding the psychological response to anticipation of imminent drug availability, its neural substrates, and its relationship to other phenomena implicated in addiction. Naturalistic and laboratory studies indicate that drug anticipation increases cue-provoked craving and attentional biases for drug-related cues. As predicted by existing theoretical models, these effects reflect hyper-valuation of drugs that are perceived as available for consumption, which is linked to activation of the dorsolateral prefrontal cortex that, in turn, innervates subcortical regions associated with reward processing. Drug expectancy is necessary for the formation of conditioned responses to drug-related cues and it modulates the strength of conditioned responses. Furthermore, the role of impulsivity in addiction can be understood in terms of its interaction with the response to imminent drug availability. These results have a number of implications for the treatment of addiction, ranging from government policies that restrict the perceived availability of drugs to novel biological and psychological interventions that could blunt the response to signals of drug availability.Keywords: attentional bias, availability, conditioning, cue-reactivity, expectancy, substance use disorders

  1. Vascular remodeling, macro- and microvessels: therapeutic implications.

    Science.gov (United States)

    Rizzoni, Damiano; Muiesan, Maria Lorenza; Porteri, Enzo; De Ciuceis, Carolina; Boari, Gianluca E M; Salvetti, Massimo; Paini, Anna; Rosei, Enrico Agabiti

    2009-01-01

    Macrovasculature and microvasculature are deeply interrelated, since microvascular structure is not only the site of vascular resistance but probably also the origin of most of the wave reflections generating increased central systolic blood pressure. In fact, preliminary data suggest that some index of large artery stiffness is related with the media to lumen ratio of subcutaneous small resistance arteries of hypertensive patients. Microvascular structural alterations and changes in the mechanical properties of the macrovessels represent potent predictors of prognosis. Hypertension-related damage to the micro- and macrovascular system may be corrected by pharmacological agents. Among them, beta-blocking agents and diuretics have a negligible effect on microvascular structure, while renin-angiotensin system antagonists and calcium entry blockers have favorable actions, improving large artery mechanics and possibly reducing central wave reflections.

  2. CONCEPT OF DRUG INTERACTION

    Directory of Open Access Journals (Sweden)

    Singh Nidhi

    2012-07-01

    Full Text Available Drug interaction is an increasingly important cause of adverse reactions (ADR, and is the modification of the effect of one drug (object by the prior or concomitant administration of another drug (precipitant drug. Drug interaction may either enhance or diminish the intended effect of one or both drugs. For example severe haemorrhage may occur if warfarin and salicylates (asprin are combined. Precipitant drugs modify the object drug's absorption, distribution, metabolism, excretion or actual clinical effect. Nonsteroidal anti-inflammatory drugs, antibiotics and, in particular, rifampin are common precipitant drugs prescribed in primary care practice. Drugs with a narrow therapeutic range or low therapeutic index are more likely to be the objects for serious drug interactions. Object drugs in common use include warfarin, fluoroquinolones, antiepileptic drugs, oral contraceptives, cisapride and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Many other drugs, act as precipitants or objects, and a number of drugs act as both. The aim of present review is to throw light on the concept of drug interaction.

  3. Gamma-hydroxybutyrate: A drug of abuse

    DEFF Research Database (Denmark)

    Drasbek, Kim Ryun; Christensen, Jakob; Jensen, Kimmo

    2006-01-01

    γ-hydroxybutyrate (GHB) is a drug of abuse that causes euphoria, anxiolysis and hypnosis. The recent rise in the recreational intake of GHB, as well as its association with “drug rape”, has turned the attention to GHB in acute hospital settings. Acutely admitted GHB intoxicated patients may display...... available. As a basis for understanding the clinical features of GHB intoxication and abuse, we here review the pharmacological and neurophysiological knowledge about GHB, which stems from decades of clinical and basic GHB research. Also, we discuss the latest discoveries in the quest for distinct GHB...... receptors in the brain, and their possible implications for future therapies of GHB abuse....

  4. Cardiologic side effects of psychotropic drugs

    Institute of Scientific and Technical Information of China (English)

    Giuseppe Marano; Gianandrea Traversi; Enrico Romagnoli; Valeria Catalano; Marzia Lotrionte; Antonio Abbate; Giuseppe Biondi-Zoccai; Marianna Mazza

    2011-01-01

    Psychotropic drugs can produce cardiovascular side effects associated with a degree of cardiotoxicity.The coexistence of a heart disease complicates the management of mental illness,can contribute to a reduced quality of life and a worse illness course.The co-occurrence of psychiatric disorders in cardiac patients might affect the clinical outcome and morbidity.Moreover,the complex underlying mechanism that links these two conditions remains unclear.This paper discusses the known cardiovascular complications of psychotropic drugs and analyzes the important implications of antidepressive treatment in patients with previous cardiac history.

  5. Neoadjuvant breast cancer therapy and drug development.

    Science.gov (United States)

    Cortazar, Patricia; Kluetz, Paul G

    2015-11-01

    Neoadjuvant treatment of breast cancer initially was limited to patients with locally advanced breast cancer in which downstaging was necessary. Now, neoadjuvant trials have become an increasingly common way to facilitate the rapid assessment of new cancer therapies. The appeal of neoadjuvant trials is that they provide the opportunity to study translational science, tumor biomarkers, and intermediate endpoints in response to systemic therapy within a shortened period. This review summarizes the data that contribute to our understanding of the association between pathological complete response and long-term outcomes, describes the implications of drug development and accelerated approval in neoadjuvant treatment of breast cancer, and provides a perspective on future neoadjuvant drug development.

  6. Treatment of drug addiction and psychopathology: A field study

    Directory of Open Access Journals (Sweden)

    Antonio Souto

    2010-01-01

    Full Text Available Field study to assess the concurrence of the psychopathology of drug addiction, and to evaluate the efficacy of pharmacological treatment versus drug-free treatments for the psychopathology of drug addiction. A total of 261 patients treated for drug addiction, 131 on a drug-free treatment and the remaining 130 patients received a drug regime, of which 113 were, according to the Prochaska and Decrement’s Transtheorical Model, in a initial phase of the treatment (from 15 days to 6 months of treatment and 148 in a maintenance phase in drug treatment (> 6 months, were psychopathologically assessed using the SCL-90-R (Derogatis, 2002. A field study with a 2 X 2 design (treatment: drug-free vs. drug-regime and (treatment phase: initial phase vs. maintenance in drug treatment was carried out. The results support the hypothesis of a dual diagnosis, that is, the comorbidity of psychopathology and drug addiction. On the whole, treatment for drug addiction had a significant impact on reducing associated psychopathology. Finally, the results are discussed in the light of the implications for the treatment of drug addiction.

  7. Pattern analysis of drug-induced skin diseases.

    Science.gov (United States)

    Justiniano, Hildamari; Berlingeri-Ramos, Alma C; Sánchez, Jorge L

    2008-08-01

    Drug eruptions are common adverse reactions to drug therapy and are a frequent reason for consultation in clinical practice. Even though any medication can potentially cause an adverse cutaneous reaction, some drugs are implicated more commonly than others. Histologically, drugs can elicit a variety of inflammatory disease patterns in the skin and panniculus, no pattern being specific for a particular drug. The most common pattern elicited by systemically administered medications is the perivascular pattern. Psoriasiform or granulomatous patterns are rarely caused by medications. The usual histologic patterns of drug eruptions are discussed in this review using the basic patterns of inflammatory diseases. Clinicopathologic correlation is established for relevant patterns. However, the changes of drug-induced skin disease must be made considering clinical presentation, histopathological analysis, and course of the disease.

  8. Illicit drug use and HIV risk in the Dominican Republic: tourism areas create drug use opportunities.

    Science.gov (United States)

    Guilamo-Ramos, Vincent; Lee, Jane J; Ruiz, Yumary; Hagan, Holly; Delva, Marlyn; Quiñones, Zahira; Kamler, Alexandra; Robles, Gabriel

    2015-01-01

    While the Caribbean has the second highest global human immunodeficiency virus (HIV) prevalence, insufficient attention has been paid to contributing factors of the region's elevated risk. Largely neglected is the potential role of drugs in shaping the Caribbean HIV/acquired immune deficiency syndrome epidemic. Caribbean studies have almost exclusively focused on drug transportation and seldom acknowledged local user economies and drug-related health and social welfare consequences. While tourism is consistently implicated within the Caribbean HIV epidemic, less is known about the intersection of drugs and tourism. Tourism areas represent distinct ecologies of risk often characterised by sex work, alcohol consumption and population mixing between lower and higher risk groups. Limited understanding of availability and usage of drugs in countries such as the Dominican Republic (DR), the Caribbean country with the greatest tourist rates, presents barriers to HIV prevention. This study addresses this gap by conducting in-depth interviews with 30 drug users in Sosúa, a major sex tourism destination of the DR. A two-step qualitative data analysis process was utilised and interview transcripts were systematically coded using a well-defined thematic codebook. Results suggest three themes: (1) local demand shifts drug routes to tourism areas, (2) drugs shape local economies and (3) drug use facilitates HIV risk behaviours in tourism areas.

  9. Novel chemical permeation enhancers for transdermal drug delivery

    Directory of Open Access Journals (Sweden)

    Yang Chen

    2014-04-01

    Full Text Available Transdermal drug delivery has been accepted as a potential non-invasive route of drug administration, with advantages of prolonged therapeutic action, decreased side effect, easy use and better patient compliance. However, development of transdermal products is primarily hindered by the low permeability of the skin. To overcome this barrier effect, numerous new chemicals have been synthesized as potential permeation enhancers for transdermal drug delivery. In this review, we presented an overview of the investigations in this field, and further implications on selection or design of suitable permeation enhancers for transdermal drug delivery were also discussed.

  10. Drug-Induced Oxidative Stress and Toxicity

    Directory of Open Access Journals (Sweden)

    Damian G. Deavall

    2012-01-01

    Full Text Available Reactive oxygen species (ROS are a byproduct of normal metabolism and have roles in cell signaling and homeostasis. Species include oxygen radicals and reactive nonradicals. Mechanisms exist that regulate cellular levels of ROS, as their reactive nature may otherwise cause damage to key cellular components including DNA, protein, and lipid. When the cellular antioxidant capacity is exceeded, oxidative stress can result. Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities. In this paper, we examine the nature of ROS-induced damage on key cellular targets of oxidative stress. We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity.

  11. Fighting the Drug War.

    Science.gov (United States)

    The Journal of State Government, 1990

    1990-01-01

    All nine articles in this periodical issue focus on the theme of the war against illegal drug use, approaching the topic from a variety of perspectives. The articles are: "The Drug War: Meeting the Challenge" (Stanley E. Morris); "Ways to Fight Drug Abuse" (Bruce A. Feldman); "Treatment Key to Fighting Drugs" (Stan…

  12. Drugs and Young People

    Science.gov (United States)

    ... fully developed. As a result, the brains of young people may be more susceptible to drug abuse and addiction than adult brains. Abused drugs include Amphetamines Anabolic ... better to prevent drug abuse in the first place. NIH: National Institute on Drug Abuse

  13. Utah Drug Use Questionnaire.

    Science.gov (United States)

    Governor's Citizen Advisory Committee on Drugs, Salt Lake City, UT.

    This questionnaire assesses drug use practices in junior and senior high school students. The 21 multiple choice items pertain to drug use practices, use history, available of drugs, main reason for drug use, and demographic data. The questionnaire is untimed, group administered, and may be given by the classroom teacher in about 10 minutes. Item…

  14. Drug: D06758 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available component: Zizyphus saponin Therapeutic category of drugs in Japan [BR:br08301] 5 Crude drugs and Chinese m...edicine formulations 51 Crude drugs 510 Crude drugs 5100 Crude drugs D06758 Jujub...e (JP16) Traditional Chinese Medicine in Japan [BR:br08304] Crude Drugs Stomachic and antidiarrheal drugs St...omachic and antidiarrheal drugs D06758 *Jujube; Jujube Drugs for Qi Drugs for replenishing Qi D06758 *Jujube; Jujube Crude drugs

  15. Herbicidal properties of antimalarial drugs.

    Science.gov (United States)

    Corral, Maxime G; Leroux, Julie; Stubbs, Keith A; Mylne, Joshua S

    2017-03-31

    The evolutionary relationship between plants and the malarial parasite Plasmodium falciparum is well established and underscored by the P. falciparum apicoplast, an essential chloroplast-like organelle. As a result of this relationship, studies have demonstrated that herbicides active against plants are also active against P. falciparum and thus could act as antimalarial drug leads. Here we show the converse is also true; many antimalarial compounds developed for human use are highly herbicidal. We found that human antimalarial drugs (e.g. sulfadiazine, sulfadoxine, pyrimethamine, cycloguanil) were lethal to the model plant Arabidopsis thaliana at similar concentrations to market herbicides glufosinate and glyphosate. Furthermore, the physicochemical properties of these herbicidal antimalarial compounds were similar to commercially used herbicides. The implications of this finding that many antimalarial compounds are herbicidal proffers two novel applications: (i) using the genetically tractable A. thaliana to reveal mode-of-action for understudied antimalarial drugs, and (ii) co-opting antimalarial compounds as a new source for much needed herbicide lead molecules.

  16. New drug update: 2010.

    Science.gov (United States)

    Hussar, Daniel A

    2010-10-01

    Five new drugs that are used for medical problems often encountered in the elderly have been selected for consideration in this review. The uses and most important properties of these agents are considered, and a rating for each new drug is determined using the New Drug Comparison Rating (NDCR) system developed by the author. In the NDCR system, a rating from 1 to 5 (5 being the highest rating) is assigned for each new drug. The rating is based on a comparison of the new drug with related drugs already marketed. Advantages, disadvantages, and other important information regarding the new drug are identified and used as the basis for determining the rating.

  17. 2016 New Drug Update.

    Science.gov (United States)

    Hussar, Daniel A

    2016-04-01

    Six new drugs marketed within the last year, which are used for medical problems often experienced by the elderly, have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating (NDCR) system developed by the author. Advantages, disadvantages, and other important information regarding the new drug are identified and used as the basis for determining the rating. The drugs include a hypnotic, an anticoagulant, two drugs for heart failure, and two drugs to reduce low-density lipoprotein cholesterol.

  18. New drug update: 2011.

    Science.gov (United States)

    Hussar, Daniel A

    2012-04-01

    Five new drugs that are used for medical problems often encountered in the elderly have been selected for consideration in this review. The uses and most important properties of these agents are considered, and a rating for each new drug is determined using the New Drug Comparison Rating (NDCR) system developed by the author. In the NDCR system, a rating from 1 to 5 (5 being the highest rating) is assigned for each new drug. The rating is based on a comparison of the new drug with related drugs already marketed. Advantages, disadvantages, and other important information regarding the new drug are identified and used as the basis for determining the rating.

  19. Network-based drugs and biomarkers

    DEFF Research Database (Denmark)

    Erler, Janine Terra; Linding, Rune

    2010-01-01

    The structure and dynamics of protein signalling networks governs cell decision processes and the formation of tissue boundaries. Complex diseases such as cancer and diabetes are diseases of such networks. Therefore approaches that can give insight into how these networks change during disease pr...... associated technologies. We then focus on the multivariate nature of cellular networks and how this has implications for biomarker and drug discovery using cancer metastasis as an example....

  20. Food and drugs

    OpenAIRE

    Đaković-Švajcer Kornelija

    2002-01-01

    Food can exert a significant influence on the effects of certain drugs. The interactions between food and drugs can be pharmacokinetic and pharmacodynamic. Pharmacokinetic interactions most often take place on absorption and drug metabolism levels. Absorption can be either accelerated or delayed, increased or decreased, while drug metabolism can be either stimulated or inhibited. The factors which influence food-drug interactions are as follows: composition and physic-chemical properties of d...