The effect of interferon-{beta} on mouse neural progenitor cell survival and differentiation

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Hirsch, Marek [Neurology Department, University of Vermont College of Medicine, Burlington, VT (United States); Knight, Julia [Neuroscience Department, University of Vermont College of Medicine, Burlington, VT (United States); Tobita, Mari; Soltys, John; Panitch, Hillel [Neurology Department, University of Vermont College of Medicine, Burlington, VT (United States); Mao-Draayer, Yang, E-mail: yang.mao-draayer@vtmednet.org [Neurology Department, University of Vermont College of Medicine, Burlington, VT (United States)

2009-10-16

Interferon-{beta} (IFN-{beta}) is a mainstay therapy for relapse-remitting multiple sclerosis (MS). However, the direct effects of IFN-{beta} on the central nervous system (CNS) are not well understood. To determine whether IFN-{beta} has direct neuroprotective effects on CNS cells, we treated adult mouse neural progenitor cells (NPCs) in vitro with IFN-{beta} and examined the effects on proliferation, apoptosis, and differentiation. We found that mouse NPCs express high levels of IFN{alpha}/{beta} receptor (IFNAR). In response to IFN-{beta} treatment, no effect was observed on differentiation or proliferation. However, IFN-{beta} treated mouse NPCs demonstrated decreased apoptosis upon growth factor withdrawal. Pathway-specific polymerase chain reaction (PCR) arrays demonstrated that IFN-{beta} treatment upregulated the STAT 1 and 2 signaling pathway, as well as GFRA2, NOD1, Caspases 1 and 12, and TNFSF10. These results suggest that IFN-{beta} can directly affect NPC survival, possibly playing a neuroprotective role in the CNS by modulating neurotrophic factors.

Interferon beta 1, an intermediate in the tumor necrosis factor alpha- induced increased MHC class I expression and an autocrine regulator of the constitutive MHC class I expression

OpenAIRE

1987-01-01

In conclusion, our observations indicate that the constitutive MHC class I expression is regulated by autocrine production of IFN-beta 1. TNF-alpha acts as an enhancer of the autocrine production of IFN-beta 1, and consequently as an enhancer of the MHC class I expression and viral protection.

Relative bioavailability of three formulations of galunisertib administered as monotherapy in patients with advanced or metastatic cancer

Directory of Open Access Journals (Sweden)

Ivelina Gueorguieva

2016-12-01

Full Text Available Objective: Galunisertib (LY2157299 monohydrate, an inhibitor of the transforming growth factor β (TGFβ pathway, is currently under investigation in several clinical trials involving multiple tumor types. The primary objective of this study was to assess relative bioavailability of two new galunisertib formulations developed using the roller compaction (RC dry-milled (RCD and RC slurry-milled (RCS processes, compared with the existing formulation developed using the high-sheer wet granulation (HSWG process. The secondary objective was to report the safety profile after a single dose of the three formulations. Methods: Patients with advanced or metastatic cancer were enrolled into this single-center, 3-period, 6-sequence crossover study. Patients were assigned sequentially to 1 of 6 sequences in blocks of 6 to ensure that all 6 sequences have the same number of completers. A patient entering a sequence received a different galunisertib formulation as a single 150 mg dose orally during each of the 3 periods. Each period was separated from the next by a washout interval of at least 48 hours. Pharmacokinetic (PK parameters, including area under curve (AUC and Cmax, were computed using standard non-compartmentalized methods of analysis. For comparison of exposures between formulations, log-transformed AUC and Cmax values were analyzed using a linear mixed-effects model. Safety assessments included adverse event monitoring, physical examinations, and laboratory tests. Results: Of the 14 patients who entered and completed the study, 13 patients were included in the final statistical analysis. AUC(0-tlast, AUC(0-48 h, and AUC(0-∞ for the RC formulations and the HSWG formulation were similar. Cmax was reduced by approximately 22% and tmax was longer by at least 1.00 h for the RCD and RCS formulations compared with the HSWG formulation. The RC formulations demonstrated a safety profile after a single dose similar to the HSWG formulation. Conclusions

Pharmacokinetic evaluation of novel midazolam gel formulations following buccal administration to healthy dogs.

Science.gov (United States)

Aldawsari, Mohammed F; Lau, Vivian W; Babu, Ramapuram J; Arnold, Robert D; Platt, Simon R

2018-01-01

OBJECTIVE To determine the physiochemical properties and pharmacokinetics of 3 midazolam gel formulations following buccal administration to dogs. ANIMALS 5 healthy adult hounds. PROCEDURES In phase 1 of a 2-phase study, 2 gel formulations were developed that contained 1% midazolam in a poloxamer 407 (P1) or hydroxypropyl methylcellulose (H1) base and underwent rheological and in vitro release analyses. Each formulation was buccally administered to 5 dogs such that 0.3 mg of midazolam/kg was delivered. Each dog also received midazolam hydrochloride (0.3 mg/kg, IV). There was a 3-day interval between treatments. Blood samples were collected immediately before and at predetermined times for 8 hours after drug administration for determination of plasma midazolam concentration and pharmacokinetic analysis. During phase 2, a gel containing 2% midazolam in a hydroxypropyl methylcellulose base (H2) was developed on the basis of phase 1 results. That gel was buccally administered such that midazolam doses of 0.3 and 0.6 mg/kg were delivered. Each dog also received midazolam (0.3 mg/kg, IV). All posttreatment procedures were the same as those for phase 1. RESULTS The H1 and H2 formulations had lower viscosity, greater bioavailability, and peak plasma midazolam concentrations that were approximately 2-fold as high, compared with those for the P1 formulation. The mean peak plasma midazolam concentration for the H2 formulation was 187.0 and 106.3 ng/mL when the midazolam dose administered was 0.6 and 0.3 mg/kg, respectively. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that buccal administration of gel formulations might be a viable alternative for midazolam administration to dogs.

Improved oral bioavailability of cyclosporin A in male Wistar rats. Comparison of a Solutol HS 15 containing self-dispersing formulation and a microsuspension.

Science.gov (United States)

Bravo González, Roberto Carlos; Huwyler, Jörg; Walter, Isabelle; Mountfield, Richard; Bittner, Beate

2002-10-01

Oral bioavailability of the highly lipophilic and poorly water-soluble immunosuppressive agent cyclosporin A (CyA) in two different formulations was investigated in male Wistar rats. An aqueous microsuspension and a self-dispersing formulation composed of the surface-active ingredients Solutol HS 15:Labrafil M2125CS:oleic acid=7:2:1 (v/v/v) were administered to the animals at a dose level of 20 mg/kg. In order to calculate the absolute oral bioavailability, CyA was additionally administered intravenously at 10 mg/kg as microsuspension. It was found that the oral bioavailability of CyA in the Solutol HS 15-based formulation was twofold higher as compared to the microsuspension (69.9+/-2.8 vs. 35.7+/-3.3%, P=0.001). By contrast, the time to reach maximum plasma concentration (t(max)) and the terminal half-life (t(1/2)) did not differ significantly with the different formulations (t(max): 7.0+/-1.0 vs. 6.3+/-1.7 h; t(1/2): 20.5+/-2.9 vs. 16.7+/-4.7 h). In vitro solubility experiments demonstrated a marked increase in the aqueous solubility of CyA in the presence of the self-dispersing formulation as compared to the micronized powder alone (solubility after 120 min at 37 degrees C: 136 vs. 23.2 microg/ml in human gastric juice; 133 vs. 10.8 microg/ml in simulated intestinal juice). Most likely, the enhanced systemic exposure of CyA in the self-dispersing formulation was caused by improved solubility of CyA in the gastrointestinal fluids in the presence of the surface-active ingredients. Additional factors that may have contributed to increased oral bioavailability are inhibition of metabolism and/or transport processes as well as permeability enhancement by the co-administered excipients.

The relative bioavailability of loratadine administered as a chewing gum formulation in healthy volunteers

DEFF Research Database (Denmark)

Nøhr-Jensen, Lene; Damkier, Per; Bidstrup, Tanja Busk

2006-01-01

OBJECTIVE: The aim of this study was to investigate the pharmacokinetics of loratadine and its active metabolite desloratadine after single-dose administration of loratadine as a conventional tablet, orally disintegrating tablet (smelt tablet) and a chewing gum formulation with and without...... of medicated chewing gum without collection of saliva and a 30-mg portion of medicated chewing gum with collection of saliva. Blood samples were taken at predefined sampling points 0-24 h after medication, and the plasma concentrations of loratadine and desloratadine were determined by high-performance liquid...... chromatography. Each study period was separated by a wash-out period of at least 7 days. RESULTS: The mean dose-corrected area under the plasma concentration-time curve extrapolated to infinity AUC(0-infinity) for the chewing gum formulation was statistically significantly increased compared to the tablet...

Bioequivalence of a new cyclosporine a formulation to Neoral.

Science.gov (United States)

David-Neto, Elias; Kakehashi, Erica; Alves, Cristiane Feres; Pereira, Lilian M; de Castro, Maria Cristina R; de Mattos, Renata Maciel; Sumita, Nairo Massakazu; Romano, Paschoalina; Mendes, Maria Elizabete; Nahas, William Carlos; Ianhez, Luiz Estevam

2004-02-01

New cyclosporine A (CsA) formulations must prove their bioequivalence to Neoral, the reference CsA formulation, to allow free prescription for the patients. The aim of this study was to compare the pharmacokinetics (PK) of a new CsA formulation (Zinograf-ME), produced by Strides-Arcolab, to Neoral and to demonstrate their interchangeability in stable renal transplant recipients. Twelve-hour PK studies were obtained from 18 (13 M/5 F) adult patients (mean age 44.7 +/- 12 years). They received their renal allografts from 13 cadaver and 5 living donors. Before enrollment, all patients were receiving a third generic CsA for a mean of 48 months. Nine patients were also under azathioprine and 9 under mycophenolate mofetil; 17 received prednisone. A single oral dose of either Zinograf or Neoral was administered. The first PK study was performed with one formulation, and 1 week later, a second PK was done with the other formulation. During the washout period, patients continued taking the third CsA formulation. The drug substitution was done milligram-for-milligram. The CsA whole-blood level was measured by TDx immunoassay. Mean +/- SD of area under the curve (AUC), maximum concentration (C(max)), and concentration at the second hour (C2) of Zinograf were not statistically different from those with Neoral (4019 +/- 1466 vs 3971 +/- 1325 ng x h/mL, 998 +/- 376 vs 1021 +/- 356 ng/mL, and 707 +/- 254 vs 734 +/- 229 ng/mL, respectively). In the same way, the Zinograf 90% confidence interval for either C(max) (-123, +77 ng/mL) or AUC (-214, +311 ng.mL/h) were within the Neoral bioequivalence interval for the same parameters (+/-204 ng/mL and +/-794 ng x mL/h, respectively). These data demonstrate that the ZinografME CsA formulation is bioequivalent to Neoral.

Clinical trial: a multicentre, randomized, double-blind, placebo-controlled, dose-finding, phase II study of subcutaneous interferon-beta-1a in moderately active ulcerative colitis

DEFF Research Database (Denmark)

Pena-Rossi, C; Schreiber, S; Golubovic, G

2008-01-01

Background Ulcerative colitis (UC) pathophysiology is characterized by an imbalance between pro- and anti-inflammatory cytokines. Interferon (IFN)-beta-1a has potent immunoregulatory properties, including stimulation of host defence mechanisms, and thus represents a potential treatment. Aim...

Pulmonary delivery of influenza vaccine formulations in cotton rats: site of deposition plays a minor role in the protective efficacy against clinical isolate of H1N1pdm virus.

Science.gov (United States)

Bhide, Yoshita; Tomar, Jasmine; Dong, Wei; de Vries-Idema, Jacqueline; Frijlink, Henderik W; Huckriede, Anke; Hinrichs, Wouter L J

2018-11-01

Administration of influenza vaccines to the lungs could be an attractive alternative to conventional parenteral administration. In this study, we investigated the deposition site of pulmonary delivered liquid and powder influenza vaccine formulations and its relation to their immunogenicity and protective efficacy. In vivo deposition studies in cotton rats revealed that, the powder formulation was mainly deposited in the trachea ( ∼ 65%) whereas the liquid was homogenously distributed throughout the lungs ( ∼ 96%). In addition, only 60% of the antigen in the powder formulation was deposited in the respiratory tract with respect to the liquid formulation. Immunogenicity studies showed that pulmonary delivered liquid and powder influenza formulations induced robust systemic and mucosal immune responses (significantly higher by liquids than by powders). When challenged with a clinical isolate of homologous H1N1pdm virus, all animals pulmonary administered with placebo had detectable virus in their lungs one day post challenge. In contrast, none of the vaccinated animals had detectable lung virus titers, except for two out of eight animals from the powder immunized group. Also, pulmonary vaccinated animals showed no or little signs of infection like increase in breathing frequency or weight loss upon challenge as compared to animals from the negative control group. In conclusion, immune responses induced by liquid formulation were significantly higher than responses induced by powder formulation, but the overall protective efficacy of both formulations was comparable. Thus, pulmonary immunization is capable of inducing protective immunity and the site of antigen deposition seems to be of minor relevance in inducing protection.

Clinical trial: a multicentre, randomized, double-blind, placebo-controlled, dose-finding, phase II study of subcutaneous interferon-beta-1a in moderately active ulcerative colitis

DEFF Research Database (Denmark)

Pena-Rossi, C; Schreiber, S; Golubovic, G

2008-01-01

Background Ulcerative colitis (UC) pathophysiology is characterized by an imbalance between pro- and anti-inflammatory cytokines. Interferon (IFN)-beta-1a has potent immunoregulatory properties, including stimulation of host defence mechanisms, and thus represents a potential treatment. Aim To ex...

Is serum neopterin level a marker of responsiveness to interferon beta-1a therapy in multiple sclerosis?

Science.gov (United States)

Casoni, F; Merelli, E; Bedin, R; Sola, P; Bertolotto, A; Faglioni, P

2004-01-01

Interferon beta (INFbeta) may induce the expression of several proteins, including neopterin, considered a biological marker of INFbeta activity. The aim of this study was to determine the serum neopterin concentration at the beginning of, and during, IFNbeta-1a therapy in relapsing-remitting multiple sclerosis (r-r MS) patients, and to look for a possible correlation between protein synthesis and the clinical course of the disease. Thirteen r-r MS patients were treated with INFbeta-1a (i.m. 6 MIU/week) for 2 years. Blood samples for neopterin determinations were taken daily over a period of 1 week at the end of each 6 months of therapy, and tested for neutralizing antibodies (NABs). Neopterin levels peaked 24-48 h post-injection and returned to baseline after 120 h. After 1 year of therapy, four patients dropped out of the study because of progression of the disease: in these subjects a significant decrement of neopterin was observed. Neopterin baseline values were not found to decrease over the 2 years of therapy, and neopterin may be considered to be a useful marker of responsiveness to IFNbeta.

Pharmacokinetics and pharmacodynamics of the injectable formulation of methadone hydrochloride and methadone in lipid nanocarriers administered orally to horses.

Science.gov (United States)

Crosignani, N; Luna, S P; Dalla Costa, T; Pimenta, E L; Detoni, C B; Guterres, S S; Puoli Filho, J N; Pantoja, J C; Pigatto, M C

2017-08-01

We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and abdominal auscultation score), and pharmacokinetics, of 0.5 mg/kg of the injectable formulation (ORAL) or nanoparticulated methadone (NANO) given orally, in six adult mares, using a crossover, blind and prospective design. Repeated-measure models were used to compare parametric data between and within treatments, followed by Tukey's test. Nonparametric data were analysed with Wilcoxon signed-rank, adjusted by Bonferroni tests. Blood samples were also collected up to 6 h after dosing for plasma drug quantification by LC-MS/MS. Methadone pharmacokinetic parameters were determined by noncompartmental and compartmental approaches. There were no differences in pharmacodynamic parameters. No statistical differences were observed in the pharmacokinetic parameters from noncompartmental analysis for both groups, except a significant decrease in peak plasma concentration, increase in apparent volume of distribution per fraction absorbed (Vd ss /F) and increased mean residence time (MRT) for NANO. One-compartment open model with first order elimination best described the pharmacokinetic profiles for both groups. Neither ORAL nor NANO administered orally to horses produced antinociception. The nanoencapsulated formulation of methadone given orally to horses did not improve methadone pharmacokinetic parameters or increased systemic body exposure to methadone. © 2017 John Wiley & Sons Ltd.

Preparation of radiopharmaceutical formulations

International Nuclear Information System (INIS)

Simon, J.; Garlich, J.R.; Frank, R.K.; McMillan, K.

1998-01-01

Radiopharmaceutical formulations for complexes comprising at least one radionuclide complexed with a ligand, or its physiologically-acceptable salts thereof, especially 153 samarium-ethylenediaminetetramethylenephosphonic acid, which optionally contains a divalent metal ion, e.g. calcium, and is frozen, thawed, and then administered by injection. Alternatively, the radiopharmaceutical formulations must contain the divalent metal and are frozen only if the time before administration is sufficiently long to cause concern for radiolysis of the ligand. 2 figs., 9 tabs

Increased IL-10 mRNA and IL-23 mRNA expression in multiple sclerosis

DEFF Research Database (Denmark)

Krakauer, Martin; Sorensen, P; Khademi, M

2008-01-01

BACKGROUND: Interferon (IFN)-beta therapy in multiple sclerosis (MS) has been suggested to promote a deviation from T lymphocyte production of pathogenic Th1 cytokines to less detrimental Th2 cytokines, but this is still controversial. We studied patterns of in vivo blood mononuclear cell (MNC...... of any Th1 or Th2 cytokines. The largest changes in cytokine mRNA levels occurred early (~9-12 h) after an IFN-beta injection. CONCLUSION: We found no evidence of a Th1- or Th2-mRNA-promoting effect of IFN-beta therapy. The therapeutic effect of IFN-beta is more likely attributable to the induction...

A gamma scintigraphic study of gastric coating by Expidet, tablet and liquid formulations

International Nuclear Information System (INIS)

Washington, N.; Wilson, C.G.; Greaves, J.L.; Norman, S.

1989-01-01

The gastric residence time and gastric coating properties of 10 mg of radiolabelled micronised resin incorporated into Expidet formulations, chewable tablets and 10 ml of a liquid formulation were measued by gamma scintigraphy in twelve fasted, healthy subjects. All preparations emptied from the stomach in a similar manner for the first 1.5 h; however, the final 10% of the activity from the Expidet formulation emptied considerably more slowly than the initial phase. The total mean gastric emptying times for the three formulations were 2.3, 2.5 and 5.5 h for the tablet, liquid and Expidet formulation, respectively. The amount of activity following administration of the table or Expidet formulation was the same in the three regions of the stomach, but the coating of the mucosa by the Expidet formulation within each area was observed to be more uniform due to the greater dispersion of the dose form. The table broke up into a number of small discrete pieces. The gastric residence time of 99m Tc-labelled resin delivered in an Expidet formulation is significantly longer than the same marker administered in a table or in 10 ml of a liquid formulation. Moreover, coating of the gastric mucosa was more uniform with the Expidet formulation than the other two formulations studied. (author) 10 refs.; 6 figs

Bioequivalence of a new liquid formulation of benazepril compared with the reference tablet product.

Science.gov (United States)

Kelers, K; Devi, J L; Anderson, G A; Zahra, P; Vine, J H; Whittem, T

2013-08-01

To compare the bioequivalence and 'switchability' of two formulations of benazepril (tablet and liquid) after oral administration. Randomised cross-over design, followed by parallel comparison. Twelve mixed-breed dogs were administered either a tablet (Group A) or liquid formulation (Group B) of benazepril orally at 0.45 mg/kg daily for 4 days. With no washout period, the dogs then received the alternative treatment at the same dose for a further 4 days. Blood samples taken prior to treatment and serially after treatment were analysed for plasma concentrations of benazepril and benazeprilat and the activity and concentration of angiotensin-converting enzyme (ACE). The calculated percentage inhibition of ACE was defined as the primary outcome variable. No statistically significant differences were found between groups A and B for any variable evaluated. The mean (± SD) percentage of ACE inhibition was 85.5 ± 7.04% for the liquid formulation and 85.9 ± 6.66% for the tablet formulation. The mean of the ratios was 1.00 (80% confidence interval 0.96-1.04). No evaluated effect term (sequence, formulation or period) had any statistical effect on any outcome variable. This study supports a conclusion that, based on pharmacodynamic response, the liquid formulation of benazepril is bioequivalent to the reference tablet formulation. Further, the lack of a sequence effect supports the switchability of these two formulations. © 2013 Australian Veterinary Association.

Interferon-beta treatment associated with a biochemical profile suggestive of acromegaly. A case report of a patient treated for multiple sclerosis

DEFF Research Database (Denmark)

Andreassen, Mikkel; Frystyk, Jan; Miller, K.K.

2010-01-01

We describe a 34-year-old female treated with IFN-beta for 8 years with a biochemical profile suggestive of acromegaly. The patient presented with elevated serum insulin-like growth factor-I (IGF-I) and insufficient suppression of growth hormone (GH) during oral glucose tolerance test (OGTT......). There were no clinical features of acromegaly. A 5-day profile showed higher GH levels on the 3 days following IFN-beta injections. Total and bioactive IGF-I were also elevated but did not fluctuate. Four weeks off IFN-beta normalized suppression of GH during OGTT but did not reduce serum IGF-I or bioactive...... IGF-I. In conclusion, IFN-beta treatment mimicked acromegaly biochemically. The changes were partially reversible...

Wound Healing Activity of a New Formulation from Platelet Lysate

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Akram Jamshidzadeh

2016-03-01

Full Text Available Platelet-rich plasma (PRP is an attractive preparation in regenerative medicine due to its potential role in the healing process in different experimental models. This study was designed to investigate the wound healing activity of a new formulation of PRP. Different gel-based formulations of PRP were prepared. Open excision wounds were made on the back of male Sprague-Dawley rats, and PRP gel was administered topically once daily until the wounds healed completely (12 days. The results revealed that the tested PRP formulation significantly accelerated the wound healing process by increasing the wound contraction, tissue granulization, vascularization, and collagen regeneration. Interestingly, this study showed that there were no significant differences between the PRP and its gel-based formulation in all the above mentioned parameters. Although this investigation showed that PRP formulation had significant wound healing effects, the PRP gel-based formulation also had significant wound healing properties. This might indicate the wound healing properties of the PRP gel ingredients in the current investigation.

SO(9,1) invariant matrix formulation of a supermembrane

International Nuclear Information System (INIS)

Fujikawa, K.; Okuyama, K.

1998-01-01

An SO(9,1) invariant formulation of an 11-dimensional supermembrane is presented by combining an SO(10,1) invariant treatment of reparametrization symmetry with an SO(9,1) invariant θ R = 0 gauge of κ-symmetry. The Lagrangian thus defined consists of polynomials in dynamical variables (up to quartic terms in X μ and up to the eighth power in θ), and reparametrization BRST symmetry is manifest. The area preserving diffeomorphism is consistently incorporated and the area preserving gauge symmetry is made explicit. The SO(9,1) invariant theory contains terms which cannot be induced by a naive dimensional reduction of higher-dimensional supersymmetric Yang-Mills theory. The SO(9,1) invariant Hamiltonian and the generator of area preserving diffeomorphism together with the supercharge are matrix regularized by applying the standard procedure. As an application of the present formulation, we evaluate the possible central charges in superalgebra both in the path integral and in the canonical (Dirac) formalism, and we find only the two-form charge [ X μ , X ν ]. (orig.)

Preclinical evaluation of nephroprotective potential of a probiotic formulation LOBUN on Cyclosporine-A induced renal dysfunction in Wistar rats

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Kambham Venkateswarlu

2017-06-01

Full Text Available ABSTRACT The aim of present study was to evaluate the nephroprotective effect of probiotic formulation LOBUN on Cyclosporine A (CsA induced renal dysfunction in Wistar rats. CsA (20 mg/kg body weight s.c was administered for 15 days to cause renal dysfunction in Wistar rats. The probiotic formulation LOBUN was administered with the dose of 500 mg/kg body weight (p.o for twice (TGI and thrice a day (TGII. The samples were analyzed for the parameters like blood urine nitrogen (BUN, serum creatinine, serum uric acid, total serum protein and urine proteins, urine potassium, urine sodium. The renal functional and histopathological studies revealed that the oral administration of probiotic formulation LOBUN has provided appreciable renoprotection and possibly alleviated the symptoms of Chronic Kidney Disease (CKD at the dose of 500 mg/kg body weight administered thrice a day and also the results were supported by histopathological findings.

Vozy formule 1

OpenAIRE

Zbožínek, Adam

2009-01-01

Tato práce uvádí základní pravidla a předpoklady pro konstrukci a použití vozů formule 1. Hlavní zaměření je na aerodynamiku, která je nejdůležitější disciplínou v tomto motoristickém sportu, dále je tato práce zaměřena na základní faktory týkající se motoru vozu, kol, nové technologie KERS a provedení volantu. This work shows basic rules and conditions for construction and use of cars formula 1. The main part of this work focus on the aerodynamics which is the most important discipline of...

New tablet formulation of tacrolimus with smaller interindividual variability may become a better treatment option than the conventional capsule formulation in organ transplant patients

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Kim YK

2017-09-01

Full Text Available Yu Kyong Kim,1 Anhye Kim,1,2 Shin Jung Park,3 Howard Lee1,4 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, 2Clinical Trial Center, Ajou University Medical Center, Suwon, 3Research Institute, Chong Kun Dang Pharmaceutical Corp, Yongin, 4Department of Transdisciplinary Studies, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Republic of Korea Abstract: To evaluate the pharmacokinetic (PK and tolerability profiles of a new tablet formulation of tacrolimus and its interindividual variability (IIV in the systemic exposure, and to compare them with those of the conventional capsule formulation, a randomized, open-label, two-treatment, two-period, two-sequence, crossover study was performed in 47 healthy males. The capsule or tablet formulation of tacrolimus was orally administered, and serial blood samples were collected up to 96 hours after dosing. Whole-blood tacrolimus concentration was determined using liquid chromatography–tandem mass spectrometry. The maximum whole-blood tacrolimus concentration (Cmax and the area under the whole-blood tacrolimus concentration–time curve from 0 hour to the last quantifiable concentration (AUClast were compared between the two formulations. The similarity factor (f2 of the in vitro dissolution profiles was calculated. The geometric mean ratio (90% confidence interval of tablet to capsule was 0.9680 (0.8873–1.0560 and 1.0322 (0.9359–1.1385 for Cmax and AUClast, respectively. The IIV of Cmax and AUClast of the tablet was smaller than the capsule. The f2 values were >50 in all media. Both formulations were well tolerated. Thus, the tablet formulation of tacrolimus has smaller IIV in the systemic exposure than capsule, while having comparable PK and tolerability profiles, which may render it as a better treatment option for organ transplant patients. Keywords: new formulation, incrementally

Audits of radiopharmaceutical formulations

International Nuclear Information System (INIS)

Castronovo, F.P. Jr.

1992-01-01

A procedure for auditing radiopharmaceutical formulations is described. To meet FDA guidelines regarding the quality of radiopharmaceuticals, institutional radioactive drug research committees perform audits when such drugs are formulated away from an institutional pharmacy. All principal investigators who formulate drugs outside institutional pharmacies must pass these audits before they can obtain a radiopharmaceutical investigation permit. The audit team meets with the individual who performs the formulation at the site of drug preparation to verify that drug formulations meet identity, strength, quality, and purity standards; are uniform and reproducible; and are sterile and pyrogen free. This team must contain an expert knowledgeable in the preparation of radioactive drugs; a radiopharmacist is the most qualified person for this role. Problems that have been identified by audits include lack of sterility and apyrogenicity testing, formulations that are open to the laboratory environment, failure to use pharmaceutical-grade chemicals, inadequate quality control methods or records, inadequate training of the person preparing the drug, and improper unit dose preparation. Investigational radiopharmaceutical formulations, including nonradiolabeled drugs, must be audited before they are administered to humans. A properly trained pharmacist should be a member of the audit team

Efficacies of Gel Formulations Containing Foscarnet, Alone or Combined with Sodium Lauryl Sulfate, against Establishment and Reactivation of Latent Herpes Simplex Virus Type 1

Science.gov (United States)

Piret, Jocelyne; Lamontagne, Julie; Désormeaux, André; Bergeron, Michel G.

2001-01-01

The influence of sodium lauryl sulfate (SLS) on the efficacies of gel formulations of foscarnet against herpes simplex virus type 1 (HSV-1) cutaneous lesions and on the establishment and reactivation of latent virus has been evaluated in a murine model of orofacial infection. Topical treatments were given twice daily for 3 days and were initiated at 6, 24, and 48 h after virus inoculation. The gel formulation that contained both 3% foscarnet and 5% SLS and that was administered within 48 h postinfection reduced the rate of development of herpetic skin lesions. This formulation also significantly decreased the viral content in skin tissues and in ipsilateral trigeminal ganglia when it was given within 24 and 6 h postinfection, respectively. A lower level of efficacy was observed for the gel formulation containing 3% foscarnet alone. Of prime interest, the gel formulation containing 5% SLS reduced significantly the mortality rate among mice in a zosteriform model of infection. Both formulations of foscarnet had no effect on the mean titers of reactivated virus in explant cultures of ipsilateral and contralateral trigeminal ganglia from latently infected mice. The use of a gel formulation containing combinations of foscarnet and SLS could represent an attractive approach for the treatment of herpetic mucocutaneous infections. PMID:11257012

Application of a Compact Magnetic Resonance Imaging System with 1.5 T Permanent Magnets to Visualize Release from and the Disintegration of Capsule Formulations in Vitro and in Vivo.

Science.gov (United States)

Takeshita, Keizo; Okazaki, Shoko; Shinada, Kyosuke; Shibamoto, Yuma

2017-01-01

Although magnetic resonance imaging (MRI) has potential in assessments of formulations, few studies have been conducted because of the size and expense of the instrument. In the present study, the processes of in vitro and in vivo release in a gelatin capsule formulation model were visualized using a compact MRI system with 1.5 T permanent magnets, which is more convenient than the superconducting MRI systems typically used for clinical and experimental purposes. A Gd-chelate of diethylenetriamine-N,N,N',N″,N″-pentaacetic acid, a contrast agent that markedly enhances proton signals via close contact with water, was incorporated into capsule formulations as a marker compound. In vitro experiments could clearly demonstrate the preparation-dependent differences in the release/disintegration of the formulations. In some preparations, the penetration of water into the formulation and generation of bubbles in the capsule were also observed prior to the disintegration of the formulation. When capsule formulations were orally administered to rats, the release of the marker into the stomach and its transit to the duodenum were visualized. These results strongly indicate that the compact MRI system is a powerful tool for pharmaceutical studies.

Beneficial Effects of Long-Term Administration of an Oral Formulation of Angiotensin-(1–7 in Infarcted Rats

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Fúlvia D. Marques

2012-01-01

Full Text Available In this study was evaluated the chronic cardiac effects of a formulation developed by including angiotensin(Ang-(1–7 in hydroxypropyl β-cyclodextrin (HPβCD, in infarcted rats. Myocardial infarction (MI was induced by left coronary artery occlusion. HPβCD/Ang-(1–7 was administered for 60 days (76 μg/Kg/once a day/gavage starting immediately before infarction. Echocardiography was utilized to evaluate usual cardiac parameters, and radial strain method was used to analyze the velocity and displacement of myocardial fibers at initial time and 15, 30, and 50 days after surgery. Real-time PCR was utilized to evaluate the fibrotic signaling involved in the remodeling process. Once-a-day oral HPβCD/Ang-(1–7 administration improved the cardiac function and reduced the deleterious effects induced by MI on TGF-β and collagen type I expression, as well as on the velocity and displacement of myocardial fibers. These findings confirm cardioprotective effects of Ang-(1–7 and indicate HPβCD/Ang-(1–7 as a feasible formulation for long-term oral administration of this heptapeptide.

Serum IFN neutralizing antibodies and neopterin levels in a cross-section of MS patients.

Science.gov (United States)

Cook, S D; Quinless, J R; Jotkowitz, A; Beaton, P

2001-09-25

To determine levels of serum interferon beta (IFNbeta) neutralizing antibody (NAb) and neopterin-an IFN biologic response marker-in patients with MS treated with Betaseron or Avonex. Controversy exists over the relative immunogenicity of IFNbeta-1a and IFNbeta-1b and the reasons for any such difference. To determine the role of patient profile and test methodology in IFNbeta, NAb levels need to be measured blindly and simultaneously in a predefined closely matched MS patient cohort. Serum NAb and neopterin levels were measured in closely matched patients on Avonex (n = 98) or Betaseron (n = 64). NAb were determined by Athena Diagnostics and serum neopterin levels by Covance Laboratories using a competitive binding radioimmunoassay. More patients taking Betaseron (22%) than Avonex (7%) had elevated titers of NAb (p = 0.008). Mean serum neopterin levels were lower in patients with high as compared to low NAb titers (p = 0.0002). No difference in mean neopterin levels was found comparing the total Betaseron group to the Avonex group; however, in the subset of patients with low NAb titers, mean neopterin levels were higher in the Betaseron than in the Avonex group (p = 0.027). A random cross-sectional sampling of patients on Avonex showed a decrease in neopterin levels over time between weekly doses. NAb are more commonly found with Betaseron than Avonex. More studies are needed to determine the correlation among serum neopterin levels, other biologic response markers, NAb, and disease activity in patients with MS being treated with IFNbeta.

Pharmacokinetics of the injectable formulation of methadone hydrochloride administered orally in horses.

Science.gov (United States)

Linardi, R L; Stokes, A M; Barker, S A; Short, C; Hosgood, G; Natalini, C C

2009-10-01

Methadone hydrochloride is a synthetic mu-opioid receptor agonist with potent analgesic properties. Oral methadone has been successfully used in human medicine and may overcome some limitations of other analgesics in equine species for producing analgesia with minimal adverse effects. However, there are no studies describing the pharmacokinetics (PK) of oral opioids in horses. The aim of this study was to describe the PK of orally administered methadone (0.1, 0.2 and 0.4 mg/kg) and physical effects in 12 healthy adult horses. Serum methadone concentrations were measured by gas chromatography/mass spectrometry at predetermined time points for 24 h, and PK parameters were estimated using a noncompartmental model. Physical effects were observed and recorded by experienced clinicians. No drug toxicity, behavioural or adverse effects were observed in the horses. The disposition of methadone followed first order elimination and a biphasic serum profile with rapid absorption and elimination phases. The PK profile of methadone was characterized by high clearance (Cl/F), small volume of distribution (V(d)/F) and short elimination half-life (t(1/2)). The mean of the estimated t(1/2) (SD) for each dose (0.1, 0.2 and 0.4 mg/kg) was 2.2 (35.6), 1.3 (46.1) and 1.5 (40.8), and the mean for the estimated C(max) (SD) was 33.9 (6.7), 127.9 (36.0) and 193.5 (65.8) respectively.

Reversal of methylation silencing of Apo2L/TRAIL receptor 1 (DR4) expression overcomes resistance of SK-MEL-3 and SK-MEL-28 melanoma cells to interferons (IFNs) or Apo2L/TRAIL.

Science.gov (United States)

Bae, S I; Cheriyath, V; Jacobs, B S; Reu, F J; Borden, E C

2008-01-17

Human melanoma cell lines, SK-MEL-3 and SK-MEL-28, despite induction of the proapoptotic cytokine, Apo2L/TRAIL, did not undergo apoptosis in response to interferons (IFN-alpha2b or IFN-beta). Postulating that genes important for apoptosis induction by IFNs might be silenced by methylation, the DNA demethylating agent 5-aza-2'-deoxycytidine (5-AZAdC) was assessed. DR4 (TRAIL-R1) was identified as one of the genes reactivated by 5-AZAdC with a >3-fold increase in 8 of 10 melanoma cell lines. Pretreatment with 5-AZAdC sensitized SK-MEL-3 and SK-MEL-28 cells to apoptosis induced by IFN-alpha2b and IFN-beta; methylation-specific PCR and bisulfite sequencing confirmed demethylation of 5'CpG islands of DR4 and flow cytometry showed an increase in DR4 protein on the cell surface. In cells with reactivated DR4, neutralizing mAB to TRAIL reduced apoptosis in response to IFN-beta or Apo2L/TRAIL. To further confirm the role of DR4, it was expressed by retroviral vector in SK-MEL-3 and SK-MEL-28 cells with reversal of resistance to IFN-beta and Apo2L/TRAIL. Thus, reexpressing DR4 by 5-AZAdC or retroviral transfection in melanoma cell in which promoter methylation had suppressed its expression, potentiated apoptosis by IFN-alpha2b, IFN-beta and Apo2L/TRAIL. Reactivation of silenced proapoptotic genes by inhibitors of DNA methylation may enhance clinical response to IFNs or Apo2L/TRAIL.

Bioavailability of everolimus administered as a single 5 mg tablet versus five 1 mg tablets: a randomized, open-label, two-way crossover study of healthy volunteers.

Science.gov (United States)

Thudium, Karen; Gallo, Jorge; Bouillaud, Emmanuel; Sachs, Carolin; Eddy, Simantini; Cheung, Wing

2015-01-01

The mammalian target of rapamycin (mTOR) inhibitor everolimus has a well-established pharmacokinetics profile. We conducted a randomized, single-center, open-label, two-sequence, two-period crossover study of healthy volunteers to assess the relative bioavailability of everolimus administered as one 5 mg tablet or five 1 mg tablets. Subjects were randomized 1:1 to receive everolimus dosed as one 5 mg tablet or as five 1 mg tablets on day 1, followed by a washout period on days 8-14 and then the opposite formulation on day 15. Blood sampling for pharmacokinetic evaluation was performed at prespecified time points, with 17 samples taken for each treatment period. Primary variables for evaluation of relative bioavailability were area under the concentration-time curve from time zero to infinity (AUCinf) and maximum blood concentration (Cmax). Safety was assessed by reporting the incidence of adverse events (AEs). Twenty-two participants received everolimus as one 5 mg tablet followed by five 1 mg tablets (n=11) or the opposite sequence (n=11). The Cmax of five 1 mg tablets was 48% higher than that of one 5 mg tablet (geometric mean ratio, 1.48; 90% confidence interval [CI], 1.35-1.62). AUCinf was similar (geometric mean ratio, 1.08; 90% CI, 1.02-1.16), as were the extent of absorption and the distribution and elimination kinetics. AEs, all grade 1 or 2, were observed in 54.5% of subjects. Although the extent of absorption was similar, the Cmax of five 1 mg tablets was higher than that of one 5 mg tablet, suggesting these formulations lead to different peak blood concentrations and are not interchangeable at the dose tested.

34 CFR 461.1 - What is the Adult Education State-administered Basic Grant Program?

Science.gov (United States)

2010-07-01

... 34 Education 3 2010-07-01 2010-07-01 false What is the Adult Education State-administered Basic...-ADMINISTERED BASIC GRANT PROGRAM General § 461.1 What is the Adult Education State-administered Basic Grant Program? The Adult Education State-administered basic Grant Program (the program) is a cooperative effort...

Pharmacokinetics of Short- and Long-acting Formulations of Oxytetracycline After Intramuscular Administration in Chickens.

Science.gov (United States)

Gberindyer, Aondover F; Okpeh, Ene R; Semaka, Asaaga A

2015-12-01

Both short- and long-acting formulations of oxytetracycline are commonly used in veterinary medicine to treat animals infected with gram-negative and gram-positive bacteria, rickettsiae, mycoplasma, and chlamydiae. To compare pharmacokinetics of short- and long-acting oxytetracycline in chickens, injectable formulations from the same pharmaceutical company were administered to healthy 6-week-old broiler chickens in accordance to the labeled instructions. Fourteen chickens were separated into 2 groups: chickens in group A (n = 7) were administered the short-acting formulation (10 mg/kg IM q24h) for 4 consecutive days, whereas those in group B (n = 7) were treated with a single dose (20 mg/kg IM) of the long-acting formulation. Blood samples were collected into heparinized tubes before and at 0.25, 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 24 hours after initial treatment. Thereafter, blood samples were taken every 24 hours up to 120 hours. Plasma concentrations of oxytetracycline were determined by competitive enzyme-linked immunoabsorbent assay, and pharmacokinetic parameters were obtained. Both formulations delivered therapeutic plasma concentrations of oxytetracycline for approximately 100% of their respective dosing intervals as recommended. However, considering the additional labor, patient stress, and mortalities associated with handling, in addition to rejection of the carcass due to tissue necrosis resulting from multiple injections, we recommend use of the long-acting instead of the short-acting injectable formulation in broiler chickens.

Antinociception by systemically-administered acetaminophen (paracetamol) involves spinal serotonin 5-HT7 and adenosine A1 receptors, as well as peripheral adenosine A1 receptors.

Science.gov (United States)

Liu, Jean; Reid, Allison R; Sawynok, Jana

2013-03-01

Acetaminophen (paracetamol) is a widely used analgesic, but its sites and mechanisms of action remain incompletely understood. Recent studies have separately implicated spinal adenosine A(1) receptors (A(1)Rs) and serotonin 5-HT(7) receptors (5-HT(7)Rs) in the antinociceptive effects of systemically administered acetaminophen. In the present study, we determined whether these two actions are linked by delivering a selective 5-HT(7)R antagonist to the spinal cord of mice and examining nociception using the formalin 2% model. In normal and A(1)R wild type mice, antinociception by systemic (i.p.) acetaminophen 300mg/kg was reduced by intrathecal (i.t.) delivery of the selective 5-HT(7)R antagonist SB269970 3μg. In mice lacking A(1)Rs, i.t. SB269970 did not reverse antinociception by systemic acetaminophen, indicating a link between spinal 5-HT(7)R and A(1)R mechanisms. We also explored potential roles of peripheral A(1)Rs in antinociception by acetaminophen administered both locally and systemically. In normal mice, intraplantar (i.pl.) acetaminophen 200μg produced antinociception in the formalin test, and this was blocked by co-administration of the selective A(1)R antagonist DPCPX 4.5μg. Acetaminophen administered into the contralateral hindpaw had no effect, indicating a local peripheral action. When acetaminophen was administered systemically, its antinociceptive effect was reversed by i.pl. DPCPX in normal mice; this was also observed in A(1)R wild type mice, but not in those lacking A(1)Rs. In summary, we demonstrate a link between spinal 5-HT(7)Rs and A(1)Rs in the spinal cord relevant to antinociception by systemic acetaminophen. Furthermore, we implicate peripheral A(1)Rs in the antinociceptive effects of locally- and systemically-administered acetaminophen. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

An exploratory, randomized, parallel-group, open-label, relative bioavailability study with an additional two-period crossover food-effect study exploring the pharmacokinetics of two novel formulations of pexmetinib (ARRY-614

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Wollenberg LA

2015-09-01

Full Text Available Lance A Wollenberg,1 Donald T Corson,2,3 Courtney A Nugent,1 Farran L Peterson,1 Ann M Ptaszynski,1 Alisha Arrigo,2,3 Coralee G Mannila,2,3 Kevin S Litwiler,1 Stacie J Bell1,4 1Array BioPharma, Boulder, 2Array BioPharma, Longmont, CO, 3Avista Pharma Solutions, Longmont, CO, 4Mallinckrodt Pharmaceuticals, Ellicott City, MD, USA Background: Pexmetinib (ARRY-614 is a dual inhibitor of p38 mitogen-activated protein kinase and Tie2 signaling pathways implicated in the pathogenesis of myelodysplastic syndromes. Previous clinical experience in a Phase I dose-escalation study of myelodysplastic syndrome patients using pexmetinib administered as neat powder-in-capsule (PIC exhibited high variability in pharmacokinetics and excessive pill burden, prompting an effort to improve the formulation of pexmetinib. Methods: A relative bioavailability assessment encompassed three parallel treatment cohorts of unique subjects comparing the two new formulations (12 subjects per cohort, a liquid oral suspension (LOS and liquid-filled capsule (LFC and the current clinical PIC formulation (six subjects in a fasted state. The food-effect assessment was conducted as a crossover of the LOS and LFC formulations administered under fed and fasted conditions. Subjects were divided into two groups of equal size to evaluate potential period effects on the food-effect assessment. Results: The geometric mean values of the total plasma exposures based upon area-under-the-curve to the last quantifiable sample (AUClast of pexmetinib were approximately four- and twofold higher after administration of the LFC and LOS formulations, respectively, than after the PIC formulation, when the formulations were administered in the fasted state. When the LFC formulation was administered in the fed state, pexmetinib AUClast decreased by <5% compared with the fasted state. After administration of the LOS formulation in the fed state, pexmetinib AUClast was 34% greater than observed in the fasted

Design and formulation of nano-sized spray dried Efavirenz-Part 1: Influence of formulation parameters

CSIR Research Space (South Africa)

Tshweu, L

2012-10-01

Full Text Available to examine a seven factor system at two levels, as shown in Table 1. Table 1: Taguchi L8 experimental parameters and levels for preparation of PCL-EFV nanoparticles (NPs) Symbol Formulation parameters Levels 1 2 A W1 PVA PBS B Sugar Lactose...

Increased antigen presentation but impaired T cells priming after upregulation of interferon-beta induced by lipopolysaccharides is mediated by upregulation of B7H1 and GITRL.

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Fang Wang

Full Text Available Dendritic cells are able to present Ag-derived peptides on MHC class I and II molecules and induce T cells priming. Lipopolysaccharides (LPS, an activator of Toll-like 4 receptor (TLR4 signaling, has been demonstrated to facilitate Ag-presentation, up-regulate surface molecules expression but impair T cells priming. In this study, we investigated the effect of LPS on nicotine-enhanced DCs-dependent T cells priming and the mechanisms of LPS orchestrating the immunosuppressive program. We could demonstrate that the treatment with LPS resulted in increased surface molecules expression, enhanced Ag-presentation, up-regulated release of TGF-beta, TNF-alpha, IL-6, and IFN-beta. Concomititantly, the upregulation of IFN-beta in DCs induces the up-regulation of coinhibitory molecules B7H1 and GITRL, which cause an impaired activation of naïve Ag-specific T cells and the induction of T cell tolerance by enhancing B7H1-PD-1 interactions and promoting GITRL-GITL facilitated Treg generation, respectively. These data provide a mechanistic basis for the immunomodulatory action of IFN-beta which might open new possibilities in the development of therapeutic approaches aimed at the control of excessive immune response and persistent infection.

A randomised comparison of oral desmopressin lyophilisate (MELT) and tablet formulations in children and adolescents with primary nocturnal enuresis

DEFF Research Database (Denmark)

Lottmann, H; Froeling, F; Alloussi, S

2007-01-01

(MELT) vs. tablet treatment, and the efficacy, safety, compliance and ease of use associated with each formulation. In total, 221 patients aged 5-15 years who were already receiving desmopressin tablets were randomised 1 : 1 to receive desmopressin treatment in the order MELT/tablet (n = 110) or tablet....../MELT (n = 111) for 3 weeks each. Each formulation was administered in bioequivalent doses (0.2/0.4 mg tablets identical with 120/240 microg MELT). Following treatment, patients were questioned regarding treatment preference. Diary card data and 100 mm Visual Analogue Scale scores were also recorded....... RESULTS: Overall, patients preferred the MELT formulation to the tablet (56% vs. 44%; p = 0.112). This preference was age dependent (p = 0.006); patients aged

Clinical studies with oral lipid based formulations of poorly soluble compounds

DEFF Research Database (Denmark)

Fatouros, Dimitrios; Karpf, Ditte M; Nielsen, Flemming S

2007-01-01

. Several drug products intended for oral administration have been marketed utilizing lipid and surfactant based formulations. Sandimmune((R)) and Sandimmune Neoral((R)) (cyclosporin A, Novartis), Norvir((R)) (ritonavir), and Fortovase((R)) (saquinavir) have been formulated in self-emulsifying drug delivery...... systems (SEDDS). This review summarizes published pharmacokinetic studies of orally administered lipid based formulations of poorly aqueous soluble drugs in human subjects. Special attention has been paid to the physicochemical characteristics of the formulations, when available and the impact...

Cost effectiveness and budget impact of natalizumab in patients with relapsing multiple sclerosis.

Science.gov (United States)

Chiao, Evelyn; Meyer, Kellie

2009-06-01

Disease-modifying therapy (DMT) is the largest single-cost item that contributes to the total per-patient cost of multiple sclerosis (MS), a disabling disorder of the central nervous system. Natalizumab is the most recent DMT to be approved for the treatment of relapsing MS and may be an attractive alternative to interferon beta and glatiramer acetate (GA). To determine from the perspective of a United States payer (1) the incremental cost effectiveness of natalizumab compared with other DMTs and (2) the budgetary impact of utilization of natalizumab for the treatment of relapsing MS. A combined cost effectiveness and budget impact model was developed. Model inputs were drug acquisition costs (wholesale acquisition cost), costs of drug administration and monitoring, costs of treating relapses, anticipated reduction in relapse rates after 2 years of therapy, and estimated market utilization of natalizumab. Outcomes included total 2-year costs of therapy per patient, costs per relapse avoided for each treatment, and overall 2-year costs to the health plan and per member per month (PMPM) costs. Drug acquisition costs are in 2008 US dollars, and all other costs were inflated to 2008 US dollars when necessary. Univariate sensitivity analyses were performed to determine the model inputs with the greatest influence on the cost per relapse avoided for natalizumab. The overall 2-year cost of therapy per patient was $72,120 for natalizumab, $56,790 for intramuscular (IM) interferon beta-1a (IFNbeta-1a), $56,773 for IFNbeta-1b, $57,180 for GA, and $58,538 for subcutaneous (SC) IFNbeta-1a. The cost per relapse avoided was lowest for natalizumab at $56,594, followed by $87,791 for IFNbeta-1b, $93,306 for IM IFNbeta-1a, $96,178 for SC IFNbeta-1a, and $103,665 for GA. The incremental cost-effectiveness ratios of natalizumab relative to IM IFNbeta-1a, IFNbeta-1b, GA, and SC IFNbeta-1a were $23,029, $24,452, $20,671, and $20,403 per additional relapse avoided, respectively. An

The effects of formulation on the immunostimulatory activity of dihydroheptaprenol.

Science.gov (United States)

Roth, James A; Hibbard, Beth; Frank, Dagmar E; Kesl, Lyle; Robb, Edward J

2002-01-01

Holstein steer calves received a single injection of Miglyol (Sasol Chemical Industries, Ltd.) subcutaneously as a placebo, dihydroheptaprenol (DHP) (4 mg/kg) emulsified with lecithin subcutaneously, DHP in solution in Miglyol (4 mg/kg) subcutaneously, or DHP in solution in Miglyol (4 mg/kg) intranasally. The DHP emulsified in lecithin emulsion administered subcutaneously caused a substantial increase in body temperature, total leukocyte count, total neutrophil count, neutrophil cytochrome-c reduction, and neutrophil iodination 24 hours after administration and, for some of the parameters, at 48 hours. The DHP formulation in Miglyol did not have any of these effects when administered subcutaneously or intranasally. The carrier and formulation of DHP apparently have major effects on the biologic activity of DHP.

In vivo release of bupivacaine from subcutaneously administered oily solution. Comparison with in vitro release

DEFF Research Database (Denmark)

Larsen, Dorrit Bjerg; Joergensen, Stig; Olsen, Niels Vidiendal

2002-01-01

A non-randomized cross-over study was performed with bupivacaine HCl (5 mg x ml(-1)) aqueous solution and bupivacaine free base (4.44 mg x ml(-1)) in Viscoleo/castor oil 2:1 (v/v) administered s.c. to male Wistar rats. Plasma levels were analyzed by LC-MS. Plasma profiles obtained after...... administration of oily solution showed a prolonged bupivacaine release with lower peak plasma levels as compared to administration of an aqueous formulation applied in the same compartment. t(1/2), t(max), C(max) and AUC(0-infinity) for the aqueous solution were 63+/-8 min, 19+/-16 min, 194+/-46 ng x ml(-1......) and 25,000+/-3000 ng min x ml(-1), respectively, while the corresponding data for the oil solution were 368+/-89 min, 334+/-186 min, 36+/-25 ng x ml(-1) and 25,000+/-6000 ng x min x ml(-1). The present data indicate the potential of designing an oil formulation of bupivacaine with a prolonged local...

Pharmacokinetic and Pharmacodynamic Characteristics of a New Pediatric Formulation of Artemether-Lumefantrine in African Children with Uncomplicated Plasmodium falciparum Malaria▿

OpenAIRE

Djimdé, Abdoulaye A.; Tekete, Mamadou; Abdulla, Salim; Lyimo, John; Bassat, Quique; Mandomando, Inacio; Lefèvre, Gilbert; Borrmann, Steffen

2011-01-01

The pharmacokinetic and pharmacodynamic properties of a new pediatric formulation of artemether-lumefantrine, dispersible tablet, were determined within the context of a multicenter, randomized, parallel-group study. In an exploratory approach, we compared a new pediatric formulation with the tablet formulation administered crushed in the treatment of African children with uncomplicated Plasmodium falciparum malaria. Patients were randomized to 3 different dosing groups (weights of 5 to

Gene expression analysis of interferon-beta treatment in multiple sclerosis

DEFF Research Database (Denmark)

Sellebjerg, F.; Datta, P.; Larsen, J.

2008-01-01

by treatment with IFN-beta. We use DNA microarrays to study gene expression in 10 multiple sclerosis (MS) patients who began de novo treatment with IFN-beta. After the first injection of IFN-beta, the expression of 74 out of 3428 genes changed at least two-fold and statistically significantly (after Bonferroni......Treatment with interferon-beta (IFN-beta) induces the expression of hundreds of genes in blood mononuclear cells, and the expression of several genes has been proposed as a marker of the effect of treatment with IFN-beta. However, to date no molecules have been identified that are stably induced...

Pharmacokinetics of a once-daily extended-release formulation of pramipexole in healthy male volunteers: three studies.

Science.gov (United States)

Jenner, Peter; Könen-Bergmann, Michael; Schepers, Cornelia; Haertter, Sebastian

2009-11-01

Pramipexole is a dopamine agonist used in the treatment of Parkinson's disease. The currently available immediate-release (IR) formulation is taken orally 3 times daily. These studies were conducted to evaluate the pharmacokinetic properties of a variety of prototypes for a once-daily extended-release (ER) formulation of pramipexole and to further characterize the prototype whose pharmacokinetics best matched those of the IR formulation. Three Phase I studies were conducted, all in healthy adult men aged food effect. In the third study, steady-state pharmacokinetics of the optimal ER formulation were assessed across a range of pramipexole doses (0.375-4.5 mg/d), including investigation of the food effect at steady state for the highest dose. Tolerability was assessed throughout all studies based on physical examinations, laboratory measurements, and adverse events (AEs). The 3 studies included 18, 15, and 39 subjects, respectively. Among the ER prototypes tested at 0.75 mg once daily in study 1, a matrix tablet had the optimal pharmacokinetic resemblance to IR pramipexole 0.25 mg TID, with a geometric mean AUC(0-24h,ss) of 17.4 ng.h/mL (vs 16.0 ng.h/mL for the IR formulation), C(max,ss) of 0.967 ng/mL (vs 1.09 ng/mL), and C(min,ss) of 0.455 ng/mL (vs 0.383 ng/mL). For single-dose ER 0.375 mg administered in the fasted state in study 2, in vivo bioavailability was predictable from in vitro dissolution data, with internal mean absolute percent prediction errors of 3.18% for AUC(0-30h) and 4.87% for C(max), and external mean absolute prediction errors of 6.61% and 3.34%, respectively, satisfying current guidelines for a level A IVIVC. For single-dose ER 0.375 mg administered in the fed state, the upper bound of the 90% CI for fed:fasted values was 119.8 for AUC(0-30h) (within the bioequivalence limits of 80%-125%) and 134.1 for C(max). At steady state in study 3 (subjects' 5th treatment day), dosing at 0.375 to 4.5 mg in the fasted state was associated with a linear

Preparation of radiopharmaceutical formulations; Fremstilling av radioaktive farmasoeytiske blandinger

Energy Technology Data Exchange (ETDEWEB)

Simon, J.; Garlich, J.R.; Frank, R.K.; McMillan, K

1998-03-16

Radiopharmaceutical formulations for complexes comprising at least one radionuclide complexed with a ligand, or its physiologically-acceptable salts thereof, especially {sup 153}samarium-ethylenediaminetetramethylenephosphonic acid, which optionally contains a divalent metal ion, e.g. calcium, and is frozen, thawed, and then administered by injection. Alternatively, the radiopharmaceutical formulations must contain the divalent metal and are frozen only if the time before administration is sufficiently long to cause concern for radiolysis of the ligand. 2 figs., 9 tabs.

A large, multicentre, observational, post-marketing surveillance study of the 2:1 formulation of follitropin alfa and lutropin alfa in routine clinical practice for assisted reproductive technology.

Science.gov (United States)

Bühler, Klaus; Naether, Olaf G J; Bilger, Wilma

2014-01-14

Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) both have a role to play in follicular development during the natural menstrual cycle. LH supplementation during controlled ovarian stimulation (COS) for assisted reproductive technology (ART) is used for patients with hypogonadotropic hypogonadism. However, the use of exogenous LH in COS in normogonadotropic women undergoing ART is the subject of debate. The aim of this study was to investigate characteristics of infertile women who received the 2:1 formulation of follitropin alfa and lutropin alfa (indicated for stimulation of follicular development in women with severe LH and FSH deficiency) in German clinical practice. A 3-year, multicentre, open-label, observational/non-interventional, post-marketing surveillance study of women (21-45 years) undergoing ART. Primary endpoint: reason for prescribing the 2:1 formulation of follitropin alfa and lutropin alfa. Secondary variables included: COS duration/dose; oocytes retrieved; fertilization; clinical pregnancy; ovarian hyperstimulation syndrome (OHSS). In total, 2220 cycles were assessed; at least one reason for prescribing the 2:1 formulation was given in 1834/2220 (82.6%) cycles. Most common reasons were: poor ovarian response (POR) (39.4%), low baseline LH (17.8%), and age (13.8%). COS: mean dose of the 2:1 formulation on first day, 183.1/91.5 IU; mean duration, 10.8 days. In 2173/2220 (97.9%) cycles, human chorionic gonadotrophin was administered. Oocyte pick-up (OPU) was attempted in 2108/2220 (95.0%) cycles; mean (standard deviation) 8.0 (5.4) oocytes retrieved/OPU cycle. Fertilization (≥1 oocyte fertilized) rates: in vitro fertilization (IVF), 391/439 (89.1%) cycles; intracytoplasmic sperm injection (ICSI)/IVF + ICSI, 1524/1613 (94.5%) cycles. Clinical pregnancy rate: all cycles, 25.9%; embryo transfer cycles, 31.3%. OHSS: hospitalization for OHSS, 8 (0.36%) cycles, Grade 2, 60 (2.7%), and Grade 3, 1 (0.05%). In German routine clinical

Bioequivalence assessment of two formulations of ibuprofen

Directory of Open Access Journals (Sweden)

Al-Talla ZA

2011-10-01

Full Text Available Zeyad A Al-Talla1, Sabah H Akrawi2, Luke T Tolley3, Salim H Sioud1, Mohammed F Zaater4, Abdul-Hamid M Emwas1 1Analytical and NMR Core Laboratories, King Abdullah University of Science and Technology, Thuwal, Kingdom of Saudia Arabia; 2College of Pharmacy, Al-Ain University, Al-Ain, United Arab Emirates; 3Department of Chemistry and Biochemistry, Southern Illinois University Carbondale, Carbondale, IL, USA; 4Department of Chemistry, Jordan University of Science and Technology, Jordan University of Science and Technology, Irbid, Jordan Background: This study assessed the relative bioavailability of two formulations of ibuprofen. The first formulation was Doloraz®, produced by Al-Razi Pharmaceutical Company, Amman, Jordan. The second forumulation was Brufen®, manufactured by Boots Company, Nottingham, UK. Methods and results: A prestudy validation of ibuprofen demonstrated long-term stability, freeze-thaw stability, precision, and accuracy. Twenty-four healthy volunteers were enrolled in this study. After overnight fasting, the two formulations (test and reference of ibuprofen (100 mg ibuprofen/5 mL suspension were administered as a single dose on two treatment days separated by a one-week washout period. After dosing, serial blood samples were drawn for a period of 14 hours. Serum harvested from the blood samples was analyzed for the presence of ibuprofen by high-pressure liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were determined from serum concentrations for both formulations. The 90% confidence intervals of the ln-transformed test/reference treatment ratios for peak plasma concentration and area under the concentration-time curve (AUC parameters were found to be within the predetermined acceptable interval of 80%–125% set by the US Food and Drug Administration. Conclusion: Analysis of variance for peak plasma concentrations and AUC parameters showed no significant difference between the two formulations and

Multiple excitation of supports - Part 1. Formulation

International Nuclear Information System (INIS)

Galeao, A.C.N.R.; Barbosa, H.J.C.

1980-12-01

The formulation and the solution of a simple specific problem of support movement are presented. The formulation is extended to the general case of infinitesimal elasticity where the approximated solutions are obtained by the variational formulation with spatial discretization by Finite Element Method. Finally, the present usual numerical techniques for the treatment of the resulting ordinary differential equations system are discused: Direct integration, Modal overlap, Spectral response. (E.G.) [pt

Accelerated Growth Programme with Polyherbal Formulations for Dairy Calves

Directory of Open Access Journals (Sweden)

K.Hadiya

2009-04-01

Full Text Available An experimental field study in approximately one month old, forty eight Jaffrabadi buffalo calves was carried out to evaluate efficacy of herbal formulations on growth & average daily gain. Calves were randomly divided into four groups, one control & three treatments. Treated groups were administered herbal formulations; Ruchamax, AV/DAC/16 @5gm/calf/day & Yakrifit @1 bolus/calf/day following treatment regimen of once a week per month for three consecutive months therapy. Growth related parameters were recorded for ninety days of experimental trial. It was observed that supplementation of herbal growth promoter & liver tonic products significantly improved liver function, feed assimilation & digestibility of ration ultimately leading to gain in body weight as compared to untreated control group. [Vet. World 2009; 2(2.000: 62-64

Development of formulation Q1As method for quadrupole noise prediction around a submerged cylinder

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Yo-Seb Choi

2017-09-01

Full Text Available Recent research has shown that quadrupole noise has a significant influence on the overall characteristics of flow-induced noise and on the performance of underwater appendages such as sonar domes. However, advanced research generally uses the Ffowcs Williams–Hawkings analogy without considering the quadrupole source to reduce computational cost. In this study, flow-induced noise is predicted by using an LES turbulence model and a developed formulation, called the formulation Q1As method to properly take into account the quadrupole source. The noise around a circular cylinder in an underwater environment is examined for two cases with different velocities. The results from the method are compared to those obtained from the experiments and the permeable FW–H method. The results are in good agreement with the experimental data, with a difference of less than 1 dB, which indicates that the formulation Q1As method is suitable for use in predicting quadrupole noise around underwater appendages.

Physiologically-based pharmacokinetic model of vaginally administered dapivirine ring and film formulations.

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Kay, Katherine; Shah, Dhaval K; Rohan, Lisa; Bies, Robert

2018-05-01

A physiologically-based pharmacokinetic (PBPK) model of the vaginal space was developed with the aim of predicting concentrations in the vaginal and cervical space. These predictions can be used to optimize the probability of success of vaginally administered dapivirine (DPV) for HIV prevention. We focus on vaginal delivery using either a ring or film. A PBPK model describing the physiological structure of the vaginal tissue and fluid was defined mathematically and implemented in MATLAB. Literature reviews provided estimates for relevant physiological and physiochemical parameters. Drug concentration-time profiles were simulated in luminal fluids, vaginal tissue and plasma after administration of ring or film. Patient data were extracted from published clinical trials and used to test model predictions. The DPV ring simulations tested the two dosing regimens and predicted PK profiles and area under the curve of luminal fluids (29 079 and 33 067 mg h l -1 in groups A and B, respectively) and plasma (0.177 and 0.211 mg h l -1 ) closely matched those reported (within one standard deviation). While the DPV film study reported drug concentration at only one time point per patient, our simulated profiles pass through reported concentration range. HIV is a major public health issue and vaginal microbicides have the potential to provide a crucial, female-controlled option for protection. The PBPK model successfully simulated realistic representations of drug PK. It provides a reliable, inexpensive and accessible platform where potential effectiveness of new compounds and the robustness of treatment modalities for pre-exposure prophylaxis can be evaluated. © 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Relative bioavailability of diclofenac potassium from softgel capsule versus powder for oral solution and immediate-release tablet formulation.

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Bende, Girish; Biswal, Shibadas; Bhad, Prafulla; Chen, Yuming; Salunke, Atish; Winter, Serge; Wagner, Robert; Sunkara, Gangadhar

2016-01-01

The oral bioavailability of diclofenac potassium 50 mg administered as a soft gelatin capsule (softgel capsule), powder for oral solution (oral solution), and tablet was evaluated in a randomized, open-label, 3-period, 6-sequence crossover study in healthy adults. Plasma diclofenac concentrations were measured using a validated liquid chromatography-mass spectrometry/mass spectrometry method, and pharmacokinetic analysis was performed by noncompartmental methods. The median time to achieve peak plasma concentrations of diclofenac was 0.5, 0.25, and 0.75 hours with the softgel capsule, oral solution, and tablet formulations, respectively. The geometric mean ratio and associated 90%CI for AUCinf, and Cmax of the softgel capsule formulation relative to the oral solution formulation were 0.97 (0.95-1.00) and 0.85 (0.76-0.95), respectively. The geometric mean ratio and associated 90%CI for AUCinf and Cmax of the softgel capsule formulation relative to the tablet formulation were 1.04 (1.00-1.08) and 1.67 (1.43-1.96), respectively. In conclusion, the exposure (AUC) of diclofenac with the new diclofenac potassium softgel capsule formulation was comparable to that of the existing oral solution and tablet formulations. The peak plasma concentration of diclofenac from the new softgel capsule was 67% higher than the existing tablet formulation, whereas it was 15% lower in comparison with the oral solution formulation. © 2015, The American College of Clinical Pharmacology.

Colon dysregulation in methamphetamine self-administering HIV-1 transgenic rats.

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Amanda L Persons

Full Text Available The integrity and function of the gut is impaired in HIV-infected individuals, and gut pathogenesis may play a role in several HIV-associated disorders. Methamphetamine is a popular illicit drug abused by HIV-infected individuals. However, the effect of methamphetamine on the gut and its potential to exacerbate HIV-associated gut pathology is not known. To shed light on this scenario, we evaluated colon barrier pathology in a rat model of the human comorbid condition. Intestinal barrier integrity and permeability were assessed in drug-naïve Fischer 344 HIV-1 transgenic (Tg and non-Tg rats, and in Tg and non-Tg rats instrumented with jugular cannulae trained to self-administer methamphetamine or serving as saline-yoked controls. Intestinal permeability was determined by measuring the urine content of orally gavaged sugars. Intestinal barrier integrity was evaluated by immunoblotting or immunofluorescence of colon claudin-1 and zonula occludens-1 (ZO-1, two major tight junction proteins that regulate gut epithelial paracellular permeability. Both non-Tg and Tg rats self-administered moderate amounts of methamphetamine. These amounts were sufficient to increase colon permeability, reduce protein level of claudin-1, and reduce claudin-1 and ZO-1 immunofluorescence in Tg rats relative to non-Tg rats. Methamphetamine decreased tight junction immunofluorescence in non-Tg rats, with a similar, but non-significant trend observed in Tg rats. However, the effect of methamphetamine on tight junction proteins was subthreshold to gut leakiness. These findings reveal that both HIV-1 proteins and methamphetamine alter colon barrier integrity, and indicate that the gut may be a pathogenic site for these insults.

Colon dysregulation in methamphetamine self-administering HIV-1 transgenic rats.

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Persons, Amanda L; Bradaric, Brinda D; Dodiya, Hemraj B; Ohene-Nyako, Michael; Forsyth, Christopher B; Keshavarzian, Ali; Shaikh, Maliha; Napier, T Celeste

2018-01-01

The integrity and function of the gut is impaired in HIV-infected individuals, and gut pathogenesis may play a role in several HIV-associated disorders. Methamphetamine is a popular illicit drug abused by HIV-infected individuals. However, the effect of methamphetamine on the gut and its potential to exacerbate HIV-associated gut pathology is not known. To shed light on this scenario, we evaluated colon barrier pathology in a rat model of the human comorbid condition. Intestinal barrier integrity and permeability were assessed in drug-naïve Fischer 344 HIV-1 transgenic (Tg) and non-Tg rats, and in Tg and non-Tg rats instrumented with jugular cannulae trained to self-administer methamphetamine or serving as saline-yoked controls. Intestinal permeability was determined by measuring the urine content of orally gavaged sugars. Intestinal barrier integrity was evaluated by immunoblotting or immunofluorescence of colon claudin-1 and zonula occludens-1 (ZO-1), two major tight junction proteins that regulate gut epithelial paracellular permeability. Both non-Tg and Tg rats self-administered moderate amounts of methamphetamine. These amounts were sufficient to increase colon permeability, reduce protein level of claudin-1, and reduce claudin-1 and ZO-1 immunofluorescence in Tg rats relative to non-Tg rats. Methamphetamine decreased tight junction immunofluorescence in non-Tg rats, with a similar, but non-significant trend observed in Tg rats. However, the effect of methamphetamine on tight junction proteins was subthreshold to gut leakiness. These findings reveal that both HIV-1 proteins and methamphetamine alter colon barrier integrity, and indicate that the gut may be a pathogenic site for these insults.

Stromal cells and osteoclasts are responsible for exacerbated collagen-induced arthritis in interferon-beta-deficient mice

DEFF Research Database (Denmark)

Treschow, Alexandra P; Teige, Ingrid; Nandakumar, Kutty S

2005-01-01

OBJECTIVE: Clinical trials using interferon-beta (IFNbeta) in the treatment of rheumatoid arthritis have shown conflicting results. We undertook this study to understand the mechanisms of IFNbeta in arthritis at a physiologic level. METHODS: Collagen-induced arthritis (CIA) was induced in IFNbeta....... Differences in osteoclast maturation were determined in situ by histology of arthritic and naive paws and by in vitro maturation studies of naive bone marrow cells. The importance of IFNbeta-producing fibroblasts was determined by transferring fibroblasts into mice at the time of CIA immunization. RESULTS...

Decision-Tree Formulation With Order-1 Lateral Execution

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James, Mark

2007-01-01

A compact symbolic formulation enables mapping of an arbitrarily complex decision tree of a certain type into a highly computationally efficient multidimensional software object. The type of decision trees to which this formulation applies is that known in the art as the Boolean class of balanced decision trees. Parallel lateral slices of an object created by means of this formulation can be executed in constant time considerably less time than would otherwise be required. Decision trees of various forms are incorporated into almost all large software systems. A decision tree is a way of hierarchically solving a problem, proceeding through a set of true/false responses to a conclusion. By definition, a decision tree has a tree-like structure, wherein each internal node denotes a test on an attribute, each branch from an internal node represents an outcome of a test, and leaf nodes represent classes or class distributions that, in turn represent possible conclusions. The drawback of decision trees is that execution of them can be computationally expensive (and, hence, time-consuming) because each non-leaf node must be examined to determine whether to progress deeper into a tree structure or to examine an alternative. The present formulation was conceived as an efficient means of representing a decision tree and executing it in as little time as possible. The formulation involves the use of a set of symbolic algorithms to transform a decision tree into a multi-dimensional object, the rank of which equals the number of lateral non-leaf nodes. The tree can then be executed in constant time by means of an order-one table lookup. The sequence of operations performed by the algorithms is summarized as follows: 1. Determination of whether the tree under consideration can be encoded by means of this formulation. 2. Extraction of decision variables. 3. Symbolic optimization of the decision tree to minimize its form. 4. Expansion and transformation of all nested conjunctive

Characterization of absorption enhancers for orally administered therapeutic peptides in tablet formulations - Applying statistical learning

DEFF Research Database (Denmark)

Welling, Søren Havelund

. In the Caco-2 model all reagents are pre-dissolved, and therefore the assay cannot predict critical solubility issues and bile salt interactions in the final tablet formulation. A QSAR solubility model was built to foresee and avoid slow tablet dissolution. Due to enzyme kinetics, slow tablet dissolution...

In vitro characterization of a formulation of butorphanol tartrate in a poloxamer 407 base intended for use as a parenterally administered slow-release analgesic agent.

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Laniesse, Delphine; Smith, Dale A; Knych, Heather K; Mosley, Cornelia; Guzman, David Sanchez-Migallon; Beaufrère, Hugues

2017-06-01

OBJECTIVE To assess rheological properties and in vitro diffusion of poloxamer 407 (P407) and butorphanol-P407 (But-P407) hydrogels and to develop a sustained-release opioid formulation for use in birds. SAMPLE P407 powder and a commercially available injectable butorphanol tartrate formulation (10 mg/mL). PROCEDURES P407 and But-P407 gels were compounded by adding water or butorphanol to P407 powder. Effects of various concentrations of P407 (20%, 25% and 30% [{weight of P407/weight of diluent} × 100]), addition of butorphanol, and sterilization through a microfilter on rheological properties of P407 were measured by use of a rheometer. In vitro diffusion of butorphanol from But-P407 25% through a biological membrane was compared with that of a butorphanol solution. RESULTS P407 20% and 25% formulations were easily compounded, whereas it was difficult to obtain a homogenous P407 30% formulation. The P407 was a gel at avian body temperature, although its viscosity was lower than that at mammalian body temperature. The But-P407 25% formulation (butorphanol concentration, 8.3 mg/mL) was used for subsequent experiments. Addition of butorphanol to P407 as well as microfiltration did not significantly affect viscosity. Butorphanol diffused in vitro from But-P407, and its diffusion was slower than that from a butorphanol solution. CONCLUSIONS AND CLINICAL RELEVANCE But-P407 25% had in vitro characteristics that would make it a good candidate for use as a sustained-release analgesic medication. Further studies are needed to characterize the pharmacokinetic and pharmacodynamic properties of But-P407 25% in vivo before it can be recommended for use in birds.

Pharmacokinetics of a Sustained-release Formulation of Meloxicam After Subcutaneous Administration to Hispaniolan Amazon Parrots (Amazona ventralis).

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Guzman, David Sanchez-Migallon; Court, Michael H; Zhu, Zhaohui; Summa, Noémie; Paul-Murphy, Joanne R

2017-09-01

Meloxicam has been shown to have a safe and favorable pharmacodynamic profile with individual variability in Hispaniolan Amazon parrots (Amazona ventralis). In the current study, we determined the pharmacokinetics of a sustained-release formulation of meloxicam after subcutaneous administration to Hispaniolan Amazon parrots. Twelve healthy adult parrots, 6 males and 6 females, were used in the study. Blood samples were collected before (time 0) and at 0.5, 1, 2, 6, 12, 24, 48, 72, 96, and 120 hours after a single dose of the sustained-release meloxicam formulation (3 mg/kg SC). Plasma meloxicam concentrations were measured by high-pressure liquid chromatography. Pharmacokinetic parameters were determined by noncompartmental analysis. Plasma concentrations reached a mean C max of 23.4 μg/mL (range, 14.7-46.0 μg/mL) at 1.8 hours (range, 0.5-6 hours), with a terminal half-life of 7.4 hours (range, 1.4-40.9 hours). Individual variation was noticeable, such that some parrots (4 of 12 birds) had very low plasma meloxicam concentrations, similar to the high variability reported in a previous pharmacokinetic study of the standard meloxicam formulation in the same group of birds. Two birds developed small self-resolving scabs at the injection site. On the basis of these results, the sustained-release meloxicam formulation could be administered every 12 to 96 hours in Hispaniolan Amazon parrots to manage pain. Because of these highly variable results, the use of this formulation in this species cannot be recommended until further pharmacokinetic, safety, and pharmacogenomic evaluations are performed to establish accurate dosing recommendations and to understand the high pharmacokinetic variability.

Preparation of nanoscale pulmonary drug delivery formulations by spray drying

DEFF Research Database (Denmark)

Bohr, Adam; Ruge, Christian A; Beck-Broichsitter, Moritz

2014-01-01

and can offer controlled drug release. There are numerous methods for producing therapeutic nanoparticles, each with their own advantages and suitable application. Liquid atomization techniques such as spray drying can produce nanoparticle formulations in a dry powder form suitable for pulmonary...... administration in a direct one-step process. This chapter describes the different state-of-the-art techniques used to prepare drug nanoparticles (with special emphasize on spray drying techniques) and the strategies for administering such unique formulations to the pulmonary environment....

Extensive preclinical investigation of polymersomal formulation of doxorubicin versus Doxil-mimic formulation.

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Alibolandi, Mona; Abnous, Khalil; Mohammadi, Marzieh; Hadizadeh, Farzin; Sadeghi, Fatemeh; Taghavi, Sahar; Jaafari, Mahmoud Reza; Ramezani, Mohammad

2017-10-28

Due to the severe cardiotoxicity of doxorubicin, its usage is limited. This shortcoming could be overcome by modifying pharmacokinetics of the drugs via preparation of various nanoplatforms. Doxil, a well-known FDA-approved nanoplatform of doxorubicin as antineoplastic agent, is frequently used in clinics in order to reduce cardiotoxicity of doxorubicin. Since Doxil shows some shortcomings in clinics including hand and food syndrome and very slow release pattern thus, there is a demand for the development and preparation of new doxorubicin nanoformulation with fewer side effects. The new formulation of the doxorubicin, synthesized previously by our group was extensively examined in the current study. This new formulation is doxorubicin encapsulated in PEG-PLGA polymersomes (PolyDOX). The main aim of the study was to compare the distribution and treatment efficacy of a new doxorubicin-polymersomal formulation (PolyDOX) with regular liposomal formulation (Doxil-mimic) in murine colon adenocarcinoma model. Additionally, the pathological, hematological changes, pharmacodynamics, biodistribution, tolerated dose and survival rate in vivo were evaluated and compared. Murine colon cancer model was induced by subcutaneous inoculation of BALB/c mice with C26 cells. Afterwards, either Doxil-mimic or PolyDOX was administered intravenously. The obtained results from biodistribution study showed a remarkable difference in the distribution of drugs in murine organs. In this regard, Doxil-mimic exhibited prolonged (48h) presence within liver tissues while PolyDOX preferentially accumulate in tumor and the presence in liver 48h post-treatment was significantly lower than that of Doxil-mimic. Obtained results demonstrated comparable final length of life for mice receiving either Doxil-mimic or PolyDOX formulations whereas tolerated dose of mice receiving Doxil-mimic was remarkably higher than those receiving PolyDOX. Therapeutic efficacy of formulation in term of tumor growth rate

Glass formulation for phase 1 high-level waste vitrification

International Nuclear Information System (INIS)

Vienna, J.D.; Hrma, P.R.

1996-04-01

The purpose of this study is to provide potential glass formulations for prospective Phase 1 High-Level Waste (HLW) vitrification at Hanford. The results reported here will be used to aid in developing a Phase 1 HLW vitrification request for proposal (RFP) and facilitate the evaluation of ensuing proposals. The following factors were considered in the glass formulation effort: impact on total glass volume of requiring the vendor to process each of the tank compositions independently versus as a blend; effects of imposing typical values of B 2 O 3 content and waste loading in HLW borosilicate glasses as restrictions on the vendors (according to WAPS 1995, the typical values are 5--10 wt% B 2 O 3 and 20--40 wt% waste oxide loading); impacts of restricting the processing temperature to 1,150 C on eventual glass volume; and effects of caustic washing on any of the selected tank wastes relative to glass volume

Glass formulation for phase 1 high-level waste vitrification

Energy Technology Data Exchange (ETDEWEB)

Vienna, J.D.; Hrma, P.R.

1996-04-01

The purpose of this study is to provide potential glass formulations for prospective Phase 1 High-Level Waste (HLW) vitrification at Hanford. The results reported here will be used to aid in developing a Phase 1 HLW vitrification request for proposal (RFP) and facilitate the evaluation of ensuing proposals. The following factors were considered in the glass formulation effort: impact on total glass volume of requiring the vendor to process each of the tank compositions independently versus as a blend; effects of imposing typical values of B{sub 2}O{sub 3} content and waste loading in HLW borosilicate glasses as restrictions on the vendors (according to WAPS 1995, the typical values are 5--10 wt% B{sub 2}O{sub 3} and 20--40 wt% waste oxide loading); impacts of restricting the processing temperature to 1,150 C on eventual glass volume; and effects of caustic washing on any of the selected tank wastes relative to glass volume.

Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant

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Binyamin O

2015-11-01

Full Text Available Orli Binyamin,1,* Liraz Larush,2,* Kati Frid,1 Guy Keller,1 Yael Friedman-Levi,1 Haim Ovadia,1 Oded Abramsky,1 Shlomo Magdassi,2 Ruth Gabizon1 1Department of Neurology, The Agnes Ginges Center of Human Neurogenetics, Hadassah University Hospital, 2Casali Institute of Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel *These authors contributed equally to this work Abstract: Multiple sclerosis (MS is a chronic inflammatory disease of the central nervous system and is associated with demyelination, neurodegeneration, and sensitivity to oxidative stress. In this work, we administered a nanodroplet formulation of pomegranate seed oil (PSO, denominated Nano-PSO, to mice induced for experimental autoimmune encephalomyelitis (EAE, an established model of MS. PSO comprises high levels of punicic acid, a unique polyunsaturated fatty acid considered as one of the strongest natural antioxidants. We show here that while EAE-induced mice treated with natural PSO presented some reduction in disease burden, this beneficial effect increased significantly when EAE mice were treated with Nano-PSO of specific size nanodroplets at much lower concentrations of the oil. Pathological examinations revealed that Nano-PSO administration dramatically reduced demyelination and oxidation of lipids in the brains of the affected animals, which are hallmarks of this severe neurological disease. We propose that novel formulations of natural antioxidants such as Nano-PSO may be considered for the treatment of patients suffering from demyelinating diseases. On the mechanistic side, our results demonstrate that lipid oxidation may be a seminal feature in both demyelination and neurodegeneration. Keywords: nanodrops, PSO, EAE, oxidative stress, neurodegeneration

Development of Oral Flexible Tablet (OFT) Formulation for Pediatric and Geriatric Patients: a Novel Age-Appropriate Formulation Platform.

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Chandrasekaran, Prabagaran; Kandasamy, Ruckmani

2017-08-01

Development of palatable formulations for pediatric and geriatric patients involves various challenges. However, an innovative development with beneficial characteristics of marketed formulations in a single formulation platform was attempted. The goal of this research was to develop solid oral flexible tablets (OFTs) as a platform for pediatrics and geriatrics as oral delivery is the most convenient and widely used mode of drug administration. For this purpose, a flexible tablet formulation using cetirizine hydrochloride as model stability labile class 1 and 3 drug as per the Biopharmaceutical Classification System was developed. Betadex, Eudragit E100, and polacrilex resin were evaluated as taste masking agents. Development work focused on excipient selection, formulation processing, characterization methods, stability, and palatability testing. Formulation with a cetirizine-to-polacrilex ratio of 1:2 to 1:3 showed robust physical strength with friability of 0.1% (w/w), rapid in vitro dispersion within 30 s in 2-6 ml of water, and 0.2% of total organic and elemental impurities. Polacrilex resin formulation shows immediate drug release within 30 min in gastric media, better taste masking, and acceptable stability. Hence, it is concluded that ion exchange resins can be appropriately used to develop taste-masked, rapidly dispersible, and stable tablet formulations with tailored drug release suitable for pediatrics and geriatrics. Flexible formulations can be consumed as swallowable, orally disintegrating, chewable, and as dispersible tablets. Flexibility in dose administration would improve compliance in pediatrics and geriatrics. This drug development approach using ion exchange resins can be a platform for formulating solid oral flexible drug products with low to medium doses.

Lipid nanoparticles for transdermal delivery of flurbiprofen: formulation, in vitro, ex vivo and in vivo studies

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Bhaskar, Kesavan; Anbu, Jayaraman; Ravichandiran, Velayutham; Venkateswarlu, Vobalaboina; Rao, Yamsani Madhusudan

2009-01-01

The aim of the study is to prepare aqueous dispersions of lipid nanoparticles – flurbiprofen solid lipid nanoparticles (FLUSLN) and flurbiprofen nanostructured lipid carriers (FLUNLC) by hot homogenization followed by sonication technique and then incorporated into the freshly prepared hydrogels for transdermal delivery. They are characterized for particle size, for all the formulations, more than 50% of the particles were below 300 nm after 90 days of storage at RT. DSC analyses were performed to characterize the state of drug and lipid modification. Shape and surface morphology were determined by TEM which revealed fairly spherical shape of the formulations. Further they were evaluated for in vitro drug release characteristics, rheological behaviour, pharmacokinetic and pharmacodynamic studies. The pharmacokinetics of flurbiprofen in rats following application of SLN gel (A1) and NLC gel (B1) for 24 h were evaluated. The Cmax of the B1 formulation was 38.67 ± 2.77 μg/ml, which was significantly higher than the A1 formulation (Cmax = 21.79 ± 2.96 μg/ml). The Cmax and AUC of the B1 formulation were 1.8 and 2.5 times higher than the A1 gel formulation respectively. The bioavailability of flurbiprofen with reference to oral administration was found to increase by 4.4 times when gel formulations were applied. Anti-inflammatory effect in the Carrageenan-induced paw edema in rat was significantly higher for B1 and A1 formulation than the orally administered flurbiprofen. Both the SLN and NLC dispersions and gels enriched with SLN and NLC possessed a sustained drug release over period of 24 h but the sustained effect was more pronounced with the SLN and NLC gel PMID:19243632

Lipid nanoparticles for transdermal delivery of flurbiprofen: formulation, in vitro, ex vivo and in vivo studies

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Venkateswarlu Vobalaboina

2009-02-01

Full Text Available Abstract The aim of the study is to prepare aqueous dispersions of lipid nanoparticles – flurbiprofen solid lipid nanoparticles (FLUSLN and flurbiprofen nanostructured lipid carriers (FLUNLC by hot homogenization followed by sonication technique and then incorporated into the freshly prepared hydrogels for transdermal delivery. They are characterized for particle size, for all the formulations, more than 50% of the particles were below 300 nm after 90 days of storage at RT. DSC analyses were performed to characterize the state of drug and lipid modification. Shape and surface morphology were determined by TEM which revealed fairly spherical shape of the formulations. Further they were evaluated for in vitro drug release characteristics, rheological behaviour, pharmacokinetic and pharmacodynamic studies. The pharmacokinetics of flurbiprofen in rats following application of SLN gel (A1 and NLC gel (B1 for 24 h were evaluated. The Cmax of the B1 formulation was 38.67 ± 2.77 μg/ml, which was significantly higher than the A1 formulation (Cmax = 21.79 ± 2.96 μg/ml. The Cmax and AUC of the B1 formulation were 1.8 and 2.5 times higher than the A1 gel formulation respectively. The bioavailability of flurbiprofen with reference to oral administration was found to increase by 4.4 times when gel formulations were applied. Anti-inflammatory effect in the Carrageenan-induced paw edema in rat was significantly higher for B1 and A1 formulation than the orally administered flurbiprofen. Both the SLN and NLC dispersions and gels enriched with SLN and NLC possessed a sustained drug release over period of 24 h but the sustained effect was more pronounced with the SLN and NLC gel

Anti-inflammatory activity of Shirishavaleha: An Ayurvedic compound formulation.

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Yadav, Shyamlal Singh; Galib; Ravishankar, B; Prajapati, P K; Ashok, B K; Varun, B

2010-10-01

The purpose of the present study was to evaluate the anti-inflammatory activity of Shirishavaleha prepared from two different parts of Shirisha (Albizia lebbeck Benth.), viz. the bark (Twak) and the heartwood (Sara). The activity was screened in the carrageenan-induced rat paw edema model in albino rats. The raw materials were collected and authenticated in the university and the trial formulations were prepared by following standard classical guidelines. Randomly selected animals were divided into four groups of six animals each. The test drugs were administered orally at a dose of 1.8 g/kg for 5 days. Phenylbutazone was used as the standard anti-inflammatory drug for comparison. Between the two different test samples studied, the formulation made from heartwood showed a weak anti-inflammatory activity in this model while that made from the bark produced a considerable suppression of edema after 6 h. It appears that the bark sample would be preferable for clinical use.

Novel Formulation Strategy to Improve the Feasibility of Amifostine Administration.

Science.gov (United States)

Ranganathan, Kavitha; Simon, Eric; Lynn, Jeremy; Snider, Alicia; Zhang, Yu; Nelson, Noah; Donneys, Alexis; Rodriguez, Jose; Buchman, Lauren; Reyna, Dawn; Lipka, Elke; Buchman, Steven R

2018-03-19

Amifostine (AMF), a radioprotectant, is FDA-approved for intravenous administration in cancer patients receiving radiation therapy (XRT). Unfortunately, it remains clinically underutilized due to adverse side effects. The purpose of this study is to define the pharmacokinetic profile of an oral AMF formulation potentially capable of reducing side effects and increasing clinical feasibility. Calvarial osteoblasts were radiated under three conditions: no drug, AMF, and WR-1065 (active metabolite). Osteogenic potential of cells was measured using alkaline phosphatase staining. Next, rats were given AMF intravenously or directly into the jejunum, and pharmacokinetic profiles were evaluated. Finally, rats were given AMF orally or subcutaneously, and blood samples were analyzed for pharmacokinetics. WR-1065 preserved osteogenic potential of calvarial osteoblasts after XRT to a greater degree than AMF. Direct jejunal AMF administration incurred a systemic bioavailability of 61.5%. Subcutaneously administrated AMF yielded higher systemic levels, a more rapid peak exposure (0.438 vs. 0.875 h), and greater total systemic exposure of WR-1065 (116,756 vs. 16,874 ng*hr/ml) compared to orally administered AMF. Orally administered AMF achieves a similar systemic bioavailability and decreased peak plasma level of WR-1065 compared to intravenously administered AMF, suggesting oral AMF formulations maintain radioprotective efficacy without causing onerous side effects, and are clinically feasible.

Dispersible formulation of artemether/lumefantrine: specifically developed for infants and young children

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Sagara Issaka

2009-10-01

Full Text Available Abstract Infants and children under five years of age are the most vulnerable to malaria with over 1,700 deaths per day from malaria in this group. However, until recently, there were no WHO-endorsed paediatric anti-malarial formulations available. Artemisinin-based combination therapy is the current standard of care for patients with uncomplicated falciparum malaria in Africa. Artemether/lumefantrine (AL meets WHO pre-qualification criteria for efficacy, safety and quality. Coartem®, a fixed dose combination of artemether and lumefantrine, has consistently achieved cure rates of >95% in clinical trials. However, AL tablets are inconvenient for caregivers to administer as they need to be crushed and mixed with water or food for infants and young children. Further, in common with other anti-malarials, they have a bitter taste, which may result in children spitting the medicine out and not receiving the full therapeutic dose. There was a clear unmet medical need for a formulation of AL specifically designed for children. Ahead of a call from WHO for child-friendly medicines, Novartis, working in partnership with Medicines for Malaria Venture (MMV, started the development of a new formulation of AL for infants and young children: Coartem® Dispersible. The excellent efficacy, safety and tolerability already demonstrated by AL tablets were confirmed with dispersible AL in a large trial comparing the crushed tablets with dispersible tablets in 899 African children with falciparum malaria. In the evaluable population, 28-day PCR-corrected cure rates of >96% were achieved. Further, its sweet taste means that it is palatable for children, and the dispersible formulation makes it easier for caregivers to administer than bitter crushed tablets. Easing administration may foster compliance, hence improving therapeutic outcomes in infants and young children and helping to preserve the efficacy of ACT.

MAb therapy against the IFN-α/β receptor subunit 1 stimulates arteriogenesis in a murine hindlimb ischaemia model without enhancing atherosclerotic burden

NARCIS (Netherlands)

Teunissen, Paul F. A.; Boshuizen, Marieke C.; Hollander, Maurits R.; Biesbroek, Paul S.; van der Hoeven, Nina W.; Mol, Jan-Quinten; Gijbels, Marion J.; van der Velden, Saskia; van der Pouw Kraan, Tineke C.; Horrevoets, Anton J.; de Winther, Menno P.; van Royen, Niels

2015-01-01

IFN-beta (IFNβ) signalling is increased in patients with insufficient coronary collateral growth (i.e. arteriogenesis) and IFNβ hampers arteriogenesis in mice. A downside of most pro-arteriogenic agents investigated in the past has been their pro-atherosclerotic properties, rendering them unsuitable

Ocular pharmacokinetics and tolerability of bimatoprost ophthalmic solutions administered once or twice daily in rabbits, and clinical dosing implications

Science.gov (United States)

Shen, Jie; Goodkin, Margot L; Tong, Warren; Attar, Mayssa

2017-01-01

Purpose Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP), but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily. Reports of twice-daily dosing in glaucoma patients are also reviewed. Methods New Zealand White rabbits were administered bimatoprost 0.01% monotherapy or fixed-combination bimatoprost 0.01%/brimonidine 0.1%, once or twice daily in both eyes for 4 days. Ocular tissues were harvested and analyzed by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters calculated included maximum observed concentration, time to maximum concentration, and area under the concentration-time curve. Results Due to extensive metabolism, bimatoprost concentration was below the quantitation limit by 1 hour post-dose in all samples. Bimatoprost acid exposure, however, could be measured up to 6–8 hours post-dose and was similar in the aqueous humor and iris-ciliary body (pharmacological site of action) of animals treated once or twice daily with either bimatoprost 0.01% or fixed-combination bimatoprost 0.01%/brimonidine 0.1%. Increasing dosage frequency in rabbits did not raise the incidence of drug-related conjunctival hyperemia (most common adverse event associated with bimatoprost use in humans), suggesting comparable ocular tolerability of the once- and twice-daily regimens for each formulation. Conclusion Bimatoprost 0.01% administered once or twice daily as monotherapy and in fixed-combination with brimonidine 0.1% in rabbits show similar pharmacokinetic profiles of bimatoprost acid, especially in the iris-ciliary body. Key findings from previous clinical studies suggest that by varying the concentration of benzalkonium chloride (a preservative with corneal penetration-enhancing properties

Electrically atomised formulations of timolol maleate for direct and on-demand ocular lens coatings.

Science.gov (United States)

Mehta, Prina; Al-Kinani, Ali A; Haj-Ahmad, Rita; Arshad, Muhammad Sohail; Chang, Ming-Wei; Alany, Raid G; Ahmad, Zeeshan

2017-10-01

Advances in nanotechnology have enabled solutions for challenging drug delivery targets. While the eye presents numerous emerging opportunities for delivery, analysis and sensing; issues persist for conventional applications. This includes liquid phase formulation localisation on the ocular surface once administered as formulated eye-drops; with the vast majority of dosage (>90%) escaping from the administered site due to tear production and various drainage mechanisms. The work presented here demonstrates a single needle electrohydrodynamic (EHD) engineering process to nano-coat (as an on demand and controllable fiber depositing method) the surface of multiple contact lenses rendering formulations to be stationary on the lens and at the bio-interface. The coating process was operational based on ejected droplet charge and glaucoma drug timolol maleate (TM) was used to demonstrate surface coating optimisation, bio-surface permeation properties (flux, using a bovine model) and various kinetic models thereafter. Polymers PVP, PNIPAM and PVP:PNIPAM (50:50%w/w) were used to encapsulate the active. Nano-fibrous and particulate samples were characterised using SEM, FTIR, DSC and TGA to confirm structural and thermal stability of surface coated formulations. More than 52% of nano-structured coatings (for all formulations) were drainage. Crown Copyright © 2017. Published by Elsevier B.V. All rights reserved.

Ocular surface distribution and pharmacokinetics of a novel ophthalmic 1% azithromycin formulation.

Science.gov (United States)

Akpek, Esen Karamursel; Vittitow, Jason; Verhoeven, Rozemarijn S; Brubaker, Kurt; Amar, Thierry; Powell, Kendall D; Boyer, José L; Crean, Christopher

2009-10-01

To investigate the ocular distribution of 1% azithromycin ophthalmic solution and the effect of polycarbophil-based mucoadhesive formulation on ocular tissue levels of azithromycin after single and multiple topical administrations in the rabbit eye. Rabbits were treated with either a single administration of 1% azithromycin solution with or without polycarbophil, or with multiple administrations of 1% azithromycin solution in polycarbophil. Drug concentrations were measured using LC/MS/MS. Conjunctiva, cornea, aqueous humor, and tear samples were analyzed over a period of 144 h after a single administration of azithromycin with or without polycarbophil. Eyelid, conjunctiva, cornea, aqueous humor, and tear samples were collected over a period of 288 h during and after multiple administrations of azithromycin. Azithromycin was rapidly absorbed and distributed in the ocular tissues, reaching within 5 min, concentrations of 10,539 microg/mL in tear film, 108 microg/g in conjunctiva, and 40 microg/g in the cornea. The drug demonstrated tissue-specific half-lives of 15, 63, and 67 h, respectively. Following multiple administrations, the drug gradually accumulated. The polycarbophil formulation increased the bioavailability of the drug, producing peak concentrations that were between 5- and 12-fold higher than those without polycarbophil. Azithromycin also distributed rapidly in the eyelids, reaching peak concentrations of 180 mug/g at the end of the 7-day treatment, and was eliminated with a half-life of 125 h. Six days after treatment was discontinued, eyelid levels of azithromycin were above 40 microg/g. Sustained and high concentrations were encountered with 7-day approved administration of 1% azithromycin formulation (AzaSite, Inspire Pharmaceuticals, Inc., Durham, NC) within all ocular surface tissues, particularly the lids. Many ocular surface disorders involving the tear film, eyelids, and adnexal structures are associated with chronic, low-grade bacterial

Formulation and characterization of a multiple emulsion containing 1% L-ascorbic acid

Directory of Open Access Journals (Sweden)

Naveed Akhtar

2010-04-01

Full Text Available The purpose of the study was to prepare a stable multiple emulsion containing a skin anti-aging agent and using paraffin oil. Vitamin C, was incorporated into the inner aqueous phase of water-in-oil-in-water (w/o/w multiple emulsion at a concentration of 1%. Multiple emulsion was prepared by two step method. Stability studies were performed at different accelerated conditions, i.e. 8 oC (in refrigerator, 25 oC (in oven, 40 oC (in oven, and 40 oC at 75% RH (in stability cabin for 28 days to predict the stability of formulations. Different parameters, namely pH, globule size, electrical conductivity and effect of centrifugation (simulating gravity were determined during stability studies. Data obtained was evaluated statistically using ANOVA two way analyses and LSD tests. Multiple emulsion formulated was found to be stable at lower temperatures (i.e. 8 and 25 oC for 28 days. No phase separation was observed in the samples during stability testing. It was found that there was no significant change (p > 0.05 in globule sizes in most of the samples kept at various conditions. Insignificant changes (p > 0.05 in both pH and conductivity values were determined for the samples kept at 8, 40, and 40 oC at 75% RH, throughout the study period. Further studies are needed to formulate more stable emulsions with other emulsifying agents.

Bioequivalence assessment of two formulations of ibuprofen

KAUST Repository

Al-Talla, Zeyad

2011-10-19

Background: This study assessed the relative bioavailability of two formulations of ibuprofen. The first formulation was Doloraz , produced by Al-Razi Pharmaceutical Company, Amman, Jordan. The second forumulation was Brufen , manufactured by Boots Company, Nottingham, UK. Methods and results: A prestudy validation of ibuprofen demonstrated long-term stability, freeze-thaw stability, precision, and accuracy. Twenty-four healthy volunteers were enrolled in this study. After overnight fasting, the two formulations (test and reference) of ibuprofen (100 mg ibuprofen/5 mL suspension) were administered as a single dose on two treatment days separated by a one-week washout period. After dosing, serial blood samples were drawn for a period of 14 hours. Serum harvested from the blood samples was analyzed for the presence of ibuprofen by high-pressure liquid chromatography with ultraviolet detection. Pharmacokinetic parameters were determined from serum concentrations for both formulations. The 90% confidence intervals of the ln-transformed test/reference treatment ratios for peak plasma concentration and area under the concentration-time curve (AUC) parameters were found to be within the predetermined acceptable interval of 80%-125% set by the US Food and Drug Administration. Conclusion: Analysis of variance for peak plasma concentrations and AUC parameters showed no significant difference between the two formulations and, therefore, Doloraz was considered bioequivalent to Brufen. 2011 Al-Talla et al, publisher and licensee Dove Medical Press Ltd.

Dissolution efficiency and bioequivalence study using urine data from healthy volunteers: a comparison between two tablet formulations of cephalexin

Directory of Open Access Journals (Sweden)

Cristina Helena dos Reis Serra

2015-06-01

Full Text Available The aim of the present study was to assess the bioequivalence of two cephalexin tablet formulations available in the Brazilian market (product A as reference formulation and product B as test formulation. Dissolution efficiency (DE% was calculated for both formulations to evaluate their in vitrobiopharmaceutical features. The oral bioequivalence study was performed in twenty-four healthy volunteers in a crossover design. Single oral dose (tablet containing 500 mg of cephalexin of each product was administered with two weeks of washout period. Urinary concentrations of cephalexin were measured by high-performance liquid chromatography (HPLC method and pharmacokinetics parameters were estimated by urinary excretion data. The bioequivalence was determined by the following parameters: the cumulative amount of cephalexin excreted in the urine, the total amount of cephalexin excreted in the urine and the maximum urinary excretion rate of cephalexin. DE values of immediate-release cephalexin tablets (500 mg were 68.69±4.18% for product A and 71.03±6.63% for product B. Regarding the dissolution test of the two brands (A and B analysed, both were in compliance with the official pharmacopeial specifications, since the dissolution of both formulations was superior to 80% of the amount declared in the label after 45 minutes of test (A=92.09%±1.84; B=92.84%±1.08. The results obtained indicated that the products A and B are pharmaceutical equivalents. Confidence intervals for the pharmacokinetic parameters were in compliance with the international standards, indicating that products A and B can be considered bioequivalents and, therefore, interchangeable.

Is switching from brand name to generic formulations of phenobarbital associated with loss of antiepileptic efficacy?: a pharmacokinetic study with two oral formulations (Luminal® vet, Phenoleptil®) in dogs

Science.gov (United States)

2013-01-01

Background In human medicine, adverse outcomes associated with switching between bioequivalent brand name and generic antiepileptic drug products is a subject of concern among clinicians. In veterinary medicine, epilepsy in dogs is usually treated with phenobarbital, either with the standard brand name formulation Luminal® or the veterinary products Luminal® vet and the generic formulation Phenoleptil®. Luminal® and Luminal® vet are identical 100 mg tablet formulations, while Phenoleptil® is available in the form of 12.5 and 50 mg tablets. Following approval of Phenoleptil® for treatment of canine epilepsy, it was repeatedly reported by clinicians and dog owners that switching from Luminal® (human tablets) to Phenoleptil® in epileptic dogs, which were controlled by treatment with Luminal®, induced recurrence of seizures. In the present study, we compared bioavailability of phenobarbital after single dose administration of Luminal® vet vs. Phenoleptil® with a crossover design in 8 healthy Beagle dogs. Both drugs were administered at a dose of 100 mg/dog, resulting in 8 mg/kg phenobarbital on average. Results Peak plasma concentrations (Cmax) following Luminal® vet vs. Phenoleptil® were about the same in most dogs (10.9 ± 0.92 vs. 10.5 ± 0.77 μg/ml), and only one dog showed noticeable lower concentrations after Phenoleptil® vs. Luminal® vet. Elimination half-life was about 50 h (50.3 ± 3.1 vs. 52.9 ± 2.8 h) without differences between the formulations. The relative bioavailability of the two products (Phenoleptil® vs. Luminal® vet.) was 0.98 ± 0.031, indicating that both formulations resulted in about the same bioavailability. Conclusions Overall, the two formulations did not differ significantly with respect to pharmacokinetic parameters when mean group parameters were compared. Thus, the reasons for the anecdotal reports, if true, that switching from the brand to the generic formulation of phenobarbital may lead to

Is switching from brand name to generic formulations of phenobarbital associated with loss of antiepileptic efficacy?: a pharmacokinetic study with two oral formulations (Luminal(®) vet, Phenoleptil(®)) in dogs.

Science.gov (United States)

Bankstahl, Marion; Bankstahl, Jens P; Löscher, Wolfgang

2013-10-09

In human medicine, adverse outcomes associated with switching between bioequivalent brand name and generic antiepileptic drug products is a subject of concern among clinicians. In veterinary medicine, epilepsy in dogs is usually treated with phenobarbital, either with the standard brand name formulation Luminal(®) or the veterinary products Luminal(®) vet and the generic formulation Phenoleptil(®). Luminal(®) and Luminal(®) vet are identical 100 mg tablet formulations, while Phenoleptil(®) is available in the form of 12.5 and 50 mg tablets. Following approval of Phenoleptil(®) for treatment of canine epilepsy, it was repeatedly reported by clinicians and dog owners that switching from Luminal(®) (human tablets) to Phenoleptil(®) in epileptic dogs, which were controlled by treatment with Luminal(®), induced recurrence of seizures. In the present study, we compared bioavailability of phenobarbital after single dose administration of Luminal(®) vet vs. Phenoleptil(®) with a crossover design in 8 healthy Beagle dogs. Both drugs were administered at a dose of 100 mg/dog, resulting in 8 mg/kg phenobarbital on average. Peak plasma concentrations (Cmax) following Luminal(®) vet vs. Phenoleptil(®) were about the same in most dogs (10.9 ± 0.92 vs. 10.5 ± 0.77 μg/ml), and only one dog showed noticeable lower concentrations after Phenoleptil(®) vs. Luminal(®) vet. Elimination half-life was about 50 h (50.3 ± 3.1 vs. 52.9 ± 2.8 h) without differences between the formulations. The relative bioavailability of the two products (Phenoleptil(®) vs. Luminal(®) vet.) was 0.98 ± 0.031, indicating that both formulations resulted in about the same bioavailability. Overall, the two formulations did not differ significantly with respect to pharmacokinetic parameters when mean group parameters were compared. Thus, the reasons for the anecdotal reports, if true, that switching from the brand to the generic formulation of phenobarbital may lead to recurrence of

Investigation into the floating behaviour of a pectin-containing anti-reflux formulation by means of gamma scintigraphy

Energy Technology Data Exchange (ETDEWEB)

Washington, N.; Wilson, C.G.; Greaves, J.L.; Danneskiold-Samsoee, P.

1988-01-01

The gastric distribution and residence time of a new pectin-containing formulation, FF5005 (Farma Food A/S, Denmark) was investigated by using the technique of gamma scintigraphy in six healthy volunteers after administration with a radiolabelled meal. The formulation and test meal were radiolabelled with indium-113m and technetium-99m, respectively, and the formulation was administered to the subjects 30 min after the labelled meal. FF5005 was shown to float and form a discrete phase on top of the stomach contents, and emptied from the stomach more slowly than the food (p<0.05, Wilcoxon signed rank test). The times taken for the formulation and test meal to half-empty from the stomach (T 5 0) were 4.13 +-0.69 h (mean +-SD) and 2.17 +-0.15 h (mean +-SD), respectively. More than 50% of the formulation remained in the fundal region of the stomach for 3 h. FF5005 produced in vivo behaviour similar to that of established alginate-containing anti-reflux agents, and the pectin content of the formulation was shown to decrease the rate of emptying of the meal.

Ocular pharmacokinetics and tolerability of bimatoprost ophthalmic solutions administered once or twice daily in rabbits, and clinical dosing implications

Directory of Open Access Journals (Sweden)

Shen J

2017-09-01

Full Text Available Jie Shen,1 Margot L Goodkin,2 Warren Tong,2 Mayssa Attar3 1Clinical Pharmacology, 2Clinical Development, 3Clinical Pharmacology, Metabolism and Immunology, Allergan plc, Irvine, CA, USA Purpose: Fixed-combination medications can benefit patients requiring multiple agents to lower their intraocular pressure (IOP, but combining agents with complementary mechanisms of action is challenging if their dosing frequency differs. This study compares in vivo pharmacokinetic and ocular tolerability of bimatoprost 0.01% ophthalmic solutions dosed once or twice daily. Reports of twice-daily dosing in glaucoma patients are also reviewed.Methods: New Zealand White rabbits were administered bimatoprost 0.01% monotherapy or fixed-combination bimatoprost 0.01%/brimonidine 0.1%, once or twice daily in both eyes for 4 days. Ocular tissues were harvested and analyzed by liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters calculated included maximum observed concentration, time to maximum concentration, and area under the concentration-time curve.Results: Due to extensive metabolism, bimatoprost concentration was below the quantitation limit by 1 hour post-dose in all samples. Bimatoprost acid exposure, however, could be measured up to 6–8 hours post-dose and was similar in the aqueous humor and iris-ciliary body (pharmacological site of action of animals treated once or twice daily with either bimatoprost 0.01% or fixed-combination bimatoprost 0.01%/brimonidine 0.1%. Increasing dosage frequency in rabbits did not raise the incidence of drug-related conjunctival hyperemia (most common adverse event associated with bimatoprost use in humans, suggesting comparable ocular tolerability of the once- and twice-daily regimens for each formulation.Conclusion: Bimatoprost 0.01% administered once or twice daily as monotherapy and in fixed-combination with brimonidine 0.1% in rabbits show similar pharmacokinetic profiles of bimatoprost acid

Efficacy of a Buffered 4% Lidocaine Formulation for Incision and Drainage: A Prospective, Randomized, Double-blind Study.

Science.gov (United States)

Harreld, Taryn Kratz; Fowler, Sara; Drum, Melissa; Reader, Al; Nusstein, John; Beck, Mike

2015-10-01

Incision and drainage of symptomatic emergency patients with facial swelling is painful even after local anesthetics are administered. The purpose of this prospective, randomized, double-blind study was to compare the pain of infiltration and the pain of an incision and drainage procedure of a buffered versus a nonbuffered 4% lidocaine formulation in symptomatic emergency patients presenting with a diagnosis of pulpal necrosis, associated periapical area, and an acute clinical swelling. Eighty-eight emergency patients were randomly divided into 2 groups to receive 2 intraoral infiltration injections (mesial and distal to the swelling) of either 4% lidocaine with 1:100,000 epinephrine buffered with 0.18 mL 8.4% sodium bicarbonate using the Onpharma (Los Gatos, CA) buffering system or 4% lidocaine with 1:100,000 epinephrine. Subjects rated the pain of needle insertion, needle placement, and solution deposition for each injection using a 170-mm visual analog scale. An incision and drainage procedure was performed, and subjects rated the pain of incision, drainage, and dissection on a 170-mm visual analog scale. No significant differences between the buffered and nonbuffered 4% lidocaine formulations were found for needle insertion, placement, and solution deposition of the infiltration injections or for the treatment phases of incision, drainage, and dissection. Buffering a 4% lidocaine formulation did not significantly decrease the pain of infiltrations or significantly decrease the pain of the incision and drainage procedure when compared with a nonbuffered 4% lidocaine formulation in symptomatic patients with a diagnosis of pulpal necrosis and associated acute swelling. Copyright © 2015 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

Phase 1/2a study of the malaria vaccine candidate apical membrane antigen-1 (AMA-l) administered in adjuvant system AS01B or AS02A

NARCIS (Netherlands)

M.D. Spring (Michele Donna); J.F. Cummings (James); C.F. Ockenhouse (Christian); S. Dutta (Shantanu); R. Reidler (Randall); E. Angov (Evelina); E. Bergmann-Leitner (Elke); V.A. Stewart (Ann); S. Bittner (Stacey); L. Juompan (Laure); M.G. Kortepeter (Mark); R. Nielsen (Robin); U. Krzych (Urszula); E. Tierney (Ev); L.A. Ware (Lisa); M. Dowler (Megan); C.C. Hermsen (Cornelus); R.W. Sauerwein (Robert); S.J. de Vlas (Sake); O. Ofori-Anyinam (Opokua); D.E. Lanar (David); J.L. Williams (Jack); K.E. Kester (Kent); K. Tucker (Kathryn); M. Shi (Meng); E. Malkin (Elissa); C. Long (Carole); C.L. Diggs (Carter); L. Soisson (Lorraine Amory); M.C. Dubois; W.R. Ballou (Ripley); J. Cohen (Joe); D.G. Heppner (Gray)

2009-01-01

textabstractBackground: This Phase 1/2a study evaluated the safety, immunogenicity, and efficacy of an experimental malaria vaccine comprised of the recombinant Plasmodium falciparum protein apical membrane antigen-1 (AMA-1) representing the 3D7 allele formulated with either the AS01B or AS02A

Prednisone raw material characterization and formulation development

OpenAIRE

Leonardo Henrique Toehwé; Livia Deris Prado; Helvécio Vinícius Antunes Rocha

2018-01-01

ABSTRACT Solid dosage forms for oral use, particularly tablets, are the most highly used dosage forms in therapy because they are easily administered, have high productivity and relatively low cost and provide a more stable drug to form a semi-solid net. Numerous parameters influence the quality of the final dosage form. In this study, the dissolution profile of 20-mg prednisone tablets bioequivalent to the reference product and three test formulations were evaluated using stability testing. ...

22 CFR 196.4 - Administering office.

Science.gov (United States)

2010-04-01

... 22 Foreign Relations 1 2010-04-01 2010-04-01 false Administering office. 196.4 Section 196.4... AFFAIRS/GRADUATE FOREIGN AFFAIRS FELLOWSHIP PROGRAM § 196.4 Administering office. The Department of State's Bureau of Human Resources, Office of Recruitment is responsible for administering the Thomas R...

Relative bioavailability of methadone hydrochloride administered in chewing gum and tablets

DEFF Research Database (Denmark)

Christrup, Lona Louring; Angelo, H.R.; Bonde, J.

1990-01-01

Methadone administered in chewing gum in doses of 16.7-22.6 mg to seven patients in a study using an open balanced cross-over design, was compared with 20 mg of methadone given perorally as tablets. There was no significant difference in the AUC/D obtained after administration of chewing gum...... and tablets (p>0.05). It is concluded that the chewing gum formulation should be considered for further testing with respect to suppression of abstinence syndrome in narcotic addicts....

Relative bioavailability of methadone hydrochloride administered in chewing gum and tablets.

Science.gov (United States)

Christrup, L L; Angelo, H R; Bonde, J; Kristensen, F; Rasmussen, S N

1990-01-01

Methadone administered in chewing gum in doses of 16.7-22.6 mg to seven patients in a study using an open balanced cross-over design, was compared with 20 mg of methadone given perorally as tablets. There was no significant difference in the AUC/D obtained after administration of chewing gum and tablets (p greater than 0.05). It is concluded that the chewing gum formulation should be considered for further testing with respect to suppression of abstinence syndrome in narcotic addicts.

A study of the enhanced sensitizing capacity of a contact allergen in lipid vesicle formulations

International Nuclear Information System (INIS)

Simonsson, Carl; Madsen, Jakob Torp; Graneli, Annette; Andersen, Klaus E.; Karlberg, Ann-Therese; Jonsson, Charlotte A.; Ericson, Marica B.

2011-01-01

The growing focus on nanotechnology and the increased use of nano-sized structures, e.g. vesicles, in topical formulations has led to safety concerns. We have investigated the sensitizing capacity and penetration properties of a fluorescent model compound, rhodamine B isothiocyanate (RBITC), when administered in micro- and nano-scale vesicle formulations. The sensitizing capacity of RBITC was studied using the murine local lymph node assay (LLNA) and the skin penetration properties were compared using diffusion cells in combination with two-photon microscopy (TPM). The lymph node cell proliferation, an indicator of a compounds sensitizing capacity, increased when RBITC was applied in lipid vesicles as compared to an ethanol:water (Et:W) solution. Micro-scale vesicles showed a slightly higher cell proliferative response compared to nano-scale vesicles. TPM imaging revealed that the vesicle formulations improved the skin penetration of RBITC compared to the Et:W solution. A strong fluorescent region in the stratum corneum and upper epidermis implies elevated association of RBITC to these skin layers when formulated in lipid vesicles. In conclusion, the results indicate that there could be an elevated risk of sensitization when haptens are delivered in vehicles containing lipid vesicles. Although the size of the vesicles seems to be of minor importance, further studies are needed before a more generalized conclusion can be drawn. It is likely that the enhanced sensitizing capacity is a consequence of the improved penetration and increased formation of hapten-protein complexes in epidermis when RBITC is delivered in ethosomal formulations. - Graphical Abstract: Display Omitted

Effect of a polyherbal formulation cream on diabetic neuropathic pain among patients with type 2 diabetes – A pilot study

Science.gov (United States)

Viswanathan, Vijay; Rajsekar, Seena; Selvaraj, Bamila; Kumpatla, Satyavani

2016-01-01

Background & objectives: Painful diabetic neuropathy is a common complication of diabetes and can severely limit patients’ daily functions. The aim of this pilot study was to evaluate the safety and effect of using a polyherbal formulation in reducing the symptoms of diabetic neuropathic pain in comparison with placebo among patients with type 2 diabetes. Methods: A total of 50 (M:F = 33:17) consecutive type 2 diabetes patients with painful diabetic neuropathy were enrolled in this study. All these patients had either two or more symptoms of diabetic neuropathy such as pain, burning and pricking sensations and numbness in their feet. They were randomly assigned to two groups: group 1 (n = 26) patients were treated with polyherbal formulation cream and group 2 (n = 24) patients were administered placebo. The patients were followed up for six months. Changes in the symptoms of painful diabetic neuropathy of each patient were recorded at baseline, third and sixth month using the Diabetic Neuropathic Score. Results: The mean age of the patients, duration of diabetes and glycated haemoglobin (HbA1c) were similar in both groups at baseline. During follow up visits, there was a decrease in the HbA1c levels in the study and control groups. The symptoms of painful diabetic neuropathy were also similar in both groups at baseline. A significant decrease in symptoms of neuropathic pain was observed among the group of patients treated with polyherbal formulation cream (76.9 per cent) compared to the placebo-treated group (12.5 per cent) (P<0.001), at the end of the final follow up. Interpretation & conclusions: In this pilot study polyherbal formulation cream was found to be effective as well as safe to treat painful diabetic neuropathy. However, its long term use needs to be evaluated for any further effectiveness and side effects. PMID:27934800

Formulation, in vitro and in vivo evaluation of transdermal patches containing risperidone.

Science.gov (United States)

Aggarwal, Geeta; Dhawan, Sanju; Hari Kumar, S L

2013-01-01

The efficacy of oral risperidone treatment in prevention of schizophrenia is well known. However, oral side effects and patient compliance is always a problem for schizophrenics. In this study, risperidone was formulated into matrix transdermal patches to overcome these problems. The formulation factors for such patches, including eudragit RL 100 and eudragit RS 100 as matrix forming polymers, olive oil, groundnut oil and jojoba oil in different concentrations as enhancers and amount of drug loaded were investigated. The transdermal patches containing risperidone were prepared by solvent casting method and characterized for physicochemical and in vitro permeation studies through excised rat skin. Among the tested preparations, formulations with 20% risperidone, 3:2 ERL 100 and ERS 100 as polymers, mixture of olive oil and jojoba oil as enhancer, exhibited greatest cumulative amount of drug permeated (1.87 ± 0.09 mg/cm(2)) in 72 h, so batch ROJ was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic and skin irritation potential. The pharmacokinetic characteristics of the optimized risperidone patch were determined using rabbits, while orally administered risperidone in solution was used for comparison. The calculated relative bioavailability of risperidone transdermal patch was 115.20% with prolonged release of drug. Neuroleptic efficacy of transdermal formulation was assessed by rota-rod and grip test in comparison with control and marketed oral formulations with no skin irritation. This suggests the transdermal application of risperidone holds promise for improved bioavailability and better management of schizophrenia in long-term basis.

An investigation into the floating behaviour of a pectin-containing anti-reflux formulation by means of gamma scintigraphy

International Nuclear Information System (INIS)

Washington, N.; Wilson, C.G.; Greaves, J.L.; Danneskiold-Samsoee, P.

1988-01-01

The gastric distribution and residence time of a new pectin-containing formulation, FF5005 (Farma Food A/S, Denmark) was investigated by using the technique of gamma scintigraphy in six healthy volunteers after administration with a radiolabelled meal. The formulation and test meal were radiolabelled with indium-113m and technetium-99m, respectively, and the formulation was administered to the subjects 30 min after the labelled meal. FF5005 was shown to float and form a discrete phase on top of the stomach contents, and emptied from the stomach more slowly than the food (p<0.05, Wilcoxon signed rank test). The times taken for the formulation and test meal to half-empty from the stomach (T 5 0) were 4.13 ±0.69 h (mean ±SD) and 2.17 ±0.15 h (mean ±SD), respectively. More than 50% of the formulation remained in the fundal region of the stomach for 3 h. FF5005 produced in vivo behaviour similar to that of established alginate-containing anti-reflux agents, and the pectin content of the formulation was shown to decrease the rate of emptying of the meal

Pharmacokinetics of a concentrated buprenorphine formulation in red-tailed hawks (Buteo jamaicensis).

Science.gov (United States)

Gleeson, Molly D; Guzman, David Sanchez-Migallon; Knych, Heather K; Kass, Philip H; Drazenovich, Tracy L; Hawkins, Michelle G

2018-01-01

OBJECTIVE To determine the pharmacokinetics and sedative effects of 2 doses of a concentrated buprenorphine formulation after SC administration to red-tailed hawks (Buteo jamaicensis). ANIMALS 6 adult red-tailed hawks. PROCEDURES Concentrated buprenorphine (0.3 mg/kg, SC) was administered to all birds. Blood samples were collected at 10 time points over 24 hours after drug administration to determine plasma buprenorphine concentrations. After a 4-week washout period, the same birds received the same formulation at a higher dose (1.8 mg/kg, SC), and blood samples were collected at 13 time points over 96 hours. Hawks were monitored for adverse effects and assigned agitation-sedation scores at each sample collection time. Plasma buprenorphine concentrations were quantified by liquid chromatography-tandem mass spectrometry. RESULTS Mean time to maximum plasma buprenorphine concentration was 7.2 minutes and 26.1 minutes after administration of the 0.3-mg/kg and 1.8-mg/kg doses, respectively. Plasma buprenorphine concentrations were > 1 ng/mL for mean durations of 24 and 48 hours after low- and high-dose administration, respectively. Mean elimination half-life was 6.23 hours for the low dose and 7.84 hours for the high dose. Mean agitation-sedation scores were higher (indicating some degree of sedation) than the baseline values for 24 hours at both doses. No clinically important adverse effects were observed. CONCLUSIONS AND CLINICAL RELEVANCE Concentrated buprenorphine was rapidly absorbed, and plasma drug concentrations considered to have analgesic effects in other raptor species were maintained for extended periods. Most birds had mild to moderate sedation. Additional studies are needed to evaluate the pharmacodynamics of these doses of concentrated buprenorphine in red-tailed hawks.

Township Administered Roads

Data.gov (United States)

Minnesota Department of Natural Resources — This data set contains roadway centerlines for township administered roads found on the USGS 1:24,000 mapping series. In some areas, these roadways are current...

Microscopic description of rotational spectra including band-mixing. 1. Formulation in a microscopic basis

International Nuclear Information System (INIS)

Brut, F.; Jang, S.

1982-05-01

Within the framework of the projection theory of collective motion, a microscopic description of the rotational energy with band-mixing is formulated using a method based on an inverse power perturbation expansion in a quantity related to the expectation value of the operator Jsub(y)sup(2). The reliability of the present formulation is discussed in relation to the difference between the individual wave functions obtained from the variational equations which are established before and after projection. In addition to the various familiar quantities which appear in the phenomenological energy formula, such as the moment of inertia parameter, the decoupling factor and the band-mixing matrix element for ΔK=1, other unfamiliar quantities having the factors with peculiar phases, (-1)sup(J+1)J(J+1), (-1)sup(J+3/2)(J-1/2)(J+1/2)(J+3/2), (-1)sup(J+1/2)(J+1/2)J(J+1), (-1)sup(J)J(J+1)(J-1)(J+2) and [J(J+1)] 2 are obtained. The band-mixing term for ΔK=2 is also new. All these quantities are expressed in terms of two-body interactions and expectation values of the operator Jsub(y)sup(m), where m is an integer, within the framework of particle-hole formalism. The difference between the moment of inertia of an even-even and a neighboring even-odd nucleus, as well as the effect of band-mixing on the moment of inertia are studied. All results are put into the forms so as to facilitate comparisons with the corresponding phenomenological terms and also for further application

Absence of MxA induction by interferon beta in patients with MS reflects complete loss of bioactivity

DEFF Research Database (Denmark)

Hesse, D.; Sellebjerg, F.; Sorensen, P.S.

2009-01-01

BACKGROUND: In patients with multiple sclerosis (MS), neutralizing antibodies (NAbs) appearing during treatment with interferon (IFN) beta reduce or in high concentrations abolish bioactivity and therapeutic efficacy. In vivo MxA induction by IFNbeta is used as a marker of biologic response....... Lack of MxA in vivo response in patients with multiple sclerosis with NAbs is a reliable marker of a completely blocked biologic response to IFNbeta, with no indication of residual bioactivity Udgivelsesdato: 2009/8/4...

Selected HIV-1 Env trimeric formulations act as potent immunogens in a rabbit vaccination model

DEFF Research Database (Denmark)

Heyndrickx, Leo; Stewart-Jones, Guillaume; Jansson, Marianne Bendixen

2013-01-01

Ten to 30% of HIV-1 infected subjects develop broadly neutralizing antibodies (bNAbs) during chronic infection. We hypothesized that immunizing rabbits with viral envelope glycoproteins (Envs) from these patients may induce bNAbs, when formulated as a trimeric protein and in the presence of an ad...

Selected HIV-1 Env Trimeric Formulations Act as Potent Immunogens in a Rabbit Vaccination Model

NARCIS (Netherlands)

Heyndrickx, Leo; Stewart-Jones, Guillaume; Jansson, Marianne; Schuitemaker, Hanneke; Bowles, Emma; Buonaguro, Luigi; Grevstad, Berit; Vinner, Lasse; Vereecken, Katleen; Parker, Joe; Ramaswamy, Meghna; Biswas, Priscilla; Vanham, Guido; Scarlatti, Gabriella; Fomsgaard, Anders

2013-01-01

Ten to 30% of HIV-1 infected subjects develop broadly neutralizing antibodies (bNAbs) during chronic infection. We hypothesized that immunizing rabbits with viral envelope glycoproteins (Envs) from these patients may induce bNAbs, when formulated as a trimeric protein and in the presence of an

Pharmacokinetics of a new diclofenac sodium formulation developed for subcutaneous and intramuscular administration.

Science.gov (United States)

Zeitlinger, Markus; Rusca, Antonio; Oraha, Alhan Z; Gugliotta, Barbara; Müller, Markus; Ducharme, Murray P

2012-06-01

To assess the relative bioavailability of diclofenac sodium hydroxypropyl β-cyclodextrin (HPβCD) administered via the subcutaneous (s.c.) and intramuscular (i.m.) route versus Voltaren® i.m. and to evaluate the dose linearity and pharmacokinetics of the s.c. formulation at three dose levels. Safety and local tolerability were also assessed. One single-dose, randomized, three-way, crossover relative bioavailability study and one linearity single escalating dose, randomized, three-way cross-over pharmacokinetic study were conducted at two different clinical sites. A total of 42 healthy male and female subjects participated in both studies. Subjects received 75 mg/ml diclofenac sodium HPβCD (i.m. and s.c.) and Voltaren® 75 mg/3 ml (i.m.) in Study 1 and 25, 50, or 75 mg/ml diclofenac sodium HPβCD (s.c.) in Study 2. Study 1 demonstrated bioequivalence of the s.c. test formulation with Voltaren® i.m. with respect to Cmax and AUC. Bioequivalence of the test i.m. with Voltaren® i.m. was also demonstrated (except the upper limit of the 90% confidence interval (CI) for Cmax which marginally exceeded the 80 - 125% range (125.78%)). Study 2 demonstrated that after s.c. administration of the test formulation, both Cmax and AUC are linearly related to the tested diclofenac doses. All tested doses were safe and locally well-tolerated with no serious adverse events reported. Bioequivalence of diclofenac HPβCD 75 mg/ml after s.c. and i.m. administration with Voltaren® i.m. was demonstrated, except for the marginal deviation in Cmax when comparing the i.m. test and Voltaren®. Linearity was also demonstrated for the three doses intended for marketing.

Superactive cellulase formulation using cellobiohydrolase-1 from Penicillium funiculosum

Science.gov (United States)

Adney, William S.; Baker, John O.; Decker, Stephen R.; Chou, Yat-Chen; Himmel, Michael E.; Ding, Shi-You

2012-10-09

Purified cellobiohydrolase I (glycosyl hydrolase family 7 (Cel7A)) enzymes from Penicillium funiculosum demonstrate a high level of specific performance in comparison to other Cel7 family member enzymes when formulated with purified EIcd endoglucanase from A. cellulolyticus and tested on pretreated corn stover. This result is true of the purified native enzyme, as well as recombinantly expressed enzyme, for example, that enzyme expressed in a non-native Aspergillus host. In a specific example, the specific performance of the formulation using purified recombinant Cel7A from Penicillium funiculosum expressed in A. awamori is increased by more than 200% when compared to a formulation using purified Cel7A from Trichoderma reesei.

Superactive cellulase formulation using cellobiohydrolase-1 from Penicillium funiculosum

Science.gov (United States)

Adney, William S.; Baker, John O.; Decker, Stephen R.; Chou, Yat-Chen; Himmel, Michael E.; Ding, Shi-You

2008-11-11

Purified cellobiohydrolase I (glycosyl hydrolase family 7 (Cel7A) enzymes from Penicillium funiculosum demonstrate a high level of specific performance in comparison to other Cel7 family member enzymes when formulated with purified EIcd endoglucanase from A. cellulolyticus and tested on pretreated corn stover. This result is true of the purified native enzyme, as well as recombinantly expressed enzyme, for example, that enzyme expressed in a non-native Aspergillus host. In a specific example, the specific performance of the formulation using purified recombinant Cel7A from Penicillium funiculosum expressed in A. awamori is increased by more than 200% when compared to a formulation using purified Cel7A from Trichoderma reesei.

A formulation to encapsulate nootkatone for tick control.

Science.gov (United States)

Behle, Robert W; Flor-Weiler, Lina B; Bharadwaj, Anuja; Stafford, Kirby C

2011-11-01

Nootkatone is a component of grapefruit oil that is toxic to the disease-vectoring tick, Ixodes scapularis Say, but unfortunately causes phytotoxicity to treated plants and has a short residual activity due to volatility. We prepared a lignin-encapsulated nootkatone formulation to compare with a previously used emulsifiable formulation for volatility, plant phytotoxicity, and toxicity to unfed nymphs of I. scapularis. Volatility of nootkatone was measured directly by trapping nootkatone vapor in a closed system and indirectly by measuring nootkatone residue on treated filter paper after exposure to simulated sunlight (Xenon). After 24 h in the closed system, traps collected only 15% of the nootkatone applied as the encapsulated formulation compared with 40% applied as the emulsifiable formulation. After a 1-h light exposure, the encapsulated formulation retained 92% of the nootkatone concentration compared with only 26% retained by the emulsifiable formulation. For plant phytotoxicity, cabbage, Brassica oleracea L., leaves treated with the encapsulated formulation expressed less necrosis, retaining greater leaf weight compared with leaves treated with the emusifiable formulation. The nootkatone in the emulsifiable formulation was absorbed by cabbage and oat, Avena sativa L., plants (41 and 60% recovered 2 h after application, respectively), as opposed to 100% recovery from the plants treated with encapsulated nootkatone. Using a treated vial technique, encapsulated nootkatone was significantly more toxic to I. scapularis nymphs (LC50 = 20 ng/cm2) compared with toxicity of the emulsifiable formulation (LC50 = 35 ng/cm2). Thus, the encapsulation of nootkatone improved toxicity for tick control, reduced nootkatone volatility, and reduced plant phytotoxicity.

How reliable are case formulations? A systematic literature review.

Science.gov (United States)

Flinn, Lucinda; Braham, Louise; das Nair, Roshan

2015-09-01

This systematic literature review investigated the inter-rater and test-retest reliability of case formulations. We considered the reliability of case formulations across a range of theoretical modalities and the general quality of the primary research studies. A systematic search of five electronic databases was conducted in addition to reference list trawling to find studies that assessed the reliability of case formulation. This yielded 18 studies for review. A methodological quality assessment tool was developed to assess the quality of studies, which informed interpretation of the findings. Results indicated inter-rater reliability mainly ranging from slight (.1-.4) to substantial (.81-1.0). Some studies highlighted that training and increased experience led to higher levels of agreement. In general, psychodynamic formulations appeared to generate somewhat increased levels of reliability than cognitive or behavioural formulations; however, these studies also included methods that may have served to inflate reliability, for example, pooling the scores of judges. Only one study investigated the test-retest reliability of case formulations yielding support for the stability of formulations over a 3-month period. Reliability of case formulations is varied across a range of theoretical modalities, but can be improved; however, further research is required to strengthen our conclusions. Clinical implications: The findings from the review evidence some support for case formulation being congruent with the scientist-practitioner approach. The reliability of case formulation is likely to be improved through training and clinical experience. Limitations: The broad inclusion criteria may have introduced heterogeneity into the sample, which may have affected the results. Studies reviewed were limited to peer-reviewed journal articles written in the English language, which may represent a source of publication and selection bias. © 2014 The British Psychological Society.

Formulation, stability study, and pre-clinical evaluation of a vaginal cream containing curcumin in a rat model of vulvovaginal candidiasis.

Science.gov (United States)

de Souza Fernandes, Lígia; Amorim, Yuri Martins; Silva, Elton Libério da; Silva, Samuel Calixto; Santos, Alécia Junia Aparecida; Peixoto, Franciele Natália; Pires, Luara Moniele Neves; Sakamoto, Raquel Yumi; Pinto, Flávia do Carmo Horta; Scarpa, Maria Virgínia Costa; Gonzaga de Freitas Araújo, Marcelo

2018-03-08

Owing to the growing resistance among isolates of Candida species to usual antifungal agents and the well-known therapeutic potential of curcumin, the purpose of this study was to develop and validate a vaginal formulation containing this substance and to evaluating its effectiveness in the treatment of experimental vulvovaginal candidiasis METHODS: Curcumin was incorporated in a vaginal cream in three concentrations (0.01, 0.1 and 1.0%). The different concentrations of the cream and its controls were intravaginally administered in an immunosuppressed rat model to evaluate the efficacy in the treatment of experimental vulvovaginal candidiasis. Samples of the cream were also subjected to centrifugation and physical stability tests and an analytical method for quantification of curcumin was validated based on HPLC RESULTS: The formulation was stable and the HPLC method could be considered suitable for the quantitative determination of curcumin in the cream. After six days of pre-clinical study, the number of infected animals was 1/6 in all groups treated with curcumin vaginal cream and the fungal burden showed a progressive reduction. Reduction of the inflammatory infiltrate was observed in the group treated with 1.0% cream CONCLUSION: Vaginal cream containing curcumin could be considered a promising effective antifungal medicine in the treatment of vulvovaginal candidiasis. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Phytoremediation of lowland soil contaminated with a formulated mixture of Imazethapyr and Imazapic1

Directory of Open Access Journals (Sweden)

Kelen Müller Souto

Full Text Available The use of plants to decontaminate water and soil contaminated with both organic and inorganic pollutants is a promising technology for sustainable agriculture. The aim of this work was to evaluate the efficiency of plant species in the remediation of formulated mixtures of imazethapyr and imazapic, using the irrigated rice cultivar IRGA 417 as bioindicator. The treatments consisted of the combination of 13 plant species with seven rates of a formulated mixture of imazethapyr and Imazapic (75+25 g e.a. L-1 respectively: 0, 200, 300, 400, 500, 1000 and 4000 mL ha-1. To evaluate the potential for phytoremediation in these species, symptoms of injury and plant height were measured in rice plants at 7, 14, 21 and 28 days after emergence and shoot dry weight at 28 days after emergence. Glycine max, Lolium multiflorum and Lotus corniculatus are potentially promising species in the phytoremediation of soils contaminated with the herbicide imazethapyr and imazapic (up to 4000 mL ha-1, due to being more adapted to hydromorphic environments, which is a feature found in soils cultivated with irrigated rice. Crotalaria juncea, Canavalia ensiformis, Stizolobium aterrimum, Vicia sativa, Raphanus sativus and Triticum aestivum are species capable of the phytoremediation of soils contaminated with imazethapyr + imazapic, however the occurrence of anoxia in hydromorphic soils reduce the establishment and development of these plants.

The Schwinger Model on S 1: Hamiltonian Formulation, Vacuum and Anomaly

Science.gov (United States)

Stuart, David

2014-12-01

We present a Hamiltonian formulation of the Schwinger model with spatial domain taken to be the circle. It is shown that, in Coulomb gauge, the Hamiltonian is a semi-bounded, self-adjoint operator which is invariant under the group of large gauge transformations. There is a nontrivial action of on fermionic Fock space and its vacuum. This action plays a role analogous to that played by the spectral flow in the infinite Dirac sea formalism. The formulation allows (1) a description of the anomaly and its relation to the group action, and (2) an explicit identification of the vacuum. The anomaly in the chiral conservation law appears as a consequence of insisting upon semi-boundedness and gauge invariance of the quantized Hamiltonian.

Comparative pharmacokinetic and pharmacodynamic evaluation of branded and generic formulations of meloxicam in healthy male volunteers

Directory of Open Access Journals (Sweden)

Del Tacca M

2013-07-01

Full Text Available Mario Del Tacca,1,2 Giuseppe Pasqualetti,3 Giovanni Gori,1 Pasquale Pepe,1 Antonello Di Paolo,2 Marianna Lastella,2 Ferdinando De Negri,1 Corrado Blandizzi2 1Clinical Pharmacology Centre for Drug Experimentation, Pisa University Hospital, 2Department of Clinical and Experimental Medicine, 3Geriatrics Unit, University of Pisa, Pisa, Italy Purpose: The primary aim of the present study was to assess the pharmacokinetic bioequivalence between a generic formulation of meloxicam 15 mg tablets (Meloxicam Hexal and its respective brand product (Mobic, in order to verify whether the generic product conforms to the regulatory standards of bioequivalence in the postmarketing setting. As a secondary exploratory aim, the pharmacodynamic effects of the two formulations were also evaluated by means of rating scales following hyperalgesia induced by cutaneous freeze injury. Subjects and methods: A single 15 mg dose of generic or branded meloxicam tablets was administered to 24 healthy male volunteers in a crossover fashion. Plasma samples, collected for 24 hours after dosing, were assayed for meloxicam concentration by a validated high-performance liquid chromatography method. Results: The analysis of pharmacokinetic parameters did not show any significant difference between the two meloxicam formulations: the 90% confidence intervals fell within the acceptance range of 80%–125% (0.84–1.16 for area under the curve [0–24], and 0.89–1.23 for peak concentration. No difference in the pharmacodynamic end point was observed between the two groups. Conclusion: The pharmacokinetic profiles of the two meloxicam formulations confirm the regulatory criteria for bioequivalence; pharmacodynamic data indicate a similar antihyperalgesic effect. The two formulations can be used interchangeably in the clinical setting. Keywords: meloxicam, pharmacokinetics, healthy volunteers, generic drug, bioequivalence, postmarketing

The tensor calculus and matter coupling of the alternative minimal auxiliary field formulation of N = 1 supergravity

International Nuclear Information System (INIS)

Sohnius, M.; West, P.

1982-01-01

The tensor calculus for the new alternative minimal auxiliary field formulation of N = 1 supergravity is given. It is used to construct the couplings of this formulation of supergravity to matter. These couplings are found to be different, in several respects to those of the old minimal formulation of N = 1 supergravity. (orig.)

Inventory of oral anticancer agents : Pharmaceutical formulation aspects with focus on the solid dispersion technique

NARCIS (Netherlands)

Sawicki, E.; Schellens, J. H M; Beijnen, J. H.; Nuijen, B.

2016-01-01

Dissolution from the pharmaceutical formulation is a prerequisite for complete and consistent absorption of any orally administered drug, including anticancer agents (oncolytics). Poor dissolution of an oncolytic can result in low oral bioavailability, high variability in blood concentrations and

20 CFR 1.6 - How were many of OWCP's current functions administered in the past?

Science.gov (United States)

2010-04-01

... 20 Employees' Benefits 1 2010-04-01 2010-04-01 false How were many of OWCP's current functions administered in the past? 1.6 Section 1.6 Employees' Benefits OFFICE OF WORKERS' COMPENSATION PROGRAMS, DEPARTMENT OF LABOR ORGANIZATION AND PROCEDURES PERFORMANCE OF FUNCTIONS § 1.6 How were many of OWCP's...

Sodium Lauryl Sulfate Increases the Efficacy of a Topical Formulation of Foscarnet against Herpes Simplex Virus Type 1 Cutaneous Lesions in Mice

Science.gov (United States)

Piret, Jocelyne; Désormeaux, André; Cormier, Hélène; Lamontagne, Julie; Gourde, Pierrette; Juhász, Julianna; Bergeron, Michel G.

2000-01-01

The influence of sodium lauryl sulfate (SLS) on the efficacies of topical gel formulations of foscarnet against herpes simplex virus type 1 (HSV-1) cutaneous infection has been evaluated in mice. A single application of the gel formulation containing 3% foscarnet given 24 h postinfection exerted only a modest effect on the development of herpetic skin lesions. Of prime interest, the addition of 5% SLS to this gel formulation markedly reduced the mean lesion score. The improved efficacy of the foscarnet formulation containing SLS could be attributed to an increased penetration of the antiviral agent into the epidermis. In vitro, SLS decreased in a concentration-dependent manner the infectivities of herpesviruses for Vero cells. SLS also inhibited the HSV-1 strain F-induced cytopathic effect. Combinations of foscarnet and SLS resulted in subsynergistic to subantagonistic effects, depending on the concentration used. Foscarnet in phosphate-buffered saline decreased in a dose-dependent manner the viability of cultured human skin fibroblasts. This toxic effect was markedly decreased when foscarnet was incorporated into the polymer matrix. The presence of SLS in the gel formulations did not alter the viabilities of these cells. The use of gel formulations containing foscarnet and SLS could represent an attractive approach to the treatment of herpetic mucocutaneous lesions, especially those caused by acyclovir-resistant strains. PMID:10952566

Identification of new sensitive biomarkers for the in vivo response to interferon-beta treatment in multiple sclerosis using DNA-array evaluation

DEFF Research Database (Denmark)

Sellebjerg, F.; Krakauer, M.; Hesse, D.

2009-01-01

Neutralizing antibodies (NAbs) occur in a proportion of multiple sclerosis (MS) patients treated with interferon (IFN)-beta. NAbs impair the effect of treatment. The biological effect of IFN-beta can be measured as the induction of the myxovirus resistance protein A (MxA) molecule. However, other...

Using reverse genetics to manipulate the NSs gene of the Rift Valley fever virus MP-12 strain to improve vaccine safety and efficacy.

Science.gov (United States)

Kalveram, Birte; Lihoradova, Olga; Indran, Sabarish V; Ikegami, Tetsuro

2011-11-01

Rift Valley fever virus (RVFV), which causes hemorrhagic fever, neurological disorders or blindness in humans, and a high rate abortion and fetal malformation in ruminants, has been classified as a HHS/USDA overlap select agent and a risk group 3 pathogen. It belongs to the genus Phlebovirus in the family Bunyaviridae and is one of the most virulent members of this family. Several reverse genetics systems for the RVFV MP-12 vaccine strain as well as wild-type RVFV strains, including ZH548 and ZH501, have been developed since 2006. The MP-12 strain (which is a risk group 2 pathogen and a non-select agent) is highly attenuated by several mutations in its M- and L-segments, but still carries virulent S-segment RNA, which encodes a functional virulence factor, NSs. The rMP12-C13type (C13type) carrying 69% in-frame deletion of NSs ORF lacks all the known NSs functions, while it replicates as efficient as does MP-12 in VeroE6 cells lacking type-I IFN. NSs induces a shut-off of host transcription including interferon (IFN)-beta mRNA and promotes degradation of double-stranded RNA-dependent protein kinase (PKR) at the post-translational level. IFN-beta is transcriptionally upregulated by interferon regulatory factor 3 (IRF-3), NF-kB and activator protein-1 (AP-1), and the binding of IFN-beta to IFN-alpha/beta receptor (IFNAR) stimulates the transcription of IFN-alpha genes or other interferon stimulated genes (ISGs), which induces host antiviral activities, whereas host transcription suppression including IFN-beta gene by NSs prevents the gene upregulations of those ISGs in response to viral replication although IRF-3, NF-kB and activator protein-1 (AP-1) can be activated by RVFV7. Thus, NSs is an excellent target to further attenuate MP-12, and to enhance host innate immune responses by abolishing the IFN-beta suppression function. Here, we describe a protocol for generating a recombinant MP-12 encoding mutated NSs, and provide an example of a screening method to identify

7 CFR 1.29 - Subpoenas relating to investigations under statutes administered by the Secretary of Agriculture.

Science.gov (United States)

2010-01-01

... 7 Agriculture 1 2010-01-01 2010-01-01 false Subpoenas relating to investigations under statutes administered by the Secretary of Agriculture. 1.29 Section 1.29 Agriculture Office of the Secretary of Agriculture ADMINISTRATIVE REGULATIONS Departmental Proceedings § 1.29 Subpoenas relating to investigations...

Preclinical safety evaluation of intravenously administered mixed micelles.

Science.gov (United States)

Teelmann, K; Schläppi, B; Schüpbach, M; Kistler, A

1984-01-01

Mixed micelles, with their main constituents lecithin and glycocholic acid, form a new principle for the parenteral administration of compounds which are poorly water-soluble. Their composition of mainly physiological substances as well as their comparatively good stability substantiate their attractivity in comparison to existing solvents. A decomposition due to physical influences such as heat or storage for several years will almost exclusively affect the lecithin component in the form of hydrolysis into free fatty acids and lysolecithin. Their toxicity was examined experimentally in various studies using both undecomposed and artificially decomposed mixed micelles. In these studies the mixed micelles were locally and systemically well tolerated and proved to be neither embryotoxic, teratogenic nor mutagenic. Only when comparatively high doses of the undecomposed mixed micelles were administered, corresponding to approximately 30 to 50 times the anticipated clinical injection volume (of e.g. diazepam mixed micelles), did some vomitus (dogs), slight liver enzyme elevation (rats and dogs), and slightly increased liver weights (dogs) occur. After repeated injections of the artificially decomposed formulation (approximately 25% of lecithin hydrolyzed to free fatty acids and lysolecithin) effects such as intravascular haemolysis, liver enzyme elevations and intrahepatic cholestasis (dogs only) were observed but only when doses exceeding a threshold of approximately 40 to 60 mg lysolecithin/kg body weight were administered. All alterations were reversible after cessation of treatment.

Need for appropriate formulations for children: the national institute of child health and human development-pediatric formulations initiative, part 1.

Science.gov (United States)

Giacoia, George P; Taylor-Zapata, Perdita; Mattison, Donald

2007-01-01

The development and compounding of pharmacotherapeutic formulations that are suitable for infants and young children can be a challenging problem. This problem results from the lack of knowledge on the acceptability of different dosage forms and formulations in children in relation to age and developmental status, as well as the lack of reliable documentation of formulations used in pediatric clinical trials. As part of its mandate under the Best Pharmaceuticals for Children Act to improve pediatric therapeutics, the National Institute of Child Health and Human Development has sponsored the Pediatric Formulation Initiative. The goal of this ongoing initiative is to address the issues and concnerns associated with pediatric therapeutics by convening groups of researchers and experts in pediatric formulations from academia, pharmaceutical companies, the National Institutes of Health, and the U.S. Food and Drug Administration.

Efficient basis formulation for 1+1 dimensional SU(2) lattice gauge theory. Spectral calculations with matrix product states

Energy Technology Data Exchange (ETDEWEB)

Banuls, Mari Carmen; Cirac, J. Ignacio; Kuehn, Stefan [Max-Planck-Institut fuer Quantenoptik (MPQ), Garching (Germany); Cichy, Krzysztof [Frankfurt Univ. (Germany). Inst. fuer Theoretische Physik; Adam Mickiewicz Univ., Poznan (Poland). Faculty of Physics; Jansen, Karl [Deutsches Elektronen-Synchrotron (DESY), Zeuthen (Germany). John von Neumann-Inst. fuer Computing NIC

2017-07-20

We propose an explicit formulation of the physical subspace for a 1+1 dimensional SU(2) lattice gauge theory, where the gauge degrees of freedom are integrated out. Our formulation is completely general, and might be potentially suited for the design of future quantum simulators. Additionally, it allows for addressing the theory numerically with matrix product states. We apply this technique to explore the spectral properties of the model and the effect of truncating the gauge degrees of freedom to a small finite dimension. In particular, we determine the scaling exponents for the vector mass. Furthermore, we also compute the entanglement entropy in the ground state and study its scaling towards the continuum limit.

Efficient Basis Formulation for (1+1-Dimensional SU(2 Lattice Gauge Theory: Spectral Calculations with Matrix Product States

Directory of Open Access Journals (Sweden)

Mari Carmen Bañuls

2017-11-01

Full Text Available We propose an explicit formulation of the physical subspace for a (1+1-dimensional SU(2 lattice gauge theory, where the gauge degrees of freedom are integrated out. Our formulation is completely general, and might be potentially suited for the design of future quantum simulators. Additionally, it allows for addressing the theory numerically with matrix product states. We apply this technique to explore the spectral properties of the model and the effect of truncating the gauge degrees of freedom to a small finite dimension. In particular, we determine the scaling exponents for the vector mass. Furthermore, we also compute the entanglement entropy in the ground state and study its scaling towards the continuum limit.

Efficient Basis Formulation for (1 +1 )-Dimensional SU(2) Lattice Gauge Theory: Spectral Calculations with Matrix Product States

Science.gov (United States)

Bañuls, Mari Carmen; Cichy, Krzysztof; Cirac, J. Ignacio; Jansen, Karl; Kühn, Stefan

2017-10-01

We propose an explicit formulation of the physical subspace for a (1 +1 )-dimensional SU(2) lattice gauge theory, where the gauge degrees of freedom are integrated out. Our formulation is completely general, and might be potentially suited for the design of future quantum simulators. Additionally, it allows for addressing the theory numerically with matrix product states. We apply this technique to explore the spectral properties of the model and the effect of truncating the gauge degrees of freedom to a small finite dimension. In particular, we determine the scaling exponents for the vector mass. Furthermore, we also compute the entanglement entropy in the ground state and study its scaling towards the continuum limit.

Efficient basis formulation for 1+1 dimensional SU(2) lattice gauge theory. Spectral calculations with matrix product states

International Nuclear Information System (INIS)

Banuls, Mari Carmen; Cirac, J. Ignacio; Kuehn, Stefan; Cichy, Krzysztof; Adam Mickiewicz Univ., Poznan; Jansen, Karl

2017-01-01

We propose an explicit formulation of the physical subspace for a 1+1 dimensional SU(2) lattice gauge theory, where the gauge degrees of freedom are integrated out. Our formulation is completely general, and might be potentially suited for the design of future quantum simulators. Additionally, it allows for addressing the theory numerically with matrix product states. We apply this technique to explore the spectral properties of the model and the effect of truncating the gauge degrees of freedom to a small finite dimension. In particular, we determine the scaling exponents for the vector mass. Furthermore, we also compute the entanglement entropy in the ground state and study its scaling towards the continuum limit.

Variation in the binding of 125I-labeled interferon-beta ser to cellular receptors during growth of human renal and bladder carcinoma cells in vitro

International Nuclear Information System (INIS)

Ruzicka, F.J.; Schmid, S.M.; Groveman, D.S.; Cummings, K.B.; Borden, E.C.

1987-01-01

Studies of various established human bladder and renal carcinoma cell lines cultured in vitro demonstrated the presence of specific, saturable, high affinity binding sites for 125 I-labeled human interferon Beta ser IFN-beta ser). This recombinant produced interferon labeled with approximately one atom of 125 I/molecule of IFN expressed minimal or no loss of antiviral activity. A single class of binding sites (1000-2000/cell) with an affinity constant of 10(10)-10(11) L/M was measured at 4 degrees C for cells exhibiting widely different sensitivity to the antiproliferative effect of IFN-beta ser. Major fluctuations in the binding of 125 I-labeled IFN-beta ser to cellular receptors were observed during in vitro proliferation of four of five cell lines examined. A significant decrease (P less than 0.001) in specific binding was observed 48 h after cultures were established. Cell cycle analysis suggested that within the first 24 h and in the very late log and stationary phase of growth of ACHN (human renal carcinoma) cells, variations in the binding of 125 I-labeled IFN-beta ser were partially attributable to binding fluctuations during the mitotic cycle. The 2- to 3-fold decline 24 h following plating of ACHN cells corresponded to a 70% decrease in the number of cells in G0-G1. T24 (human transitional cell carcinoma) and ACHN cells, synchronized by serum starvation, demonstrated increased binding of 125 I-labeled IFN-beta ser 4-16 h following serum replenishment. This increase in receptor binding occurred prior to the onset of DNA and protein synthesis and was followed by a decline immediately prior to cell division. Binding site analysis indicated that the increased binding prior to DNA synthesis was due to a 5- to 6-fold increase in receptor affinity for the radiolabeled ligand

Insulin degludec in type 1 diabetes: a randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine

NARCIS (Netherlands)

Birkeland, Kåre I.; Home, Philip D.; Wendisch, Ulrich; Ratner, Robert E.; Johansen, Thue; Endahl, Lars A.; Lyby, Karsten; Jendle, Johan H.; Roberts, Anthony P.; DeVries, J. Hans; Meneghini, Luigi F.

2011-01-01

Insulin degludec (IDeg) is a basal insulin that forms soluble multihexamers after subcutaneous injection, resulting in an ultra-long action profile. We assessed the efficacy and safety of IDeg formulations administered once daily in combination with mealtime insulin aspart in people with type 1

Pharmacokinetic and pharmacodynamic characteristics of a new pediatric formulation of artemether-lumefantrine in African children with uncomplicated Plasmodium falciparum malaria.

Science.gov (United States)

Djimdé, Abdoulaye A; Tekete, Mamadou; Abdulla, Salim; Lyimo, John; Bassat, Quique; Mandomando, Inacio; Lefèvre, Gilbert; Borrmann, Steffen

2011-09-01

The pharmacokinetic and pharmacodynamic properties of a new pediatric formulation of artemether-lumefantrine, dispersible tablet, were determined within the context of a multicenter, randomized, parallel-group study. In an exploratory approach, we compared a new pediatric formulation with the tablet formulation administered crushed in the treatment of African children with uncomplicated Plasmodium falciparum malaria. Patients were randomized to 3 different dosing groups (weights of 5 to DHA), were determined at 1 and 2 h after the first dose of dispersible (n = 91) and crushed (n = 93) tablets. A full pharmacokinetic profile of lumefantrine was reconstituted on the basis of 310 (dispersible tablet) and 315 (crushed tablet) plasma samples, collected at 6 different time points (1 sample per patient). Dispersible and crushed tablets showed similar artemether and DHA maximum concentrations in plasma (C(max)) for the different body weight groups, with overall means of 175 ± 168 and 190 ± 168 ng/ml, respectively, for artemether and 64.7 ± 58.1 and 63.7 ± 65.0 ng/ml, respectively, for DHA. For lumefantrine, the population C(max) were 6.3 μg/ml (dispersible tablet) and 7.7 μg/ml (crushed tablet), whereas the areas under the concentration-time curves from time zero to the time of the last quantifiable plasma concentration measured were 574 and 636 μg · h/ml, respectively. For both formulations, descriptive quintile analyses showed no apparent association between artemether/DHA C(max) and parasite clearance time or between the lumefantrine C(max) and the occurrence of adverse events or corrected QT interval changes. The results suggest that the dispersible tablet provides adequate systemic exposure to artemether, DHA, and lumefantrine in African children with uncomplicated P. falciparum malaria.

Safety and immunogenicity of a recombinant parvovirus B19 vaccine formulated with MF59C.1.

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Ballou, W Ripley; Reed, Jennifer L; Noble, William; Young, Neal S; Koenig, Scott

2003-02-15

A recombinant human parvovirus B19 vaccine (MEDI-491; MedImmune) composed of the VP1 and VP2 capsid proteins and formulated with MF59C.1 adjuvant was evaluated in a randomized, double-blind, phase 1 trial. Parvovirus B19-seronegative adults (n=24) received either 2.5 or 25 microg MEDI-491 at 0, 1, and 6 months. MEDI-491 was safe and immunogenic. All volunteers developed neutralizing antibody titers that peaked after the third immunization and were sustained through study day 364.

Safety and immunogenicity of a malaria vaccine, Plasmodium falciparum AMA-1/MSP-1 chimeric protein formulated in montanide ISA 720 in healthy adults.

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Jinhong Hu

Full Text Available BACKGROUND: The P. falciparum chimeric protein 2.9 (PfCP-2.9 consisting of the sequences of MSP1-19 and AMA-1 (III is a malaria vaccine candidate that was found to induce inhibitory antibodies in rabbits and monkeys. This was a phase I randomized, single-blind, placebo-controlled, dose-escalation study to evaluate the safety and immunogenicity of the PfCP-2.9 formulated with a novel adjuvant Montanide ISA720. Fifty-two subjects were randomly assigned to 4 dose groups of 10 participants, each receiving the test vaccine of 20, 50, 100, or 200 microg respectively, and 1 placebo group of 12 participants receiving the adjuvant only. METHODS AND FINDINGS: The vaccine formulation was shown to be safe and well-tolerated, and none of the participants withdrew. The total incidence of local adverse events (AEs was 75%, distributed among 58% of the placebo group and 80% of those vaccinated. Among the vaccinated, 65% had events that were mild and 15% experienced moderate AEs. Almost all systemic adverse reactions observed in this study were graded as mild and required no therapy. The participants receiving the test vaccine developed detectable antibody responses which were boosted by the repeated vaccinations. Sixty percent of the vaccinated participants had high ELISA titers (>1:10,000 of antigen-specific antibodies which could also recognize native parasite proteins in an immunofluorescence assay (IFA. CONCLUSION: This study is the first clinical trial for this candidate and builds on previous investigations supporting PfCP-2.9/ISA720 as a promising blood-stage malaria vaccine. Results demonstrate safety, tolerability (particularly at the lower doses tested and immunogenicity of the formulation. Further clinical development is ongoing to explore optimizing the dose and schedule of the formulation to decrease reactogenicity without compromising immunogenicity. TRIAL REGISTRATION: Chinese State Food and Drug Administration (SFDA 2002SL0046; Controlled

Intranasal delivery of paroxetine nanoemulsion via the olfactory region for the management of depression: formulation, behavioural and biochemical estimation

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Pandey, Yogendra Raj; Kumar, Shobhit; Gupta, Bijay Kumar; Ali, Javed; Baboota, Sanjula

2016-01-01

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) and is used for the treatment of depression and anxiety problems, but suffers from the drawback of poor oral bioavailability (less than 50%) due to its extensive first pass metabolism. The objective of the present study was to develop a paroxetine loaded nanoemulsion (o/w type) for direct nose-to-brain delivery. Nanoemulsions were prepared by the spontaneous emulsification technique using Capmul MCM, Solutol HS 15 and propylene glycol as oil phase, surfactant and co-surfactant, respectively, for delivery of drug directly to the brain through the nasal route for better management of depression. Formulations were studied for droplet size, polydispersity index (PDI), percentage transmittance, refractive index, viscosity, zeta potential, surface morphology and in vitro permeation study. TEM images of optimized formulation showed spherical droplets with a mean diameter of 58.47 ± 3.02 nm, PDI of 0.339 ± 0.007 and zeta potential values of -33 mV. The formulation showed good results for transmittance (100.60 ± 0.577%), refractive index (1.412 ± 0.003) and viscosity (40.85 ± 6.40 cP). Permeation studies revealed a 2.57-fold enhancement in permeation as compared to the paroxetine suspension. Behavioural studies such as the forced swimming test and locomotor activity test were done on Wistar rats to study the antidepressant effect of the optimized formulation. Treatment of depressed rats with paroxetine nanoemulsion (administered intranasally) significantly improved the behavioural activities in comparison to paroxetine suspension (orally administered). Biochemical estimation results revealed that the prepared nanoemulsion was effective in enhancing the depressed levels of glutathione and decreasing the elevated levels of TBARS.

Intranasal delivery of paroxetine nanoemulsion via the olfactory region for the management of depression: formulation, behavioural and biochemical estimation.

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Pandey, Yogendra Raj; Kumar, Shobhit; Gupta, Bijay Kumar; Ali, Javed; Baboota, Sanjula

2016-01-15

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) and is used for the treatment of depression and anxiety problems, but suffers from the drawback of poor oral bioavailability (less than 50%) due to its extensive first pass metabolism. The objective of the present study was to develop a paroxetine loaded nanoemulsion (o/w type) for direct nose-to-brain delivery. Nanoemulsions were prepared by the spontaneous emulsification technique using Capmul MCM, Solutol HS 15 and propylene glycol as oil phase, surfactant and co-surfactant, respectively, for delivery of drug directly to the brain through the nasal route for better management of depression. Formulations were studied for droplet size, polydispersity index (PDI), percentage transmittance, refractive index, viscosity, zeta potential, surface morphology and in vitro permeation study. TEM images of optimized formulation showed spherical droplets with a mean diameter of 58.47 ± 3.02 nm, PDI of 0.339 ± 0.007 and zeta potential values of -33 mV. The formulation showed good results for transmittance (100.60 ± 0.577%), refractive index (1.412 ± 0.003) and viscosity (40.85 ± 6.40 cP). Permeation studies revealed a 2.57-fold enhancement in permeation as compared to the paroxetine suspension. Behavioural studies such as the forced swimming test and locomotor activity test were done on Wistar rats to study the antidepressant effect of the optimized formulation. Treatment of depressed rats with paroxetine nanoemulsion (administered intranasally) significantly improved the behavioural activities in comparison to paroxetine suspension (orally administered). Biochemical estimation results revealed that the prepared nanoemulsion was effective in enhancing the depressed levels of glutathione and decreasing the elevated levels of TBARS.

Ivermectin disposition kinetics after subcutaneous and intramuscular administration of an oil-based formulation to cattle.

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Lifschitz, A; Virkel, G; Pis, A; Imperiale, F; Sanchez, S; Alvarez, L; Kujanek, R; Lanusse, C

1999-10-01

Slight differences in formulation may change the plasma kinetics and ecto-endoparasiticide activity of endectocide compounds. This work reports on the disposition kinetics and plasma availability of ivermectin (IVM) after subcutaneous (SC) and intramuscular (IM) administration as an oil-based formulation to cattle. Parasite-free Aberdeen Angus calves (n = 24; 240-280 kg) were divided into three groups (n = 8) and treated (200 microg/kg) with either an IVM oil-based pharmaceutical preparation (IVM-TEST formulation) (Bayer Argentina S.A.) given by subcutaneous (Group A) and intramuscular (Group B) injections or the IVM-CONTROL (non-aqueous formulation) (Ivomec, MSD Agvet) subcutaneously administered (Group C). Blood samples were taken over 35 days post-treatment and the recovered plasma was extracted and analyzed by HPLC using fluorescence detection. IVM was detected in plasma between 12 h and 35 days post-administration of IVM-TEST (SC and IM injections) and IVM-CONTROL formulations. Prolonged IVM absorption half-life (p oil-based formulation examined in this trial, compared to the standard preparation, may positively impact on its strategic use in cattle.

Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant.

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Binyamin, Orli; Larush, Liraz; Frid, Kati; Keller, Guy; Friedman-Levi, Yael; Ovadia, Haim; Abramsky, Oded; Magdassi, Shlomo; Gabizon, Ruth

2015-01-01

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and is associated with demyelination, neurodegeneration, and sensitivity to oxidative stress. In this work, we administered a nanodroplet formulation of pomegranate seed oil (PSO), denominated Nano-PSO, to mice induced for experimental autoimmune encephalomyelitis (EAE), an established model of MS. PSO comprises high levels of punicic acid, a unique polyunsaturated fatty acid considered as one of the strongest natural antioxidants. We show here that while EAE-induced mice treated with natural PSO presented some reduction in disease burden, this beneficial effect increased significantly when EAE mice were treated with Nano-PSO of specific size nanodroplets at much lower concentrations of the oil. Pathological examinations revealed that Nano-PSO administration dramatically reduced demyelination and oxidation of lipids in the brains of the affected animals, which are hallmarks of this severe neurological disease. We propose that novel formulations of natural antioxidants such as Nano-PSO may be considered for the treatment of patients suffering from demyelinating diseases. On the mechanistic side, our results demonstrate that lipid oxidation may be a seminal feature in both demyelination and neurodegeneration.

Bioequivalence study of a new sildenafil 100 mg orodispersible film compared to the conventional film-coated 100 mg tablet administered to healthy male volunteers

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Radicioni M

2017-04-01

Full Text Available Milko Radicioni,1 Chiara Castiglioni,1 Andrea Giori,2 Irma Cupone,3 Valeria Frangione,4 Stefano Rovati4 1CROSS Research S.A., Phase I Unit, Arzo, Switzerland; 2IBSA Farmaceutici Italia, Lodi, Italy; 3Bouty S.p.A., Strada Padana Superiore, Cassina De’ Pecchi, Italy; 4IBSA Institut Biochimique S.A., Pambio-Noranco, Switzerland Abstract: A new orodispersible film formulation of the phosphodiesterase type 5 inhibitor, sildenafil, has been developed to examine the advantages of an orally disintegrating film formulation and provide an alternative to the current marketed products for the treatment of erectile dysfunction. The pharmacokinetics of the sildenafil 100 mg orodispersible film (IBSA was compared to that of the conventional marketed 100 mg film-coated tablet (Viagra® after single-dose administration to 53 healthy male volunteers (aged 18–51 years in a randomized, open, two-way crossover bioequivalence study. Each subject received a single oral dose of 100 mg of sildenafil as test or reference formulation administered under fasting conditions at each of the two study periods according to a randomized crossover design. There was a washout interval of ≥7 days between the two administrations of the investigational medicinal products. Blood samples for pharmacokinetic analysis were collected up to 24 h post-dosing. The primary objective was to compare the rate (peak plasma concentration; Cmax and extent (area under the curve [AUC] from administration to last observed concentration time; AUC0–t of sildenafil absorption after single-dose administration of test and reference. Secondary endpoints were observed to describe the plasma pharmacokinetic profiles of sildenafil and its metabolite N-desmethyl-sildenafil relative bioavailability and safety profile after single-dose administration. The mean sildenafil and N-desmethyl-sildenafil plasma concentration–time profiles up to 24 h after single-dose administration of sildenafil 100 mg

Biochemical Tolerance During Low Dose Propylene Glycol Exposure in Neonates: A Formulation-Controlled Evaluation

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Aida Kulo

2012-07-01

Full Text Available Background and purpose of the study: Propylene glycol (PG is a frequently co-administered solvent in formulations administered to neonates, but reports on its (intolerance are limited. We aimed to report on renal, metabolic and hepatic tolerance before, during and following intravenous (iv PG-paracetamol exposure and compared these data with similar datasets reported in literature on neonates exposed to PG without paracetamol or paracetamol without PG.Methods: Renal (diuresis, creatinemia, sodium, metabolic (Base Excess, Anion Gap, lactate, bicarbonate and hepatic (liver enzymes, bilirubinemia indicators before, during and following iv paracetamol-PG exposure in neonates as included in the PARANEO (paracetamol in neonates study (intra-individual trends, ANOVA were collected and analysed.Comparison with observations collected in cases exposed to either iv phenobarbital-PG or iv paracetamol-mannitol (inter-individual comparison, Mann Whitney-U test were made. Results: PG exposure (median 34.1 mg/kg/24 h did not affect postnatal renal, metabolic and hepatic adaptations in 60 cases exposed to paracetamol-PG. These indicators were similar when compared to 29 cases exposed to phenobarbital- PG or 172 cases exposed to paracetamol-mannitol.Major conclusion: Based on observations in 89 neonates, low dose PG exposure was tolerated well. Studies on PG pharmacokinetics and its covariates are needed to estimate the upper level of PG tolerance in neonates.

Influenza A virus protein PB1-F2 exacerbates IFN-beta expression of human respiratory epithelial cells.

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Le Goffic, Ronan; Bouguyon, Edwige; Chevalier, Christophe; Vidic, Jasmina; Da Costa, Bruno; Leymarie, Olivier; Bourdieu, Christiane; Decamps, Laure; Dhorne-Pollet, Sophie; Delmas, Bernard

2010-10-15

The PB1-F2 protein of the influenza A virus (IAV) contributes to viral pathogenesis by a mechanism that is not well understood. PB1-F2 was shown to modulate apoptosis and to be targeted by the CD8(+) T cell response. In this study, we examined the downstream effects of PB1-F2 protein during IAV infection by measuring expression of the cellular genes in response to infection with wild-type WSN/33 and PB1-F2 knockout viruses in human lung epithelial cells. Wild-type virus infection resulted in a significant induction of genes involved in innate immunity. Knocking out the PB1-F2 gene strongly decreased the magnitude of expression of cellular genes implicated in antiviral response and MHC class I Ag presentation, suggesting that PB1-F2 exacerbates innate immune response. Biological network analysis revealed the IFN pathway as a link between PB1-F2 and deregulated genes. Using quantitative RT-PCR and IFN-β gene reporter assay, we determined that PB1-F2 mediates an upregulation of IFN-β expression that is dependent on NF-κB but not on AP-1 and IFN regulatory factor-3 transcription factors. Recombinant viruses knocked out for the PB1-F2 and/or the nonstructural viral protein 1 (the viral antagonist of the IFN response) genes provide further evidence that PB1-F2 increases IFN-β expression and that nonstructural viral protein 1 strongly antagonizes the effect of PB1-F2 on the innate response. Finally, we compared the effect of PB1-F2 variants taken from several IAV strains on IFN-β expression and found that PB1-F2-mediated IFN-β induction is significantly influenced by its amino acid sequence, demonstrating its importance in the host cell response triggered by IAV infection.

Effects of cytokines on the pituitary-adrenal axis in cancer patients.

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Nolten, W E; Goldstein, D; Lindstrom, M; McKenna, M V; Carlson, I H; Trump, D L; Schiller, J; Borden, E C; Ehrlich, E N

1993-10-01

Cytokines, which include interferons (IFNs), interleukins (ILs), and tumor necrosis factor (TNF), are immunoregulatory proteins produced by lymphocytes and inflammatory cells. Several cytokines, most noteworthy IFNs and ILs, stimulate glucocorticoid secretion. In this study, the effects of variable doses and repetitive administration of IFNs and TNF on secretion of pituitary hormones and cortisol were measured. Patients were given for a period of 15 days on alternating days injections of IFN-beta (IFN-beta ser), 90 or 450 x 10(6) IU, IFN-gamma, 0.1-100 x 10(6) IU, or TNF 125-275 micrograms/m2. Sixty to 120 min after IFN-beta ser injection median levels of cortisol, adrenocorticotropin (ACTH), prolactin (PRL), and growth hormone (GH) rose two-fold. Urinary free cortisol excretion increased significantly during the day following IFN-beta ser administration. IFN-gamma > or = 30 x 10(6) IU caused a comparable rise in plasma cortisol. TNF induced two- to four-fold increases in ACTH and cortisol. The fact that increased cortisol secretion was associated with a rise in the level of ACTH as well as PRL and GH suggests that the cytokines increased cortisol by stimulating the anterior pituitary. The hormonal response induced by cytokines was unrelated to their pyrogenic effect, undiminished with repetitive treatment, and not dose-dependent above a threshold level. These observations reinforce the concept of a physiologic link between the immune system and the hypothalamic-pituitary-adrenal (HPA) axis.

Dissolution rates of over-the-counter painkillers: a comparison among formulations.

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Alemanni, Matteo; Gatoulis, Sergio C; Voelker, Michael

2016-06-01

We wanted to compare the dissolution profile of several over-the-counter analgesics to understand whether the different formulation techniques employed to enhance absorption were associated with variations in the dissolution rate, a parameter known to affect drug absorption. We considered 5 formulations currently marketed in Italy: aspirin tablets (Aspirina Dolore e Infiammazione®), ibuprofen tablets and liquid capsules (Moment®), ibuprofen lysine tablets (Nurofenimmedia®) and dexketoprofen trometamol tablets (Enantyum®). Dissolution tests were performed according to the current USP/NF monograph dissolution procedure. Drug dissolution was evaluated at 1, 3, 6, 15, and 30 minutes since the start of the test. Dissolution was evaluated at three different pH: 1.2, 4.5 and 6.8. Every test was repeated 12 times. The aspirin formulation was by far the most rapid dissolving formulation, among those tested, with more than 80% of the tablet dissolved at 6 minutes for every pH considered. At pH 1.2 and 4.5, only the dexketoprofen formulation was able to reach the dissolution level of aspirin at 30 minutes, but had lower levels of dissolution at the previous time points. Instead, at pH 6.8, most of the formulations approached aspirin dissolution level, but only after 15 minutes. Ibuprofen capsules had the slowest kinetics, with a lag phase the first 6 minutes. Different formulation strategies can lead to great differences in the dissolution rates even among drugs of the same class, suggesting that enhancements in the formulation of painkillers can lead to improvements in drug absorption, and thus in the onset of analgesia.

Formulation and development of bicontinuous nanostructured liquid crystalline particles of efavirenz.

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Avachat, Amelia M; Parpani, Shreekrishna S

2015-02-01

Efavirenz is a lipophilic non-nucleoside reverse transcriptase inhibitor used in the first-line pediatric therapeutic cocktail. Due to its high lipophilicity (logP = 5.4) and poor aqueous solubility (intrinsic water solubility = 8.3 μg/mL) efavirenz has low bioavailability. A 30 mg/mL solution in a medium-chain triglyceride vehicle is the only pediatric formulation available with an oral bioavailability 20% lower than the solid form. The current work was aimed at formulating and characterizing liquid crystal nanoparticles for oral delivery of efavirenz to improve oral bioavailability, provide sustained release, minimize side effects and drug resistance. Formulation of cubosomes was done by two methods; sonication and spray drying. Sonication gave highest entrapment efficiency and least particle size. Further, monoolein was substituted with phytantriol as monoolein gets degraded in the presence of lipase when administered orally with consequent loss of liquid crystalline structure. It was confirmed that there was no difference in particle size, entrapment efficiency and nature of product formed by using monoolein or phytantriol. The best formulation was found to be F9, having particle size 104.19 ± 0.21 nm and entrapment efficiency 91.40 ± 0.10%. In vitro release at the end of 12h was found to be 56.45% and zeta potential to be -23.14 mV which stabilized the cubic phase dispersions. It was further characterized for TEM, small angle X-ray scattering (SAXS), DSC and stability studies. SAXS revealed Pn3m space group, indicating a diamond cubic phase which was further confirmed by TEM. Pharmacokinetics of EFV was studied in male Wistar rats. EFV-loaded cubosome dispersions exhibited 1.93 and 1.62-fold increase in peak plasma concentration (Cmax) and 1.48 and 1.42-fold increase in AUC in comparison to that of a suspension prepared with the contents of EFV capsules suspended in 1.5% carboxymethylcellulose PBS solution (pH 5.0), and an EFV solution in medium

A randomized trial comparing surgeon-administered intraoperative transversus abdominis plane block with anesthesiologist-administered transcutaneous block.

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Narasimhulu, D M; Scharfman, L; Minkoff, H; George, B; Homel, P; Tyagaraj, K

2018-04-27

Injection of local anesthetic into the transversus abdominis plane (TAP block) decreases systemic morphine requirements after abdominal surgery. We compared intraoperative surgeon-administered TAP block (surgical TAP) to anesthesiologist-administered transcutaneous ultrasound-guided TAP block (conventional TAP) for post-cesarean analgesia. We hypothesized that surgical TAP blocks would take less time to perform than conventional TAP blocks. We performed a randomized trial, recruiting 41 women undergoing cesarean delivery under neuraxial anesthesia, assigning them to either surgical TAP block (n=20) or conventional TAP block (n=21). Time taken to perform the block was the primary outcome, while postoperative pain scores and 24-hour opioid requirements were secondary outcomes. Student's t-test was used to compare block time and Kruskal-Wallis test opioid consumption and pain-scores. Time taken to perform the block (2.4 vs 12.1 min, P consumption (P=0.17) and postoperative pain scores at 4, 8, 24 and 48 h were not significantly different between the groups. Surgical TAP blocks are feasible and less time consuming than conventional TAP blocks, while providing comparable analgesia after cesarean delivery. Copyright © 2018 Elsevier Ltd. All rights reserved.

Comparative bioavailability and tolerability of a single 20-mg dose of two fluoxetine hydrochloride dispersible tablet formulations in fasting, healthy Chinese male volunteers: an open-label, randomized-sequence, two-period crossover study.

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Shi, Shaojun; Liu, Yani; Wu, Jianhong; Li, Zhongfang; Zhao, Yan; Zhong, Dafang; Zeng, Fandian

2010-10-01

The proprietary formulation of fluoxetine hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. Pharmacokinetic studies investigating the bioequivalence of generic and branded formulations are needed to market generic fluoxetine in China. The aim of this study was to compare the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of fluoxetine hydrochloride 20 mg in a fasting, healthy Chinese male population. This 10-week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 20-mg dose of the test or reference formulation, followed by a 35-day washout period and administration of the alternate formulation. Doses were administered after a 12-hour overnight fast. For analysis of pharmacokinetic properties (including C(max), T(max), AUC(0-t), AUC(0-∞), and t(½)), blood samples were obtained over a 672-hour period after dosing. Plasma concentrations of fluoxetine and its active metabolite, norfluoxetine, were analyzed using a validated LC-MS/MS method. The formulations were to be considered bioequivalent if the ln-transformed ratios (test/ reference) of C(max) and AUC were within the predetermined bioequivalence range of 80% to 125%, as established by the US Food and Drug Administration, and if the P values were fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated. Copyright © 2010 Excerpta Medica Inc. All rights reserved.

Head-To-Head Comparison of Different Solubility-Enabling Formulations of Etoposide and Their Consequent Solubility-Permeability Interplay.

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Beig, Avital; Miller, Jonathan M; Lindley, David; Carr, Robert A; Zocharski, Philip; Agbaria, Riad; Dahan, Arik

2015-09-01

The purpose of this study was to conduct a head-to-head comparison of different solubility-enabling formulations, and their consequent solubility-permeability interplay. The low-solubility anticancer drug etoposide was formulated in several strengths of four solubility-enabling formulations: hydroxypropyl-β-cyclodextrin, the cosolvent polyethylene glycol 400 (PEG-400), the surfactant sodium lauryl sulfate, and an amorphous solid dispersion formulation. The ability of these formulations to increase the solubility of etoposide was investigated, followed by permeability studies using the parallel artificial membrane permeability assay (PAMPA) and examination of the consequent solubility-permeability interplay. All formulations significantly increased etoposide's apparent solubility. The cyclodextrin-, surfactant-, and cosolvent-based formulations resulted in a concomitant decreased permeability that could be modeled directly from the proportional increase in the apparent solubility. On the contrary, etoposide permeability remained constant when using the ASD formulation, irrespective of the increased apparent solubility provided by the formulation. In conclusion, supersaturation resulting from the amorphous form overcomes the solubility-permeability tradeoff associated with other formulation techniques. Accounting for the solubility-permeability interplay may allow to develop better solubility-enabling formulations, thereby maximizing the overall absorption of lipophilic orally administered drugs. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

Dose escalation of a curcuminoid formulation

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Crowell James

2006-03-01

Full Text Available Abstract Background Curcumin is the major yellow pigment extracted from turmeric, a commonly-used spice in India and Southeast Asia that has broad anticarcinogenic and cancer chemopreventive potential. However, few systematic studies of curcumin's pharmacology and toxicology in humans have been performed. Methods A dose escalation study was conducted to determine the maximum tolerated dose and safety of a single dose of standardized powder extract, uniformly milled curcumin (C3 Complex™, Sabinsa Corporation. Healthy volunteers were administered escalating doses from 500 to 12,000 mg. Results Seven of twenty-four subjects (30% experienced only minimal toxicity that did not appear to be dose-related. No curcumin was detected in the serum of subjects administered 500, 1,000, 2,000, 4,000, 6,000 or 8,000 mg. Low levels of curcumin were detected in two subjects administered 10,000 or 12,000 mg. Conclusion The tolerance of curcumin in high single oral doses appears to be excellent. Given that achieving systemic bioavailability of curcumin or its metabolites may not be essential for colorectal cancer chemoprevention, these findings warrant further investigation for its utility as a long-term chemopreventive agent.

Formulation, Characterization and Physicochemical Evaluation of Ranitidine Effervescent Tablets

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Abolfazl Aslani

2013-08-01

Full Text Available Purpose: The aim of this study was to design, formulate and physicochemically evaluate effervescent ranitidine hydrochloride (HCl tablets since they are easily administered while the elderly and children sometimes have difficulties in swallowing oral dosage forms. Methods: Effervescent ranitidine HCl tablets were prepared in a dosage of 300 mg by fusion and direct compression methods. The powder blend and granule mixture were evaluated for various pre-compression characteristics, such as angle of repose, compressibility index, mean particle size and Hausner's ratio. The tablets were evaluated for post-compression features including weight variation, hardness, friability, drug content, dissolution time, carbon dioxide content, effervescence time, pH, content uniformity and water content. Effervescent systems with appropriate pre and post-compression qualities dissolved rapidly in water were selected as the best formulations. Results: The results showed that the flowability of fusion method is more than that of direct compression and the F5 and F6 formulations of 300 mg tablets were selected as the best formulations because of their physicochemical characteristics. Conclusion: In this study, citric acid, sodium bicarbonate and sweeteners (including mannitol, sucrose and aspartame were selected. Aspartame, mint and orange flavors were more effective for masking the bitter taste of ranitidine. The fusion method is the best alternative in terms of physicochemical and physical properties.

Subunit Rotavirus Vaccine Administered Parenterally to Rabbits Induces Active Protective Immunity

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Ciarlet, Max; Crawford, Sue E.; Barone, Christopher; Bertolotti-Ciarlet, Andrea; Ramig, Robert F.; Estes, Mary K.; Conner, Margaret E.

1998-01-01

Virus-like particles (VLPs) are being evaluated as a candidate rotavirus vaccine. The immunogenicity and protective efficacy of different formulations of VLPs administered parenterally to rabbits were tested. Two doses of VLPs (2/6-, G3 2/6/7-, or P[2], G3 2/4/6/7-VLPs) or SA11 simian rotavirus in Freund’s adjuvants, QS-21 (saponin adjuvant), or aluminum phosphate (AlP) were administered. Serological and mucosal immune responses were evaluated in all vaccinated and control rabbits before and after oral challenge with 103 50% infective doses of live P[14], G3 ALA lapine rotavirus. All VLP- and SA11-vaccinated rabbits developed high levels of rotavirus-specific serum and intestinal immunoglobulin G (IgG) antibodies but not intestinal IgA antibodies. SA11 and 2/4/6/7-VLPs afforded similar but much higher mean levels of protection than 2/6/7- or 2/6-VLPs in QS-21. The presence of neutralizing antibodies to VP4 correlated (P < 0.001, r = 0.55; Pearson’s correlation coefficient) with enhanced protection rates, suggesting that these antibodies are important for protection. Although the inclusion of VP4 resulted in higher mean protection levels, high levels of protection (87 to 100%) from infection were observed in individual rabbits immunized with 2/6/7- or 2/6-VLPs in Freund’s adjuvants. Therefore, neither VP7 nor VP4 was absolutely required to achieve protection from infection in the rabbit model when Freund’s adjuvant was used. Our results show that VLPs are immunogenic when administered parenterally to rabbits and that Freund’s adjuvant is a better adjuvant than QS-21. The use of the rabbit model may help further our understanding of the critical rotavirus proteins needed to induce active protection. VLPs are a promising candidate for a parenterally administered subunit rotavirus vaccine. PMID:9765471

Statistical analysis of Japanese Thorotrast-administered autopsy cases--1980

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Mori, T. (National Inst. of Radiological Sciences, Anagawa, Japan); Kato, Y.; Aoki, N.; Hatakeyama, S.

1983-01-01

In 193 cases autopsied between 1945 and 1980, all persons who had been intravascularly injected with Thorotrast in life, the authors found 131 malignant hepatic tumors, 20 liver cirrhoses, 6 myeloid leukemias, 4 erythroleukemias, 5 aplastic anemias, 4 lung cancers, 1 mesothelioma and 1 osteosarcoma. The causes of death in the Thorotrast-administered autopsy group (193 cases) were compared with those of a non-Thorotrast-administered autopsy group (95,000 cases) of the same sex and age at death as recorded in the Annals of Japanese Pathological Autopsy cases from 1958 to 1978. This comparison revealed that the frequencies of malignant hepatic tumors, liver cirrhosis, erythroleukemia, and aplastic anemia were significantly higher in the Thorotrast-administered group than in the non-Thorotrast-administered group.

Bioequivalence of Liposome-Entrapped Paclitaxel Easy-To-Use (LEP-ETU) formulation and paclitaxel in polyethoxylated castor oil: a randomized, two-period crossover study in patients with advanced cancer.

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Slingerland, Marije; Guchelaar, Henk-Jan; Rosing, Hilde; Scheulen, Max E; van Warmerdam, Laurence J C; Beijnen, Jos H; Gelderblom, Hans

2013-12-01

Preclinical studies comparing paclitaxel formulated with polyethoxylated castor oil with the sonicated formulation of liposome-entrapped paclitaxel (LEP) have demonstrated that LEP was associated with reduced toxicity while maintaining similar efficacy. Preliminary studies on the pharmacokinetics in patients support earlier preclinical data, which suggested that the LEP Easy-to-Use (LEP-ETU) formulation and paclitaxel formulated with castor oil may have comparable pharmacokinetic properties. Our objectives were: (1) to determine bioequivalence of paclitaxel pharmaceutically formulated as LEP-ETU (test) and paclitaxel formulated with castor oil (reference); and (2) to assess the tolerability of LEP-ETU following intravenous administration. Patients with advanced cancer were studied in a randomized, 2-period crossover bioequivalence study. Patients received paclitaxel 175 mg/m(2) administered as an intravenous infusion over 180 minutes, either as a single-treatment cycle of the test formulation followed by a single-treatment cycle of the reference formulation, or vice versa. Thirty-two of 58 patients were evaluable and were included in the analysis for bioequivalence. Mean total paclitaxel Cmax values for the test and reference formulations were 4955.0 and 5108.8 ng/mL, respectively. Corresponding AUC0-∞ values were 15,853.8 and 18,550.8 ng·h/mL, respectively. Treatment ratios of the geometric means were 97% (90% CI, 91%-103%) for Cmax and 84% (90% CI, 80%-90%) for AUC0-∞. These results met the required 80% to 125% bioequivalence criteria. The most frequently reported adverse events after LEP-ETU administration were fatigue, alopecia, and myalgia. At the studied dose regimen, LEP-ETU showed bioequivalence with paclitaxel formulated with polyethoxylated castor oil. © 2013 Elsevier HS Journals, Inc. All rights reserved.

Towards a methodology to formulate sustainable diets for livestock: accounting for environmental impact in diet formulation.

Science.gov (United States)

Mackenzie, S G; Leinonen, I; Ferguson, N; Kyriazakis, I

2016-05-28

The objective of this study was to develop a novel methodology that enables pig diets to be formulated explicitly for environmental impact objectives using a Life Cycle Assessment (LCA) approach. To achieve this, the following methodological issues had to be addressed: (1) account for environmental impacts caused by both ingredient choice and nutrient excretion, (2) formulate diets for multiple environmental impact objectives and (3) allow flexibility to identify the optimal nutritional composition for each environmental impact objective. An LCA model based on Canadian pig farms was integrated into a diet formulation tool to compare the use of different ingredients in Eastern and Western Canada. By allowing the feed energy content to vary, it was possible to identify the optimum energy density for different environmental impact objectives, while accounting for the expected effect of energy density on feed intake. A least-cost diet was compared with diets formulated to minimise the following objectives: non-renewable resource use, acidification potential, eutrophication potential, global warming potential and a combined environmental impact score (using these four categories). The resulting environmental impacts were compared using parallel Monte Carlo simulations to account for shared uncertainty. When optimising diets to minimise a single environmental impact category, reductions in the said category were observed in all cases. However, this was at the expense of increasing the impact in other categories and higher dietary costs. The methodology can identify nutritional strategies to minimise environmental impacts, such as increasing the nutritional density of the diets, compared with the least-cost formulation.

Formulation of Pine Tar Antidandruff Shampoo Assessment and Comparison With Some Commercial Formulations

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M. Gharavi

1990-07-01

Full Text Available In this study a pine tar shampoo as a new antidandruff formulation is presented. Assessment of antidandruff preparations has been hampered by the lack of standardized schedules, and reliable methods of evaluation.Some antidandruff agents such as : Zinc pyri-thione pine tar, selenium sulphide and (sulfure were used in shampoos. Samples were coded as numbers 1,2 formulated by us and 3,4 formulated commercially. The grading scheme based on 10 point scale, and corneocyte count was carried out on 50 selected volunte¬ers. Corneocyte count and fungal study proved that pine tor shampoo is effective against pityrosporum ovale. Draize lest was used for determination of the irritancy potential of the samples. Results showed that samples numbered 1,2 were relatively innocous in comparison with the others. I urthermore,s kin sensitination test on rabbit also confirmed the results obtained by Draize test. Consumer judgments proved that all formulations were acceptable.

Intranasal delivery of paroxetine nanoemulsion via the olfactory region for the management of depression: formulation, behavioural and biochemical estimation

International Nuclear Information System (INIS)

Pandey, Yogendra Raj; Kumar, Shobhit; Gupta, Bijay Kumar; Ali, Javed; Baboota, Sanjula

2016-01-01

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) and is used for the treatment of depression and anxiety problems, but suffers from the drawback of poor oral bioavailability (less than 50%) due to its extensive first pass metabolism. The objective of the present study was to develop a paroxetine loaded nanoemulsion (o/w type) for direct nose-to-brain delivery. Nanoemulsions were prepared by the spontaneous emulsification technique using Capmul MCM, Solutol HS 15 and propylene glycol as oil phase, surfactant and co-surfactant, respectively, for delivery of drug directly to the brain through the nasal route for better management of depression. Formulations were studied for droplet size, polydispersity index (PDI), percentage transmittance, refractive index, viscosity, zeta potential, surface morphology and in vitro permeation study. TEM images of optimized formulation showed spherical droplets with a mean diameter of 58.47 ± 3.02 nm, PDI of 0.339 ± 0.007 and zeta potential values of −33 mV. The formulation showed good results for transmittance (100.60 ± 0.577%), refractive index (1.412 ± 0.003) and viscosity (40.85 ± 6.40 cP). Permeation studies revealed a 2.57-fold enhancement in permeation as compared to the paroxetine suspension. Behavioural studies such as the forced swimming test and locomotor activity test were done on Wistar rats to study the antidepressant effect of the optimized formulation. Treatment of depressed rats with paroxetine nanoemulsion (administered intranasally) significantly improved the behavioural activities in comparison to paroxetine suspension (orally administered). Biochemical estimation results revealed that the prepared nanoemulsion was effective in enhancing the depressed levels of glutathione and decreasing the elevated levels of TBARS. (paper)

Variable thickness transient ground-water flow model. Volume 1. Formulation

International Nuclear Information System (INIS)

Reisenauer, A.E.

1979-12-01

Mathematical formulation for the variable thickness transient (VTT) model of an aquifer system is presented. The basic assumptions are described. Specific data requirements for the physical parameters are discussed. The boundary definitions and solution techniques of the numerical formulation of the system of equations are presented

Fractionation of radioactivity in the milk of goats administered 14C-aflatoxin B1

International Nuclear Information System (INIS)

Goto, T.; Hsieh, D.P.

1985-01-01

A detailed fractionation of radioactivity in the milk of goats administered 14 C-aflatoxin B1 at low doses was performed. The milk collected in the first 24 h following dosing contained radioactivity equivalent to 0.45-1.1% of the dose given. The radioactivity in each sample was partitioned into 4 fractions: ether, protein, dichloromethane, and water-alcohol. Over 80% of the radioactivity was detected in the dichloromethane fraction, of which over 95% was attributable to aflatoxin M1. No aflatoxin B1 or other known aflatoxin metabolites were detected in any fraction. The results indicate that the major metabolite of aflatoxin B1 in goat milk is aflatoxin M1 and that other metabolites, including conjugates, are of minor significance

Effects of a new foam formulation of ketoprofen lysine salt in experimental models of inflammation and hyperalgesia.

Science.gov (United States)

Daffonchio, L; Bestetti, A; Clavenna, G; Fedele, G; Ferrari, M P; Omini, C

1995-05-01

The anti-inflammatory and analgesic profile of a new topical foam formulation of ketoprofen lysine salt (CAS 57469-78-0, Artrosilene Schiuma, KLS-foam) was characterized in comparison with marketed gel formulations containing KLS (KLS-gel) or diclofenac diethylammonium salt (DCF-gel). KLS-foam dose-dependently inhibited oedema formation and hyperalgesia induced by subplantar injection of carrageenan or substance P, being more potent than KLS-gel. At equieffective anti-inflammatory doses, KLS-foam provided a more pronounced analgesic effect than DCF-gel. KLS-foam also markedly inhibited exudate formation and prostaglandin production induced by subcutaneous implantation of carrageenan soaked sponges. In carrageenan induced paw inflammation, KLS-foam provided the same anti-inflammatory effect as orally administered KLS, but induced significantly less gastric damages. Oral administration of KLS resulted in sustained systemic absorption of ketoprofen, whereas after topical application of KLS-foam no appreciable ketoprofen plasma levels were detected. These data support the anti-inflammatory and particularly the analgesic effectiveness of the new foam formulation of KLS, a finding that, together with the high gastric tolerability, further emphasizes the usefulness of KLS-foam in the treatment of localized flogistic diseases and associated pain.

Tribal formulations for treatment of pain: a study of the Bede community traditional medicinal practitioners of Porabari Village in Dhaka District, Bangladesh.

Science.gov (United States)

Seraj, Syeda; Jahan, Farhana Israt; Chowdhury, Anita Rani; Monjur-Ekhuda, Mohammad; Khan, Mohammad Shamiul Hasan; Aporna, Sadia Afrin; Jahan, Rownak; Samarrai, Walied; Islam, Farhana; Khatun, Zubaida; Rahmatullah, Mohammed

2012-01-01

body pain. A total of 65 plants belonging to 39 families were used in the formulations. The Fabaceae family provided 7 plants followed by the Solanaceae family with 4 plants. 47 out of the 53 formulations were used topically, 5 formulations were orally administered, and 1 formulation had both topical and oral uses. 8 formulations for treatment of rheumatic pain contained Calotropis gigantea, suggesting that the plant has strong potential for further scientific studies leading to discovery of novel efficacious compounds for rheumatic pain treatment.

[Preoperatively administered flomoxef sodium concentration in aqueous humor].

Science.gov (United States)

Miyamoto, Mariko; Watanabe, Yoichiro; Mizuki, Nobuhisa

2007-04-01

We intravenously administered flomoxef sodium (FMOX) 0.5-3.5 hours before cataract surgery and measured the concentration of the agent in the aqueous humor to investigate its penetration into the aqueous humor and its efficacy in the prevention of postoperative endophthalmitis. 56 patients who underwent cataract surgery were enrolled in this study. They received 1 g FMOX via a 20-minute intravenous drip beginning 0.5-3.5 hours before the operation. Aqueous humor was aspirated from the anterior chamber and assayed for FMOX concentration using high-performance liquid chromatography. The mean intraoperative FMOX concentrations in the patients' aqueous humor were 0.79 +/- 0.24 microg/ml (administered 3.5 hours before surgery)--1.47 0.79 microg/ml (administered 1.5 hours before surgery). These concentrations administered 0.5-3.0 hours before surgery sufficiently exceeded the minimum inhibitory concentration (MIC) 90 values against Staphylococcus epidermidis, Staphylococcus aureus and Propionibacterium acnes, but did not achieve the MIC90 values against Enterococcus faecalis and Pseudomonas aeruginosa. The FMOX concentrations in the aqueous humor sampling were adequate to kill bacteria in vitro. This drug may be efficacious in the prevention of postoperative endophthalmitis in patients undergoing cataract surgery.

Antimalarial Activity of Orally Administered Curcumin Incorporated in Eudragit®-Containing Liposomes

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Elisabet Martí Coma-Cros

2018-05-01

Full Text Available Curcumin is an antimalarial compound easy to obtain and inexpensive, having shown little toxicity across a diverse population. However, the clinical use of this interesting polyphenol has been hampered by its poor oral absorption, extremely low aqueous solubility and rapid metabolism. In this study, we have used the anionic copolymer Eudragit® S100 to assemble liposomes incorporating curcumin and containing either hyaluronan (Eudragit-hyaluronan liposomes or the water-soluble dextrin Nutriose® FM06 (Eudragit-nutriosomes. Upon oral administration of the rehydrated freeze-dried nanosystems administered at 25/75 mg curcumin·kg−1·day−1, only Eudragit-nutriosomes improved the in vivo antimalarial activity of curcumin in a dose-dependent manner, by enhancing the survival of all Plasmodium yoelii-infected mice up to 11/11 days, as compared to 6/7 days upon administration of an equal dose of the free compound. On the other hand, animals treated with curcumin incorporated in Eudragit-hyaluronan liposomes did not live longer than the controls, a result consistent with the lower stability of this formulation after reconstitution. Polymer-lipid nanovesicles hold promise for their development into systems for the oral delivery of curcumin-based antimalarial therapies.

Protective efficacy of a live attenuated anti-coccidial vaccine administered to 1-day-old chickens.

Science.gov (United States)

Crouch, C F; Andrews, S J; Ward, R G; Francis, M J

2003-06-01

The efficacy of a live attenuated anti-coccidial vaccine, Paracox-5, administered to 1-day-old chicks was investigated by assessing protection against changes in weight gain following virulent challenge. Vaccinated birds were challenged independently 28 days later with each of the component species (Eimeria acervulina, Eimeria maxima, Eimeria mitis or Eimeria tenella), and protection was demonstrated against associated reduction in weight gain and lesion formation. In addition, an improvement in bird performance, in terms of feed conversion ratio, was also observed following vaccination. Furthermore, under conditions designed to more closely mimic those in the field and using hatchery spray administration, protection against a mixed virulent challenge introduced by 'seeder birds' was demonstrated evenly across a flock of broiler birds within 21 days after vaccination. These data demonstrate that Paracox-5 vaccine will protect broiler chickens against the adverse effects on performance induced by Eimeria spp.

[Improvement of epirubicin-induced phlebitis to switch from liquid preparation to lyophilized formulation].

Science.gov (United States)

Suga, Yukio; Kumazaki, Masafumi; Nishigami, Jun; Takeda, Kazuyoshi; Kawagishi, Atsufumi; Ishizaki, Junko; Inokuchi, Masafumi; Miyamoto, Ken-Ichi; Arai, Kunizo

2009-01-01

Adjuvant chemotherapy containing epirubicin is commonly used to treat patients with pre- or post-operative breast cancer. It is known that the epirubicin(FarmorubicinRTU)preparation often caused phlebitis, whereas dexamethasone has been used to prevent that reaction. We examined whether the lyophilized formulation of epirubicin(Farmorubicin)can reduces the incidence of phlebitis compared with the preparation. All infusions were administered through a peripheral vein. Adverse drug reaction including phlebitis was evaluated after each infusion and at the subsequent visit to four or six cycles. Sixty-two patients were given the preparation and 35 the lyophilized formulation. Epirubicininduced phlebitis was observed in 45.7% of patients given the preparation and in 48.4% of those given the lyophilized formulation. There was no statistically significant difference between the two groups(p=0.41). However, the incidence of severe phlebitis requiring treatment with steroid ointment was significantly increased among patients treated with the preparation(27.4% vs 9.7%, pphlebitis between the two groups. In this study, lyophilized formulations of epirubicin significantly reduced the incidence of severe phlebitis compared with that among patients receiving the preparation. Using lyophilized formulations of epirubicin should be considered to prevent a reduction in QOL with epirubicin-induced phlebitis in patients with breast cancer.

Application of attenuated total reflectance Fourier transform infrared spectroscopy for determination of cefixime in oral pharmaceutical formulations.

Science.gov (United States)

Kandhro, Aftab A; Laghari, Abdul Hafeez; Mahesar, Sarfaraz A; Saleem, Rubina; Nelofar, Aisha; Khan, Salman Tariq; Sherazi, S T H

2013-11-01

A quick and reliable analytical method for the quantitative assessment of cefixime in orally administered pharmaceutical formulations is developed by using diamond cell attenuated total reflectance (ATR) Fourier transform infrared (FT-IR) spectroscopy as an easy procedure for quality control laboratories. The standards for calibration were prepared in aqueous medium ranging from 350 to 6000mg/kg. The calibration model was developed based on partial least square (PLS) using finger print region of FT-IR spectrum in the range from 1485 to 887cm(-1). Excellent coefficient of determination (R(2)) was achieved as high as 0.99976 with root mean square error of 44.8 for calibration. The application of diamond cell (smart accessory) ATR FT-IR proves a reliable determination of cefixime in pharmaceutical formulations to assess the quality of the final product. Copyright © 2013 Elsevier B.V. All rights reserved.

Bioavailability of isoniazid, rifampicin and pyrazinamide (in free combination or fixed-triple formulation) in intermittent antituberculous chemotherapy.

Science.gov (United States)

Acocella, G; Luisetti, M; Grassi, G G; Peona, V; Pozzi, E; Grassi, C

1993-01-01

A study was carried out in six human volunteers, to assess the blood kinetics of isoniazid, rifampicin and pyrazinamide, administered in a fixed-triple combination intended for use in intermittent chemotherapy of tuberculosis. The formulation employed contained 125 mg of isoniazid (H), 100 mg of rifampicin (R) and 375 mg of pyrazinamide (Z) per tablet; six tablets were administered to every subject, giving a total dosage of 750 mg of isoniazid, 600 mg of rifampicin and 2,250 mg of pyrazinamide. In each subject, the same dose of each drug was administered individually in separate sessions and the results compared. The results indicated that, at the level of dose of the intermittent tablet, no negative interactions between the drugs were observed.

Interlaboratory validation of 1% pluronic l92 surfactant as a suitable, aqueous vehicle for testing pesticide formulations using the murine local lymph node assay.

Science.gov (United States)

Boverhof, Darrell R; Wiescinski, Connie M; Botham, Phil; Lees, David; Debruyne, Eric; Repetto-Larsay, Marina; Ladics, Gregory; Hoban, Denise; Gamer, Armin; Remmele, Marina; Wang-Fan, Weizheng; Ullmann, Ludwig G; Mehta, Jyotigna; Billington, Richard; Woolhiser, Michael R

2008-09-01

The mouse local lymph node assay (LLNA) has become the preferred test for evaluating the dermal sensitization potential of chemicals and requirements are now emerging for its use in the evaluation of their formulated products, especially in the European Union. However, despite its widespread use and extensive validation, the use of this assay for directly testing mixtures and formulated products has been questioned, which could lead to repeat testing using multiple animal models. As pesticide formulations are typically a specific complex blend of chemicals for use as aqueous-based dilutions, traditional vehicles prescribed for the LLNA may change the properties of these formulations leading to inaccurate test results and hazard identification. The objective of this study was to evaluate the effectiveness of an aqueous solution of Pluronic L92 block copolymer surfactant (L92) as a vehicle in the mouse LLNA across five laboratories. Three chemicals with known sensitization potential and four pesticide formulations for which the sensitization potential in guinea pigs and/or humans had previously been assessed were used. Identical LLNA protocols and test materials were used in the evaluation. Assessment of the positive control chemicals, hexylcinnamaldehyde, formaldehyde, and potassium dichromate revealed positive results when using 1% aqueous L92 as the vehicle. Furthermore, results for these chemicals were reproducible among the five laboratories and demonstrated consistent relative potency determinations. The four pesticide formulations diluted in 1% aqueous L92 also demonstrated reproducible results in the LLNA among the five laboratories. Results for these test materials were also consistent with those generated previously using guinea pigs or from human experience. These data support testing aqueous compatible chemicals or pesticide formulations using the mouse LLNA, and provide additional support for the use of 1% aqueous L92 as a suitable, aqueous-based vehicle.

Efficacy of Topical Therapy with Newly Developed Terbinafine and Econazole Formulations in the Treatment of Dermatophytosis in Cats.

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Ivaskiene, M; Matusevicius, A P; Grigonis, A; Zamokas, G; Babickaite, L

2016-09-01

In the field of veterinary dermatology dermatophytosis is one of the most frequently occurring infectious diseases, therefore its treatment should be effective, convenient, safe and inexpensive. The aim of this study was to evaluate the efficacy of newly developed topical formulations in the treatment of cats with dermatophytosis. Evaluation of clinical efficacy and safety of terbinafine and econazole formulations administered topically twice a day was performed in 40 cats. Cats, suffering from the most widely spread Microsporum canis-induced dermatophytosis and treated with terbinafine hydrochloride 1% cream, recovered within 20.3±0.88 days; whereas when treated with econazole nitrate 1% cream, they recovered within 28.4±1.14 days. A positive therapeutic effect was yielded by combined treatment with local application of creams and whole coat spray with enilconazole 0.2% emulsion "Imaverol". Most cats treated with econazole cream revealed redness and irritation of the skin at the site of application. This study demonstrates that terbinafine tended to have superior clinical efficacy (p<0.001) in the treatment of dermatophytosis in cats compared to the azole tested.

Immunogenicity and safety of cell-derived MF59®-adjuvanted A/H1N1 influenza vaccine for children

Science.gov (United States)

Knuf, Markus; Leroux-Roels, Geert; Rümke, Hans; Rivera, Luis; Pedotti, Paola; Arora, Ashwani Kumar; Lattanzi, Maria; Kieninger, Dorothee; Cioppa, Giovanni Della

2015-01-01

Mass immunization of children has the potential to decrease infection rates and prevent the transmission of influenza. We evaluated the immunogenicity, safety, and tolerability of different formulations of cell-derived MF59-adjuvanted and nonadjuvanted A/H1N1 influenza vaccine in children and adolescents. This was a randomized, single-blind, multicenter study with a total of 666 healthy subjects aged 6 months–17 y in one of 3 vaccination groups, each receiving formulations containing different amounts of influenza A/H1N1 antigen with or without MF59. A booster trivalent seasonal MF59 vaccine was administered one year after primary vaccinations. Antibody titers were assessed by hemagglutination inhibition (HI) and microneutralization assays obtained on days 1, 22, 43, 366, and 387 (3 weeks post booster). Safety was monitored throughout the study. One vaccination with 3.75 μg of A/H1N1 antigen formulated with 50% MF59 (3.75_halfMF59) or 7.5 μg of A/H1N1 antigen formulated with 100% MF59 (7.5_fullMF59) induced an HI titer ≥1:40 in >70% of children in the 1–vaccinations with nonadjuvanted 15 μg A/H1N1 antigen were needed to achieve this response in the 1–children aged 6–11 months, 1 dose of 7.5_fullMF59 resulted in an HI titer ≥1:40 in >70% while 2 doses of 3.75_halfMF59 were required to achieve this result. All vaccines were well tolerated. Our findings support the immunogenicity and safety of the 3.75_halfMF59 (2 doses for children vaccine formulations for use in children and adolescents aged 6 months to 17 y The use of the 3.75_halfMF59 could have the benefit of antigen and adjuvant sparing, increasing the available vaccine doses allowing vaccination of more people. PMID:25621884

Pharmacological and clinical evidence of nevirapine immediate- and extended-release formulations

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Ena J

2012-11-01

Full Text Available Javier Ena, Concepción Amador, Conxa Benito, Francisco PasquauHIV Unit, Hospital Marina Baixa, Villajoyosa, SpainAbstract: We reviewed the current information available on nevirapine immediate- and extended-release formulations and its role in single-dose and combination antiretroviral therapy. Nevirapine was approved in 1996 and was the first non-nucleoside reverse-transcriptase inhibitor available for the treatment of HIV-1 infection. Nevirapine has demonstrated good efficacy and a well-characterized safety profile. A major drawback is the low genetic barrier, allowing the emergence of resistance in the presence of single mutations in the reverse-transcriptase gene. This shortcoming is particularly relevant when nevirapine is administered in a single dose to prevent mother-to-child transmission of HIV-1 infection, compromising the efficacy of future non-nucleoside reverse transcriptase–inhibitor regimens. Studies published recently have probed the noninferiority of nevirapine compared to ritonavir-boosted atazanavir with both tenofovir disoproxil fumarate and emtricitabine in antiretroviral treatment–naïve patients. In 2011, a new formulation of nevirapine (nevirapine extended release that allowed once-daily dosing was approved by the Food and Drug Administration and by the European Medicines Agency. VERxVe, a study comparing nevirapine extended release with nevirapine immediate release in antiretroviral treatment–naïve patients, and TRANxITION, a study carried out in antiretroviral treatment–experienced patients who switched therapy from nevirapine immediate release to nevirapine extended release, provided data on the noninferiority of the new formulation of nevirapine compared with nevirapine immediate release in terms of efficacy and safety. Nevirapine extended release will further increase the durability and persistence of nevirapine-containing antiretroviral therapy, allowing once-daily dosing regimens.Keywords: nevirapine

Formulated Beta-Cyfluthrin Shows Wide Divergence in Toxicity among Bird Species

OpenAIRE

Addy-Orduna, Laura M.; Zaccagnini, María-Elena; Canavelli, Sonia B.; Mineau, Pierre

2011-01-01

It is generally assumed that the toxicity of pyrethroid insecticides to birds is negligible, though few species have been tested. The oral acute toxicity of formulated beta-cyfluthrin was determined for canaries (Serinus sp.), shiny cowbirds (Molothrus bonariensis), and eared doves (Zenaida auriculata). Single doses were administered to adults by gavage. Approximate lethal doses 50 (LD50) and their confidence intervals were determined by approximate D-optimal design. Canaries were found to be...

Soft, chewable gelatin-based pharmaceutical oral formulations: a technical approach.

Science.gov (United States)

Dille, Morten J; Hattrem, Magnus N; Draget, Kurt I

2018-06-01

Hard tablets and capsules for oral drug delivery cause problems for people experiencing dysphagia. This work describes the formulation and properties of a gelatin based, self-preserved, and soft chewable tablet as an alternative and novel drug delivery format. Gelatin (8.8-10% in 24.7-29% water) constituted the matrix of the soft, semi-solid tablets. Three different pharmaceuticals (Ibuprofen 10%, Acetaminophen 15%, and Meloxicam 1.5%) were tested in this formulation. Microbial stability was controlled by lowering the water activity with a mixture of sorbitol and xylitol (45.6-55%). Rheological properties were tested applying small strain oscillation measurements. Taste masking of ibuprofen soft-chew tablets was achieved by keeping the ibuprofen insoluble at pH 4.5 and keeping the processing temperature below the crystalline-to-amorphous transition temperature. Soft-chew formulations showed good stability for all three pharmaceuticals (up to 24 months), and the ibuprofen containing formulation exhibited comparable dissolution to a standard oral tablet as well as good microbial stability. The rheological properties of the ibuprofen/gelatin formulation had the fingerprint of a true gelatin gel, albeit higher moduli, and melting temperature. The results suggest that easy-to-swallow and well taste-masked soft chewable tablet formulations with extended shelf life are within reach for several active pharmaceutical ingredients (APIs).

A systematic review of team formulation in clinical psychology practice: Definition, implementation, and outcomes.

Science.gov (United States)

Geach, Nicole; Moghaddam, Nima G; De Boos, Danielle

2017-10-03

Team formulation is promoted by professional practice guidelines for clinical psychologists. However, it is unclear whether team formulation is understood/implemented in consistent ways - or whether there is outcome evidence to support the promotion of this practice. This systematic review aimed to (1) synthesize how team formulation practice is defined and implemented by practitioner psychologists and (2) analyse the range of team formulation outcomes in the peer-reviewed literature. Seven electronic bibliographic databases were searched in June 2016. Eleven articles met inclusion criteria and were quality assessed. Extracted data were synthesized using content analysis. Descriptions of team formulation revealed three main forms of instantiation: (1) a structured, consultation approach; (2) semi-structured, reflective practice meetings; and (3) unstructured/informal sharing of ideas through routine interactions. Outcome evidence linked team formulation to a range of outcomes for staff teams and service users, including some negative outcomes. Quality appraisal identified significant issues with evaluation methods; such that, overall, outcomes were not well-supported. There is weak evidence to support the claimed beneficial outcomes of team formulation in practice. There is a need for greater specification and standardization of 'team formulation' practices, to enable a clearer understanding of any relationships with outcomes and implications for best-practice implementations. Under the umbrella term of 'team formulation', three types of practice are reported: (1) highly structured consultation; (2) reflective practice meetings; and (3) informal sharing of ideas. Outcomes linked to team formulation, including some negative outcomes, were not well evidenced. Research using robust study designs is required to investigate the process and outcomes of team formulation practice. © 2017 The British Psychological Society.

Development and validation of an in vitro–in vivo correlation (IVIVC model for propranolol hydrochloride extended-release matrix formulations

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Chinhwa Cheng

2014-06-01

Full Text Available The objective of this study was to develop an in vitro–in vivo correlation (IVIVC model for hydrophilic matrix extended-release (ER propranolol dosage formulations. The in vitro release characteristics of the drug were determined using USP apparatus I at 100 rpm, in a medium of varying pH (from pH 1.2 to pH 6.8. In vivo plasma concentrations and pharmacokinetic parameters in male beagle dogs were obtained after administering oral, ER formulations and immediate-release (IR commercial products. The similarity factor f2 was used to compare the dissolution data. The IVIVC model was developed using pooled fraction dissolved and fraction absorbed of propranolol ER formulations, ER-F and ER-S, with different release rates. An additional formulation ER-V, with a different release rate of propranolol, was prepared for evaluating the external predictability. The results showed that the percentage prediction error (%PE values of Cmax and AUC0–∞ were 0.86% and 5.95%, respectively, for the external validation study. The observed low prediction errors for Cmax and AUC0–∞ demonstrated that the propranolol IVIVC model was valid.

In vitro and preclinical assessment of an intranasal spray formulation of parathyroid hormone PTH 1-34 for the treatment of osteoporosis.

Science.gov (United States)

Williams, Allan J; Jordan, Faron; King, Gareth; Lewis, Andrew L; Illum, Lisbeth; Masud, Tahir; Perkins, Alan C; Pearson, Richard G

2018-01-15

Osteoporosis treatment with PTH 1-34 injections significantly reduces the incidence of bone fracture. Potential further reductions in fracture rate should be observed through nasal spray delivery to address the poor compliance associated with patient dislike of repeated PTH 1-34 subcutaneous injections. In vitro human osteoblast-like Saos-2 cell intracellular cAMP levels were used to define PTH 1-34 nasal spray formulation bioactivity. The chemically synthesised PTH 1-34 had an EC 50 of 0.76nM. Absorption enhancers polyethylene glycol (15)-hydroxystearate (Solutol ® HS15), poloxamer 407, chitosan or sodium hyaluronate did not diminish the bioactivity of PTH 1-34 within an in vitro cell culture model (p >0.05). We also demonstrated the effectiveness of the transmucosal absorption enhancer Solutol ® HS15 in a nasal spray formulation using a preclinical pharmacokinetic model. In Sprague-Dawley rats without the absorption enhancer the uptake of PTH 1-34 into the blood via intranasal delivery produced a Cmax of 2.1±0.5ng/ml compared to 13.7±1.6ng/ml with Solutol ® HS15 enhancer (p=0.016) and a Cmax14.8±8ng/ml in subcutaneous injections. Together these data illustrate that the nasal spray formulation bioactivity in vitro is not affected by the nasal spray absorption enhancers investigated, and the Solutol ® HS15 nasal spray formulation had an equivalent pharmacokinetic profile to subcutaneous injection in the rat model. The Solutol ® HS15 formulation therefore demonstrated potential as a PTH 1-34 nasal spray formulation for the treatment of osteoporosis. Copyright © 2017. Published by Elsevier B.V.

34 CFR 692.30 - How does a State administer its community service-learning job program?

Science.gov (United States)

2010-07-01

...-learning job program? 692.30 Section 692.30 Education Regulations of the Offices of the Department of... Administer Its Community Service-Learning Job Program? § 692.30 How does a State administer its community service-learning job program? (a)(1) Each year, a State may use up to 20 percent of its allotment for a...

Formulation, evaluation and comparison of the herbal shampoo with the commercial shampoos

Directory of Open Access Journals (Sweden)

Khaloud Al Badi

2014-12-01

Full Text Available The study aimed to formulate a pure herbal shampoo and to evaluate and compare its physicochemical properties with the marketed synthetic and herbal shampoos. The herbal shampoo was formulated by adding the extracts of Acacia concinna, Sapindus mukorossi, Phyllanthus emblica, Ziziphus spina-christi and Citrus aurantifolia in different proportions to a 10% aqueous gelatin solution. Small amount of methyl paraben was added as a preservative and pH was adjusted with citric acid. Several tests such as visual inspection, pH, wetting time, % of solid contents, foam volume and stability, surface tension, detergency, dirt dispersion etc, were performed to determine the physicochemical properties of both prepared and marketed shampoos. The formulated herbal shampoo was also evaluated for conditioning performance by administering a blind test to 20 student volunteers. The formulated herbal shampoo was clear and appealing. It showed good cleansing and detergency, low surface tension, small bubble size and good foam stability after 5 min. The prepared shampoo and commercial shampoos showed comparable results for % solid contents also. The score of the conditioning performance of the tress washed with herbal shampoo was found to be 3.0 out of 4, while the score of the marketed synthetic and herbal shampoo was 3.4 and 3.3 respectively. The results indicated the formulated shampoo is having excellent conditioning performance, at par with commercially available shampoo. However, further research and development is required to improve it's quality and safety.

Efficacy and Safety of a Multistrain Probiotic Formulation Depends from Manufacturing

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Vito Trinchieri

2017-11-01

Full Text Available BackgroundVariability in probiotics manufacturing may affect their properties, with potential implications for their efficacy and safety. This is of particular concern with probiotic products destined for use in patients with serious medical conditions, including human immunodeficiency virus (HIV infection. The purpose of the study was to carry out a series of experiments comparing the properties of the US-made probiotic formulation originally commercialized under the brand name VSL#3®, with those of the Italian-made formulation now commercialized under the same name. The US-made formulation has previously shown beneficial effects at the intestinal and neurological levels in HIV-infected subjects as well as in patients with inflammatory bowel diseases and hepatic encephalopathy.MethodsEleven subjects receiving combined antiretroviral therapy for HIV-1 were treated for 6 months with the US-made VSL#3 formulation. At baseline and 6 months, T-cells were analyzed for phenotype and activation markers, and fecal samples were analyzed for bifidobacteria, lactobacilli, and their metabolites. The fecal metabolome was assessed using 1H-NMR spectroscopy. Production of metabolites of interest by bacteria obtained from sachets of the two formulations was compared in vitro and their effects on a rat intestinal epithelial cell line (IEC-6 were assessed. Particular attention was paid to the metabolite 1,3-dihydroxyacetone (DHA.ResultsAt 6 months, fecal samples showed a significant increase in the specific bacterial genera contained in the probiotic supplement. Immune activation was reduced as shown by a significant reduction in the percentage of CD4+CD38+HLA-DR+ T-cells at 6 months. Fecal concentrations of DHA decreased significantly. In vitro, significant differences in the production and metabolism of DHA were found between bacteria from the US-made and Italian-made formulations: the US-made formulation was able to metabolize DHA whereas the bacteria

Immunogenicity of a virosomally-formulated Plasmodium falciparum GLURP-MSP3 chimeric protein-based malaria vaccine candidate in comparison to adjuvanted formulations

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Tamborrini Marco

2011-12-01

Full Text Available Abstract Background In clinical trials, immunopotentiating reconstituted influenza virosomes (IRIVs have shown great potential as a versatile antigen delivery platform for synthetic peptides derived from Plasmodium falciparum antigens. This study describes the immunogenicity of a virosomally-formulated recombinant fusion protein comprising domains of the two malaria vaccine candidate antigens MSP3 and GLURP. Methods The highly purified recombinant protein GMZ2 was coupled to phosphatidylethanolamine and the conjugates incorporated into the membrane of IRIVs. The immunogenicity of this adjuvant-free virosomal formulation was compared to GMZ2 formulated with the adjuvants Montanide ISA 720 and Alum in three mouse strains with different genetic backgrounds. Results Intramuscular injections of all three candidate vaccine formulations induced GMZ2-specific antibody responses in all mice tested. In general, the humoral immune response in outbred NMRI mice was stronger than that in inbred BALB/c and C57BL/6 mice. ELISA with the recombinant antigens demonstrated immunodominance of the GLURP component over the MSP3 component. However, compared to the Al(OH3-adjuvanted formulation the two other formulations elicited in NMRI mice a larger proportion of anti-MSP3 antibodies. Analyses of the induced GMZ2-specific IgG subclass profiles showed for all three formulations a predominance of the IgG1 isotype. Immune sera against all three formulations exhibited cross-reactivity with in vitro cultivated blood-stage parasites. Immunofluorescence and immunoblot competition experiments showed that both components of the hybrid protein induced IgG cross-reactive with the corresponding native proteins. Conclusion A virosomal formulation of the chimeric protein GMZ2 induced P. falciparum blood stage parasite cross-reactive IgG responses specific for both MSP3 and GLURP. GMZ2 thus represents a candidate component suitable for inclusion into a multi-valent virosomal

Delta inulin-derived adjuvants that elicit Th1 phenotype following vaccination reduces respiratory syncytial virus lung titers without a reduction in lung immunopathology.

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Wong, Terianne M; Petrovsky, Nikolai; Bissel, Stephanie J; Wiley, Clayton A; Ross, Ted M

2016-08-02

Respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract infections resulting in bronchiolitis and even mortality in the elderly and young children/infants. Despite the impact of this virus on human health, no licensed vaccine exists. Unlike many other viral infections, RSV infection or vaccination does not induce durable protective antibodies in humans. In order to elicit high titer, neutralizing antibodies against RSV, we investigated the use of the adjuvant Advax™, a novel polysaccharide adjuvant based on delta inulin microparticles, to enhance antibody titers following vaccination. BALB/c mice were vaccinated intramuscularly with live RSV as a vaccine antigen in combination with one of two formulations of Advax™. Advax-1 was comprised of the standard delta inulin adjuvant and Advax-2 was formulated delta inulin plus CpG oligodendronucleotides (ODNs). An additional group of mice were either mock vaccinated, immunized with vaccine only, or administered vaccine plus Imject Alum. Following 3 vaccinations, mice had neutralizing antibody titers that correlated with reduction in viral titers in the lungs. Advax-1 significantly enhanced serum RSV-specific IgG1 levels at week 6 indicative of a Th2 response, similar to titers in mice administered vaccine plus Imject Alum. In contrast, mice vaccinated with vaccine plus Advax-2 had predominately IgG2a titers indicative of a Th1 response that was maintained during the entire study. Interestingly, regardless of which Advax TM adjuvant was used, the neutralizing titers were similar between groups, but the viral lung titers were significantly lower (∼10E+3pfu/g) in mice administered vaccine with either Advax TM adjuvant compared to mice administered adjuvants only. The lung pathology in vaccinated mice with Advax TM was similar to Imject Alum. Overall, RSV vaccine formulated with Advax TM had high neutralizing antibody titers with low lung viral titers, but exacerbated lung pathology compared

Study of quality and stability of ursodeoxycholic acid formulations for oral pediatric administration.

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Santoveña, A; Sánchez-Negrín, E; Charola, L; Llabrés, M; Fariña, J B

2014-12-30

This paper describes a rational method of characterizing the biopharmaceutical stability of two oral suspensions of ursodeoxycholic acid (UDCA) used in pediatrics. Because there is no commercial presentation of UDCA that can administer appropriate doses for infants and children, an active pharmaceutical ingredient (API) formulation is required. Due to its very low solubility and low dose in the formula (1.5%), two different suspensions with minimal use of excipients were studied, avoiding the use of complex additives and those not recommended by the European Medicines Agency (EMA). Adherence to Standard Operating Procedure (SOP) allows the preparation of formulations with appropriately sized and stable particles, and suitable rheological behavior in withdrawing the dose after stirring. Dose uniformity, expressed as mass and content variability, was determined using the criteria of the European and the United States Pharmacopoeia. Additionally, dose content variation of every mass determined was studied. A rational method was developed for determining the dose uniformity of UDCA in suspensions, whether freshly prepared or after storage under different conditions for 30 and 60 days. This method permits detection of differences between doses taken at different heights in the vessel at various times and storage conditions. UDCA was stable under all conditions studied, requiring the presence of glycerol in the formulation to obtain the declared API value after stirring. Storage of UDCA suspensions in a refrigerator increased variability between doses. Copyright © 2014 Elsevier B.V. All rights reserved.

Topical formulations with superoxide dismutase: influence of formulation composition on physical stability and enzymatic activity.

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Di Mambro, Valéria M; Borin, Maria F; Fonseca, Maria J V

2003-04-24

Three different topical formulations were supplemented with superoxide dismutase (SOD) and evaluated concerning physical and chemical stabilities in order to determine the most stable formulation that would maintain SOD activity. Physical stability was evaluated by storing the formulation at room temperature, and at 37 and 45 degrees C for 28 days. Samples were collected at 7-day intervals for assessment of rheological behavior. Chemical stability was evaluated by the measurement of enzymatic activity in formulations stored at room temperature and at 45 degrees C for 75 days. The formulations showed a pseudoplastic behavior, with a flow index of less than 1. There was no significant difference in the initial values of flow index, hysteresis loop or minimum apparent viscosity. The simple emulsion and the one stabilized with hydroxyethylcellulose showed decreased viscosity by the 21st day and with higher temperature, but no significant changes concerning the presence of SOD. Although there were no significant changes concerning storage time or temperature, the formulation stabilized with hydroxyethylcellulose showed a marked loss of SOD activity. The addition of SOD to the formulations studied did not affect their physical stability. Simple emulsions or emulsions stabilized with carboxypolymethylene seem to be better bases for enzyme addition than emulsion stabilized with hydroxyethylcellulose.

BACE1 inhibition by microdose lithium formulation NP03 rescues memory loss and early stage amyloid neuropathology.

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Wilson, E N; Do Carmo, S; Iulita, M F; Hall, H; Ducatenzeiler, A; Marks, A R; Allard, S; Jia, D T; Windheim, J; Cuello, A C

2017-08-01

Lithium is first-line therapy for bipolar affective disorder and has recently been shown to have protective effects in populations at risk for Alzheimer's disease (AD). However, the mechanism underlying this protection is poorly understood and consequently limits its possible therapeutic application in AD. Moreover, conventional lithium formulations have a narrow therapeutic window and are associated with a severe side effect profile. Here we evaluated a novel microdose formulation of lithium, coded NP03, in a well-characterized rat model of progressive AD-like amyloid pathology. This formulation allows microdose lithium delivery to the brain in the absence of negative side effects. We found that NP03 rescued key initiating components of AD pathology, including inactivating GSK-3β, reducing BACE1 expression and activity, and reducing amyloid levels. Notably, NP03 rescued memory loss, impaired CRTC1 promoter binding of synaptic plasticity genes and hippocampal neurogenesis. These results raise the possibility that NP03 be of therapeutic value in the early or preclinical stages of AD.

Relative bioavailability of two oral formulations of risperidone 2 mg: A single-dose, randomized-sequence, open-label, two-period crossover comparison in healthy Brazilian volunteers.

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Belotto, Karisa Cristina Rodrigues; Raposo, Nádia Rezende Barbosa; Ferreira, Aline Siqueira; Gattaz, Wagner Farid

2010-11-01

Risperidone (RSP) is a benzisoxazole antipsychotic agent used to treat schizophrenia and other psychiatric illnesses in adults and children (including those with autism). After oral administration, RSP is completely absorbed from the gastrointestinal tract and undergoes hydroxylation to yield 9-hydroxyrisperidone (9-OH-RSP), an active metabolite that has a pharmacologic profile and potency similar to RSP. The aims of this study were to compare the relative bioavailability of a pharmaceutical-equivalent (test) formulation with a reference formulation of oral RSP 2 mg, both available commercially on the Brazilian pharmaceutical market, and to generate data regarding the oral bioavailability of the tested drug in healthy Brazilian volunteers. This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in healthy Brazilian volunteers from August to December 2008. Subjects were randomly assigned to receive the test formulation followed by the reference formulation or vice versa, with a 30-day washout period between doses. Study drugs were administered after a 12-hour overnight fast. For pharmacokinetic analysis, blood samples were drawn at 0 (baseline), 0.25, 0.5, 1, 1.5, 3, 5, 8, 12, 24, 48, 72, 96, and 120 hours after administration. Plasma concentrations of RSP and 9-OH-RSP were determined using LC-MS/MS. The test and reference formulations were to be considered bioequivalent if the 90% CIs for the geometric mean test/reference ratios were within a predetermined range of 80% to 125%, in accordance with the policies of the Brazilian Sanitary Surveillance Agency and the US Food and Drug Administration. Tolerability was determined using clinical assessments, monitoring of vital signs, analysis of laboratory test results, and subject interviews regarding adverse events. A total of 22 subjects were enrolled (11 men, 11 women; mean [SD] age, 32 [12] years [range, 1858 years]; weight, 70.4 [11.9] kg [range, 50-103 kg]; height, 1.67 [0.08] m

Development of a sedation protocol using orally administered tiletamine-zolazepam-acepromazine in free-roaming dogs.

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Huang, Hsiao-Chun; Huang, Shih-Wei; Yu, Kuan-Hua; Wang, Jiann-Hsiung; Wu, Jui-Te

2017-09-01

To investigate the sedative effects in dogs of tiletamine-zolazepam-acepromazine (TZA) or ketamine-flunitrazepam (KF) administered orally and to evaluate the effectiveness of encapsulated TZA for capturing free-roaming dogs. Experimental study followed by a field trial. Six research dogs and 27 free-roaming dogs. In a pilot study, six research dogs were administered liquid TZA (20 mg kg -1 tiletamine-zolazepam and 2 mg kg -1 acepromazine) or liquid KF (50 mg kg -1 ketamine and 2 mg kg -1 flunitrazepam) orally: treatment 1, forcefully squirting liquid medication into the mouth; treatment 2, encapsulating liquid medication for administration in canned food; treatment 3, administering liquid medication mixed with gravy. Sedation was scored. A follow-up field trial attempted capture of 27 free-roaming dogs. In the pilot study, the median time (range) to lateral recumbency (% dogs) after TZA administration was: treatment 1, 47.5 (35-80) minutes (67%); treatment 2, 30 (15-65) minutes (83%); and treatment 3, 75 (45-110) minutes (100%). No dogs in KF treatment 2 or 3 achieved lateral recumbency. Based on these results, 20 free-roaming dogs were offered encapsulated TZA in canned food: TZ (20 mg kg -1 ) and acepromazine (2 mg kg -1 ). Of these, no further drugs to four dogs (one dog captured), 10 dogs were administered a second dose within 30 minutes (five dogs captured) and six dogs were administered TZ (5 mg kg -1 ) and xylazine (1.1-2.2 mg kg -1 ) intramuscularly by blow dart (six dogs captured). Seven dogs were initially offered twice the TZA dose (five dogs captured). In total, 63% free-roaming dogs were captured after administration of encapsulated TZA in canned food. Oral administration of encapsulated TZA in canned dog food can aid in the capture of free-roaming dogs, but additional drugs may be required. The sedation onset time and medication palatability influenced the capture rate. Copyright © 2017 Association of Veterinary Anaesthetists and

42 CFR 2a.5 - Contents of application; research projects in which drugs will be administered.

Science.gov (United States)

2010-10-01

... application; research projects in which drugs will be administered. (a) In addition to the information... drug shall contain: (1) Identification of the drugs to be administered in the research project and a... project will be conducted. (b) An application for an authorization of confidentiality with respect to a...

Bioequivalence study of a new sildenafil 100 mg orodispersible film compared to the conventional film-coated 100 mg tablet administered to healthy male volunteers

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Radicioni, Milko; Castiglioni, Chiara; Giori, Andrea; Cupone, Irma; Frangione, Valeria; Rovati, Stefano

2017-01-01

A new orodispersible film formulation of the phosphodiesterase type 5 inhibitor, sildenafil, has been developed to examine the advantages of an orally disintegrating film formulation and provide an alternative to the current marketed products for the treatment of erectile dysfunction. The pharmacokinetics of the sildenafil 100 mg orodispersible film (IBSA) was compared to that of the conventional marketed 100 mg film-coated tablet (Viagra®) after single-dose administration to 53 healthy male volunteers (aged 18–51 years) in a randomized, open, two-way crossover bioequivalence study. Each subject received a single oral dose of 100 mg of sildenafil as test or reference formulation administered under fasting conditions at each of the two study periods according to a randomized crossover design. There was a washout interval of ≥7 days between the two administrations of the investigational medicinal products. Blood samples for pharmacokinetic analysis were collected up to 24 h post-dosing. The primary objective was to compare the rate (peak plasma concentration; Cmax) and extent (area under the curve [AUC] from administration to last observed concentration time; AUC0–t) of sildenafil absorption after single-dose administration of test and reference. Secondary endpoints were observed to describe the plasma pharmacokinetic profiles of sildenafil and its metabolite N-desmethyl-sildenafil relative bioavailability and safety profile after single-dose administration. The mean sildenafil and N-desmethyl-sildenafil plasma concentration–time profiles up to 24 h after single-dose administration of sildenafil 100 mg orodispersible film and film-coated tablet were nearly superimposable. The bioequivalence test was fully satisfied for sildenafil and N-desmethyl-sildenafil in terms of rate and extent of bioavailability. Adverse events occurred at similar rates for the two formulations and were of mild-to-moderate severity. The results suggest that the new orodispersible film

Gauge stability of 3+1 formulations of general relativity

International Nuclear Information System (INIS)

Khokhlov, A M; Novikov, I D

2002-01-01

We present a general approach to the analysis of gauge stability of 3+1 formulations of general relativity (GR). Evolution of coordinate perturbations and the corresponding perturbations of lapse and shift can be described by a system of eight quasi-linear partial differential equations. Stability with respect to gauge perturbations depends on the choice of gauge and a background metric, but it does not depend on a particular form of a 3+1 system if its constrained solutions are equivalent to those of the Einstein equations. Stability of a number of known gauges is investigated in the limit of short-wavelength perturbations. All fixed gauges except a synchronous gauge are found to be ill posed. A maximal slicing gauge and its parabolic extension are shown to be ill posed as well. A necessary condition is derived for well-posedness of metric-dependent algebraic gauges. Well-posed metric-dependent gauges are found, however, to be generally unstable. Both instability and ill-posedness are associated with the existence of growing modes of coordinate perturbations related to perturbations of physical accelerations of reference frames

Standardization Of A Siddha Formulation Amukkara Curanam By ...

African Journals Online (AJOL)

Amukkara curanam, a Siddha formulation, currently used in all types of gastric disorders, rheumatic pain, insomnia and sexual insufficiency, was investigated for the estimation of the marker compounds, withaferine A and piperine contents in a prepared standard formulation and a commercial formulation by using HPTLC ...

Optimization of a Functional Cookie Formulation by Using Response Surface Methodology

International Nuclear Information System (INIS)

Lee, L.Y.; Tan, K.S.; Liew, S.L.

2011-01-01

A functional cookie formulation containing oligo fructose, dietary fibre and lower calorie, fat and sugar contents than conventional cookies was optimized using Response Surface Methodology (RSM). Instant N-Oil II was used as a fat replacer, while Raftilose P95 was used as a sugar substitute with the addition of fructose to enhance sweetness. Selection of the optimal formulation was based on caloric content. An optimized formulation, V1, was obtained from the model Y = 4927.70 - 152.34X 1 - 155.42X 3 + 104.20X 3 2 + 151.71X 3 3 - 95.08X 3 4 , where Instant N-Oil II replaced 30 % of butter and 24.4 %, w/w (30.5 g) fructose replaced 40.0 %, w/w (50.0 g) sucrose. Two additional optimized formulations, S1 and S2, were proposed which contained the same ingredients as V1, but both contained 19.0 %, w/w (23.8 g) Raftilose P95. Also, S2 had a higher fat replacement level (42 %). A reference cookie prepared from a conventional recipe received significantly higher scores (P < 0.05) than the functional cookies V1, S1 and S2 in the sensory evaluation. However, when health benefits of the functional cookies were explained to the panel after the sensory evaluation had concluded, majority of the panelists stated that they would prefer S1, had they known of its health benefits. S1 contained 19.04 % fat, 8.62 % fructose and 0.74 % sucrose, namely, significantly lower fat and sucrose levels and higher fructose content than the conventional cookie. (author)

A phase 1 study to evaluate effect of food on veliparib pharmacokinetics and relative bioavailability in subjects with solid tumors.

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Mostafa, Nael M; Chiu, Yi-Lin; Rosen, Lee S; Bessudo, Alberto; Kovacs, Xenia; Giranda, Vincent L

2014-09-01

A phase 1 study was conducted to evaluate the bioavailability and food effect of a new veliparib formulation in subjects with solid tumors. Subjects (planned: Stage I, N = 20; Stage II, N = 16) received four regimens of a single oral dose of veliparib utilizing a group-sequential design. Subjects were administered single doses of 40 mg veliparib supplied as four 10 mg current formulation, four 10 mg new formulation and one 40 mg new formulation under fasting conditions and under non-fasting conditions. Serial blood samples were collected for the determination of veliparib pharmacokinetics. At the end of Stage I, the relative bioavailability between each pair of regimens was assessed by a two one-sided tests procedure from the analyses of the natural logarithms of C(max) and AUC. A 92.7 % confidence interval within the 0.80-1.25 range between each regimen pair determined bioequivalence. Four 10 mg current formulation capsules, four 10 mg new formulation and one 40 mg new formulation were bioequivalent with respect to C(max) and AUC under fasting conditions. The administration of a high-fat meal did not have a significant effect on AUC and only caused a slight decrease in veliparib C(max) (17 %) and a delay of approximately 1 h in T(max). The 40 mg new capsule was bioequivalent to currently used formulation. Food had no effect on the extent of veliparib absorption and only a small (17 %) decrease in peak exposure of veliparib.

A phase I randomized clinical trial of candidate human immunodeficiency virus type 1 vaccine MVA.HIVA administered to Gambian infants.

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Muhammed O Afolabi

Full Text Available A vaccine to decrease transmission of human immunodeficiency virus type 1 (HIV-1 during breast-feeding would complement efforts to eliminate infant HIV-1 infection by antiretroviral therapy. Relative to adults, infants have distinct immune development, potentially high-risk of transmission when exposed to HIV-1 and rapid progression to AIDS when infected. To date, there have been only three published HIV-1 vaccine trials in infants.We conducted a randomized phase I clinical trial PedVacc 001 assessing the feasibility, safety and immunogenicity of a single dose of candidate vaccine MVA.HIVA administered intramuscularly to 20-week-old infants born to HIV-1-negative mothers in The Gambia.Infants were followed to 9 months of age with assessment of safety, immunogenicity and interference with Expanded Program on Immunization (EPI vaccines. The trial is the first stage of developing more complex prime-boost vaccination strategies against breast milk transmission of HIV-1.From March to October 2010, 48 infants (24 vaccine and 24 no-treatment were enrolled with 100% retention. The MVA.HIVA vaccine was safe with no difference in adverse events between vaccinees and untreated infants. Two vaccine recipients (9% and no controls had positive ex vivo interferon-γ ELISPOT assay responses. Antibody levels elicited to the EPI vaccines, which included diphtheria, tetanus, whole-cell pertussis, hepatitis B virus, Haemophilus influenzae type b and oral poliovirus, reached protective levels for the vast majority and were similar between the two arms.A single low-dose of MVA.HIVA administered to 20-week-old infants in The Gambia was found to be safe and without interference with the induction of protective antibody levels by EPI vaccines, but did not alone induce sufficient HIV-1-specific responses. These data support the use of MVA carrying other transgenes as a boosting vector within more complex prime-boost vaccine strategies against transmission of HIV-1 and

Laboratory-based testing to evaluate abuse-deterrent formulations and satisfy the Food and Drug Administration's recommendation for Category 1 Testing.

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Altomare, Christopher; Kinzler, Eric R; Buchhalter, August R; Cone, Edward J; Costantino, Anthony

The US Food and Drug Administration (FDA) considers the development of abuse-deterrent formulations of solid oral dosage forms a public health priority and has outlined a series of premarket studies that should be performed prior to submitting an application to the Agency. Category 1 studies are performed to characterize whether the abuse-deterrent properties of a new formulation can be easily defeated. Study protocols are designed to evaluate common abuse patterns of prescription medications as well as more advanced methods that have been reported on drug abuse websites and forums. Because FDA believes Category 1 testing should fully characterize the abuse-deterrent characteristics of an investigational formulation, Category 1 testing is time consuming and requires specialized laboratory resources as well as advanced knowledge of prescription medication abuse. Recent Advisory Committee meetings at FDA have shown that Category 1 tests play a critical role in FDA's evaluation of an investigational formulation. In this article, we will provide a general overview of the methods of manipulation and routes of administration commonly utilized by prescription drug abusers, how those methods and routes are evaluated in a laboratory setting, and discuss data intake, analysis, and reporting to satisfy FDA's Category 1 testing requirements.

SPECTROPHOTOMETRIC DETERMINATION OF ACETYLCYSTEINE IN PHARMACEUTICAL FORMULATIONS USING 2,3-DICHLORO-1,4-NAPTHOQUINONE

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A. O. Donchenko

2015-04-01

Full Text Available The aim of research was the development and validation ofspectrophotometric method foracetylcysteine assay in pharmaceutical formulations.Тhe proposed method is based on the reaction with 2,3-dichloro-1,4-naphthoquinone and the formation of colored products that exhibit absorption maxima at 425 nm. Introduction Many analytical methods have been published for acetylcysteine assay in pharmaceutical formulations as high-performance liquid chromatography (HPLC, fluorimetry and chemiluminescence. Some of these methods are time consuming or require expensive equipment. Other published methods suffer from lack of selectivity and sensitivity. Spectrophotometry is the most widely used technique in pharmaceutical analysis because it is simple, economic, and easily available to most quality control laboratories. In the present work, we propose a simple and accurate spectrophotometric method for acetylcysteine assay in pharmaceutical formulations. Materials and Methods Reagents: Reference standard acetylcysteinesubstance; 2,3-dichloro-1,4-naphthoquinone. All chemicals and solvents were of analytical grade. DMFA was used as a solvent. Pharmaceutical preparations:powder for oral solution «ACC 200» 200 mgseries number50026151 (Salutas Pharma CmbH, Germany; effervescent tablets «Fluimucil» 600 mg (Zambon S.P.A., Italy and «ACC LONG» 600 mg (Salutas Pharma CmbH, Germany series numbers 321284 and DH2740; solution for injections «Fluimucil» 100 mg/ml (Zambon S.P.A., Italyseries number28002492. Solutions: Acetylcysteine stock solution (0,16%; DMFAsolution of 2,3-dichloro-1,4-naphthoquinone (4%. Equipment Analytical balance (ABT-120-5DM; UV-VIS spectrophotometer (Specord 200; water bath (MemmertWNB 7-45;quartz cells. Results Acetylcysteine was determined using a spectrophotometric method based on the reaction with 2,3-dichloro-1,4-naphthoquinone to form yellow colored reaction products with absorption maxima at 425 nm. The effect of reaction time and

Human kinetics of orally and intravenously administered low-dose 1,2-(13)C-dichloroacetate.

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Jia, Minghong; Coats, Bonnie; Chadha, Monisha; Frentzen, Barbara; Perez-Rodriguez, Javier; Chadik, Paul A; Yost, Richard A; Henderson, George N; Stacpoole, Peter W

2006-12-01

Dichloroacetate (DCA) is a putative environmental hazard, owing to its ubiquitous presence in the biosphere and its association with animal and human toxicity. We sought to determine the kinetics of environmentally relevant concentrations of 1,2-(13)C-DCA administered to healthy adults. Subjects received an oral or intravenous dose of 2.5 microg/kg of 1,2-(13)C-DCA. Plasma and urine concentrations of 1,2-(13)C-DCA were measured by a modified gas chromatography-tandem mass spectrometry method. 1,2-(13)C-DCA kinetics was determined by modeling using WinNonlin 4.1 software. Plasma concentrations of 1,2-(13)C-DCA peaked 10 minutes and 30 minutes after intravenous or oral administration, respectively. Plasma kinetic parameters varied as a function of dose and duration. Very little unchanged 1,2-(13)C-DCA was excreted in urine. Trace amounts of DCA alter its own kinetics after short-term exposure. These findings have important implications for interpreting the impact of this xenobiotic on human health.

A phase 1, open-label, randomized study to compare the immunogenicity and safety of different administration routes and doses of virosomal influenza vaccine in elderly.

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Levin, Yotam; Kochba, Efrat; Shukarev, Georgi; Rusch, Sarah; Herrera-Taracena, Guillermo; van Damme, Pierre

2016-10-17

Influenza remains a significant problem in elderly despite widespread vaccination coverage. This randomized, phase-I study in elderly compared different strategies of improving vaccine immunogenicity. A total of 370 healthy participants (⩾65years) were randomized equally 1:1:1:1:1:1 to six influenza vaccine treatments (approximately 60-63 participants per treatment arm) at day 1 that consisted of three investigational virosomal vaccine formulations at doses of 7.5, 15, and 45μg HA antigen/strain administered intradermally (ID) by MicronJet600™ microneedle device (NanoPass Technologies) or intramuscularly (IM), and three comparator registered seasonal vaccines; Inflexal V™ (Janssen) and MF59 adjuvanted Fluad™ (Novartis) administered IM and Intanza™ (Sanofi Pasteur) administered ID via Soluvia™ prefilled microinjection system (BD). Serological evaluations were performed at days 22 and 90 and safety followed-up for 6months. Intradermal delivery of virosomal vaccine using MicronJet600™ resulted in significantly higher immunogenicity than the equivalent dose of virosomal Inflexal V™ administered intramuscularly across most of the parameters and strains, as well as in some of the readouts and strains as compared with the 45μg dose of virosomal vaccine formulation. Of 370 participants, 300 (81.1%) reported ⩾1 adverse event (AE); more participants reported solicited local AEs (72.2%) than solicited systemic AEs (12.2%). Intradermal delivery significantly improved influenza vaccine immunogenicity compared with intramuscular delivery. Triple dose (45μg) virosomal vaccine did not demonstrate any benefit on vaccine's immunogenicity over 15μg commercial presentation. All treatments were generally safe and well-tolerated. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

Metaheuristics applied to vehicle routing. A case study. Parte 1: formulating the problem

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Guillermo González Vargas

2006-09-01

Full Text Available This paper deals with VRP (vehicle routing problem mathematical formulation and presents some methodologies used by different authors to solve VRP variation. This paper is presented as the springboard for introducing future papers about a manufacturing company’s location decisions based on the total distance traveled to distribute its product.

25 CFR 26.4 - Who administers the Job Placement and Training Program?

Science.gov (United States)

2010-04-01

... 25 Indians 1 2010-04-01 2010-04-01 false Who administers the Job Placement and Training Program... PLACEMENT AND TRAINING PROGRAM General Applicability § 26.4 Who administers the Job Placement and Training Program? The Job Placement and Training Program is administered by the Bureau of Indian Affairs or a...

From diets to foods: using linear programming to formulate a nutritious, minimum-cost porridge mix for children aged 1 to 2 years.

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De Carvalho, Irene Stuart Torrié; Granfeldt, Yvonne; Dejmek, Petr; Håkansson, Andreas

2015-03-01

Linear programming has been used extensively as a tool for nutritional recommendations. Extending the methodology to food formulation presents new challenges, since not all combinations of nutritious ingredients will produce an acceptable food. Furthermore, it would help in implementation and in ensuring the feasibility of the suggested recommendations. To extend the previously used linear programming methodology from diet optimization to food formulation using consistency constraints. In addition, to exemplify usability using the case of a porridge mix formulation for emergency situations in rural Mozambique. The linear programming method was extended with a consistency constraint based on previously published empirical studies on swelling of starch in soft porridges. The new method was exemplified using the formulation of a nutritious, minimum-cost porridge mix for children aged 1 to 2 years for use as a complete relief food, based primarily on local ingredients, in rural Mozambique. A nutritious porridge fulfilling the consistency constraints was found; however, the minimum cost was unfeasible with local ingredients only. This illustrates the challenges in formulating nutritious yet economically feasible foods from local ingredients. The high cost was caused by the high cost of mineral-rich foods. A nutritious, low-cost porridge that fulfills the consistency constraints was obtained by including supplements of zinc and calcium salts as ingredients. The optimizations were successful in fulfilling all constraints and provided a feasible porridge, showing that the extended constrained linear programming methodology provides a systematic tool for designing nutritious foods.

Formulated Beta-Cyfluthrin Shows Wide Divergence in Toxicity among Bird Species

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Laura M. Addy-Orduna

2011-01-01

Full Text Available It is generally assumed that the toxicity of pyrethroid insecticides to birds is negligible, though few species have been tested. The oral acute toxicity of formulated beta-cyfluthrin was determined for canaries (Serinus sp., shiny cowbirds (Molothrus bonariensis, and eared doves (Zenaida auriculata. Single doses were administered to adults by gavage. Approximate lethal doses 50 (LD50 and their confidence intervals were determined by approximate D-optimal design. Canaries were found to be substantially more sensitive to formulated beta-cyfluthrin (LD50=(170±41 mg/kg than the other two species tested (LD50=(2234±544 mg/kg and LD50=(2271±433 mg/kg, resp.. The LD50 obtained for canaries was also considerably lower than typical toxicity values available in the literature for pyrethroids. This study emphasizes the need for testing a broader range of species with potentially toxic insecticides, using modern up and down test designs with minimal numbers of birds.

Formulated Beta-Cyfluthrin Shows Wide Divergence in Toxicity among Bird Species.

Science.gov (United States)

Addy-Orduna, Laura M; Zaccagnini, María-Elena; Canavelli, Sonia B; Mineau, Pierre

2011-01-01

It is generally assumed that the toxicity of pyrethroid insecticides to birds is negligible, though few species have been tested. The oral acute toxicity of formulated beta-cyfluthrin was determined for canaries (Serinus sp.), shiny cowbirds (Molothrus bonariensis), and eared doves (Zenaida auriculata). Single doses were administered to adults by gavage. Approximate lethal doses 50 (LD(50)) and their confidence intervals were determined by approximate D-optimal design. Canaries were found to be substantially more sensitive to formulated beta-cyfluthrin (LD(50) = (170 ± 41) mg/kg) than the other two species tested (LD(50) = (2234 ± 544) mg/kg and LD(50) = (2271 ± 433) mg/kg, resp.). The LD(50) obtained for canaries was also considerably lower than typical toxicity values available in the literature for pyrethroids. This study emphasizes the need for testing a broader range of species with potentially toxic insecticides, using modern up and down test designs with minimal numbers of birds.

Use of an in vitro human skin permeation assay to assess bioequivalence of two topical cream formulations containing butenafine hydrochloride (1%, w/w).

Science.gov (United States)

Mitra, Amitava; Kim, Nanhye; Spark, Darren; Toner, Frank; Craig, Susan; Roper, Clive; Meyer, Thomas A

2016-12-01

The primary objective of this work was to investigate, using an in vitro human skin permeation study, whether changes in the excipients of butenafine hydrochloride cream would have any effect on bioperformance of the formulation. Such in vitro data would be a surrogate for any requirement of a bioequivalence (BE) study to demonstrate formulation similarity. A LC-MS/MS method for quantitation of butenafine in various matrices was developed and validated. A pilot study was performed to validate the in vitro skin permeation methodology using three cream formulations containing butenafine hydrochloride at concentrations of 0.5, 1.0 and 1.5% (w/w). Finally, a definitive in vitro human skin permeation study was conducted, comparing the extent of butenafine hydrochloride permeation from the new formulation to that from the current formulation. The results of the study comparing the two formulations showed that there was no statistically significant difference in the extent of butenafine permeation into human skin. In conclusion, these in vitro data demonstrated that the formulation change is likely to have no significant impact on the bioperformance of 1% (w/w) butenafine hydrochloride cream. Copyright © 2016 Elsevier Inc. All rights reserved.

Are Branded and Generic Extended-Release Ropinirole Formulations Equally Efficacious? A Rater-Blinded, Switch-Over, Multicenter Study

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Edit Bosnyák

2014-01-01

Full Text Available The aim of this study was to compare the efficacy of the branded and a generic extended-release ropinirole formulation in the treatment of advanced Parkinson’s disease (PD. Of 22 enrolled patients 21 completed the study. A rater blinded to treatment evaluated Unified Parkinson’s Disease Rating Scale, Fahn-Tolosa-Marin Tremor Rating Scale, Nonmotor Symptoms Assessment Scale, and a structured questionnaire on ropinirole side effects. Besides, the patients self-administered EQ-5D, Parkinson’s Disease Sleep Scale (PDSS-2, and Beck Depression Inventories. Branded and generic ropinirole treatment achieved similar scores on all tests measuring severity of motor symptoms (primary endpoint, UPDRS-III: 27.0 versus 28.0 points, P=0.505. Based on patient diaries, the lengths of “good time periods” were comparable (10.5 and 10.0 hours for branded and generic ropinirole, resp., P=0.670. However, generic ropinirole therapy achieved almost 3.0 hours shorter on time without dyskinesia (6.5 versus. 9.5 hours, P<0.05 and 2.5 hours longer on time with slight dyskinesia (3.5 versus. 1.0 hours, P<0.05 than the branded ropinirole did. Except for gastrointestinal problems, nonmotor symptoms were similarly controlled. Patients did not prefer either formulation. Although this study has to be interpreted with limitations, it demonstrated that both generic and branded ropinirole administration can achieve similar control on most symptoms of PD.

Formulation design of oral pediatric Acetazolamide suspension: dose uniformity and physico-chemical stability study.

Science.gov (United States)

Santoveña, Ana; Suárez-González, Javier; Martín-Rodríguez, Cristina; Fariña, José B

2017-03-01

The formulation of an active pharmaceutical ingredient (API) as oral solution or suspension in pediatrics is a habitual practice, due to the non-existence of many commercialized medicines in pediatric doses. It is also the simplest way to prepare and administer them to this vulnerable population. The design of a formulation that assures the dose and the system stability depends on the physico-chemical properties of the API. In this study, we formulate a class IV API, Acetazolamide (AZM) as suspension for oral administration to pediatric population. The suspension must comply attributes of quality, safety and efficacy for this route of administration. We use simple compounding procedures, as well as fewer pure excipients, as recommended for children. Mass and uniformity content assays and physical and chemical stability studies were performed. To quantify the API an UPLC method was used. We verified the physico-chemical stability of the suspensions and that they passed the mass test of the European Pharmacopeia (EP), but not the dose uniformity test. This reveals that AZM must be formulated as liquid forms with a more complex system of excipients (not usually indicated in pediatrics), or otherwise solid forms capable of assuring uniformity of mass and dose for every dosage unit.

A novel method to prepare concentrated conidial biomass formulation of Trichoderma harzianum for seed application.

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Singh, P C; Nautiyal, C S

2012-12-01

To prepare concentrated formulation of Trichoderma harzianum MTCC-3841 (NBRI-1055) with high colony forming units (CFU), long shelf life and efficient in root colonization by a simple scrapping method. NBRI-1055 spores scrapped from potato dextrose agar plates were used to prepare a concentrated formulation after optimizing carrier material, moisture content and spore harvest time. The process provides an advantage of maintaining optimum moisture level by the addition of water rather than dehydration. The formulation had an initial 11-12 log(10) CFU g(-1). Its concentrated form reduces its application amount by 100 times (10 g 100 kg(-1) seed) and provides 3-4 log(10) CFU seed(-1). Shelf life of the product was experimentally determined at 30 and 40 °C and predicted at other temperatures following Arrhenius equation. The concentrated formulation as compared to similar products provides an extra advantage of smaller packaging for storage and transportation, cutting down product cost. Seed application of the formulation recorded significant increase in plant growth promotion. Stable and effective formulation of Trichoderma harzianum NBRI-1055 was obtained by a simple scrapping method. A new method for the production of concentrated, stable, effective and cost efficient formulation of T. harzianum has been validated for seed application. © 2012 The Society for Applied Microbiology.

Comparison of a new metamizole formulation and carprofen for extended post-operative analgesia in dogs undergoing ovariohysterectomy.

Science.gov (United States)

Kalchofner Guerrero, K S; Schwarz, A; Wuhrmann, R; Feldmann, S; Hartnack, S; Bettschart-Wolfensberger, R

2015-04-01

A newly developed slow-release tablet formulation of metamizole was compared with carprofen for post-operative analgesia in dogs undergoing ovariohysterectomy. Twenty-three dogs were randomly assigned to one of two groups, and administered 50 mg/kg metamizole PO (Group M) or 4 mg/kg carprofen PO (Group C) 1 h before anaesthetic induction and 24 and 48 h later. Anaesthesia was induced with propofol and maintained with isoflurane and fentanyl, after premedication with 0.005 mg/kg medetomidine and 0.3 mg/kg methadone IM. A blinded observer assessed post-operative sedation, and analgesia using a visual analogue scale, a dynamic interactive visual analogue scale, the Glasgow composite pain scale (GCPS), and a mechanical nociceptive threshold device (T = 0.5, 1, 2, 4, 8, 12, 18, 21, 24, 36, 45, 60 and 70 h after surgery). Rescue methadone was administered if the GCPS was >6/24 in ambulatory dogs, or >5/20 in non-ambulatory dogs. Plasma concentrations of test drugs were quantified. The dose range for metamizole was 39-56 mg/kg. At T = 0.5 h sedation scores were significantly higher in Group C and GCPS scores were significantly higher in Group M. Three dogs required rescue methadone (Group M, n = 1; Group C, n = 2). Vomiting occurred post-operatively in 45% of dogs in Group M. Carprofen and metamizole were both well absorbed; peak concentrations occurred within 4-24 h, and 4-16 h for carprofen and metamizole, respectively. Both drugs provided adequate analgesia of similar duration. No side effects were observed with carprofen while vomiting was frequent following administration of metamizole. Copyright © 2015 Elsevier Ltd. All rights reserved.

Superspace formulation of new nonlinear sigma models

International Nuclear Information System (INIS)

Gates, S.J. Jr.

1983-07-01

The superspace formulation of two classes of supersymmetric nonlinear σ-models are presented. Two alternative N=1 superspace formulations are given for the d=2 supersymmetric nonlinear σ-models with Killing vector potentials: (a) formulation uses an active central charge and, (b) formulation uses a spurion superfield without inducing a classical breakdown of supersymmetry. The N=2 vector multiplet is used to construct a new class of d=4 nonlinear σ-models which when reduced to d=2 possess N=4 supersymmetry. Implications of these two classes of nonlinear σ-models for N>=4 superfield supergravity are discussed. (author)

A Surface Formulation for Characteristic Modes of Material Bodies

Science.gov (United States)

1974-10-01

42 CHAPTER 3 4: CHARACTERISTIC MODES - A SURFACE FORMULATION 3.1 Theoretical Development The treatment of characteristic modes for perfectly...cgs* i + y mp ein•£ (A6 V; 1 TP At • CA6 I --- 4 1 o#i ajk(X MPcoeo* + umpsin# ) Iim n p-l1 Tp -Ax sin#i + Ay co* ] i (A-7) A4 APPWOIX II fill I vIal

A dilute chemical decontaminant formulation containing gallic acid as a reductant

International Nuclear Information System (INIS)

Kishore, K.; Rajesh, P.; Kumbhar, A.G.

2001-01-01

Gallic acid (GA) was tried as a reductant in place of ascorbic acid in dilute chemical decontaminant (DCD) formulations. Dissolution of magnetite in GA based DCD formulations was studied at 50 C as well as 80 C. It was found to be a good substitute for ascorbic acid in EDTA/ascorbic acid/citric acid, i.e., EAC formulation. The efficiency of EDTA/GA/CA formulation was as good as that of EAC formulation. 2.8 was found to be the optimum pH for this formulation and dissolution decreased at lower as well as higher pHs. The ion exchange behaviour of GA is also appropriate for using it in a regenerating type of formulation. Being an aromatic compound, Gallic acid has inherent stability against radiation degradation. (orig.)

Formulation studies for mirtazapine orally disintegrating tablets.

Science.gov (United States)

Yıldız, Simay; Aytekin, Eren; Yavuz, Burçin; Bozdağ Pehlivan, Sibel; Ünlü, Nurşen

2016-01-01

Orally disintegrating tablets (ODTs) recently have gained much attention to fulfill the needs for pediatric, geriatric, and psychiatric patients with dysphagia. Aim of this study was to develop new ODT formulations containing mirtazapine, an antidepressant drug molecule having bitter taste, by using simple and inexpensive preparation methods such as coacervation, direct compression and to compare their characteristics with those of reference product (Remereon SolTab). Coacervation method was chosen for taste masking of mirtazapine. In vitro characterization studies such as diameter and thickness, weight variation, tablet hardness, tablet friability and disintegration time were performed on tablet formulations. Wetting time and in vitro dissolution tests of developed ODTs also studied using 900 mL 0.1 N HCl medium, 900 mL pH 6.8 phosphate buffer or 900 mL pH 4.5 acetate buffer at 37 ± 0.2 °C as dissolution medium. Ratio of Eudragit® E-100 was chosen as 6% (w/w) since the dissolution profile of A1 (6% Eudragit® E-100) was found closer to the reference product than A2 (4% Eudragit® E-100) and A3 (8% Eudragit® E-100). Group D, E and F formulations were presented better results in terms of disintegration time. Dissolution results indicated that Group E and F formulations showed optimum properties in all three dissolution media. Formulations D1, D4, D5, E3, E4, F1 and F5 found suitable as ODT formulations due to their favorable disintegration times and dissolution profiles. Developed mirtazapine ODTs were found promising in terms of showing the similar characteristics to the original formulation.

Evaluation of two novel tablet formulations of artemether-lumefantrine (Coartem) for bioequivalence in a randomized, open-label, two-period study.

Science.gov (United States)

Lefèvre, Gilbert; Bhad, Prafulla; Jain, Jay Prakash; Kalluri, Sampath; Cheng, Yi; Dave, Hardik; Stein, Daniel S

2013-09-08

Artemether-lumefantrine (Coartem; AL) is a standard of care for malaria treatment as an oral six-dose regimen, given twice daily over three days with one to four tablets (20/120 mg) per dose, depending on patient body weight. In order to reduce the pill burden at each dose and potentially enhance compliance, two novel fixed-dose tablet formulations (80/480 mg and 60/360 mg) have been developed and tested in this study for bioequivalence with their respective number of standard tablets. A randomized, open-label, two-period, single-dose, within formulation crossover bioequivalence study comparing artemether and lumefantrine exposure between the novel 80/480 mg tablet and four standard tablets, and the novel 60/360 mg tablet and three standard tablets, was conducted in 120 healthy subjects under fed conditions. Artemether, dihydroartemisinin, and lumefantrine were measured in plasma by HPLC/UPLC-MS/MS. Pharmacokinetic (PK) parameters were determined by non-compartmental analyses. Adjusted geometric mean AUClast for artemether were 345 and 364 ng·h/mL (geometric mean ratio (GMR) 0.95; 90% CI 0.89-1.01) and for lumefantrine were 219 and 218 μg·h/mL (GMR 1.00; 90% CI 0.93-1.08) for 80/480 mg tablet versus four standard tablets, respectively. Corresponding Cmax for artemether were 96.8 and 99.7 ng/mL (GMR 0.97; 90% CI 0.89-1.06) and for lumefantrine were 8.42 and 8.71 μg/mL (GMR 0.97; 90% CI 0.89-1.05). For the 60/360 mg tablet versus three standard tablets, adjusted geometric mean AUClast for artemether were 235 and 231 ng·h/mL (GMR 1.02; 90% CI 0.94-1.10), and for lumefantrine were 160 and 180 μg·h/mL (GMR 0.89; 90% CI 0.83-0.96), respectively. Corresponding Cmax for artemether were 75.5 and 71.5 ng/mL (GMR 1.06; 90% CI 0.95-1.18), and for lumefantrine were 6.64 and 7.61 μg/mL (GMR 0.87; 90% CI 0.81-0.94), respectively. GMR for Cmax and AUClast for artemether and lumefantrine for all primary comparisons were within the bioequivalence acceptance criteria (0.80-1

Analysis and calculation of macrosegregation in a casting ingot. MPS solidification model. Volume 1: Formulation and analysis

Science.gov (United States)

Maples, A. L.; Poirier, D. R.

1980-01-01

The physical and numerical formulation of a model for the horizontal solidification of a binary alloy is described. It can be applied in an ingot. The major purpose of the model is to calculate macrosegregation in a casting ingot which results from flow of interdendritic liquid during solidification. The flow, driven by solidification contractions and by gravity acting on density gradients in the interdendritic liquid, was modeled as flow through a porous medium. The symbols used are defined. The physical formulation of the problem leading to a set of equations which can be used to obtain: (1) the pressure field; (2) the velocity field: (3) mass flow and (4) solute flow in the solid plus liquid zone during solidification is presented. With these established, the model calculates macrosegregation after solidification is complete. The numerical techniques used to obtain solution on a computational grid are presented. Results, evaluation of the results, and recommendations for future development of the model are given. The macrosegregation and flow field predictions for tin-lead, aluminum-copper, and tin-bismuth alloys are included as well as comparisons of some of the predictions with published predictions or with empirical data.

Bioavailability of oxycodone after administration of a new prolonged-release once-daily tablet formulation in healthy subjects, in comparison to an established twice-daily tablet
.

Science.gov (United States)

Scheidel, Bernhard; Maritz, Martina A; Gschwind, Yves J; Steigerwald, Kerstin; Guth, Volker; Kovacs, Peter; Rey, Helene

2017-11-01

To evaluate and to compare the bioavailability, the influence of food intake on the bioavailability, and the safety and tolerability of a newly-developed oxycodone once-daily (OOD) prolonged-release tablet with an established oxycodone twice-daily (OTD) prolonged-release tablet after single-dose administration under fasting or fed conditions as well as after multiple-dose administration. Three single-center, open-label, randomized, balanced, two-treatment, two-period, two-sequence crossover studies were conducted. In each study, 36 healthy volunteers were randomized to receive 10 mg oxycodone daily as OOD (oxycodone HCL 10-mg PR tablets XL (Develco Pharma Schweiz AG, Pratteln, Switzerland); administration of 1 tablet in the morning) or as OTD (reference formulation: oxygesic 5-mg tablets (Mundipharma GmbH, Limburg an der Lahn, Germany); administration of 1 tablet in the morning and 1 tablet in the evening). Tablets were administered once daily or twice daily under fasting conditions (study 1) or under fed conditions (study 2) as well as after multiple-dose administration (study 3). A sufficient number of blood samples were taken for describing plasma profiles and for calculation of pharmacokinetic parameters. Plasma concentrations of oxycodone were determined by LC-MS/MS. Safety and tolerability were monitored and assessed in all three studies. Plasma profiles of OOD reveal sustained concentrations of oxycodone over the complete dosing interval of 24 hours. In comparison to the OTD reference formulation, the OOD test formulation showed a slightly slower increase of concentrations within the absorption phase and similar plasma concentrations at the maximum and at the end of the dosing interval (24 hours). Extent of bioavailability (AUC), maximum plasma concentrations (Cmax), and plasma concentrations at the end of the dosing interval (Cτ,ss,24h) of OOD could be classified as comparable to OTD considering 90% confidence intervals (CIs) and acceptance limits of 80

Oral immunization with F4 fimbriae and CpG formulated with carboxymethyl starch enhances F4-specific mucosal immune response and modulates Th1 and Th2 cytokines in weaned pigs.

Science.gov (United States)

Delisle, Benjamin; Calinescu, Carmen; Mateescu, Mircea Alexandru; Fairbrother, John Morris; Nadeau, Éric

2012-01-01

F4 fimbriae are a potential candidate for an oral subunit vaccine for prevention of post-weaning diarrhea in swine due to infection with F4-positive enterotoxigenic Escherichia coli. However, large quantities of F4 fimbriae are required to induce a specific antibody response. The aim of the present study was to evaluate the effect of supplementation of F4 fimbriae with Cytosine-phosphate-Guanosine-oligodeoxynucleotide (CpG-A D19) or with complete cholera toxin (CT) as adjuvants on the F4-specific antibody response and cytokine production in weaned pigs following oral administration of F4 fimbrial antigen formulated with Carboxymethyl Starch (CMS). Oral dosage forms of F4 fimbriae alone or supplemented with CpG-A D19 or with CT were formulated with CMS as monolithic tablets, obtained by direct compression, and administered to weaned pigs. Blood and faecal samples were collected to determine the systemic and mucosal immune status of animals at various times until necropsy. During necropsy, contents of the jejunum and ileum were collected for determination of mucosal F4 specific antibodies. Segments of jejunum and ileum were also used to measure mRNA cytokine production. The presence of CpG in the formulation of the fimbriae significantly increased F4-specific immunoglobulin (Ig) IgM and IgG levels in intestinal secretions, and enhanced Th1 (Interferon-gamma / IFN-γ, Tumour Necrosis Factor-alpha / TNF-α, Interleukin-12p40 / IL-12p40, IL-1β) and Th2 (IL-4, IL-6) cytokine production in intestinal tissues. Supplementation with CT did not result in induction of F4-specific antibodies in secretions, although a significant Th1 response (IFN-α, IFN-γ, IL-18) was detected in tissues. Neither F4-specific systemic antibodies, nor intestinally secreted IgA were detected throughout the immunization trial for all groups. CpG-A D19 appeared to be a promising adjuvant for an oral F4 subunit vaccine formulated with CMS excipient as monolithic tablets. This matrix afforded gastro

Controlled-release tablet formulation of isoniazid.

Science.gov (United States)

Jain, N K; Kulkarni, K; Talwar, N

1992-04-01

Guar (GG) and Karaya gums (KG) alone and in combination with hydroxy-propylmethylcellulose (HPMC) were evaluated as release retarding materials to formulate a controlled-release tablet dosage form of isoniazid (1). In vitro release of 1 from tablets followed non-Fickian release profile with rapid initial release. Urinary excretion studies in normal subjects showed steady-state levels of 1 for 13 h. In vitro and in vivo data correlated (r = 0.9794). The studies suggested the potentiality of GG and KG as release retarding materials in formulating controlled-release tablet dosage forms of 1.

Formulation and Evaluation of Fast-Disintegrating Sublingual Tablets of Atropine Sulfate: the Effect of Tablet Dimensions and Drug Load on Tablet Characteristics.

Science.gov (United States)

Aodah, Alhussain; Bafail, Rawan S; Rawas-Qalaji, Mutasem

2017-07-01

In this study, we formulated and evaluated the effects of tablet dimensions and drug load on the characteristics of atropine sulfate (AS) fast-disintegrating sublingual tablets (FDSTs). We aim to develop AS FDSTs as an alternative non-invasive and portable dosage form for the emergency treatment of organophosphate (OP) toxicity. AS autoinjector, AtroPen®, is the only self-administered dosage form available as an antidote for-out-of-hospital emergency use, but it is associated with several limitations and drawbacks. Seven FDST formulations of two tablet sizes, 150 mg (A) and 50 mg (B), and of several AS loads, 0 mg (A1, B1), 2 mg (A2, B2), 4 mg (B3), and 8 mg (B4a, B4b), were formulated and manufactured by direct compression. AS FDST characteristics were evaluated using USP and non-USP tests. Results were statistically compared at p < 0.05. All FDSTs passed the USP content uniformity and friability tests, disintegrated and released AS in ≤30 and 60 s. B1 and B2 were significantly harder than A1 and A2. Water uptake of A1 was significantly the highest. However, B1 and B2 had shorter disintegration and wetting times and higher amounts of AS dissolved than did A1 and A2 (p < 0.05). Increasing AS negatively affected FDST tensile strength (p < 0.05 for B4a) and water uptake (p < 0.05 for B3, B4a and B4b), however, without affecting AS dissolution. Formulation of AS up to 16% into smaller FDSTs was successful. Smaller FDSTs were harder and disintegrated more quickly. These AS FDSTS have the potential for further in vivo testing to evaluate their OP antidote potential.

A Phase 1 Randomized, Open Label, Rectal Safety, Acceptability, Pharmacokinetic, and Pharmacodynamic Study of Three Formulations of Tenofovir 1% Gel (the CHARM-01 Study.

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Ian Mcgowan

Full Text Available The CHARM-01 study characterized the safety, acceptability, pharmacokinetics (PK, and pharmacodynamics (PD of three tenofovir (TFV gels for rectal application. The vaginal formulation (VF gel was previously used in the CAPRISA 004 and VOICE vaginal microbicide Phase 2B trials and the RMP-02/MTN-006 Phase 1 rectal safety study. The reduced glycerin VF (RGVF gel was used in the MTN-007 Phase 1 rectal microbicide trial and is currently being evaluated in the MTN-017 Phase 2 rectal microbicide trial. A third rectal specific formulation (RF gel was also evaluated in the CHARM-01 study.Participants received 4 mL of the three TFV gels in a blinded, crossover design: seven daily doses of RGVF, seven daily doses of RF, and six daily doses of placebo followed by one dose of VF, in a randomized sequence. Safety, acceptability, compartmental PK, and explant PD were monitored throughout the trial.All three gels were found to be safe and acceptable. RF and RGVF PK were not significantly different. Median mucosal mononuclear cell (MMC TFV-DP trended toward higher values for RF compared to RGVF (1136 and 320 fmol/106 cells respectively. Use of each gel in vivo was associated with significant inhibition of ex vivo colorectal tissue HIV infection. There was also a significant negative correlation between the tissue levels of TFV, tissue TFV-DP, MMC TFV-DP, rectal fluid TFV, and explant HIV-1 infection.All three formulations were found to be safe and acceptable. However, the safety profile of the VF gel was only based on exposure to one dose whereas participants received seven doses of the RGVF and RF gels. There was a trend towards higher tissue MMC levels of TFV-DP associated with use of the RF gel. Use of all gels was associated with significant inhibition of ex vivo tissue HIV infection.ClinicalTrials.gov NCT01575405.

Etodolac Containing Topical Niosomal Gel: Formulation Development and Evaluation

Directory of Open Access Journals (Sweden)

Gyati Shilakari Asthana

2016-01-01

Full Text Available The present study aimed to investigate the delivery potential of Etodolac (ETD containing topical niosomal gel. Niosomal formulations were prepared by thin film hydration method at various ratios of cholesterol and Span 60 and were evaluated with respect to particle size, shape, entrapment efficiency, and in vitro characteristics. Dicetyl phosphate (DCP was also added in the niosomal formulation. Mean particle size of niosomal formulation was found to be in the range of 2 μm to 4 μm. Niosomal formulation N2 (1 : 1 ratio of cholesterol and surfactant displayed good entrapment efficiency (96.72%. TEM analyses showed that niosomal formulation was spherical in shape. Niosomal formulation (N2 displayed high percentage of drug release after 24 h (94.91 at (1 : 1 ratio of cholesterol : surfactant. Further selected niosomal formulation was used to formulate topical gel and was characterized with respect to its various parameters such as pH, viscosity, spreadability, ex vivo study, and in vivo potential permeation. Ex vivo study showed that niosomal gel possessed better skin permeation study than the plain topical gel. Further in vivo study revealed good inhibition of inflammation in case of topical niosomal gel than plain gel and niosomal formulation. The present study suggested that topical niosomal gel formulations provide sustained and prolonged delivery of drug.

A New Resistance Formulation for Carbon Nanotubes

Directory of Open Access Journals (Sweden)

Ji-Huan He

2008-01-01

Full Text Available A new resistance formulation for carbon nanotubes is suggested using fractal approach. The new formulation is also valid for other nonmetal conductors including nerve fibers, conductive polymers, and molecular wires. Our theoretical prediction agrees well with experimental observation.

The effect of beta-interferon therapy on myelin basic protein-elicited CD4+ T cell proliferation and cytokine production in multiple sclerosis

DEFF Research Database (Denmark)

Hedegaard, Chris J; Krakauer, Martin; Bendtzen, Klaus

2008-01-01

Interferon (IFN)-beta therapy has well-established clinical benefits in multiple sclerosis (MS), but the underlying modulation of cytokine responses to myelin self-antigens remains poorly understood. We analysed the CD4+ T cell proliferation and cytokine responses elicited by myelin basic protein...... (MBP) and a foreign recall antigen, tetanus toxoid (TT), in mononuclear cell cultures from fourteen MS patients undergoing IFN-beta therapy. The MBP-elicited IFN-gamma-, TNF-alpha- and IL-10 production decreased during therapy (p...

Lymphatic fatty acids in canine with pharmaceutical formulations containing structured triacylglycerols

DEFF Research Database (Denmark)

Holm, R.; Porsgaard, Trine; Porter, C.J.H.

2006-01-01

The intramolecular structure of dietary triacylglycerols (TAG) influences absorption. In this study, two different pharmaceutical formulations were compared containing TAG differing in fatty acid profiles and intramolecular structures: LML and MLM, where M represented medium-chain fatty acids (MCFA...... was generally higher than from the animals dosed with the MLM vehicle; however, statistically significant differences were only found for 18:0 and 18:3n-3. In conclusion, these results indicated that the fatty acid profile and intramolecular structure of administered TAG influenced the absorption of fatty acids...

REUSING STOCKS SOLUTIONS WITH DIFFERENT FORMULATED FOR ORCHID FERTILIZER ACCLIMATIZATION PHASE

Directory of Open Access Journals (Sweden)

C. G. C. Issa

2018-04-01

Full Text Available Orchids are ornamental plants that stand out by their colors, types, shapes, size, beauty. Additionally, some species have aromas. This diversity of orchids makes it be greatly appreciated as potted plants, landscaping, with high commercial value. The aim of this study was to evaluate the development of orchids at different levels of fertilization by reusing nutrients added to the culture medium for cultivation in vitro is also analyzing the different times of acclimatization. The micropropagated orchids removed from the growth chamber, were transported to greenhouse composing the different treatments for acclimatization (0, 10, 20, 30, 40 and 50 days. To be transplanted were placed in pine bark substrate and Sphagnum being placed in trays. After 30 days the seedlings were transplanted to styrofoam trays was initiated plant fertilization weekly with different formulated by administering 5 ml each (1 humic acid, 2nd potassium nitrate (KNO3, 3rd humic acid + Nitrate potassium (KNO3, 4th calcium chloride (CaCl2, 5 ° control. Six months after withdrawal of the growth room the plants was carried out the evaluation of the experiment where the plant survival was evaluated by the number of shoots, number of leaves, the length of the largest leaf and root presence. The experimental design was completely randomized in a factorial 6x5, with the time of acclimatization (0, 10, 20, 30, 40 and 50 days the first factor and the second, the type of fertilizer used (4 formulated and the witness with 8 replicates per treatment. The data were submitted to deviance analysis in the software R. In this study, the need to fertilize with nutrient rich formulations for orchids in the acclimatization phase was contacted and that these should remain for a few days inside the jars in a greenhouse environment.

Platelet lysate mucohadesive formulation to treat oral mucositis in graft versus host disease patients: a new therapeutic approach.

Science.gov (United States)

Del Fante, Claudia; Perotti, Cesare; Bonferoni, Maria Cristina; Rossi, Silvia; Sandri, Giuseppina; Ferrari, Franca; Scudeller, Luigia; Caramella, Carla Marcella

2011-09-01

Optimal treatment of oral mucositis (OM) due to graft versus host disease (GvHD) is currently not available. Platelet-derived growth factors (PDGFs) have high capability for tissue healing and may play a role in repairing the mucosal barrier. The aim of the present work was to develop a mucoadhesive formulation to administer platelet lysate to oral cavity prolonging contact time of platelet lysate with oral mucosa. The mucoadhesive formulation was characterized for in vitro properties (PDGF-AB concentration, mucoadhesive properties, cytotoxicity, fibroblast proliferation, wound healing). Moreover, a preliminary clinical study on seven GvHD patients with OM refractory to other therapies was conducted, to evaluate feasibility, safety, and efficacy. GVPL (mucoadhesive gel vehicle mixed with platelet lysate)showed good mucoadhesive properties; additionally, it was characterized by good biocompatibility in vitro on fibroblasts and it was able to enhance fibroblast proliferation and wound healing, maintaining the efficacy for up to 14 days following storage at 2-8°C. In vivo, clinical response was good-to-complete in five, fair in one, none in the remaining one. The in vitro results indicate that GVPL has optimal mucoadhesive and healing enhancer properties, maintained over time (up to 14 days); preliminary clinical results suggest that oral application of platelet lysate-loaded mucoadhesive formulation is feasible, safe, well tolerated, and effective. A larger controlled randomized study is needed.

A novel nasal powder formulation of glucagon: toxicology studies in animal models

OpenAIRE

Reno, Frederick E.; Normand, Patrick; McInally, Kevin; Silo, Sherwin; Stotland, Patricia; Triest, Myriam; Carballo, Dolores; Pich?, Claude

2015-01-01

Background Glucagon nasal powder (GNP), a novel intranasal formulation of glucagon being developed to treat insulin-induced severe hypoglycemia, contains synthetic glucagon (10?% w/w), beta-cyclodextrin, and dodecylphosphocholine. The safety of this formulation was evaluated in four studies in animal models. Methods The first study evaluated 28-day sub-chronic toxicology in rats treated intranasally with 1 and 2?mg of GNP/day (0.1 and 0.2?mg glucagon/rat/day). The second study evaluated 28-da...

Formulation and characterization of lipid-based drug delivery system of raloxifene-microemulsion and self-microemulsifying drug delivery system

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Hetal Thakkar

2011-01-01

Full Text Available Background : Raloxifene, a second-generation selective estrogen receptor modulator (SERM used to prevent osteoporosis in postmenopausal women is administered orally in the form of a tablet. The absolute bioavailability of the drug is only 2% because of extensive hepatic first-pass metabolism. Lipid-based formulations are reported to reduce the first-pass metabolism by promoting its lymphatic uptake. Materials and Methods : In the present investigation, microemulsion and Self-Microemulsifying Drug Delivery System (SMEDDS formulations of Raloxifene were prepared. The prepared formulations were characterized for drug loading, size, transparency, zeta potential, Transmission Electron Microscopy (TEM and in vitro intestinal permeability. Results : The results indicated that high drug loading, optimum size and desired zeta potential and transparency could be achieved with both SMEDDS and microemulsion. The TEM studies indicated the absence of aggregation with both the systems. The in vitro intestinal permeability results showed that the permeation of the drug from the microemulsion and SMEDDs was significantly higher than that obtained from the drug dispersion and marketed formulation. Conclusion : Lipid based formulations such as microemulsion and Self Microemulsifying drug delivery systems are expected to increase the oral bioavailability as evidenced by the increased intestinal permeation.

Formulation and characterization of lipid-based drug delivery system of raloxifene-microemulsion and self-microemulsifying drug delivery system

Science.gov (United States)

Thakkar, Hetal; Nangesh, Jitesh; Parmar, Mayur; Patel, Divyakant

2011-01-01

Background: Raloxifene, a second-generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women is administered orally in the form of a tablet. The absolute bioavailability of the drug is only 2% because of extensive hepatic first-pass metabolism. Lipid-based formulations are reported to reduce the first-pass metabolism by promoting its lymphatic uptake. Materials and Methods: In the present investigation, microemulsion and Self-Microemulsifying Drug Delivery System (SMEDDS) formulations of Raloxifene were prepared. The prepared formulations were characterized for drug loading, size, transparency, zeta potential, Transmission Electron Microscopy (TEM) and in vitro intestinal permeability. Results: The results indicated that high drug loading, optimum size and desired zeta potential and transparency could be achieved with both SMEDDS and microemulsion. The TEM studies indicated the absence of aggregation with both the systems. The in vitro intestinal permeability results showed that the permeation of the drug from the microemulsion and SMEDDs was significantly higher than that obtained from the drug dispersion and marketed formulation. Conclusion: Lipid based formulations such as microemulsion and Self Microemulsifying drug delivery systems are expected to increase the oral bioavailability as evidenced by the increased intestinal permeation. PMID:21966167

A new topical formulation enhances relative diclofenac bioavailability in healthy male subjects.

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Brunner, Martin; Davies, David; Martin, Wolfgang; Leuratti, Chiara; Lackner, Edith; Müller, Markus

2011-06-01

• Therapy with topical non-steroidal anti-inflammatory drugs (NSAIDs) relies on the ability of the active drug to penetrate the skin in sufficiently high amounts to exert a clinical effect, which is linked to the specific galenic properties of the formulation. • This phase 1 study characterizes the transdermal penetration and plasma exposure of different dose levels with galenic differences of a novel topical diclofenac formulation under development and indicates greater diclofenac penetration through the skin when compared with a commercially available formulation. To evaluate the relative plasma and tissue availability of diclofenac after repeated topical administration of a novel diclofenac acid-based delivery system under development (DCF100C). This was a single-centre, open-label, three-period, crossover clinical trial of five discrete diclofenac formulations. Test preparations comprised two concentrations (1.0% and 2.5%) of DCF100C, with and without menthol and eucalyptus oil (total daily doses of 5 mg and 12.5 mg). Voltaren Emulgel gel (1.0%) was the commercially available comparator (total daily dose of 40 mg). Topical application was performed onto the thigh of 20 male healthy subjects for 3 days. Applying a Youden square design, each drug was evaluated in 12 subjects, with each subject receiving three test preparations. Blood sampling and in vivo microdialysis in subcutaneous adipose and skeletal muscle tissues were performed for 10 h after additional final doses on the morning of day 4. All four DCF100C formulations demonstrated a three- to fivefold, dose-dependent increase in systemic diclofenac availability compared with Voltaren Emulgel and were approximately 30-40 times more effective at facilitating diclofenac penetration through the skin, taking different dose levels into account. Tissue concentrations were low and highly variable. The 2.5% DCF100C formulation without sensory excipients reached the highest tissue concentrations. AUC(0,10 h) was

Development of a 186Re-HEDP formulation and radio pharmacokinetics comparison with 153Sm-EDTMP

International Nuclear Information System (INIS)

Bribiesca C, A.I.

1998-01-01

Because of the growing interest in the use of the beta emitters radiopharmaceuticals applied to therapy in different cancer cases, we developed a formulation of 186 Re-HEDP (hydroxy ethylidene diphosphonate) as a pain palliative in osseous metastases. Besides serving like therapeutic agent, together with the 153 Sm-EDTMP (ethylene diamine tetra methylene phosphonate), which has already been synthesized and proved, labels EHDP could be very useful like a diagnostic agent in the pursuit of the illness. The irradiation conditions for Rhenium-186 were established by ORIGIN 2 codes for TRIGA reactors. A pharmaceutical formulation was developed employing a factorial experimental design obtaining a complex with a radiochemical purity over 90 %. The complexes 186 Re-HEDP 153 Sm-EDTMP were intravenous administered in BALB-C mice sacrifying them in several intervals of time in order to determine the cumulated activity in each organ to perform absorbed dose calculation by MIRD methodology (Medical Internal Radiation Dose). Radio pharmacokinetic data demonstrated that both complexes follow a biexponential kinetic of first order behavior. In the case of the 186 Re-HEDP the value of the α constant was 0.2789 and β 0.0006 with an effective dose of 2.56 (mSv)/MBq , while for the complex 153 Sm-EDTMP the values of α to and β were 0.9012 and and 0.616 respectively and the effective dose was 0.262 (mSv)/MBq. In conclusion, radiopharmaceutical 153 Sm-EDTMP, showed a greater bone uptake and a minor effective dose, for which it is a better radiopharmaceutical, respect to with the formulation of 186 Re-HEDP. (Author)

A web-based online collaboration platform for formulating engineering design projects

Science.gov (United States)

Varikuti, Sainath

Effective communication and collaboration among students, faculty and industrial sponsors play a vital role while formulating and solving engineering design projects. With the advent in the web technology, online platforms and systems have been proposed to facilitate interactions and collaboration among different stakeholders in the context of senior design projects. However, there are noticeable gaps in the literature with respect to understanding the effects of online collaboration platforms for formulating engineering design projects. Most of the existing literature is focused on exploring the utility of online platforms on activities after the problem is defined and teams are formed. Also, there is a lack of mechanisms and tools to guide the project formation phase in senior design projects, which makes it challenging for students and faculty to collaboratively develop and refine project ideas and to establish appropriate teams. In this thesis a web-based online collaboration platform is designed and implemented to share, discuss and obtain feedback on project ideas and to facilitate collaboration among students and faculty prior to the start of the semester. The goal of this thesis is to understand the impact of an online collaboration platform for formulating engineering design projects, and how a web-based online collaboration platform affects the amount of interactions among stakeholders during the early phases of design process. A survey measuring the amount of interactions among students and faculty is administered. Initial findings show a marked improvement in the students' ability to share project ideas and form teams with other students and faculty. Students found the online platform simple to use. The suggestions for improving the tool generally included features that were not necessarily design specific, indicating that the underlying concept of this collaborative platform provides a strong basis and can be extended for future online platforms

The nature and combination of subunits used in epitope-based Schistosoma japonicum vaccine formulations affect their efficacy

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Liu Feng

2010-11-01

Full Text Available Abstract Background Schistosomiasis remains a major public health problem in endemic countries and is caused by infections with any one of three primary schistosome species. Although there are no vaccines available to date, this strategy appears feasible since natural immunity develops in individuals suffering from repeated infection during a lifetime. Since vaccinations resulting in both Th1- and Th2-type responses have been shown to contribute to protective immunity, a vaccine formulation with the capacity for stimulating multiple arms of the immune response will likely be the most effective. Previously we developed partially protective, single Th- and B cell-epitope-based peptide-DNA dual vaccines (PDDV (T3-PDDV and B3-PDDV, respectively capable of eliciting immune responses against the Schistosoma japonicum 22.6 kDa tegument antigen (Sj22.6 and a 62 kDa fragment of myosin (Sj62, respectively. Results In this study, we developed PDDV cocktails containing multiple epitopes of S. japonicum from Sj22.6, Sj62 and Sj97 antigens by predicting cytotoxic, helper, and B-cell epitopes, and evaluated vaccine potential in vivo. Results showed that mice immunized with a single-epitope PDDV elicited either Tc, Th, or B cell responses, respectively, and mice immunized with either the T3- or B3- single-epitope PDDV formulation were partially protected against infection. However, mice immunized with a multicomponent (3 PDDV components formulation elicited variable immune responses that were less immunoprotective than single-epitope PDDV formulations. Conclusions Our data show that combining these different antigens did not result in a more effective vaccine formulation when compared to each component administered individually, and further suggest that immune interference resulting from immunizations with antigenically distinct vaccine targets may be an important consideration in the development of multicomponent vaccine preparations.

Quality evaluation of extemporaneous delayed-release liquid formulations of lansoprazole.

Science.gov (United States)

Melkoumov, Alexandre; Soukrati, Amina; Elkin, Igor; Forest, Jean-Marc; Hildgen, Patrice; Leclair, Grégoire

2011-11-01

The quality attributes of extemporaneous delayed-release liquid formulations of lansoprazole for oral administration were evaluated. A novel liquid formulation (3 mg/mL) of Prevacid FasTab in an Ora-Blend vehicle was prepared and compared with the Prevacid FasTab 30 mg and Prevacid-sodium bicarbonate 1 M formulation (3 mg/mL). The latter formulation was combined with hydrochloric acid 0.1 N, and the remaining lansoprazole content was assayed by high-performance liquid chromatography (HPLC). A batch of delayed-release liquid formulation was prepared to evaluate content uniformity. For content assay, three samples were prepared for each evaluated condition and each sample was analyzed in triplicate by HPLC. The lansoprazole in the sodium bicarbonate formulation was extensively degraded by quantities of hydrochloric acid 0.1 N in excess of 100 mL. Storage time and temperature had a significant effect on lansoprazole stability in the Ora-Blend formulation. The drug remained stable for seven days when the formulation was stored at 4.5-5.5 °C, but storage at 21-22 °C or the reduction of pH with citric acid accelerated lansoprazole degradation. The amount of lansoprazole released from the Ora-Blend formulation during the buffer stage of the dissolution test decreased with increases in formulation storage time, in formulation storage temperature, and in the amount of lansoprazole released and degraded during the acid stage of the test. An extemporaneous formulation consisting of lansoprazole microgranules in Ora-Blend maintained acceptable quality attributes when stored for three days at 4.5-5.5 °C.

Peripherally administered nanoparticles target monocytic myeloid cells, secondary lymphoid organs and tumors in mice.

Science.gov (United States)

Kourtis, Iraklis C; Hirosue, Sachiko; de Titta, Alexandre; Kontos, Stephan; Stegmann, Toon; Hubbell, Jeffrey A; Swartz, Melody A

2013-01-01

Nanoparticles have been extensively developed for therapeutic and diagnostic applications. While the focus of nanoparticle trafficking in vivo has traditionally been on drug delivery and organ-level biodistribution and clearance, recent work in cancer biology and infectious disease suggests that targeting different cells within a given organ can substantially affect the quality of the immunological response. Here, we examine the cell-level biodistribution kinetics after administering ultrasmall Pluronic-stabilized poly(propylene sulfide) nanoparticles in the mouse. These nanoparticles depend on lymphatic drainage to reach the lymph nodes and blood, and then enter the spleen rather than the liver, where they interact with monocytes, macrophages and myeloid dendritic cells. They were more readily taken up into lymphatics after intradermal (i.d.) compared to intramuscular administration, leading to ∼50% increased bioavailability in blood. When administered i.d., their distribution favored antigen-presenting cells, with especially strong targeting to myeloid cells. In tumor-bearing mice, the monocytic and the polymorphonuclear myeloid-derived suppressor cell compartments were efficiently and preferentially targeted, rendering this nanoparticulate formulation potentially useful for reversing the highly suppressive activity of these cells in the tumor stroma.

Peripherally administered nanoparticles target monocytic myeloid cells, secondary lymphoid organs and tumors in mice.

Directory of Open Access Journals (Sweden)

Iraklis C Kourtis

Full Text Available Nanoparticles have been extensively developed for therapeutic and diagnostic applications. While the focus of nanoparticle trafficking in vivo has traditionally been on drug delivery and organ-level biodistribution and clearance, recent work in cancer biology and infectious disease suggests that targeting different cells within a given organ can substantially affect the quality of the immunological response. Here, we examine the cell-level biodistribution kinetics after administering ultrasmall Pluronic-stabilized poly(propylene sulfide nanoparticles in the mouse. These nanoparticles depend on lymphatic drainage to reach the lymph nodes and blood, and then enter the spleen rather than the liver, where they interact with monocytes, macrophages and myeloid dendritic cells. They were more readily taken up into lymphatics after intradermal (i.d. compared to intramuscular administration, leading to ∼50% increased bioavailability in blood. When administered i.d., their distribution favored antigen-presenting cells, with especially strong targeting to myeloid cells. In tumor-bearing mice, the monocytic and the polymorphonuclear myeloid-derived suppressor cell compartments were efficiently and preferentially targeted, rendering this nanoparticulate formulation potentially useful for reversing the highly suppressive activity of these cells in the tumor stroma.

On a covariant 2+2 formulation of the initial value problem in general relativity

International Nuclear Information System (INIS)

Smallwood, J.

1980-03-01

The initial value problems in general relativity are considered from a geometrical standpoint with especial reference to the development of a covariant 2+2 formalism in which space-time is foliated by space-like 2-surfaces under the headings; the Cauchy problem in general relativity, the covariant 3+1 formulation of the Cauchy problem, characteristic and mixed initial value problems, on locally imbedding a family of null hypersurfaces, the 2+2 formalism, the 2+2 formulation of the Cauchy problem, the 2+2 formulation of the characteristic and mixed initial value problems, and a covariant Lagrangian 2+2 formulation. (U.K.)

Formulation, Characterization, and Antitumor Properties of Trans- and Cis-Citral in the 4T1 Breast Cancer Xenograft Mouse Model.

Science.gov (United States)

Zeng, San; Kapur, Arvinder; Patankar, Manish S; Xiong, May P

2015-08-01

Citral is composed of a random mixture of two geometric stereoisomers geranial (trans-citral) and neral (cis-citral) yet few studies have directly compared their in vivo antitumor properties. A micelle formulation was therefore developed. Geranial and neral were synthesized. Commercially-purchased citral, geranial, and neral were formulated in PEG-b-PCL (block sizes of 5000:10,000, Mw/Mn 1.26) micelles. In vitro degradation, drug release, cytotoxicity, flow cytometry, and western blot studies were conducted. The antitumor properties of drug formulations (40 and 80 mg/kg based on MTD studies) were evaluated on the 4T1 xenograft mouse model and tumor tissues were analyzed by western blot. Micelles encapsulated drugs with >50% LE at 5-40% drug to polymer (w/w), displayed sustained release (t1/2 of 8-9 h), and improved drug stability at pH 5.0. The IC50 of drug formulations against 4T1 cells ranged from 1.4 to 9.9 μM. Western blot revealed that autophagy was the main cause of cytotoxicity. Geranial at 80 mg/kg was most effective at inhibiting tumor growth. Geranial is significantly more potent than neral and citral at 80 mg/kg (p < 0.001) and western blot of tumor tissues confirms that autophagy and not apoptosis is the major mechanism of tumor growth inhibition in p53-null 4T1 cells.

Aluminum phosphate shows more adjuvanticity than Aluminum hydroxide in recombinant hepatitis –B vaccine formulation

Directory of Open Access Journals (Sweden)

2008-08-01

Full Text Available Background: Although a number of investigation have been carried out to find alternative adjuvants to aluminum salts in vaccine formulations, they are still extensively used due to their good track record of safety, low cost and proper adjuvanticity with a variety of antigens. Adsorption of antigens onto aluminum compounds depends heavily on electrostatic forces between adjuvant and antigen. Commercial recombinant protein hepatitis B vaccines containing aluminum hydroxide as adjuvant is facing low induction of immunity in some sections of the vaccinated population. To follow the current global efforts in finding more potent hepatitis B vaccine formulation, adjuvanticity of aluminum phosphate has been compared to aluminum hydroxide. Materials and methods: The adjuvant properties of aluminum hydroxide and aluminum phosphate in a vaccine formulation containing a locally manufactured hepatitis B (HBs surface antigen was evaluated in Balb/C mice. The formulations were administered intra peritoneally (i.p. and the titers of antibody which was induced after 28 days were determined using ELISA technique. The geometric mean of antibody titer (GMT, seroconversion and seroprotection rates, ED50 and relative potency of different formulations were determined. Results: All the adjuvanicity markers obtained in aluminum phosphate formulation were significantly higher than aluminum hydroxide. The geometric mean of antibody titer of aluminum phosphate was approximately three folds more than aluminum hydroxide. Conclusion: Aluminum phosphate showed more adjuvanticity than aluminum hydroxide in hepatitis B vaccine. Therefore the use of aluminum phosphate as adjuvant in this vaccine may lead to higher immunity with longer duration of effects in vaccinated groups.

Beyond the flavor: A green formulation of Ferula asafoetida oleo-gum-resin with fenugreek dietary fibre and its gut health potential

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Liju Vijayasteltar

Full Text Available Albeit the fact that asafotida is a popular kitchen spice and Indian folklore medicine for gut disorders, its consumption at physiologically relevant dosage is greatly challenged by the unpleasant flavor characteristics. Herein we report a green approach to derive stable powder formulations of asafoetida gum with minimized taste and odor suitable for dietary applications and gut health-related disorders. Employing a water based ultrasound mediated gel-phase dispersion of asafoetida gum on fenugreek derived soluble galactomannan fibre matrix. Microencapsulated particles (1 ± 0.3 μm of asafoetida was prepared as water dispersible free flowing powder (Asafin. Fourier-transform infrared spectroscopy (FTIR, scanning electron microscopy (SEM, accelerated stability and in vitro dissolution studies confirmed the stability, sustained release and microencapsulated structure of Asafin. Further investigations revealed significant (p < 0.01 reduction in acetic acid-induced writings and inhibition of ethanol-induced ulcer (94.1% in rats orally administered with Asafin at 250 mg kg−1 b.w. Asafin also exhibited anti-inflammatory effects (p < 0.01, in acute and chronic paw edema mice models. The safety of Asafin was further demonstrated by acute toxicity studies at 4 g kg−1  b.w. and by 28 days of sub-acute toxicity studies at 2.0 g kg−1 b.w. Keywords: Ferula asafoetida, Green formulation, Oral delivery, Gastroprotective, Ethanol-induced ulcer, Gut health

Rheological effect of gamma radiation on gel-like formulation: Appraisal for the construction of radiopharmaceuticals for cutaneous application

Science.gov (United States)

Saez, Vivian; Khoury, Helen Jamil; da Silva, Maria Isabel Barbosa; Mansur, Claudia Regina Elias; Santos-Oliveira, Ralph

2018-04-01

Skin cancer affects a lot of people being a malignant cutaneous melanoma one of the most aggressive neoplasms. Nowadays, the FDA-approved drugs to treat them are not as efficient as needed. Thus, the development of new agents or treatments is quite urgent. In that sense, the use of radioactive materials could represent a good alternative and especially Radium-223 is already been explored with promising results. Here, a Carbopol gel-like formulation was designed and irradiated with different doses in order to prove that it is suitable to include Radium-223 for its combined application by topic route. A formulation was obtained by the addition of triethanolamine to the Carbopol solution until pH 5.0. Physical and rheological tests showed that the formulation is a weak gel with a proper consistence to be administered by both routes. The formulation kept its appearance of transparent gel without change in color, presence of grits or syneresis after all tratments. The microstructure of gels was only slightly modified when the irradiation was made with 1000 Gy while the spreadability and viscosity were more deeply affected. Since the properties of this Carbopol gel-like formulation were maintained under irradiation doses until 100 Gy it is possible to consider that the formulation is suitable to include Radium-223 in order to evaluate its performance as localized drug delivery system for topical administration.

Final Report. Baseline LAW Glass Formulation Testing, VSL-03R3460-1, Rev. 0

Energy Technology Data Exchange (ETDEWEB)

Muller, Isabelle S. [The Catholic University of America, Washington, DC (United States); Pegg, Ian L. [The Catholic University of America, Washington, DC (United States); Gan, Hao [The Catholic University of America, Washington, DC (United States); Buechele, Andrew [The Catholic University of America, Washington, DC (United States); Rielley, Elizabeth [The Catholic University of America, Washington, DC (United States); Bazemore, Gina [The Catholic University of America, Washington, DC (United States); Cecil, Richard [The Catholic University of America, Washington, DC (United States); Hight, Kenneth [The Catholic University of America, Washington, DC (United States); Mooers, Cavin [The Catholic University of America, Washington, DC (United States); Lai, Shan-Tao T. [The Catholic University of America, Washington, DC (United States); Kruger, Albert A. [The Catholic University of America, Washington, DC (United States)

2015-06-18

The major objective of the baseline glass formulation work was to develop and select glass formulations that are compliant with contractual and processing requirements for each of the LAW waste streams. Other objectives of the work included preparation and characterization of glasses with respect to the properties of interest, optimization of sulfate loading in the glasses, evaluation of ability to achieve waste loading limits, testing to demonstrate compatibility of glass melts with melter materials of construction, development of glass formulations to support ILAW qualification activities, and identification of glass formulation issues with respect to contract specifications and processing requirements.

Nonclinical Safety Assessment of SYN-004: An Oral β-lactamase for the Protection of the Gut Microbiome From Disruption by Biliary-Excreted, Intravenously Administered Antibiotics.

Science.gov (United States)

Kokai-Kun, John F; Bristol, J Andrew; Setser, John; Schlosser, Michael

2016-05-01

SYN-004 is a first in class, recombinant β-lactamase that degrades β-lactam antibiotics and has been formulated to be administered orally to patients receiving intravenous β-lactam antibiotics including cephalosporins. SYN-004 is intended to degrade unmetabolized antibiotics excreted into the intestines and thus has the potential to protect the gut microbiome from disruption by these antibiotics. Protection of the gut microbiome is expected to protect against opportunistic enteric infections such as Clostridium difficile infection as well as antibiotic-associated diarrhea. In order to demonstrate that oral SYN-004 is safe for human clinical trials, 2 Good Laboratory Practice-compliant toxicity studies were conducted in Beagle dogs. In both studies, SYN-004 was administered orally 3 times per day up to the maximum tolerated dose of the formulation. In the first study, doses of SYN-004 administered over 28 days were safe and well tolerated in dogs with the no-observed-adverse-effect level at the high dose of 57 mg/kg/day. Systemic absorption of SYN-004 was minimal and sporadic and showed no accumulation during the study. In the second study, doses up to 57 mg/kg/day were administered to dogs in combination with an intravenous dose of ceftriaxone (300 mg/kg) given once per day for 14 days. Coadministration of oral SYN-004 with intravenous ceftriaxone was safe and well tolerated, with SYN-004 having no noticeable effect on the plasma pharmacokinetics of ceftriaxone. These preclinical studies demonstrate that SYN-004 is well tolerated and, when coadministered with ceftriaxone, does not interfere with its systemic pharmacokinetics. These data supported advancing SYN-004 into human clinical trials. © The Author(s) 2015.

A displacement based FE formulation for steady state problems

NARCIS (Netherlands)

Yu, Y.

2005-01-01

In this thesis a new displacement based formulation is developed for elasto-plastic deformations in steady state problems. In this formulation the displacements are the primary variables, which is in contrast to the more common formulations in terms of the velocities as the primary variables. In a

Induction of protective immunity against H1N1 influenza A(H1N1)pdm09 with spray-dried and electron-beam sterilised vaccines in non-human primates.

Science.gov (United States)

Scherließ, Regina; Ajmera, Ankur; Dennis, Mike; Carroll, Miles W; Altrichter, Jens; Silman, Nigel J; Scholz, Martin; Kemter, Kristina; Marriott, Anthony C

2014-04-17

Currently, the need for cooled storage and the impossibility of terminal sterilisation are major drawbacks in vaccine manufacturing and distribution. To overcome current restrictions a preclinical safety and efficacy study was conducted to evaluate new influenza A vaccine formulations regarding thermal resistance, resistance against irradiation-mediated damage and storage stability. We evaluated the efficacy of novel antigen stabilizing and protecting solutions (SPS) to protect influenza A(H1N1)pdm09 split virus antigen under experimental conditions in vitro and in vivo. Original or SPS re-buffered vaccine (Pandemrix) was spray-dried and terminally sterilised by irradiation with 25 kGy (e-beam). Antigen integrity was monitored by SDS-PAGE, dynamic light scattering, size exclusion chromatography and functional haemagglutination assays. In vitro screening experiments revealed a number of highly stable compositions containing glycyrrhizinic acid (GA) and/or chitosan. The most stable composition was selected for storage tests and in vivo assessment of seroconversion in non-human primates (Macaca fascicularis) using a prime-boost strategy. Redispersed formulations with original adjuvant were administered intramuscularly. Storage data revealed high stability of protected vaccines at 4°C and 25°C, 60% relative humidity, for at least three months. Animals receiving original Pandemrix exhibited expected levels of seroconversion after 21 days (prime) and 48 days (boost) as assessed by haemagglutination inhibition and microneutralisation assays. Animals vaccinated with spray-dried and irradiated Pandemrix failed to exhibit seroconversion after 21 days whereas spray-dried and irradiated, SPS-protected vaccines elicited similar seroconversion levels to those vaccinated with original Pandemrix. Boost immunisation with SPS-protected vaccine resulted in a strong increase in seroconversion but had only minor effects in animals treated with non SPS-protected vaccine. In conclusion

An herbal formulation for hemorrhoids treatment

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S. Dehdari

2017-11-01

Full Text Available Background and objectives: Hemorrhoids is the most painful rectal disease. Straining and pregnancy seem playing chief roles in the development of hemorrhoids. Symptoms of hemorrhoids may include bleeding, inflammation and pain. Despite current medical efforts, many discomforts of hemorrhoids have not been handled. The aim of the present study was to formulate and evaluate Itrifal-e muqil (IM tablet to achieve desired pharmaceutical properties. Method: Quality control tests of Allium ampeloperasum L, Commiphora mukul (Hook. ex Stocks Engl., Phyllanthus emblica L., Terminalia chebula Retz. and Terminalia bellerica Retz. were performed. Afterwards, different formulations were prepared and their physical properties were evaluated. Subsequently, the formulation was coated and its physicochemical characteristics were assessed. Result: All of the herbs demonstrated good results in quality control tests according to United State Pharmacopeia (USP. Formulation-1 that was completely prepared based on explained manufacturing process of IM in traditional medicine manuscripts did not show suitable pharmaceutical properties. Among different formulations, Formulation-3 that consisted of A. ampeloperasum, C. mukul, P. emblica, T. chebula and T. bellerica, displayed best outcomes through different tests. Conclusion: Modern pharmaceutical approaches can excellently be adapted for IM preparations.

Formulation development of retrocyclin 1 analog RC-101 as an anti-HIV vaginal microbicide product.

Science.gov (United States)

Sassi, A B; Cost, M R; Cole, A L; Cole, A M; Patton, D L; Gupta, P; Rohan, L C

2011-05-01

RC-101 is a synthetic microbicide analog of retrocyclin, which has shown in vitro activity against X4 and R5 HIV-1. In an effort to develop a safe and effective RC-101 vaginal microbicide product, we assessed safety in ex vivo macaque and human models and efficacy using in vitro and ex vivo models. A polyvinyl-alcohol vaginal film containing RC-101 (100 μg/film) was developed. Formulation assessment was conducted by evaluating disintegration, drug content, mechanical properties, and stability. Efficacy was evaluated by in vitro peripheral blood mononuclear cells (PBMC) assay and ex vivo human ectocervical tissue explant model. Ex vivo safety studies were conducted by exposing RC-101 to an excised monkey reproductive tract and excised human ectocervical tissue. RC-101 100 μg films were shown to be safe to human and monkey tissue and effective against HIV-1 in vitro and ex vivo in human ectocervical tissue. The 90% inhibitory concentration (IC90) for RC-101 films at 2,000 μg (IC90=57.5 μM) using an ex vivo model was 10-fold higher than the IC90 observed using an in vitro model (IC90=5.0 μM). RC-101 films were stable for 1 month at 25°C, with in vitro bioactivity maintained for up to 6 months. RC-101 was developed in a quick-dissolve film formulation that was shown to be safe in an ex vivo model and effective in in vitro and ex vivo models. RC-101 film formulations were shown to maintain bioactivity for a period of 6 months. Findings from the present study contribute to the development of a safe and effective topical microbicide product.

A Controlled Study to Assess the Clinical Efficacy of Totally Self-Administered Systematic Desensitization

Science.gov (United States)

Rosen, Gerald M.; And Others

1976-01-01

Highly anxious self-referred snake phobics received either (a) therapist-administered desensitization, (b) self-administered desensitization with weekly therapist phone calls, (c) totally self-administered desensitization, (d) self-administered double-blind placebo control, or (e) no treatment. Pretreatment to posttreatment measures revealed…

Preliminary Formulation of Finite Element Solution for the 1-D, 1-G Time Dependent Neutron Diffusion Equation without Consideration about Delay Neutron

Energy Technology Data Exchange (ETDEWEB)

Ryu, Eun Hyun; Song, Yong Mann; Park, Joo Hwan [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

2013-05-15

If time-dependent equation is solved with the FEM, the limitation of the input geometry will disappear. It has often been pointed out that the numerical methods implemented in the RFSP code are not state-of-the-art. Although an acceleration method such as the Coarse Mesh Finite Difference (CMFD) for Finite Difference Method (FDM) does not exist for the FEM, one should keep in mind that the number of time steps for the transient simulation is not large. The rigorous formulation in this study will richen the theoretical basis of the FEM and lead to an extension of the dynamics code to deal with a more complicated problem. In this study, the formulation for the 1-D, 1-G Time Dependent Neutron Diffusion Equation (TDNDE) without consideration of the delay neutron will first be done. A problem including one multiplying medium will be solved. Also several conclusions from a comparison between the numerical and analytic solutions, a comparison between solutions with various element orders, and a comparison between solutions with different time differencing will be made to be certain about the formulation and FEM solution. By investigating various cases with different values of albedo, theta, and the order of elements, it can be concluded that the finite element solution is agree well with the analytic solution. The higher the element order used, the higher the accuracy improvements are obtained.

Larvicidal activity of neem oil (Azadirachta indica formulation against mosquitoes

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Dua Virendra K

2009-06-01

Full Text Available Abstract Background Mosquitoes transmit serious human diseases, causing millions of deaths every year. Use of synthetic insecticides to control vector mosquitoes has caused physiological resistance and adverse environmental effects in addition to high operational cost. Insecticides of botanical origin have been reported as useful for control of mosquitoes. Azadirachta indica (Meliaceae and its derived products have shown a variety of insecticidal properties. The present paper discusses the larvicidal activity of neem-based biopesticide for the control of mosquitoes. Methods Larvicidal efficacy of an emulsified concentrate of neem oil formulation (neem oil with polyoxyethylene ether, sorbitan dioleate and epichlorohydrin developed by BMR & Company, Pune, India, was evaluated against late 3rd and early 4th instar larvae of different genera of mosquitoes. The larvae were exposed to different concentrations (0.5–5.0 ppm of the formulation along with untreated control. Larvicidal activity of the formulation was also evaluated in field against Anopheles, Culex, and Aedes mosquitoes. The formulation was diluted with equal volumes of water and applied @ 140 mg a.i./m2 to different mosquito breeding sites with the help of pre calibrated knapsack sprayer. Larval density was determined at pre and post application of the formulation using a standard dipper. Results Median lethal concentration (LC50 of the formulation against Anopheles stephensi, Culex quinquefasciatus and Aedes aegypti was found to be 1.6, 1.8 and 1.7 ppm respectively. LC50 values of the formulation stored at 26°C, 40°C and 45°C for 48 hours against Ae. aegypti were 1.7, 1.7, 1.8 ppm while LC90 values were 3.7, 3.7 and 3.8 ppm respectively. Further no significant difference in LC50 and LC90 values of the formulation was observed against Ae. aegypti during 18 months storage period at room temperature. An application of the formulation at the rate of 140 mg a.i./m2 in different breeding

Sustained release of intravitreal flurbiprofen from a novel drug-in-liposome-in-hydrogel formulation.

Science.gov (United States)

Pachis, K; Blazaki, S; Tzatzarakis, M; Klepetsanis, P; Naoumidi, E; Tsilimbaris, M; Antimisiaris, S G

2017-11-15

A novel Flurbiprofen (FLB)-in-liposome-in-hydrogel formulation was developed, as a method to sustain the release and increase the ocular bioavailability of FLB following intravitreal injection. For this, FLB loading into liposomes was optimized and liposomes were entrapped in thermosensitive hydrogels consisted of Pluronic F-127 (P). FLB solution, liposomes, and FLB dissolved in hydrogel were also used as control formulations. Actively loaded liposomes were found to be optimal for high FLB loading and small size, while in vitro studies revealed that P concentration of 18% (w/v) was best to retain the integrity of the hydrogel-dispersed liposome, compared to a 20% concentration. The in vitro release of FLB was significantly sustained when FLB-liposomes were dispersed in the hydrogel compared to hydrogel dissolved FLB, as well as the other control formulations. In vivo studies were carried out in pigmented rabbits which were injected through a 27G needle with 1mg/mL FLB in the different formulation-types. Ophthalmic examinations after intravitreal injection of all FLB formulations, revealed no evidence of inflammation, hemorrhage, uveitis or endophthalmitis. Pharmacokinetic analysis results confirm that the hybrid drug delivery system increases the bioavailability (by 1.9 times compared to solution), and extends the presence of the drug in the vitreous cavity, while liposome and hydrogel formulations demonstrate intermediate performance. Furthermore the hybrid system increases MRT of FLB in aqueous humor and retina/choroid tissues, compared to all the control formulations. Currently the potential therapeutic advances of FLB sustained release formulations for IVT administration are being evaluated. Copyright © 2017 Elsevier B.V. All rights reserved.

An ayurvedic formulation Sankat Mochan: A potent anthelmintic medicine

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Khomendra Kumar Sarwa

2017-01-01

Full Text Available Aim and Object: Sankat Mochan is an ayurvedic formulation used in the urban and rural area of India. This polyherbal formulation is used for general stomach problems including abdominal cramping and diarrhea. The present investigation evaluated the anthelmintic activity of an aqueous solution of an ayurvedic medicine Sankat Mochan. Materials and Method: Various concentrations (1%, 5%, and 10% of medicine were used for anthelmintic activity on Pheretima posthuma. Piperazine citrate (10 mg/ml was used as a reference standard and distilled water as a control. Result and Conclusion: The result showed that the Sankat Mochan possess anthelmintic activity more potent than that of piperazine citrate. Thus, Sankat Mochan may be used as a potent anthelmintic agent against helminthiasis.

Implementation of Quality by Design for Formulation of Rebamipide Gastro-retentive Tablet.

Science.gov (United States)

Ha, Jung-Myung; Seo, Jeong-Woong; Kim, Su-Hyeon; Kim, Ju-Young; Park, Chun-Woong; Rhee, Yun-Seok; Park, Eun-Seok

2017-11-01

The purpose of the present study was to develop a rebamipide (RBM) gastro-retentive (GR) tablet by implementing quality by design (QbD). RBM GR tablets were prepared using a sublimation method. Quality target product profile (QTPP) and critical quality attributes (CQAs) of the RBM GR tablets were defined according to the preliminary studies. Factors affecting the CQAs were prioritized using failure mode and effects analysis (FMEA). Design space and optimum formulation were established through a mixture design. The validity of the design space was confirmed using runs within the area. The QTPP of the RBM GR tablets was the orally administered GR tablet containing 300 mg of RBM taken once daily. Based on the QTPP, dissolution rate, tablet friability, and floating property were chosen as CQAs. According to the risk assessment, the amount of sustained-release agent, sublimating material, and diluent showed high-risk priority number (RPN) values above 40. Based on the RPN, these factors were further investigated using mixture design methodology. Design space of formulations was depicted as an overlaid contour plot and the optimum formulation to satisfy the desired responses was obtained by determining the expected value of each response. The similarity factor (f2) of the release profile between predicted response and experimental response was 89.463, suggesting that two release profiles are similar. The validity of the design space was also confirmed. Consequently, we were able to develop the RBM GR tablets by implementing the QbD concept. These results provide useful information for development of tablet formulations using the QbD.

Optimized formulation of solid self-microemulsifying sirolimus delivery systems

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Cho W

2013-04-01

Full Text Available Wonkyung Cho,1,2 Min-Soo Kim,3 Jeong-Soo Kim,2 Junsung Park,1,2 Hee Jun Park,1,2 Kwang-Ho Cha,1,2 Jeong-Sook Park,2 Sung-Joo Hwang1,4 1Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea; 2College of Pharmacy, Chungnam National University, Daejeon, Republic of Korea; 3Department of Pharmaceutical Engineering, Inje University, Gimhae, Republic of Korea; 4College of Pharmacy, Yonsei University, Incheon, Republic of Korea Background: The aim of this study was to develop an optimized solid self-microemulsifying drug delivery system (SMEDDS formulation for sirolimus to enhance its solubility, stability, and bioavailability. Methods: Excipients used for enhancing the solubility and stability of sirolimus were screened. A phase-separation test, visual observation for emulsifying efficiency, and droplet size analysis were performed. Ternary phase diagrams were constructed to optimize the liquid SMEDDS formulation. The selected liquid SMEDDS formulations were prepared into solid form. The dissolution profiles and pharmacokinetic profiles in rats were analyzed. Results: In the results of the oil and cosolvent screening studies, Capryol™ Propylene glycol monocaprylate (PGMC and glycofurol exhibited the highest solubility of all oils and cosolvents, respectively. In the surfactant screening test, D-α-tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS was determined to be the most effective stabilizer of sirolimus in pH 1.2 simulated gastric fluids. The optimal formulation determined by the construction of ternary phase diagrams was the T32 (Capryol™ PGMC:glycofurol:vitamin E TPGS = 30:30:40 weight ratio formulation with a mean droplet size of 108.2 ± 11.4 nm. The solid SMEDDS formulations were prepared with Sucroester 15 and mannitol. The droplet size of the reconstituted solid SMEDDS showed no significant difference compared with the liquid SMEDDS. In the dissolution study, the release amounts of

Modern approach to relativity theory (radar formulation)

International Nuclear Information System (INIS)

Strel'tsov, V.N.

1991-01-01

The main peculiarities of the radar formulation of the relativity theory are presented. This formulation operates with the retarded (light) distances and relativistic or radar length introduced on their basis. 21 refs.; 1 tab

DEVELOPMENT OF A CAST STONE FORMULATION FOR HANFORD TANK WASTES

International Nuclear Information System (INIS)

COOKE; ATTERIDGE; AVILA

2005-01-01

The U.S. Department of Energy (DOE) Hanford Site, the location of plutonium production for the US. nuclear weapons program, is the focal point of a broad range of waste remediation efforts. This presentation will describe a test program to develop a ''cast stoney'' formulation for the stabilization of certain Hanford tank wastes (Lockrem 2005). The program consisted of (1) a short series of tests with nonradioactive simulant to select preferred dry reagent formulations (DRF) and determine allowable liquid addition levels, (2) waste form performance testing on cast stone made from the DRF formulations using low-activity waste (LAW) simulant, (3) waste form performance testing on cast stone made from the preferred DRF using LAW, (4) waste form validation testing on a selected nominal cast stone formulation using the preferred DRF and LAW simulant, and (5) technetium ''getter'' testing with cast stone made with LAW simulant and with LAW. In addition, nitrate leaching observations were drawn from nitrate leachability data obtained in the course of waste form performance testing. The nitrate leachability index results are presented along with data on other performance criteria The results of this study led to the selection of a specific DRF. The key attributes of the DRF/waste loading combination considered were presence of ''bleed'' (or free) water, volume change on curing, compressive strength, maximum curing temperature, toxicity characteristic leaching testing, ANSYANS-16.1 (Measurement of the Leachability of Solidified Low-Level Radioactive Wastes by a Short-Term Test Procedure) leachability, and hydraulic conductivity. Important considerations included that the monoliths could be produced using readily available, low-cost reagents. The key results from each of these testing and evaluation activity categories will be summarized

Influence of the oral dissolution time on the absorption rate of locally administered solid formulations for oromucosal use: the flurbiprofen lozenges paradigm.

Science.gov (United States)

Imberti, Roberto; De Gregori, Simona; Lisi, Lucia; Navarra, Pierluigi

2014-01-01

Flurbiprofen is a nonsteroidal anti-inflammatory agent preferentially used for local oromucosal treatment of painful and/or inflammatory conditions of the oropharynx such as gingivitis, stomatitis, periodontitis, pharyngitis and laryngitis. In this study, we have investigated the bioavailability of a new generic formulation of flurbiprofen lozenges developed by Epifarma Srl, compared to the originator Benactiv Gola® taken as reference. Within the framework of a formal bioequivalence study, we investigated in particular the putative influence of oral dissolution time (i.e. the time spent suckling the lozenge from its intake to complete dissolution) on the absorption rate, and the contribution of this factor to the total variability of plasma flurbiprofen during absorption. We found that the amount of flurbiprofen absorbed into the systemic circulation is not significantly higher for the test drug compared to that of the reference product. We observed that the length of oral dissolution time is inversely correlated to 10-min flurbiprofen plasma levels in the test but not in the reference formulation. We estimated that oral dissolution time accounts for about 14% of overall variability in flurbiprofen plasma 10 min after test drug administration. © 2014 S. Karger AG, Basel.

A cremophor-free formulation for tanespimycin (17-AAG) using PEO-b-PDLLA micelles: characterization and pharmacokinetics in rats.

Science.gov (United States)

Xiong, May P; Yáñez, Jaime A; Kwon, Glen S; Davies, Neal M; Forrest, M Laird

2009-04-01

Tanespimycin (17-allylamino-17-demethoxygeldanamycin or 17-AAG) is a promising heat shock protein 90 inhibitor currently undergoing clinical trials for the treatment of cancer. Despite its selective mechanism of action on cancer cells, 17-AAG faces challenging issues due to its poor aqueous solubility, requiring formulation with Cremophor EL (CrEL) or ethanol (EtOH). Therefore, a CrEL-free formulation of 17-AAG was prepared using amphiphilic diblock micelles of poly(ethylene oxide)-b-poly(D,L-lactide) (PEO-b-PDLLA). Dynamic light scattering revealed PEO-b-PDLLA (12:6 kDa) micelles with average sizes of 257 nm and critical micelle concentrations of 350 nM, solubilizing up to 1.5 mg/mL of 17-AAG. The area under the curve (AUC) of PEO-b-PDLLA micelles was 1.3-fold that of the standard formulation. The renal clearance (CL(renal)) increased and the hepatic clearance (CL(hepatic)) decreased with the micelle formulation, as compared to the standard vehicle. The micellar formulation showed a 1.3-fold increase in the half-life (t(1/2)) of the drug in serum and 1.2-fold increase in t(1/2) of urine. As expected, because it circulated longer in the blood, we also observed a 1.7-fold increase in the volume of distribution (V(d)) with this micelle formulation compared to the standard formulation. Overall, the new formulation of 17-AAG in PEO-b-PDLLA (12:6 kDa) micelles resulted in a favorable 150-fold increase in solubility over 17-AAG alone, while retaining similar properties to the standard formulation. Our data indicates that the nanocarrier system can retain the pharmacokinetic disposition of 17-AAG without the need for toxic agents such as CrEL and EtOH.

Standardization of Unani polyherbal formulation, Qurse-e-Hummaz: A comprehensive approach

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Y T Kamal

2016-01-01

Full Text Available Background: An increase in the awareness about the advantages of the traditional system of medicines has led to the commercialization of the formulations used for the treatments. Manufacture of these medicines to meet this increasing demand has resulted in a decline in their quality, primarily due to a lack of adequate regulations pertaining to this sector of medicine. Hence, it is necessary to come up with a systematic approach to develop well-designed methodologies for the standardization of polyherbal formulations which are used in traditional systems of medicine. Materials and Methods: Qurs-e-Hummaz formulations were prepared by a qualified “Hakim” (Unani medical practitioner of Faculty of Unani Medicine, Hamdard University, as per the formula and instruction given in National Formulary of Unani Medicine. Results: Various quality control parameters such as organoleptic evaluations (color, odor, taste, and consistency, physicochemical evaluations (loss on drying, disintegration time, moisture content, total ash, acid insoluble ash, water soluble ash, pH of 1 and 10% solution, extractive values, water soluble matter, alcohol-soluble matter, and total phenolic content and thin layer chromatography fingerprint profiling have been carried out in triplicate. The evaluation of contaminants such as heavy metals, aflatoxins, pesticide residues, and microbial contamination has also been carried out in the formulation. Conclusion: Help in maintaining the quality and batch to batch consistency of many important polyherbal formulations.

Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery

Directory of Open Access Journals (Sweden)

Wang YL

2011-07-01

Full Text Available Yonglu Wang1,4, Xueming Li1,2*, Liyao Wang3, Yuanlong Xu1, Xiaodan Cheng1, Ping Wei41College of Pharmacy, Nanjing University of Technology, Nanjing; 2State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing University of Technology, Nanjing; 3College of Life Science, Anhui Agricultural University, Hefei; 4College of Biotechnology and Pharmaceutical Engineering, Nanjing University of Technology, Nanjing, People’s Republic of China *These authors contributed equally to this work.Abstract: Paclitaxel is a diterpenoid isolated from Taxus brevifolia. It is effective for various cancers, especially ovarian and breast cancer. Due to its aqueous insolubility, it is administered dissolved in ethanol and Cremophor® EL (BASF, Ludwigshafen, Germany, which can cause serious allergic reactions. In order to eliminate Cremophor EL, paclitaxel was formulated as a nanosuspension by high-pressure homogenization. The nanosuspension was lyophilized to obtain the dry paclitaxel nanoparticles (average size, 214.4 ± 15.03 nm, which enhanced both the physical and chemical stability of paclitaxel nanoparticles. Paclitaxel dissolution was also enhanced by the nanosuspension. Differential scanning calorimetry showed that the crystallinity of paclitaxel was preserved during the high-pressure homogenization process. The pharmacokinetics and tissue distribution of paclitaxel were compared after intravenous administration of paclitaxel nanosuspension and paclitaxel injection. In rat plasma, paclitaxel nanosuspension exhibited a significantly (P < 0.01 reduced area under the concentration curve (AUC0–∞ (20.343 ± 9.119 µg · h · mL−1 vs 5.196 ± 1.426 µg · h · mL−1, greater clearance (2.050 ± 0.616 L · kg−1 · h−1 vs 0.556 ± 0.190 L · kg−1 · h−1, and shorter elimination half-life (5.646 ± 2.941 vs 3.774 ± 1.352 hours compared with the paclitaxel solution. In contrast, the paclitaxel nanosuspension resulted in a

A three-dimensional multiphase flow model for assesing NAPL contamination in porous and fractured media, 1. Formulation

Science.gov (United States)

Huyakorn, P. S.; Panday, S.; Wu, Y. S.

1994-06-01

A three-dimensional, three-phase numerical model is presented for stimulating the movement on non-aqueous-phase liquids (NAPL's) through porous and fractured media. The model is designed for practical application to a wide variety of contamination and remediation scenarios involving light or dense NAPL's in heterogeneous subsurface systems. The model formulation is first derived for three-phase flow of water, NAPL and air (or vapor) in porous media. The formulation is then extended to handle fractured systems using the dual-porosity and discrete-fracture modeling approaches The model accommodates a wide variety of boundary conditions, including withdrawal and injection well conditions which are treated rigorously using fully implicit schemes. The three-phase of formulation collapses to its simpler forms when air-phase dynamics are neglected, capillary effects are neglected, or two-phase-air-liquid, liquid-liquid systems with one or two active phases are considered. A Galerkin procedure with upstream weighting of fluid mobilities, storage matrix lumping, and fully implicit treatment of nonlinear coefficients and well conditions is used. A variety of nodal connectivity schemes leading to finite-difference, finite-element and hybrid spatial approximations in three dimensions are incorporated in the formulation. Selection of primary variables and evaluation of the terms of the Jacobian matrix for the Newton-Raphson linearized equations is discussed. The various nodal lattice options, and their significance to the computational time and memory requirements with regards to the block-Orthomin solution scheme are noted. Aggressive time-stepping schemes and under-relaxation formulas implemented in the code further alleviate the computational burden.

Training pharmacy technicians to administer immunizations.

Science.gov (United States)

McKeirnan, Kimberly C; Frazier, Kyle R; Nguyen, Maryann; MacLean, Linda Garrelts

To evaluate the effectiveness of an immunization training program for pharmacy technicians on technicians' self-reported confidence, knowledge, and number of vaccines administered. A one-group pre- and posttest study was conducted with certified pharmacy technicians from Albertsons and Safeway community pharmacies in Idaho. Thirty pharmacy technicians were recruited to participate in an immunization administration training program comprising a 2-hour home study and a 2-hour live training. Pharmacy technician scores on a 10-question knowledge assessment, responses on a pre- and posttraining survey, and number of immunizations administered in the 6-month period following the training were collected. Twenty-five pharmacy technicians completed the home study and live portions of the immunization training program. All 29 pharmacy technicians who took the home study assessment passed with greater than 70% competency on the first attempt. Technicians self-reported increased confidence with immunization skills between the pretraining survey and the posttraining survey. From December 2016 to May 2017, the technicians administered 953 immunizations with 0 adverse events reported. For the first time, pharmacy technicians have legally administered immunizations in the United States. Trained pharmacy technicians demonstrated knowledge of vaccination procedures and self-reported improved confidence in immunization skills and administered immunizations after participating in a 4-hour training program. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

Crystallization Formulation Lab

Data.gov (United States)

Federal Laboratory Consortium — The Crystallization Formulation Lab fills a critical need in the process development and optimization of current and new explosives and energetic formulations. The...

Computer-Administered Interviews and Rating Scales

Science.gov (United States)

Garb, Howard N.

2007-01-01

To evaluate the value of computer-administered interviews and rating scales, the following topics are reviewed in the present article: (a) strengths and weaknesses of structured and unstructured assessment instruments, (b) advantages and disadvantages of computer administration, and (c) the validity and utility of computer-administered interviews…

Protective effect of an elastase inhibitor in a neuromyelitis optica-like disease driven by a peptide of myelin oligodendroglial glycoprotein.

NARCIS (Netherlands)

Herges, K.; Jong, B.A. de; Kolkowitz, I.; Dunn, C.; Mandelbaum, G.; Ko, R.M.; Maini, A.; Han, M.H.; Killestein, J.; Polman, C.; Goodyear, A.L.; Dunn, J.; Steinman, L.; Axtell, R.C.

2012-01-01

BACKGROUND: The pathology of neuromyelitis optica (NMO), in contrast to multiple sclerosis, comprises granulocyte infiltrates along extensive lengths of spinal cord, as well as optic nerve. Furthermore, IFN-beta treatment worsens NMO. We recently found that experimental autoimmune encephalomyelitis

A Phase 1, open-label, multicentre study to compare the capsule and tablet formulations of AZD5363 and explore the effect of food on the pharmacokinetic exposure, safety and tolerability of AZD5363 in patients with advanced solid malignancies: OAK.

Science.gov (United States)

Dean, Emma; Banerji, Udai; Schellens, Jan H M; Krebs, Matthew G; Jimenez, Begona; van Brummelen, Emilie; Bailey, Chris; Casson, Ed; Cripps, Diana; Cullberg, Marie; Evans, Stephen; Foxley, Andrew; Lindemann, Justin; Rugman, Paul; Taylor, Nigel; Turner, Guy; Yates, James; Lawrence, Peter

2018-05-01

AZD5363 is a potent pan-AKT inhibitor originally formulated as a capsule; a tablet was developed for patient convenience and manufacturing ease. This study assessed the PK comparability of both formulations (Part A) and the effect of food (Part B) on the PK/safety of the tablet. Adults with advanced solid tumours received AZD5363 480 mg bid in a partially fasted state by tablet (Week 1) and capsule (Week 2) in a '4-days-on/3-days-off' schedule (Part A). PK parameters were evaluated using pre-defined 90% CIs for AUCτ and C max ratios of 0.75-1.33 to assess comparability. In Part B, AZD5363 tablet was given to a new cohort of patients under the same conditions as Part A, except on the morning of PK assessment days, when it was administered after an overnight fast (Week 1) and standard meal (Week 2). In evaluable patients (N = 11), the geometric least-squares mean ratios (tablet:capsule) for AUCτ and C max were 0.90 (0.77-1.06) and 1.02 (0.86-1.20), respectively, demonstrating comparable PK in the partially fasted state. Tablet and capsule safety data were also comparable. Tablet PK profiles indicated later t max and lower C max after food versus overnight fast. Fed and fasted AUCτ and C max ratios were 0.89 (0.76-1.05) and 0.67 (0.55-0.82), respectively (N = 9). The safety/tolerability profile of the tablet was comparable between fed and fasted states. PK and safety/tolerability of AZD5363 tablet and capsule were comparable. Food did not affect the bioavailability of AZD5363, but reduced the absorption rate without discernibly affecting safety/tolerability.

Repurposing rosiglitazone, a PPAR-γ agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH.

Science.gov (United States)

Rashid, Jahidur; Alobaida, Ahmad; Al-Hilal, Taslim A; Hammouda, Samia; McMurtry, Ivan F; Nozik-Grayck, Eva; Stenmark, Kurt R; Ahsan, Fakhrul

2018-06-28

Peroxisome-proliferator-activated-receptor-gamma (PPAR-γ) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-γ agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% ± 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH. Copyright © 2018 Elsevier B.V. All rights reserved.

40 CFR 147.2500 - State-administered program.

Science.gov (United States)

2010-07-01

... State-administered program: (1) Chapter 144, Water, Sewage, Refuse, Mining and Air Pollution, Wisconsin... Section 147.2500 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) WATER PROGRAMS... Treatment Works, Wisconsin Administrative Code § 210.05 Natural Resources Board Order No. WQ-25-82, approved...

Formulation of colchicine ointment for the treatment of acute gout.

Science.gov (United States)

Maduri, Sairam; Atla, Venkateshwar Reddy

2012-11-01

In spite of being the fastest acting drug available for the control of an acute gout attack, colchicine is generally considered a last alternative in gout therapy. This is mainly due to the severe adverse effects associated with its administration through the enteral and parenteral routes, as well as its high risk/benefit ratio. The preparation of dosage forms of colchicine that can be administered by alternative routes is therefore a beneficial exercise. Among the formulable substitute dosage forms of colchicine, its ointment seems to be the best option available due to its ability to deliver the drug transdermally as well as its ease of preparation and evaluation. In this study, we prepared and tested 0.2% and 0.5% colchicine ointments for their effectiveness in delivering colchicine transdermally. Colchicine ointment was prepared using a self-formulated water-in-oil type of emulsion ointment base, with the colchicine dissolved in the water portion of the ointment base. In vitro drug release studies were carried out using the Franz diffusion test apparatus and an ultraviolet (UV)-visible spectrophotometer was used to quantify the drug in the samples. Rabbits were used as test animals for in vivo studies and the blood samples were analysed using the UV-visible spectrophotometer. Colchicine was found to be well-absorbed transdermally, although absorption was not 100%. No side effects were associated with its 0.2% formulation. Ointments containing colchicine in low concentrations may be a feasible and effective treatment option for the prevention and treatment of acute gout attacks.

High-performance liquid chromatographic determination of isoniazid and 1-isonicotinyl-2-lactosylhydrazine in isoniazid tablet formulations.

Science.gov (United States)

Butterfield, A G; Lovering, E G; Sears, R W

1980-02-01

A high-performance liquid chromatographic procedure is presented for the simultaneous determination of isoniazid and 1-isonicotinyl-2-lactosylhydrazine (I) in isoniazid tablet formulations. An aliquot of a diluted aqueous tablet extract is introduced onto a microparticulate cyanopropyl bonded-phase column using a valve-loop injector and chromatographed using a mobile phase of acetonitrile--0.01 M, pH 3.5 aqueous acetate buffer (5:95). Compound I can be determined at levels as low as 0.5% of the isoniazid label claim. The relative standard deviations are 0.4 and 0.7% for the simultaneous determination of isoniazid and I, respectively. Seven commercial tablet formulations contained 93.8--97.0% of the labeled isoniazid amounts and 0.3--5.8% of I, expressed as equivalent isoniazid relative to the labeled isoniazid level.

A synthetic TLR4 agonist formulated in an emulsion enhances humoral and Type 1 cellular immune responses against GMZ2 - A GLURP-MSP3 fusion protein malaria vaccine candidate

DEFF Research Database (Denmark)

Lousada-Dietrich, Susana; Jogdand, Prajakta S; Jepsen, Søren

2011-01-01

) agonists in CB6F1 mice to identify an improved formulation of GMZ2 suitable for further human clinical studies. GMZ2 formulated in an oil-in-water emulsion plus the synthetic TLR4 agonist GLA elicits the highest (a) vaccine-specific IgG2a and total IgG titers, (b) parasite-specific IFA titers, (c) levels...... of Type 1 cytokine responses (IFN-¿), and (d) number of long-lived-plasma cells (LLPC) secreting antibodies against both the GMZ2 fusion and its two components. Thus, GLA helps to elicit a vaccine-specific Type 1 antibody profile together with high levels of LLPC, both of which are thought to be essential...

Prednisone raw material characterization and formulation development

Directory of Open Access Journals (Sweden)

Leonardo Henrique Toehwé

2018-01-01

Full Text Available ABSTRACT Solid dosage forms for oral use, particularly tablets, are the most highly used dosage forms in therapy because they are easily administered, have high productivity and relatively low cost and provide a more stable drug to form a semi-solid net. Numerous parameters influence the quality of the final dosage form. In this study, the dissolution profile of 20-mg prednisone tablets bioequivalent to the reference product and three test formulations were evaluated using stability testing. During the study, prednisone tablets and the active pharmaceutical ingredient (API prednisone from two different manufacturers were characterized with respect to their physical and physicochemical properties. The results showed that the dissolution profiles of the test batches and the reference product did not retain pharmaceutical equivalence throughout all the stability study. Notably, both samples of API prednisone were of the same crystal form, and any phase transition that occurred during the study could not be attributed to dissolution variation during stability.

Detrimental Effects of a Self-reward Contracting Program on Subjects' Involvement in Self-administered Desensitization

Science.gov (United States)

Barrera, Manuel Jr.; Rosen, Gerald M.

1977-01-01

Assesses a self-reward contracting procedure intended to facilitate completion of self-administered desensitization. Self-referred snake phobics received either (a) self-administered desensitization; (b) self-administered desensitization with self-reward contracting; or (c) a self-administered placebo with self-reward contracting. Results show the…

Formulation and Characterization of Waste Glasses with Varying Processing Temperature

Energy Technology Data Exchange (ETDEWEB)

Kim, Dong-Sang; Schweiger, M. J.; Rodriguez, Carmen P.; Lepry, William C.; Lang, Jesse B.; Crum, Jarrod V.; Vienna, John D.; Johnson, Fabienne; Marra, James C.; Peeler, David K.

2011-10-17

This report documents the preliminary results of glass formulation and characterization accomplished within the finished scope of the EM-31 technology development tasks for WP-4 and WP-5, including WP-4.1.2: Glass Formulation for Next Generation Melter, WP-5.1.2.3: Systematic Glass Studies, and WP-5.1.2.4: Glass Formulation for Specific Wastes. This report also presents the suggested studies for eventual restart of these tasks. The initial glass formulation efforts for the cold crucible induction melter (CCIM), operating at {approx}1200 C, with selected HLW (AZ-101) and LAW (AN-105) successfully developed glasses with significant increase of waste loading compared to that is likely to be achieved based on expected reference WTP formulations. Three glasses formulated for AZ-101HLW and one glass for AN-105 LAW were selected for the initial CCIM demonstration melter tests. Melter tests were not performed within the finished scope of the WP-4.1.2 task. Glass formulations for CCIM were expanded to cover additional HLWs that have high potential to successfully demonstrate the unique advantages of the CCIM technologies based on projected composition of Hanford wastes. However, only the preliminary scoping tests were completed with selected wastes within the finished scope. Advanced glass formulations for the reference WTP melter, operating at {approx}1200 C, were initiated with selected specific wastes to determine the estimated maximum waste loading. The incomplete results from these initial formulation efforts are summarized. For systematic glass studies, a test matrix of 32 high-aluminum glasses was completed based on a new method developed in this study.

Formulation and Characterization of Waste Glasses with Varying Processing Temperature

International Nuclear Information System (INIS)

Kim, Dong-Sang; Schweiger, M.J.; Rodriguez, Carmen P.; Lepry, William C.; Lang, Jesse B.; Crum, Jarrod V.; Vienna, John D.; Johnson, Fabienne; Marra, James C.; Peeler, David K.

2011-01-01

This report documents the preliminary results of glass formulation and characterization accomplished within the finished scope of the EM-31 technology development tasks for WP-4 and WP-5, including WP-4.1.2: Glass Formulation for Next Generation Melter, WP-5.1.2.3: Systematic Glass Studies, and WP-5.1.2.4: Glass Formulation for Specific Wastes. This report also presents the suggested studies for eventual restart of these tasks. The initial glass formulation efforts for the cold crucible induction melter (CCIM), operating at ∼1200 C, with selected HLW (AZ-101) and LAW (AN-105) successfully developed glasses with significant increase of waste loading compared to that is likely to be achieved based on expected reference WTP formulations. Three glasses formulated for AZ-101HLW and one glass for AN-105 LAW were selected for the initial CCIM demonstration melter tests. Melter tests were not performed within the finished scope of the WP-4.1.2 task. Glass formulations for CCIM were expanded to cover additional HLWs that have high potential to successfully demonstrate the unique advantages of the CCIM technologies based on projected composition of Hanford wastes. However, only the preliminary scoping tests were completed with selected wastes within the finished scope. Advanced glass formulations for the reference WTP melter, operating at ∼1200 C, were initiated with selected specific wastes to determine the estimated maximum waste loading. The incomplete results from these initial formulation efforts are summarized. For systematic glass studies, a test matrix of 32 high-aluminum glasses was completed based on a new method developed in this study.

Pulmonary delivery of an ultra-fine oxytocin dry powder formulation: potential for treatment of postpartum haemorrhage in developing countries.

Directory of Open Access Journals (Sweden)

Richard J Prankerd

Full Text Available Oxytocin is recommended by the World Health Organisation as the most effective uterotonic for the prevention and treatment of postpartum haemorrhage. The requirement for parenteral administration by trained healthcare providers and the need for the drug solution to be maintained under cold-chain storage limit the use of oxytocin in the developing world. In this study, a spray-dried ultrafine formulation of oxytocin was developed with an optimal particle size diameter (1-5 µm to facilitate aerosolised delivery via the lungs. A powder formulation of oxytocin, using mannitol, glycine and leucine as carriers, was prepared with a volume-based median particle diameter of 1.9 µm. Oxytocin content in the formulation was assayed using high-performance liquid chromatography-mass spectroscopy and was found to be unchanged after spray-drying. Ex vivo contractility studies utilising human and ovine uterine tissue indicated no difference in the bioactivity of oxytocin before and after spray-drying. Uterine electromyographic (EMG activity in postpartum ewes following pulmonary (in vivo administration of oxytocin closely mimicked that observed immediately postpartum (0-12 h following normal vaginal delivery of the lamb. In comparison to the intramuscular injection, pulmonary administration of an oxytocin dry powder formulation to postpartum ewes resulted in generally similar EMG responses, however a more rapid onset of uterine EMG activity was observed following pulmonary administration (129 ± 18 s than intramuscular injection (275 ± 22 s. This is the first study to demonstrate the potential for oxytocin to elicit uterine activity after systemic absorption as an aerosolised powder from the lungs. Aerosolised oxytocin has the potential to provide a stable and easy to administer delivery system for effective prevention and treatment of postpartum haemorrhage in resource-poor settings in the developing world.

Pulmonary delivery of an ultra-fine oxytocin dry powder formulation: potential for treatment of postpartum haemorrhage in developing countries.

Science.gov (United States)

Prankerd, Richard J; Nguyen, Tri-Hung; Ibrahim, Jibriil P; Bischof, Robert J; Nassta, Gemma C; Olerile, Livesey D; Russell, Adrian S; Meiser, Felix; Parkington, Helena C; Coleman, Harold A; Morton, David A V; McIntosh, Michelle P

2013-01-01

Oxytocin is recommended by the World Health Organisation as the most effective uterotonic for the prevention and treatment of postpartum haemorrhage. The requirement for parenteral administration by trained healthcare providers and the need for the drug solution to be maintained under cold-chain storage limit the use of oxytocin in the developing world. In this study, a spray-dried ultrafine formulation of oxytocin was developed with an optimal particle size diameter (1-5 µm) to facilitate aerosolised delivery via the lungs. A powder formulation of oxytocin, using mannitol, glycine and leucine as carriers, was prepared with a volume-based median particle diameter of 1.9 µm. Oxytocin content in the formulation was assayed using high-performance liquid chromatography-mass spectroscopy and was found to be unchanged after spray-drying. Ex vivo contractility studies utilising human and ovine uterine tissue indicated no difference in the bioactivity of oxytocin before and after spray-drying. Uterine electromyographic (EMG) activity in postpartum ewes following pulmonary (in vivo) administration of oxytocin closely mimicked that observed immediately postpartum (0-12 h following normal vaginal delivery of the lamb). In comparison to the intramuscular injection, pulmonary administration of an oxytocin dry powder formulation to postpartum ewes resulted in generally similar EMG responses, however a more rapid onset of uterine EMG activity was observed following pulmonary administration (129 ± 18 s) than intramuscular injection (275 ± 22 s). This is the first study to demonstrate the potential for oxytocin to elicit uterine activity after systemic absorption as an aerosolised powder from the lungs. Aerosolised oxytocin has the potential to provide a stable and easy to administer delivery system for effective prevention and treatment of postpartum haemorrhage in resource-poor settings in the developing world.

A Guide in the Process of Cognitive Behavioral Therapy in Obsessive Compulsive Disorder: Formulation

Directory of Open Access Journals (Sweden)

Nergis LAPSEKÝLÝ

2012-04-01

Discussion: When planning CBT for the treatment of OCD, the first and most important step is a good formulation created with the data obtained from a good evaluation process. Treatment planning in our case was planned on using cognitive restructing techniques for thought-action-fusion, anxiety intolerance and overestimated threat appraisals but the formulation was completed in the course of treatment when the patient could talk about his early experiences. As a result, the formulation is a roadmap that should be taken into consideration at every stage of therapy. Its presence is essential to reach the correct destination and it is a dynamic process needed to be updated according to the information from the patient. [JCBPR 2012; 1(1.000: 21-27

Nurse-administered propofol sedation for endoscopy

DEFF Research Database (Denmark)

Jensen, J T; Vilmann, P; Horsted, T

2011-01-01

The aim of the present study was to perform a risk analysis during the implementation phase of nurse-administered propofol sedation (NAPS) and to validate our structured training program.......The aim of the present study was to perform a risk analysis during the implementation phase of nurse-administered propofol sedation (NAPS) and to validate our structured training program....

Finite element analysis of structures through unified formulation

CERN Document Server

Carrera, Erasmo; Petrolo, Marco; Zappino, Enrico

2014-01-01

The finite element method (FEM) is a computational tool widely used to design and analyse  complex structures. Currently, there are a number of different approaches to analysis using the FEM that vary according to the type of structure being analysed: beams and plates may use 1D or 2D approaches, shells and solids 2D or 3D approaches, and methods that work for one structure are typically not optimized to work for another. Finite Element Analysis of Structures Through Unified Formulation deals with the FEM used for the analysis of the mechanics of structures in the case of linear elasticity. The novelty of this book is that the finite elements (FEs) are formulated on the basis of a class of theories of structures known as the Carrera Unified Formulation (CUF). It formulates 1D, 2D and 3D FEs on the basis of the same ''fundamental nucleus'' that comes from geometrical relations and Hooke''s law, and presents both 1D and 2D refined FEs that only have displacement variables as in 3D elements. It also covers 1D...

Radiopharmaceutical development of a freeze-dried kit formulation for the preparation of [99mTc-EDDA-HYNIC-D-Phe1, Tyr3]-octreotide, a somatostatin analog for tumor diagnosis.

Science.gov (United States)

Guggenberg, Elisabeth Von; Mikolajczak, Renata; Janota, Barbara; Riccabona, Georg; Decristoforo, Clemens

2004-10-01

[(99m)Tc-EDDA-HYNIC-D-Phe(1),Tyr(3)]-Octreotide ((99m)Tc-EDDA/HYNIC-TOC) is a promising new radiopharmaceutical with the potential to replace [(111)In-DTPA-D-Phe(1)]-Octreotide ((111)In-DTPA-OCT) as the radiopharmaceutical for somatostatin receptor scintigraphy due to the advantage of improved image quality, lower radiation dose for the patient, and daily availability. Here we describe the development of a freeze-dried kit formulation based on the Tricine/EDDA exchange labeling approach for the preparation of this radiopharmaceutical in a clinical setting. Three parameters were of major importance to achieve a suitable formulation with a radiochemical purity (RCP) >90%: addition of bulking agent, the pH of the freeze-drying solution, and the content of stannous chloride. The final formulation consisted of 20 mg Tricine, 10 mg EDDA, 50 mg Mannitol, 20 microg SnCl(2). 2H(2)O, and 20 microg [HYNIC-D-Phe(1), Tyr(3)]-Octreotide (HYNIC-TOC). Radiolabeling was performed by addition of 0.2 M Na(2)HPO(4) to adjust the pH to 6-7, followed by 0.5-2 GBq (99m)Tc sodium pertechnetate, in a total volume of 2 mL and incubation for 10 min in a boiling water bath. Mean RCP values of 10 batches showed values >90% over a storage period of up to 1 year, a high stability up to 24 h of the final preparation, and retained biological activity. The developed kit formulation forms the basis for further clinical evaluation of this promising new radiopharmaceutical. Copyright 2004 Wiley-Liss, Inc. and the American Pharmacists Association

Development and preventative effect against pine wilt disease of a novel liquid formulation of emamectin benzoate.

Science.gov (United States)

Takai, Kazuya; Suzuki, Toshio; Kawazu, Kazuyoshi

2003-03-01

Injection of the poorly water-soluble emamectin benzoate (EB) into pine trunks required the development of an efficient liquid formulation. For injection into big trees in forests a good rate of injection and a high active content were required. Tests on the viscosity and EB-solubilizing ability of 14 various solubilizers in diethylene glycol monobutyl ether (DGMBE) led to the selection of Sorpol SM-100PM as the solubilizer of the formulation. Relationships between the solubilizing ability and amounts of Sorpol SM-100PM and DGMBE relative to that of EB, and between the concentration of the latter and the viscosity or the injection rate of the formulation led to a novel 40 g litre(-1) emamectin benzoate formulation (Shot Wan Liquid Formulation), which was composed of EB (40), Sorpol SM-100PM (120), DGMBE (160) and distilled water (50 g litre(-1)) in methanol. Injection of this formulation at a dose of 10 g EB per unit volume of pine tree prevented over 90% of the trees from wilting caused by pine wood nematode, and this preventative effect continued for 3 years. Neither discolouration of the leaves nor injury around the injection hole on the trees was observed after injection of the formulation.

Immune activation in multiple sclerosis and interferon-beta therapy

DEFF Research Database (Denmark)

Krakauer, Martin

2007-01-01

The PhD dissertation emanated from the Danish MS Research Centre, Rigshosptalet, Copenhagen. Multiple sclerosis (MS) is an inflammatory disease of the CNS. Inflammatory responses by T helper (Th)-lymphocytes are characterised by distinct cytokine expression profiles. In MS, activated Th1...... of inflammation or secondary lymphatic organs. Chemokine receptors are differentially expressed in T cells in blood and cerebrospinal fluid, indicating their role for in T-cell-recruitment to the CNS. Interferon (IFN)-beta is a first-line treatment for MS. The mechanism of action is unclear, but probably includes...... changes in lymphocyte activation, cytokine secretion, and trafficking. The aim of the studies was to shed more light on T-cell immunology in MS and IFN-beta treatment, as well as identifying putative biomarkers of treatment response and/or disease activity. In one study we identified a Th-cell subset...

Pharmacokinetics of orally administered tramadol in domestic rabbits (Oryctolagus cuniculus).

Science.gov (United States)

Souza, Marcy J; Greenacre, Cheryl B; Cox, Sherry K

2008-08-01

To determine the pharmacokinetics of an orally administered dose of tramadol in domestic rabbits (Oryctolagus cuniculus). 6 healthy adult sexually intact female New Zealand White rabbits. Physical examinations and plasma biochemical analyses were performed to ensure rabbits were healthy prior to the experiment. Rabbits were anesthetized with isoflurane, and IV catheters were placed in a medial saphenous or jugular vein for collection of blood samples. One blood sample was collected before treatment with tramadol. Rabbits were allowed to recover from anesthesia a minimum of 1 hour before treatment. Then, tramadol (11 mg/kg, PO) was administered once, and blood samples were collected at various time points up to 360 minutes after administration. Blood samples were analyzed with high-performance liquid chromatography to determine plasma concentrations of tramadol and its major metabolite (O-desmethyltramadol). No adverse effects were detected after oral administration of tramadol to rabbits. Mean +/- SD half-life of tramadol after administration was 145.4 +/- 81.0 minutes; mean +/- SD maximum plasma concentration was 135.3 +/- 89.1 ng/mL. Although the dose of tramadol required to provide analgesia in rabbits is unknown, the dose administered in the study reported here did not reach a plasma concentration of tramadol or O-desmethyltramadol that would provide sufficient analgesia in humans for clinically acceptable periods. Many factors may influence absorption of orally administered tramadol in rabbits.

Self-administered foot reflexology for the management of chronic health conditions: a systematic review.

Science.gov (United States)

Song, Hyun Jin; Choi, Sun Mi; Seo, Hyun-Ju; Lee, Heeyoung; Son, Heejeong; Lee, Sanghun

2015-02-01

To systematically review the effect of self-administered foot reflexology in patients with chronic health conditions. Electronic databases were searched for literature published from 1948 to January 2014. The databases included MEDLINE, EMBASE, the Cochrane Library, CINAHL, CNKI, J-STAGE, Koreamed, Kmbase, KISS, NDSL, KISTI, and OASIS. Key search terms were "exp/relaxation therapy," "foot," "reflexology," "zone therapy," and "self." All study designs were included. Two raters independently extracted data and assessed study quality by using the Cochrane risk of bias tool (for randomized controlled trials) and the risk of bias assessment tool for nonrandomized studies (for nonrandomized and before-and-after studies). A qualitative and descriptive analysis was performed because of the clinical diversity associated with chronic health conditions. Of the 224 records assessed, 4 trials met the inclusion criteria: 3 nonrandomized controlled trials and 1 before-and-after study without comparison. Self-administered foot reflexology might have a positive effect in type 2 diabetes, but the low quality of the included study and the lack of adequately reported clinical outcomes obscure the results. Two studies of hypertensive patients and 1 study of patients with urinary incontinence showed that self-performed foot reflexology may exert a beneficial effect on lowering blood pressure and urinary incontinence; however, given the small sample size and the lack of any description of medications and other cointerventions, there was insufficient evidence to conclusively determine whether foot reflexology had any effect. The included studies on self-administered foot reflexology in patients with type 2 diabetes, hypertension, or urinary incontinence provided insufficient evidence to determine a treatment effect. Therefore, a well-designed, large-scale, and randomized controlled trial is needed to confirm the effect of self-administered foot reflexology for chronic conditions.

Evaluation of herb-drug interaction of a polyherbal Ayurvedic formulation through high throughput cytochrome P450 enzyme inhibition assay.

Science.gov (United States)

Pandit, Subrata; Kanjilal, Satyajyoti; Awasthi, Anshumali; Chaudhary, Anika; Banerjee, Dipankar; Bhatt, B N; Narwaria, Avinash; Singh, Rahul; Dutta, Kakoli; Jaggi, Manu; Singh, Anu T; Sharma, Neena; Katiyar, Chandra Kant

2017-02-02

Arishtas are Ayurvedic formulation made with decoction of herbs. Arjunarishta formulation is being used in Ayurveda for cardio-protective activity. Ashwagandharishta formulation possesses antioxidant, anti-atherosclerotic and anti-stress properties. Ridayarishta, a novel empirical formulation was prepared using combination of selected ingredients from these two formulations to support healthy heart functions and to reduce stress. Aim of the Study was to investigate herb-drug interaction (HDI) of Ridayarishta formulation through human hepatic cytochrome P450 (CYP450) enzyme inhibition assay. Ridayarishta formulation was phyto-chemically standardized against arjunolic acid, arjunetin, berberine, piperine, resveratrol and withaferin-A using high performance thin layer chromatography (HPTLC) analysis. The formulation was standardized with respect to ethanol by gas chromatographic (GC) analysis. HDI was evaluated with Ridayarishta formulation and amlodipine besilate, atenolol, atorvastatin, metformin, glipizide glimepiride cocktail using high throughput CYP450 enzyme inhibition assay; against CYP1A2, 2C19, 2D6 and 3A4 isozymes. Contents of arjunolic acid, arjunetin, berberine, piperine, resveratrol and withaferin-A in Ridayarishta formulation were found to be 1.76±0.12, 1.51±0.09, 1.85±0.05, 3.2±0.12, 1.21±0.08, and 2.16±0.09ppm, respectively. Quantity of ethanol in Ridayarishta was found to be 7.95±0.023% (V/V). Ridayarishta showed significantly higher (Pdrugs showed significantly (P<0.001and P<0.01) less or negligible HDI. Ridayarishta formulation alone and cocktail with amlodipine besilate, atenolol, atorvastatin, metformin, glipizide, glimepiride had negligible or insignificant effect on CYP450 inhibition. It may be concluded that consumption of Ridayarishta along with selective cardio protective, antihypertensive and anti-diabetic conventional medicine is safe with negligible or without any significant CYP450 (CYP1A2, 2C19, 2D6 and 3A4) inhibition mediated

Pharmacokinetics of an oral extended-release formulation of doxycycline hyclate containing acrylic acid and polymethacrylate in dogs.

Science.gov (United States)

Ruiz, Sara Melisa Arciniegas; Olvera, Lilia Gutiérrez; Chacón, Sara del Carmen Caballero; Estrada, Dinorah Vargas

2015-04-01

To determine the pharmacokinetics of doxycycline hyclate administered orally in the form of experimental formulations with different proportions of acrylic acid-polymethacrylate-based matrices. 30 healthy adult dogs. In a crossover study, dogs were randomly assigned (in groups of 10) to receive a single oral dose (20 mg/kg) of doxycycline hyclate without excipients (control) or extended-release formulations (ERFs) containing doxycycline, acrylic acid polymer, and polymethacrylate in the following proportions: 1:0.5:0.0075 (ERF1) or 1:1:0.015 (ERF2). Serum concentrations of doxycycline were determined for pharmacokinetic analysis before and at several intervals after each treatment. Following oral administration to the study dogs, each ERF resulted in therapeutic serum doxycycline concentrations for 48 hours, whereas the control treatment resulted in therapeutic serum doxycycline concentrations for only 24 hours. All pharmacokinetic parameters for ERF1 and ERF2 were significantly different; however, findings for ERF1 did not differ significantly from those for the control treatment. Results indicated that both ERFs containing doxycycline, acrylic acid polymer, and polymethacrylate had an adequate pharmacokinetic-pharmacodynamic relationship for a time-dependent drug and a longer release time than doxycycline alone following oral administration in dogs. Given the minimum effective serum doxycycline concentration of 0.26 μg/mL, a dose interval of 48 hours can be achieved for each tested ERF. This minimum inhibitory concentration has the potential to be effective against several susceptible bacteria involved in important infections in dogs. Treatment of dogs with either ERF may have several benefits over treatment with doxycycline alone.

Activity of a crude extract formulation in experimental hepatic amoebiasis and in immunomodulation studies.

Science.gov (United States)

Sohni, Y R; Bhatt, R M

1996-11-01

The activity of a crude extract formulation was evaluated in experimental amoebic liver abscess in golden hamsters and in immunomodulation studies. The formulation comprises the following five plants-Boerhavia diffusa, Tinospora cordifolia, Berberis aristata, Terminalia chebula and Zingiber officinale. The formulation had a maximum cure rate of 73% at a dose of 800 mg/kg/day in hepatic amoebiasis reducing the average degree of infection (ADI) to 1.3 as compared to 4.2 for sham-treated controls. In immunomodulation studies humoral immunity was enhanced as evidenced by the haemagglutination titre. The T-cell counts remained unaffected in the animals treated with the formulation but cell-mediated immune response was stimulated as observed in the leukocyte migration inhibition (LMI) tests.

Finite element formulation for a digital image correlation method

International Nuclear Information System (INIS)

Sun Yaofeng; Pang, John H. L.; Wong, Chee Khuen; Su Fei

2005-01-01

A finite element formulation for a digital image correlation method is presented that will determine directly the complete, two-dimensional displacement field during the image correlation process on digital images. The entire interested image area is discretized into finite elements that are involved in the common image correlation process by use of our algorithms. This image correlation method with finite element formulation has an advantage over subset-based image correlation methods because it satisfies the requirements of displacement continuity and derivative continuity among elements on images. Numerical studies and a real experiment are used to verify the proposed formulation. Results have shown that the image correlation with the finite element formulation is computationally efficient, accurate, and robust

Comparison between self-formulation and compounded-formulation dexamethasone mouth rinse for oral lichen planus: a pilot, randomized, cross-over trial.

Science.gov (United States)

Hambly, Jessica L; Haywood, Alison; Hattingh, Laetitia; Nair, Raj G

2017-08-01

There is a lack of appropriate, commercially-available topical corticosteroid formulations for use in oral lichen planus (OLP) and oral lichenoid reaction. Current therapy includes crushing a dexamethasone tablet and mixing it with water for use as a mouth rinse. This formulation is unpleasant esthetically and to use in the mouth, as it is a bitter and gritty suspension, resulting in poor compliance. Thus, the present study was designed to formulate and pilot an effective, esthetically-pleasing formulation. A single-blinded, cross-over trial was designed with two treatment arms. Patients were monitored for 7 weeks. Quantitative and qualitative data was assessed using VAS, numeric pain scales, the Treatment Satisfaction Questionnaire for Medication-9, and thematic analysis to determine primary patient-reported outcomes, including satisfaction, compliance, quality of life, and symptom relief. Nine patients completed the pilot trial. Data analysis revealed the new compounded formulation to be superior to existing therapy due to its convenience, positive contribution to compliance, patient-perceived faster onset of action, and improved symptom relief. Topical dexamethasone is useful in the treatment of OLP. When carefully formulated into a compounded mouth rinse, it improves patient outcomes. © 2016 John Wiley & Sons Australia, Ltd.

45 CFR 400.66 - Eligibility and payment levels in a publicly-administered RCA program.

Science.gov (United States)

2010-10-01

... 45 Public Welfare 2 2010-10-01 2010-10-01 false Eligibility and payment levels in a publicly... REFUGEE RESETTLEMENT PROGRAM Refugee Cash Assistance § 400.66 Eligibility and payment levels in a publicly-administered RCA program. (a) In administering a publicly-administered refugee cash assistance program, the...

Nanoethosomal formulation of gammaoryzanol for skin-aging protection and wrinkle improvement: a histopathological study.

Science.gov (United States)

Heydari, Saman; Ghanbarzadeh, Saeed; Anoush, Behzad; Ranjkesh, Mohammadreza; Javadzadeh, Yousef; Kouhsoltani, Maryam; Hamishehkar, Hamed

2017-07-01

Free radical scavengers and antioxidants, with the main focus on enhanced targeting to the skin layers, can provide protection against skin ageing. The aim of the present study was to prepare nanoethosomal formulation of gammaoryzanol (GO), a water insoluble antioxidant, for its dermal delivery to prevent skin aging. Nanoethosomal formulation was prepared by a modified ethanol injection method and characterized by using laser light scattering, scanning electronic microscope (SEM) and X-ray diffraction (XRD) techniques. The effects of formulation parameters on nanoparticle size, encapsulation efficiency percent (EE%) and loading capacity percent (LC%) were investigated. Antioxidant activity of GO-loaded formulation was investigated in vitro using normal African green monkey kidney fibroblast cells (Vero). The effect of control and GO-loaded nanoethosomal formulation on superoxide dismutase (SOD) and malondialdehyde (MDA) content of rat skin was also probed. Furthermore, the effect of GO-loaded nanoethosomes on skin wrinkle improvement was studied by dermoscopic and histological examination on healthy humans and UV-irradiated rats, respectively. The optimized nanoethosomal formulation showed promising characteristics including narrow size distribution 0.17 ± 0.02, mean diameter of 98.9 ± 0.05 nm, EE% of 97.12 ± 3.62%, LC% of 13.87 ± 1.36% and zeta potential value of -15.1 ± 0.9 mV. The XRD results confirmed uniform drug dispersion in the nanoethosomes structure. In vitro and in vivo antioxidant studies confirmed the superior antioxidant effect of GO-loaded nanoethosomal formulation compared with control groups (blank nanoethosomes and GO suspension). Nanoethosomes was a promising carrier for dermal delivery of GO and consequently had superior anti-aging effect.

Development of controlled release formulations of azadirachtin-A employing poly(ethylene glycol) based amphiphilic copolymers.

Science.gov (United States)

Kumar, Jitendra; Shakil, Najam A; Singh, Manish K; Singh, Mukesh K; Pandey, Alka; Pandey, Ravi P

2010-05-01

Controlled release (CR) formulations of azadirachtin-A, a bioactive constituent derived from the seed of Azadirachta indica A. Juss (Meliaceae), have been prepared using commercially available polyvinyl chloride, polyethylene glycol (PEG) and laboratory synthesized poly ethylene glycol-based amphiphilic copolymers. Copolymers of polyethylene glycol and various dimethyl esters, which self assemble into nano micellar aggregates in aqueous media, have been synthesized. The kinetics of azadirachtin-A, release in water from the different formulations was studied. Release from the commercial polyethylene glycol (PEG) formulation was faster than the other CR formulations. The rate of release of encapsulated azadirachtin-A from nano micellar aggregates is reduced by increasing the molecular weight of PEG. The diffusion exponent (n value) of azadirachtin-A, in water ranged from 0.47 to 1.18 in the tested formulations. The release was diffusion controlled with a half release time (t(1/2)) of 3.05 to 42.80 days in water from different matrices. The results suggest that depending upon the polymer matrix used, the application rate of azadirachtin-A can be optimized to achieve insect control at the desired level and period.

A quantum formulation of the Feynman-Kac formula

International Nuclear Information System (INIS)

Accardi, L.

1981-01-01

The author discusses a formulation, in the general setting of W*- (or C*)-algebras, of the classical Feynman-Kac formula. The equivalence, in the commutative case, of the present formulation and the usual one is based on the identification between stochastic processes and local algebras. (Auth.)

Formulation and evaluation of a novel matrix-type orally disintegrating Ibuprofen tablet.

Science.gov (United States)

Tayebi, Hoda; Mortazavi, Seyed Alireza

2011-01-01

Orally disintegrating tablets (ODTs) are capable of turning quickly into a liquid dosage form in contact with the saliva, thus possessing the advantages of both the solid dosage forms particularly stability and liquid dosage forms specially ease of swallowing and pre-gastric absorption of drug. The aim of this study was to prepare a novel matrix-type buccal fast disintegrating ibuprofen tablet formulation using special polymers, water soluble excipients, super-disintegrants and quickly soluble granules. For this purpose different tablet formulations of ibuprofen were prepared. The amount of ibuprofen in each formulation was 100 mg. Eight groups of formulation were prepared (A-H series), accounting for a total number of 45 formulations. Formulations prepared were examined in terms of different physicochemical tests including powder/granule flowability, appearance, thickness, uniformity of weight, hardness, friability and disintegration time. Results of formulation F22a (in series F), was found to be acceptable, making it the chosen formulation for further studies. Then, by adding various flavorants and sweeteners to this formulation, complementary series of formulations, named G and H, were prepared. Following the comparison of their taste with each other through asking 10 volunteers, the most suitable formulation regarding the taste, being formulation F22s, was chosen as the ultimate formulation. This formulation had PVP, ibuprofen and croscarmellose as the intra-granular components and xylitol and saccharin as the extra-granular ingredients. Formulation F22s was found to be acceptable in terms of physicochemical tests conducted, showing quick disintegration within the buccal cavity, appropriate hardness and rather low friability. Hence formulation F22s was selected as the final formulation.

Evaluation of skin absorption of drugs from topical and transdermal formulations

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André Luís Morais Ruela

Full Text Available ABSTRACT The skin barrier function has been attributed to the stratum corneum and represents a major challenge in clinical practice pertaining to cutaneous administration of drugs. Despite this, a large number of bioactive compounds have been successfully administered via cutaneous administration because of advances in the design of topical and transdermal formulations. In vitro and in vivo evaluations of these novel drug delivery systems are necessary to characterize their quality and efficacy. This review covers the most well-known methods for assessing the cutaneous absorption of drugs as an auxiliary tool for pharmaceutical formulation scientists in the design of drug delivery systems. In vitro methods as skin permeation assays using Franz-type diffusion cells, cutaneous retention and tape-stripping methods to study the cutaneous penetration of drugs, and in vivo evaluations as pre-clinical pharmacokinetic studies in animal models are discussed. Alternative approaches to cutaneous microdialysis are also covered. Recent advances in research on skin absorption of drugs and the effect of skin absorption enhancers, as investigated using confocal laser scanning microscopy, Raman confocal microscopy, and attenuated total reflectance Fourier-transform infrared spectroscopy, are reviewed.

Effect of a new formulation of micronized and ultramicronized N-palmitoylethanolamine in a tibia fracture mouse model of complex regional pain syndrome.

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Roberta Fusco

Full Text Available Complex regional pain syndrome type 1 (CRPS-I is a disabling and frequently chronic condition. It involves the extremities and is a frequent consequence of distal tibia and radius fractures. The inflamed appearance of the affected CRPS-I limb suggests that local production of inflammatory mediators may be implicated in the ensuing etiology. A rodent tibia fracture model, characterized by inflammation, chronic unilateral hindlimb warmth, edema, protein extravasation, allodynia and hyperalgesia resembles the clinical features of patients with acute CRPS-I. N-palmitoylethanolamine (PEA, a member of the family of naturally-occurring N-acylethanolamines, is well-known for its ability to modulate inflammatory processes and regulate pain sensitivity. However, the large particle size and lipidic nature of PEA may limit its bioavailability and solubility when given orally. Micronized formulations are frequently used to enhance the dissolution rate of drug and reduce its variability of absorption when orally administered. The aim of this study was to assess the effects of a formulation of micronized and ultramicronized PEA (PEA-MPS, given orally in a mouse model of CRPS-I. CD-1 male mice were subjected to distal tibia fracture and divided into two groups: control and treated with PEA-MPS (PEA micronized 300 mg/kg and ultramicronized 600 mg/kg. Sensibility to pain was monitored in all mice throughout the course of the experiment. Twenty-eight days after tibia fracture induction animals were sacrificed and biochemical parameters evaluated. The PEA-MPS-treated group showed an improved healing process, fracture recovery and fibrosis score. PEA-MPS administration decreased mast cell density, nerve growth factor, matrix metalloproteinase 9 and cytokine expression. This treatment also reduced (poly-ADPribose polymerase activation, peroxynitrite formation and apoptosis. Our results suggest that PEA-MPS may be a new therapeutic strategy in the treatment of CRPS-I.

A Retrospective Analysis of Clinical Laboratory Interferences Caused by Frequently Administered Medications in Burn Patients.

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Godwin, Zachary; Lima, Kelly; Greenhalgh, David; Palmieri, Tina; Sen, Soman; Tran, Nam K

2016-01-01

The goal of this study is to quantify the number of medications administered to burn patients and identify potential drugs interfering with laboratory testing. The authors reviewed the medical records of 12 adult (age ≥ 18 years) burn patients with more than 20% TBSA burns from an existing glucose control database at our institution. Dose, interval, and route of medications administered from admission to discontinuation of intensive insulin therapy were recorded. Interfering drugs were identified based on established clinical chemistry literature. The retrospective cohort of adult burn patients exhibited a mean (SD) age of 37.9 (3.0) years. Mean TBSA burn was 51.3 (9.3)%. Disease severity determined by the average multiple organ dysfunction score was 5.4 (0.2). Mean and median medications administered per day were 42.1 (9.5) and 49 (with a daily range of 0-65), respectively. A total of 666 potential laboratory test interferences caused by medications were identified. There were 261 different effects (eg, increased glucose, decreased potassium). Multiple interferences, 71.0% (475/666), were caused by more than one medication. Investigation of the number of medications administered to a burn patient and delineation of potential laboratory test interferences has not been conducted in burn patients. Given the substantial number of medications administered to burn patients, physicians and laboratory personnel should work together to identify potential interferences and define appropriate countermeasures while enhancing the laboratorians understanding of this unique population. This synergistic partnership can lead to intelligent support tools and potentially autocorrecting instruments.

Concentrated Protein Body Product Derived from Rice Endosperm as an Oral Tolerogen for Allergen-Specific Immunotherapy—A New Mucosal Vaccine Formulation against Japanese Cedar Pollen Allergy

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Wakasa, Yuhya; Takagi, Hidenori; Watanabe, Nobumasa; Kitamura, Noriko; Fujiwara, Yoshihiro; Ogo, Yuko; Hayashi, Shimpei; Yang, Lijun; Ohta, Masaru; Thet Tin, Wai Wai; Sekikawa, Kenji; Takano, Makoto; Ozawa, Kenjirou; Hiroi, Takachika; Takaiwa, Fumio

2015-01-01

The endoplasmic reticulum-derived type-I protein body (PB-I) from rice endosperm cells is an ideal candidate formulation for the oral delivery of bioencapsulated peptides as tolerogens for allergen-specific immunotherapy. In the present study, PBs containing the deconstructed Japanese cedar pollen allergens Cryptomeria japonica 1 (Cry j 1) and Cry j 2 were concentrated by treatment with thermostable α-amylase at 90°C to remove the starch from milled rice powder, which resulted in a 12.5-fold reduction of dry weight compared to the starting material. The modified Cry j 1 and Cry j 2 antigens in this concentrated PB product were more resistant to enzymatic digestion than those in the milled seed powder despite the absence of intact cell wall and starch, and remained stable for at least 10 months at room temperature without detectable loss or degradation. The high resistance of these allergens could be attributed to changes in protein physicochemical properties induced by the high temperature concentration process, as suggested by the decreased solubility of the antigens and seed proteins in PBs in step-wise-extraction experiments. Confocal microscopy showed that the morphology of antigen-containing PB-Is was preserved in the concentrated PB product. The concentrated PB product induced specific immune tolerance against Cry j 1 and Cry j 2 in mice when orally administered, supporting its potential use as a novel oral tolerogen formulation. PMID:25774686

Concentrated protein body product derived from rice endosperm as an oral tolerogen for allergen-specific immunotherapy--a new mucosal vaccine formulation against Japanese cedar pollen allergy.

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Yuhya Wakasa

Full Text Available The endoplasmic reticulum-derived type-I protein body (PB-I from rice endosperm cells is an ideal candidate formulation for the oral delivery of bioencapsulated peptides as tolerogens for allergen-specific immunotherapy. In the present study, PBs containing the deconstructed Japanese cedar pollen allergens Cryptomeria japonica 1 (Cry j 1 and Cry j 2 were concentrated by treatment with thermostable α-amylase at 90°C to remove the starch from milled rice powder, which resulted in a 12.5-fold reduction of dry weight compared to the starting material. The modified Cry j 1 and Cry j 2 antigens in this concentrated PB product were more resistant to enzymatic digestion than those in the milled seed powder despite the absence of intact cell wall and starch, and remained stable for at least 10 months at room temperature without detectable loss or degradation. The high resistance of these allergens could be attributed to changes in protein physicochemical properties induced by the high temperature concentration process, as suggested by the decreased solubility of the antigens and seed proteins in PBs in step-wise-extraction experiments. Confocal microscopy showed that the morphology of antigen-containing PB-Is was preserved in the concentrated PB product. The concentrated PB product induced specific immune tolerance against Cry j 1 and Cry j 2 in mice when orally administered, supporting its potential use as a novel oral tolerogen formulation.

Pharmacokinetic equivalence study of two formulations of the anticonvulsant pregabalin

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Tjandrawinata RR

2015-04-01

Full Text Available Raymond R Tjandrawinata,1 Effi Setiawati,2 Ratih Sofia Ika Putri,2 Vincent Angga Gunawan,2 Fenny Ong,1 Liana W Susanto,1 Dwi Nofiarny11Dexa Laboratories of Biomolecular Sciences, Cikarang, West Java, Indonesia; 2PT Equilab International Bioavailability and Bioequivalence Laboratory, Jakarta, IndonesiaPurpose: The present study was conducted to evaluate whether the bioavailability of pregabalin capsules 150 mg manufactured by PT Dexa Medica was equivalent to the reference formulation.Methods: This was a randomized, open-label, two-period, two-sequence, and crossover study under fasting condition, with a 1-week washout period. Plasma concentrations of pregabalin from 20 subjects were determined by using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS detection method. Pharmacokinetic parameters assessed in this study were: area under the plasma concentration–time curve from time zero to last observed quantifiable concentration (AUC0–t, area under the plasma concentration–time curve from time zero to infinity (AUC0–∞, maximum plasma concentration (Cmax, time to maximum plasma concentration (tmax, and terminal half-life (t1/2. The 90% confidence intervals (CIs for the geometric mean ratios of test formulation/reference formulation were calculated for the AUC and Cmax parameters; while tmax difference was analyzed nonparametrically on the original data using the Wilcoxon matched-pairs test, and t1/2 difference was analyzed using Student's paired t-test.Results: The mean (standard deviation [SD] AUC0–t, AUC0–∞, Cmax, and t1/2 of pregabalin from the test formulation were 27,845.86 (4,508.27 ng·h/mL, 28,311.70 (4,790.55 ng·h/mL, 3,999.71 (801.52 ng/mL, and 5.66 (1.20 hours, respectively; while the mean (SD AUC0–t, AUC0–∞, Cmax, and t1/2 of pregabalin from the reference formulation were 27,398.12 (4,266.28 ng·h/mL, 27,904.24 (4,507.31 ng·h/mL, 3,849.50 (814.50 ng/mL, and 5.87 (1.25 hours, respectively

An Investigation on Myanmar Traditional Medicine Formulation (TME-12) (Setkupala No.1)

International Nuclear Information System (INIS)

Shwe Sin; Aye Aye Tun; Daw Hla Ngwe; Kyaw Naing

2011-12-01

Myanmar Traditional Medicine Formulation (TMF-12) (Setkupala No.1) is such a wide use of household medicine in both rural and urban area that it was investigated. This medicine is utilized for treatment of aches and pain, blood impurity, especially eye disorder such as blurring of vision. Elemental role of Myanmar Traditional Medicine is found to be quite limited. The elemental content of TMF-12 was studied by Neutron Activation Analysis (NAA), Atomic Absorption Spectrophotometry (ASS) and Energy Dispersive X-Ray Fluorescence (EDXRF) method. A total of 28 elements were detected. Preliminary screening for radical scavenging of various extracts from TMF-12 exhibited the antioxidant activity tested by 1, 1 diphenyl 2- picrylhydrazyl (DPPH) solution. Antimicrobial activity studies showed the inhibitory activity of the soluble crude extracts against test organisms including Bacillus substilis, Bacillus pumilus, Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans and Mycobacterium species. From phytochemical investigation and FT-IR study, alkaloids, glycosides, alcohol, amino acid, aliphatic, aromatic, phenolic and olefinic compounds were present in TMF-12.

Colour and spreadability of Neem (Azadirachta Indica A. juss) ointment and cream formulations

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Zawiyyah, Azierah; Shamsul Anuar, Mohd

2018-04-01

Herbal plants are a major source of raw material for traditional medicines. Recently there has been an increase of interest to study the therapeutic potential of herbal plants as herbal care products. In this study, a preliminary study on the formulation of neem (Azadirachta Indica) ointment and cream have been conducted. The neem leaves were extracted and formulated into ointment and cream. The raw neem extract is added into the ointment and cream bases at four different concentrations (0% w/w, 0.5% w/w, 1% w/w and 2% w/w) and stored at three different storage temperatures (4°C, 25°C and 45°C). The semambu ointment and cream formulated were evaluated in terms of their colour and spreadability. It has been found that the extract content and storage temperature influence the colour and spreadability of the formulated neem ointment and cream.

Intermediate release formulations of diclofenac potassium tablets for IVIVC.

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Ali, Huma; Shoaib, Muhammad Harris; Zafar, Farya; Bushra, Rabia; Yasmin, Riffat; Siddiqui, Shehla; Alam, Zafar M

2016-07-01

In recent days response surface methodology (RSM) has widely been applied for development and optimization of cost effective formulations with required quality. Study comprised of three steps including micromeritic comparison of different powder blends of placebo and diclofenac potassium (DP), formulation designing with CCRD (Design Expert, version 7.0.0), and stability testing of selected formulations by using R Gui. Ten formulations (F11-F20) were developed using microcrystalline cellulose (Avicel PH-102) (X1) (13-72%), methocel K15M (X2) (6.59-23.4%) and magnesium stearate (X3) (1.32-4.68%), while responses were % friability and % drug release. Blending rate constant was determined at 3, 6, 9 and 12 minutes. The results of physicochemical parameters were found within acceptable limits. After in vitro testing at pH 1.2, pH 4.5 and pH 6.8, mechanism of drug release, kinetic analysis and statistical evaluation were carried out by model - independent, model-dependent and one-way ANOVA methods. Most formulations followed zero order kinetics at higher pH. Fickian release (0.326 ≤ n ≤0.449) was observed with β greater than 0.5 and less than 1. ANOVA indicated no significant variation within and between formulations as p-values were found to be > 0.05.

Assessment of Genotoxic Potential of Hridayarnava Rasa (A Herbo-Mineralo-Metallic Ayurvedic Formulation) Using Chromosomal Aberration and Sperm Abnormality Assays

Science.gov (United States)

Jagtap, Chandrashekhar Y.; Chaudhari, Swapnil Y.; Thakkar, Jalaram H.; Galib, R.; Prajapati, P. K.

2014-01-01

Objectives: Herbo-mineral formulations are being successfully used in therapeutics since centuries. But recently, they came under the scanner for their metallic contents especially the presence of heavy metals. Hence it is the need of the hour to assess and establish the safety of these formulations through toxicity studies. In line with the various toxicity studies that are being carried out, Government of India expressed the need for conducting genotoxicity studies of different metal- or mineral-based drugs. Till date very few Ayurvedic herbo-mineral formulations have been studied for their genotoxic potential. The present study is aimed to evaluate the genotoxic potential of Hridayarnava Rasa. Materials and Methods: It was prepared as per classical guidelines and administered to Swiss albino mice for 14 consecutive days. Chromosomal aberration and sperm abnormality assay were done to evaluate the genotoxic potential of the test drugs. Cyclophosphamide (CP) was taken as positive group and results were compared. Results: All treated groups exhibited significant body weight gain in comparison to CP group. Results revealed no structural deformity in the above parameters in comparison to the CP-treated group. Conclusion: Reported data showed that both tested samples of Hridayarnava Rasa does not possess genotoxic potential under the experimental conditions and can be safely used. PMID:25948961

Reactive decontamination formulation

Science.gov (United States)

Giletto, Anthony [College Station, TX; White, William [College Station, TX; Cisar, Alan J [Cypress, TX; Hitchens, G Duncan [Bryan, TX; Fyffe, James [Bryan, TX

2003-05-27

The present invention provides a universal decontamination formulation and method for detoxifying chemical warfare agents (CWA's) and biological warfare agents (BWA's) without producing any toxic by-products, as well as, decontaminating surfaces that have come into contact with these agents. The formulation includes a sorbent material or gel, a peroxide source, a peroxide activator, and a compound containing a mixture of KHSO.sub.5, KHSO.sub.4 and K.sub.2 SO.sub.4. The formulation is self-decontaminating and once dried can easily be wiped from the surface being decontaminated. A method for decontaminating a surface exposed to chemical or biological agents is also disclosed.

Cationic lipid-formulated DNA vaccine against hepatitis B virus: immunogenicity of MIDGE-Th1 vectors encoding small and large surface antigen in comparison to a licensed protein vaccine.

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Anne Endmann

Full Text Available Currently marketed vaccines against hepatitis B virus (HBV based on the small (S hepatitis B surface antigen (HBsAg fail to induce a protective immune response in about 10% of vaccinees. DNA vaccination and the inclusion of PreS1 and PreS2 domains of HBsAg have been reported to represent feasible strategies to improve the efficacy of HBV vaccines. Here, we evaluated the immunogenicity of SAINT-18-formulated MIDGE-Th1 vectors encoding the S or the large (L protein of HBsAg in mice and pigs. In both animal models, vectors encoding the secretion-competent S protein induced stronger humoral responses than vectors encoding the L protein, which was shown to be retained mainly intracellularly despite the presence of a heterologous secretion signal. In pigs, SAINT-18-formulated MIDGE-Th1 vectors encoding the S protein elicited an immune response of the same magnitude as the licensed protein vaccine Engerix-B, with S protein-specific antibody levels significantly higher than those considered protective in humans, and lasting for at least six months after the third immunization. Thus, our results provide not only the proof of concept for the SAINT-18-formulated MIDGE-Th1 vector approach but also confirm that with a cationic-lipid formulation, a DNA vaccine at a relatively low dose can elicit an immune response similar to a human dose of an aluminum hydroxide-adjuvanted protein vaccine in large animals.

Mechanism for enhanced absorption of a solid dispersion formulation of LY2300559 using the artificial stomach duodenum model.

Science.gov (United States)

Polster, Christopher S; Wu, Sy-Juen; Gueorguieva, Ivelina; Sperry, David C

2015-04-06

An artificial stomach duodenum (ASD) model has been used to demonstrate the performance difference between two formulations of LY2300559, a low-solubility acidic developmental drug. The two formulations investigated were a conventional high-shear wet granulation (HSWG) formulation and a solid dispersion formulation. A pharmacokinetic study in humans demonstrated the enhanced performance of the solid dispersion formulation relative to the HSWG formulation. The Cmax and AUC of the solid dispersion was 2.6 and 1.9 times greater, respectively, compared to the HSWG formulation. In the ASD, the solid dispersion formulation performance was characterized by three main phases: (1) rapid release in the stomach, creating a supersaturated concentration of drug, (2) precipitation in the stomach, and (3) rapid redissolution of the precipitate in the duodenum to concentration levels that are supersaturated relative to crystalline drug. A series of complementary experiments were employed to describe this performance behavior mechanistically. Imaging experiments with a pH indicating dye showed that local pH gradients from meglumine in the solid dispersion formulation were responsible for creating a high initial supersaturation concentration in the stomach. Upon dissipation of meglumine, the drug precipitated in the stomach as an amorphous solid. Because the precipitated drug is in an amorphous form, it can then rapidly redissolve as it transits to the more neutral environment of the duodenum. This unexpected sequence of physical state changes gives a mechanistic explanation for the enhanced in vivo performance of the solid dispersion formulation relative to the HSWG formulation.

Investigation of Lipid Oxidation in the Raw Materials of a Topical Skin Formulation: A Topical Skin Formulation Containing a High Lipid Content

DEFF Research Database (Denmark)

Thomsen, Birgitte Raagaard; Taylor, Richard; Madsen, Robert

2018-01-01

Several studies have demonstrated that lipid oxidation often occurs in topical skin formulations which can affect product odor (both positively and negatively). Furthermore, odor detection threshold values and odor descriptors of identified volatile oxidation products in cleansing and skin cream...... formulation prototypes were recently determined by a trained sensory panel at the Technical University of Denmark in the Division of Food Technology. In this study, we investigated lipid oxidation in a prototype skin cream formulation as well as in selected cosmetic skin care raw materials. Lipid oxidation...... was also identified. In addition, the concentrations of several well-known lipid oxidation products increased during storage and were suggested to originate primarily from rice bran wax, which oxidized more readily than other raw materials due to its unsaturated nature....

Pharmacokinetic comparison of different flubendazole formulations in pigs: A further contribution to its development as a macrofilaricide molecule

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L. Ceballos

2015-12-01

Full Text Available Despite the well established ivermectin activity against microfilaria, the success of human filariasis control programmes requires the use of a macrofilaricide compound. Different in vivo trials suggest that flubendazole (FLBZ, an anthelmintic benzimidazole compound, is a highly efficacious and potent macrofilaricide. However, since serious injection site reactions were reported in humans after the subcutaneous FLBZ administration, the search for alternative pharmaceutical strategies to improve the systemic availability of FLBZ has acquired special relevance both in human and veterinary medicine. The goal of the current experimental work was to compare the pharmacokinetic plasma behavior of FLBZ, and its metabolites, formulated as either an aqueous hydroxypropyl- β -cyclodextrin-solution (HPBCD, an aqueous carboxymethyl cellulose-suspension (CMC or a Tween 80-based formulation, in pigs. Animals were allocated into three groups and treated (2 mg/kg with FLBZ formulated as either a HPBCD-solution (oral, CMC-suspension (oral or Tween 80-based formulation (subcutaneous. Only trace amounts of FLBZ parent drug and its reduced metabolite were measured after administration of the different FLBZ formulations in pigs. The hydrolyzed FLBZ (H-FLBZ metabolite was the main analyte recovered in the bloodstream in pigs treated with the three experimental FLBZ formulations. The oral administration of the HPBCD-solution accounted for significantly higher (P < 0.05 Cmax and AUC (23.1 ± 4.4 μg h/mL values for the main metabolite (H-FLBZ, compared with those observed for the oral CMC-suspension (AUC = 3.5 ± 1.0 μg h/mL and injectable Tween 80-based formulation (AUC: 7.5 ± 1.7 μg h/mL. The oral administration of the HPBCD-solution significantly improved the poor absorption pattern (indirectly assessed as the H-FLBZ plasma concentrations observed after the oral administration of the FLBZ-CMC suspension or the subcutaneous injection of the

Lactobacillus acidophilus induces virus immune defence genes in murine dendritic cells by a Toll-like receptor-2-dependent mechanism

DEFF Research Database (Denmark)

Weiss, Gudrun Margarethe; Rasmussen, Simon; Hjerrild Zeuthen, L.

2010-01-01

Lactobacilli are probiotics that, among other health-promoting effects, have been ascribed immunostimulating and virus-preventive properties. Certain Lactobacillus spp. have been shown to possess strong interleukin-12 (IL-12) -inducing properties. As IL-12 production depends on the up......-regulation of type I interferons (IFNs), we hypothesized that the strong IL-12-inducing capacity of Lactobacillus acidophilus NCFM in murine bone-marrow-derived dendritic cells (DCs) is caused by an up-regulation of IFN-beta, which subsequently induces IL-12 and the double-stranded RNA binding Toll-like receptor-3...... detected in another L. acidophilus strain (X37), but was not a property of other probiotic strains tested, i.e. Bifidobacterium bifidum Z9 and Escherichia coli Nissle 1917. The IFN-beta expression was markedly reduced in TLR-2(-/-) DCs, dependent on endocytosis, and the major cause of the induction of Il...

A new formulation of the equivalent thermal in optimization of hydrothermal systems

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Bayón L.

2002-01-01

Full Text Available In this paper, we revise the classical formulation of the problem depriving it of the concepts that are superfluous from the mathematical point of view. We observe that a number of power stations can be substituted by a single one that behaves equivalently to the entire set. Proceeding in this way, we obtain a variational formulation in its purest sense (without restrictions. This formulation allows us to employ the theory of calculus of variations to the highest degree. We then calculate the equivalent minimizer in the case where the cost functions are second-order polynomials. We prove that the equivalent minimizer is a second-order polynomial with piece-wise constant coefficients. Moreover, it belongs to the class C 1 . Finally, we present various examples prompted by real systems and perform the proposed algorithms using Mathematica.

Administration of a Sol-Gel Formulation of Phenylephrine Using Low-Temperature Hollow Microneedle for Treatment of Intermittent Fecal Incontinence.

Science.gov (United States)

Lee, Hyunji; Park, Jung-Hwan; Park, Jung Ho

2017-12-01

A low temperature hollow microneedle system was devised to deliver sol-gel transition formulation near the surface of the skin for extended release and local delivery of drug by a non-invasive method. This new system can improve treatment of intermittent fecal incontinence. The low-temperature system was integrated with a hollow microneedle to maintain the low temperature of the sol formulation. Various sol-gel formulations using Pluronic F-127 (PF-127) and Hydroxy-propyl-methyl-cellulose (HPMC) were prepared, and their gelation temperature, flow property, and diffusion retardation were observed. Resting anal sphincter pressure in response to a phenylephrine (PE) sol-gel formulation was measured using an air-charged catheter. The biocompatibility of the sol-gel PE formulation was evaluated by observing the immunological response. When the PF-127 25%, HPMC 1% and PE formulation (PF25-HPMC1-PE) was injected through the peri-anal skin of the rat in vivo, the highest pressure on the anal sphincter muscle occurred at 6-8 h and anal pressure increased and lasted twice as long as with the phosphate-buffered saline (PBS)-PE formulation. There was no significant difference in the number of mast cells after administration into the rat in vivo between the PF25-HPMC1-PE formulation and the PBS-PE formulation. The combination of a low-pain hollow microneedle system and an injectable sol-gel formulation improved the efficacy of treatment of intermittent fecal incontinence. A low-temperature hollow microneedle system using a sol-gel formulation has many applications in medical treatments that require depot effect, local targeting, and pain control.

Two different formulations of the heavy quark effective theory

International Nuclear Information System (INIS)

Balk, S.; Ilakovac, A.; Koerner, J.G.; Pirjol, D.

1994-01-01

We point out that there exist two different formulations of the Heavy Quark Effective Theory (HQET). The one formulation of HQET was mostly developed at Harvard and involves the use of the equation of motion to eliminate the small components of the heavy quark field. The second formulation, developed in Mainz, involves a series of Foldy-Wouthuysen-type field transformations which diagonalizes the heavy quark Lagrangian in terms of an effective quark and antiquark sector. Starting at O(1/m Q 2 ) the two formulations are different in that their effective Lagrangians, their effective currents, and their effective wave functions differ. However, when these three differences are properly taken into account, the two alternative formulations lead to identical transition or S-matrix elements. This is demonstrated in an explicit example at O(1/m Q 2 ). We point to an essential difficulty of the Harvard HQET in that the Harvard effective fields are not properly normalized starting at order O(1/m Q 2 ). We provide explicit higher order expressions for the effective fields and the Lagrangian in the Mainz approach, and write down an O(1/m Q 2 ) nonabelian version of the Pauli equation for the heavy quark effective field. (orig.)

MicroRNA Expression Changes during Interferon-Beta Treatment in the Peripheral Blood of Multiple Sclerosis Patients

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Georg Füllen

2013-08-01

Full Text Available MicroRNAs (miRNAs are small non-coding RNA molecules acting as post-transcriptional regulators of gene expression. They are involved in many biological processes, and their dysregulation is implicated in various diseases, including multiple sclerosis (MS. Interferon-beta (IFN-beta is widely used as a first-line immunomodulatory treatment of MS patients. Here, we present the first longitudinal study on the miRNA expression changes in response to IFN-beta therapy. Peripheral blood mononuclear cells (PBMC were obtained before treatment initiation as well as after two days, four days, and one month, from patients with clinically isolated syndrome (CIS and patients with relapsing-remitting MS (RRMS. We measured the expression of 651 mature miRNAs and about 19,000 mRNAs in parallel using real-time PCR arrays and Affymetrix microarrays. We observed that the up-regulation of IFN-beta-responsive genes is accompanied by a down-regulation of several miRNAs, including members of the mir-29 family. These differentially expressed miRNAs were found to be associated with apoptotic processes and IFN feedback loops. A network of miRNA-mRNA target interactions was constructed by integrating the information from different databases. Our results suggest that miRNA-mediated regulation plays an important role in the mechanisms of action of IFN-beta, not only in the treatment of MS but also in normal immune responses. miRNA expression levels in the blood may serve as a biomarker of the biological effects of IFN-beta therapy that may predict individual disease activity and progression.

Effect of orally administered sodium bicarbonate on caecal pH.

Science.gov (United States)

Taylor, E A; Beard, W L; Douthit, T; Pohlman, L

2014-03-01

Caecal acidosis is a central event in the metabolic cascade that occurs following grain overload. Buffering the caecal acidosis by enterally administered sodium bicarbonate (NaHCO3 ) may be beneficial to affected horses. To determine the effect and duration of enterally administered NaHCO3 on caecal pH in healthy horses. Experimental study using horses with caecal cannulas. Nine horses had been previously fitted with a caecal cannula. Six horses received 1.0 g/kg bwt NaHCO3 and 3 control horses were given 3 l of water via nasogastric tube. Clinical parameters, water consumption, venous blood gases, caecal pH, faecal pH and faecal water content were measured at 6 h intervals over a 36 h study period. Horses that received enterally administered NaHCO3 had significantly increased caecal pH that lasted the duration of the study. Treated horses increased their water intake, and developed metabolic alkalaemia, significantly increased plasma sodium concentrations and significantly decreased plasma potassium concentrations. Enterally administered NaHCO3 may be beneficial in buffering caecal acidosis. © 2013 EVJ Ltd.

Development and Validation of a Micellar Capillary Electrophoresis Method for Determination of IFNβ-1b in Lyophilized Formulation of a Biosimilar Product.

Science.gov (United States)

Dadgarnejad, Manuchehr; Rastegar, Hosein; Ilka, Hooshmand; Shekarchi, Maryam; Adib, Nooshin; Alebouyeh, Mahmood; Keypour, Nadia; Shoeibi, Shahram; Kobarfard, Farzad; Fazeli, Mohammad Reza

2015-01-01

Human interferons (IFNs) are key cytokines secreted by immune system. They have several effects such as antiviral and anti tumors activity, activating immune cells and healing of multiple sclerosis. The type IFNs present in humans are α ,β and Υ. IFN β is a polypeptide, normally produced by fibroblasts and seems to be more species-specific than IFN. Structural properties of IFNs are important for their biologic effects. There are a few analytical techniques for separation, identification and determination of IFNs in its formulations such as mass spectroscopy, RP-HPLC and capillary electrophoresis (CE). In this study we used Micellar Electrokinetic Chromatography (MEKC) as a unique mode of CE because of its capability to separate neutral as well as charged solutes. We used sodium tetraborate (Borax) as buffer without any modifier and sodium dodecyl sulfate (SDS) as surfactant. The optimum MECK running buffer consisted of Borate 50 Mm; SDS 20 mM pH =9.6. The validated method was used for determination of the IFN β-1b formulation which is manufactured in Iran. From 9 collected different batches, all of them had acceptable potency as claimed on their label with average 102.25 ±10.030 %. This is the first time that a MEKC method is introduced for quantification of IFN β-1b in its pharmaceutical dosage forms. The method is reliable safe, rapid and accurate.

Formulation of enrofloxacin SLNs and its pharmacokinetics in emu ( Dromaius novaehollandiae) birds

Science.gov (United States)

Senthil Kumar, P.; Arivuchelvan, A.; Jagadeeswaran, A.; Punniamurthy, N.; Selvaraj, P.; Richard Jagatheesan, P. N.; Mekala, P.

2015-08-01

The study was conducted to formulate the enrofloxacin solid lipid nanoparticles (SLNs) with sustained release profile and improved pharmacological activity and evaluate the pharmacokinetic behaviour of enrofloxacin SLNs after oral routes of administration in emus. The SLNs were prepared using tripalmitin as lipid carrier, Tween 80 and Span 80 as surfactants and polyvinyl alcohol (PVA) as a stabilizer by a hot homogenization coupled with ultrasonication method. The prepared enrofloxacin SLNs formulations were characterized for further investigation in emu birds. The pharmacokinetics of native enrofloxacin was studied after i.v. and oral bolus administration at 10 mg/kg in emu birds and compared with the disposition kinetics of enrofloxacin SLNs. Enrofloxacin and its metabolite ciprofloxacin in plasma were estimated using HPLC and the pharmacokinetic parameters were calculated by a non-compartmental analysis. The results demonstrated that the particle size, polydispersity index, zeta potential, encapsulation efficiency and loading capacity of the SLNs were 154.72 ± 6.11 nm, 0.42 ± 0.11, -28.83 ± 0.60 mV, 59.66 ± 3.22 and 6.13 ± 0.32 %, respectively. AFM and TEM images showed spherical to circular particles with well-defined periphery. In vitro drug release exhibited biphasic pattern with an initial burst release of 18 % within 2 h followed by sustained release over 96 h. Pharmacokinetic results showed that the t 1/2 β , AUC0-∞, V darea/ F, MRT and bioavailability were 3.107, 1.894, 1.594, 2.993 and 1.895 times enhanced ( p enrofloxacin administered orally. The ratio of AUC0- t cipro/AUC0- t enro after administration of native enrofloxacin and enrofloxacin SLNs was less than 10 %. The t 1/2 β and MRT of the metabolite were longer than those of the parent substance. The PK/PD results confirmed that the SLNs extended the enrofloxacin concentration upto 48 h against pathogens susceptible to 0.125 μg/mL in emus. The results indicated that SLNs might be a

Microcanonical formulation of quantum field theories

International Nuclear Information System (INIS)

Iwazaki, A.

1984-03-01

A microcanonical formulation of Euclidean quantum field theories is presented. In the formulation, correlation functions are given by a microcanonical ensemble average of fields. Furthermore, the perturbative equivalence of the formulation and the standard functional formulation is proved and the equipartition low is derived in our formulation. (author)

A Mathematical Formulation of the SCOLE Control Problem. Part 2: Optimal Compensator Design

Science.gov (United States)

Balakrishnan, A. V.

1988-01-01

The study initiated in Part 1 of this report is concluded and optimal feedback control (compensator) design for stability augmentation is considered, following the mathematical formulation developed in Part 1. Co-located (rate) sensors and (force and moment) actuators are assumed, and allowing for both sensor and actuator noise, stabilization is formulated as a stochastic regulator problem. Specializing the general theory developed by the author, a complete, closed form solution (believed to be new with this report) is obtained, taking advantage of the fact that the inherent structural damping is light. In particular, it is possible to solve in closed form the associated infinite-dimensional steady-state Riccati equations. The SCOLE model involves associated partial differential equations in a single space variable, but the compensator design theory developed is far more general since it is given in the abstract wave equation formulation. The results thus hold for any multibody system so long as the basic model is linear.

Gallic acid as a corrosion inhibitor of carbon steel in chemical decontamination formulation

International Nuclear Information System (INIS)

Keny, S.J.; Kumbhar, A.G.; Thinaharan, C.; Venkateswaran, G.

2008-01-01

Gallic acid (GA) was found to provide corrosion inhibition to carbon steel (CS) at 4.25 mM concentration. Inherent stability to radiation degradation as compared to other reductant and coupled with its anionic nature with respect to removal using ion exchange column makes it suitable for using as both reductant as well as corrosion inhibitor in dilute decontamination formulations operating in the regenerative mode. A formulation containing CA (1.4 mM), EDTA/NTA (1.4 mM), AA (1.0-2.0 mM) and GA (4.25 mM) was found to be more efficient in dissolving hematite and providing 31% corrosion inhibition (passivation) to the CS

Toxicity and biodistribution of orally administered casein nanoparticles.

Science.gov (United States)

Gil, Ana Gloria; Irache, Juan Manuel; Peñuelas, Iván; González Navarro, Carlos Javier; López de Cerain, Adela

2017-08-01

In the last years, casein nanoparticles have been proposed as carriers for the oral delivery of biologically active compounds. However, till now, no information about their possible specific hazards in vivo was available. The aim of this work was to assess the safety of casein nanoparticles when administered orally to animals through a 90 days dose-repeated toxicity study (OECD guideline 408), that was performed in Wistar rats under GLP conditions. After 90 days, no evidences of significant alterations in animals treated daily with 50, 150 or 500 mg/kg bw of nanoparticles were found. This safety agrees well with the fact that nanoparticles were not absorbed and remained within the gut as observed by radiolabelling in the biodistribution study. After 28 days, there was a generalized hyperchloremia in males and females treated with the highest dose of 500 mg/kg bw, that was coupled with hypernatremia in the females. These effects were related to the presence of mannitol which was used as excipient in the formulation of casein nanoparticles. According to these results, the No Observed Adverse Effect Level (NOAEL) could be established in 150 mg/kg bw/day and the Lowest Observed Effect Level (LOEL) could be established in 500 mg/kg bw/day. Copyright © 2017. Published by Elsevier Ltd.

Biological control of strawberry Fusarium wilt caused by Fusarium oxysporum f. sp. fragariae using Bacillus velezensis BS87 and RK1 formulation.

Science.gov (United States)

Nam, Myeong Hyeon; Park, Myung Soo; Kim, Hong Gi; Yoo, Sung Joon

2009-05-01

Two isolates, Bacillus sp. BS87 and RK1, selected from soil in strawberry fields in Korea, showed high levels of antagonism towards Fusarium oxysporum f. sp. fragariae in vitro. The isolates were identified as B. velezensis based on the homology of their gyrA sequences to reference strains. BS87 and RK1 were evaluated for control of Fusarium wilt in strawberries in pot trials and field trials conducted in Nonsan, Korea. In the pot trials, the optimum applied concentration of BS87 and RK1 for pre-plant root-dip application to control Fusarium wilt was 10(5) and 10(6) colony-forming units (CFU)/ml, respectively. Meanwhile, in the 2003 and 2005 field trials, the biological control efficacies of formulations of RK1 were similar to that of a conventional fungicide (copper hydroxide) when compared with a non-treated control. The RK1 formulation was also more effective than BS87 in suppressing Fusarium wilt under field conditions. Therefore, the results indicated that formulation of B.velezensis BS87 and RK1 may have potential to control Fusarium wilt in strawberries.

In vivo efficacy of a biotherapic and eugenol formulation against Rhipicephalus microplus.

Science.gov (United States)

Valente, Paula Pimentel; Moreira, Gustavo Henrique Ferreira Abreu; Serafini, Matheus Ferreira; Facury-Filho, Elias Jorge; Carvalho, Antônio Último; Faraco, André Augusto Gomes; Castilho, Rachel Oliveira; Ribeiro, Múcio Flávio Barbosa

2017-03-01

The control of Rhipicephalus microplus is essential to prevent cattle discomfort and economic losses. However, increased resistance and acaricides inefficiency lead producers to adopt strategies that could result in the accumulation of chemical residues in meat and milk with possibilities of poisoning in animals and people. This scenario demonstrates the necessity of research into the identification of novel, effective and environmentally safe therapeutic options for cattle tick control. The objectives of this study were to develop and assess the efficacy of R. microplus biotherapic and of 5% eugenol for the control of R. microplus in artificially infested calves. Eighteen male 6-month-old Holstein calves were divided into three groups of six animals. In Group 1, the animals did not receive medication (control group); in Group 2, the animals received 1 mL of R. microplus biotherapic at dilution 6CH (centesimal Hahnemannian), orally administered twice daily. And in Group 3, they received a single application of eugenol 5% in the pour-on formulation. The median efficacy for biotherapy and eugenol 5% was respectively 10.13 and 13.97%; however, upon analyzing reproductive efficiency, it is noteworthy that the biotherapic had 45.86% efficiency and was superior to the action of eugenol (12.03%) after 37 days of treatment. The ultrastructural study provided information about the effects of R. microplus biotherapic on the ovaries of engorged females and showed disorganization in the deposition of the oocyte exochorion. The results suggest hatchability inhibition of larvae, interference in R. microplus reproduction and future possibilities for eco-friendly control of R. microplus with biotherapic 6CH.

A targeted liposome delivery system for combretastatin A4: formulation optimization through drug loading and in vitro release studies.

Science.gov (United States)

Nallamothu, Ramakrishna; Wood, George C; Kiani, Mohammad F; Moore, Bob M; Horton, Frank P; Thoma, Laura A

2006-01-01

Efficient liposomal therapeutics require high drug loading and low leakage. The objective of this study is to develop a targeted liposome delivery system for combretastatin A4 (CA4), a novel antivascular agent, with high loading and stable drug encapsulation. Liposomes composed of hydrogenated soybean phosphatidylcholine (HSPC), cholesterol, and distearoyl phosphoethanolamine-PEG-2000 conjugate (DSPE-PEG) were prepared by the lipid film hydration and extrusion process. Cyclic arginine-glycine-aspartic acid (RGD) peptides with affinity for alphav beta3-integrins overexpressed on tumor vascular endothelial cells were coupled to the distal end of polyethylene glycol (PEG) on the liposomes sterically stabilized with PEG (non-targeted liposomes; LCLs). Effect of lipid concentration, drug-to-lipid ratio, cholesterol, and DSPE-PEG content in the formulation on CA4 loading and its release from the liposomes was studied. Total liposomal CA4 levels obtained increased with increasing lipid concentration in the formulation. As the drug-to-lipid ratio increased from 10:100 to 20:100, total drug in the liposome formulation increased from 1.05+/-0.11 mg/mL to 1.55+/-0.13 mg/mL, respectively. When the drug-to-lipid ratio was further raised to 40:100, the total drug in liposome formulation did not increase, but the amount of free drug increased significantly, thereby decreasing the percent of entrapped drug. Increasing cholesterol content in the formulation decreased drug loading. In vitro drug leakage from the liposomes increased with increase in drug-to-lipid ratio or DSPE-PEG content in the formulation; whereas increasing cholesterol content of the formulation up to 30 mol-percent, decreased CA4 leakage from the liposomes. Ligand coupling to the liposome surface increased drug leakage as a function of ligand density. Optimized liposome formulation with 100 mM lipid concentration, 20:100 drug-to-lipid ratio, 30 mol-percent cholesterol, 4 mol-percent DSPE-PEG, and 1 mol

Effect of administering a diet contamined with fumonisins on the kidneys of wistar rats

Directory of Open Access Journals (Sweden)

Jade Cabestre Venancio

2014-08-01

Full Text Available Fumonisins (FBs are mycotoxins produced by Fusarium molds. Several works have shown contamination of maize by this toxin. Fumonisin B1 (FB-1 is found in greatest proportion (about 70%, resistant to several industrialization processes. In that context, the objective of this work was to analyze the effect of administering a diet contaminated with FB-1 on the morphophysiology of the kidneys of 21-day old male Wistar rats. The animals were divided into 2 groups: G0 (with animals receiving feed free of FBs and G6 (6mg of FB1 kg-1 of feed. The diet was administered during 42 days. After that period, the animals were placed in metabolic cages for urine collection, blood was collected for analysis of plasma creatinine, and the kidneys were fixed and stained with Masson's trichrome. We observed that FB1 administration did not affect feed intake, body weight gain and animal growth. The normal levels of plasma creatinine suggest that the toxin did not lead to glomerular lesion. There was also no change in water intake, osmolarity and excretion of sodium in urine. However, there was a significant increase in urine volume and potassium excretion in urine, with mild tubulointerstitial changes in the outer cortex for the group receiving the mycotoxin.

Brain structural changes in cynomolgus monkeys administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: A longitudinal voxel-based morphometry and diffusion tensor imaging study.

Science.gov (United States)

Jeong, Hyeonseok S; Lee, Sang-Rae; Kim, Jieun E; Lyoo, In Kyoon; Yoon, Sujung; Namgung, Eun; Chang, Kyu-Tae; Kim, Bom Sahn; Yang, Sejung; Im, Jooyeon J; Jeon, Saerom; Kang, Ilhyang; Ma, Jiyoung; Chung, Yong-An; Lim, Soo Mee

2018-01-01

In animal models of Parkinson's disease (PD), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is one of the most widely used agents that damages the nigrostriatal dopaminergic pathway. However, brain structural changes in response to MPTP remain unclear. This study aimed to investigate in vivo longitudinal changes in gray matter (GM) volume and white matter (WM) microstructure in primate models administered with MPTP. In six cynomolgus monkeys, high-resolution magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) scans were acquired 7 times over 32 weeks, and assessments of motor symptoms were conducted over 15 months, before and after the MPTP injection. Changes in GM volume and WM microstructure were estimated on a voxel-by-voxel basis. Mixed-effects regression models were used to examine the trajectories of these structural changes. GM volume initially increased after the MPTP injection and gradually decreased in the striatum, midbrain, and other dopaminergic areas. The cerebellar volume temporarily decreased and returned to its baseline level. The rate of midbrain volume increase was positively correlated with the increase rate of motor symptom severity (Spearman rho = 0.93, p = 0.008). Mean, axial, and radial diffusivity in the striatum and frontal areas demonstrated initial increases and subsequent decreases. The current multi-modal imaging study of MPTP-administered monkeys revealed widespread and dynamic structural changes not only in the nigrostriatal pathway but also in other cortical, subcortical, and cerebellar areas. Our findings may suggest the need to further investigate the roles of inflammatory reactions and glial activation as potential underlying mechanisms of these structural changes.

Anesthetic management of comprehensive dental restoration in a child with glutaric aciduria type 1 using volatile sevoflurane

Directory of Open Access Journals (Sweden)

Wei-Nung Teng

2014-10-01

Full Text Available Glutaric aciduria type 1 (GA1 is a rare, inherited mitochondrial disorder that results from deficiency of mitochondrial glutaryl-CoA dehydrogenase. Most patients develop neurological dysfunction early in life, which leads to severe disabilities. We present a 37-month-old girl with GA1 manifested as macrocephaly and hypotonia who received comprehensive dental restoration surgery under general anesthesia with sevoflurane. She was placed on specialized fluid management during a preoperative fasting period and anesthesia was administered without complications. All the physiological parameters, including glucose and lactate blood levels and arterial blood gas were carefully monitored and maintained within normal range perioperatively. Strategies for anesthetic management should include prevention of pulmonary aspiration, dehydration, hyperthermia and catabolic state, adequate analgesia to minimize surgical stress, and avoidance of prolonged neuromuscular blockade. We administered general anesthesia with sevoflurane uneventfully, which was well tolerated by our patient with GA1. Additionally, communication with a pediatric geneticist and surgeons should be undertaken to formulate a comprehensive anesthetic strategy in these patients.

Efficacy of a poly-aggregated formulation of amphotericin B in treating systemic sporotrichosis caused by Sporothrix brasiliensis.

Science.gov (United States)

Ishida, Kelly; Castro, Rafaela Alves; Torrado, Juan J; Serrano, Dolores Remedios; Borba-Santos, Luana Pereira; Quintella, Leonardo Pereira; de Souza, Wanderley; Rozental, Sonia; Lopes-Bezerra, Leila M

2018-04-01

In severe cases of sporotrichosis, it is recommended to use amphotericin B deoxycholate (D-AMB) or its lipid formulations and/or in association with itraconazole (ITC). Our aim was to evaluate the antifungal efficacy of a poly-aggregated amphotericin B (P-AMB), a nonlipid formulation, compared with D-AMB on systemic sporotrichosis caused by Sporothrix brasiliensis. In vitro assays showed that Sporothrix schenckii sensu stricto and S. brasiliensis yeast clinical isolates were susceptible to low concentrations of P-AMB and D-AMB. Although P-AMB presented a higher minimal inhibitory concentration (MIC) compared to D-AMB, its cytotoxic effect on renal cells and erythrocytes was lower. For the in vivo assays, male BALB/c mice were intravenously infected with S. brasiliensis yeasts, and P-AMB or D-AMB was administered 3 days post-infection. The efficacy of five therapeutic regimens was tested: intravenous monotherapy with P-AMB or D-AMB, intravenous pulsed-therapy with P-AMB or D-AMB, and intravenous therapy with P-AMB, followed by oral ITC. These treatments increased murine survival and controlled the fungal burden in the liver, spleen, lungs, and kidneys. However, only D-AMB monotherapy or the pulsed-therapies with D-AMB or P-AMB led to 100% survival of the mice 45 days post-infection; only pulsed administration of D-AMB was able to control the fungal load in all organs 45 days post-infection. Accordingly, the histopathological findings showed reductions in the fungal burden and inflammatory reactions in these treatment regimens. Together, our results suggest that the P-AMB formulation could be considered as an alternative drug to D-AMB for treating disseminated sporotrichosis.

Dry formulations of the biocontrol agent Candida sake CPA-1 using fluidised bed drying to control the main postharvest diseases on fruits.

Science.gov (United States)

Carbó, Anna; Torres, Rosario; Usall, Josep; Fons, Estanislau; Teixidó, Neus

2017-08-01

The biocontrol agent Candida sake CPA-1 is effective against several diseases. Consequently, the optimisation of a dry formulation of C. sake to improve its shelf life and manipulability is essential for increasing its potential with respect to future commercial applications. The present study aimed to optimise the conditions for making a dry formulation of C. sake using a fluidised bed drying system and then to determine the shelf life of the optimised formulation and its efficacy against Penicillium expansum on apples. The optimal conditions for the drying process were found to be 40 °C for 45 min and the use of potato starch as the carrier significantly enhanced the viability. However, none of the protective compounds tested increased the viability of the dried cells. A temperature of 25 °C for 10 min in phosphate buffer was considered as the optimum condition to recover the dried formulations. The dried formulations should be stored at 4 °C and air-packaged; moreover, shelf life assays indicated good results after 12 months of storage. The formulated products maintained their biocontrol efficacy. A fluidised bed drying system is a suitable process for dehydrating C. sake cells; moreover, the C. sake formulation is easy to pack, store and transport, and is a cost-effective process. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Development of a standardized Intranet database of formulation records for nonsterile compounding, Part 2.

Science.gov (United States)

Haile, Michael; Anderson, Kim; Evans, Alex; Crawford, Angela

2012-01-01

In part 1 of this series, we outlined the rationale behind the development of a centralized electronic database used to maintain nonsterile compounding formulation records in the Mission Health System, which is a union of several independent hospitals and satellite and regional pharmacies that form the cornerstone of advanced medical care in several areas of western North Carolina. Hospital providers in many healthcare systems require compounded formulations to meet the needs of their patients (in particular, pediatric patients). Before a centralized electronic compounding database was implemented in the Mission Health System, each satellite or regional pharmacy affiliated with that system had a specific set of formulation records, but no standardized format for those records existed. In this article, we describe the quality control, database platform selection, description, implementation, and execution of our intranet database system, which is designed to maintain, manage, and disseminate nonsterile compounding formulation records in the hospitals and affiliated pharmacies of the Mission Health System. The objectives of that project were to standardize nonsterile compounding formulation records, create a centralized computerized database that would increase healthcare staff members' access to formulation records, establish beyond-use dates based on published stability studies, improve quality control, reduce the potential for medication errors related to compounding medications, and (ultimately) improve patient safety.

Nurse administered propofol sedation for pulmonary endoscopies requires a specific protocol

DEFF Research Database (Denmark)

Jensen, Jeppe Thue; Banning, Anne-Marie; Clementsen, Paul

2012-01-01

This study provides an evaluation and risk analysis of propofol sedation for endoscopic pulmonary procedures according to our unit's "gastroenterologic nurse-administered propofol sedation (NAPS) guideline".......This study provides an evaluation and risk analysis of propofol sedation for endoscopic pulmonary procedures according to our unit's "gastroenterologic nurse-administered propofol sedation (NAPS) guideline"....

Limitations of high dose carrier based formulations.

Science.gov (United States)

Yeung, Stewart; Traini, Daniela; Tweedie, Alan; Lewis, David; Church, Tanya; Young, Paul M

2018-06-10

This study was performed to investigate how increasing the active pharmaceutical ingredient (API) content within a formulation affects the dispersion of particles and the aerosol performance efficiency of a carrier based dry powder inhalable (DPI) formulation, using a custom dry powder inhaler (DPI) development rig. Five formulations with varying concentrations of API beclomethasone dipropionate (BDP) between 1% and 30% (w/w) were formulated as a multi-component carrier system containing coarse lactose and fine lactose with magnesium stearate. The morphology of the formulation and each component were investigated using scanning electron micrographs while the particle size was measured by laser diffraction. The aerosol performance, in terms of aerodynamic diameter, was assessed using the British pharmacopeia Apparatus E cascade impactor (Next generation impactor). Chemical analysis of the API was observed by high performance liquid chromatography (HPLC). Increasing the concentration of BDP in the blend resulted in increasing numbers and size of individual agglomerates and densely packed BDP multi-layers on the surface of the lactose carrier. BDP present within the multi-layer did not disperse as individual primary particles but as dense agglomerates, which led to a decrease in aerosol performance and increased percentage of BDP deposition within the Apparatus E induction port and pre-separator. As the BDP concentration in the blends increases, aerosol performance of the formulation decreases, in an inversely proportional manner. Concurrently, the percentage of API deposition in the induction port and pre-separator could also be linked to the amount of micronized particles (BDP and Micronized composite carrier) present in the formulation. The effect of such dose increase on the behaviour of aerosol dispersion was investigated to gain greater insight in the development and optimisation of higher dosed carrier-based formulations. Copyright © 2018 Elsevier B.V. All

Microsphere based improved sunscreen formulation of ethylhexyl methoxycinnamate.

Science.gov (United States)

Gogna, Deepak; Jain, Sunil K; Yadav, Awesh K; Agrawal, G P

2007-04-01

Polymethylmethacrylate (PMMA) microspheres of ethylhexyl methoxycinnamate (EHM) were prepared by emulsion solvent evaporation method to improve its photostability and effectiveness as sunscreening agent. Process parameters like stirring speed and aqueous polyvinyl alcohol (PVA) concentration were analyzed in order to optimize the formulations. Shape and surface morphology of the microspheres were examined using scanning electron microscopy. Particle size of the microspheres was determined using laser diffraction particle size analyzer. The PMMA microspheres of EHM were incorporated in water-removable cream base. The in vitro drug release of EHM in pH 7.4 was performed using dialysis membrane. Thin layer chromatography was performed to determine photostability of EHM inside the microspheres. The formulations were evaluated for sun protection factor (SPF) and minimum erythema dose (MED) in albino rats. Cream base formulation containing microspheres prepared using EHM:PMMA in ratio of 1:3 (C(3)) showed slowest drug (EHM) release and those prepared with EHM: PMMA in ratio of 1:1 showed fastest release. The cream base formulations containing EHM loaded microspheres had shown better SPF (more than 16.0) as compared to formulation C(d) that contained 3% free EHM as sunscreen agent and showed SPF 4.66. These studies revealed that the incorporation of EHM loaded PMMA microspheres into cream base had greatly increased the efficacy of sunscreen formulation approximately four times. Further, photostability was also shown to be improved in PMMA microspheres.

Formulation and optimization of solid lipid nanoparticle formulation for pulmonary delivery of budesonide using Taguchi and Box-Behnken design.

Science.gov (United States)

Emami, J; Mohiti, H; Hamishehkar, H; Varshosaz, J

2015-01-01

Budesonide is a potent non-halogenated corticosteroid with high anti-inflammatory effects. The lungs are an attractive route for non-invasive drug delivery with advantages for both systemic and local applications. The aim of the present study was to develop, characterize and optimize a solid lipid nanoparticle system to deliver budesonide to the lungs. Budesonide-loaded solid lipid nanoparticles were prepared by the emulsification-solvent diffusion method. The impact of various processing variables including surfactant type and concentration, lipid content organic and aqueous volume, and sonication time were assessed on the particle size, zeta potential, entrapment efficiency, loading percent and mean dissolution time. Taguchi design with 12 formulations along with Box-Behnken design with 17 formulations was developed. The impact of each factor upon the eventual responses was evaluated, and the optimized formulation was finally selected. The size and morphology of the prepared nanoparticles were studied using scanning electron microscope. Based on the optimization made by Design Expert 7(®) software, a formulation made of glycerol monostearate, 1.2 % polyvinyl alcohol (PVA), weight ratio of lipid/drug of 10 and sonication time of 90 s was selected. Particle size, zeta potential, entrapment efficiency, loading percent, and mean dissolution time of adopted formulation were predicted and confirmed to be 218.2 ± 6.6 nm, -26.7 ± 1.9 mV, 92.5 ± 0.52 %, 5.8 ± 0.3 %, and 10.4 ± 0.29 h, respectively. Since the preparation and evaluation of the selected formulation within the laboratory yielded acceptable results with low error percent, the modeling and optimization was justified. The optimized formulation co-spray dried with lactose (hybrid microparticles) displayed desirable fine particle fraction, mass median aerodynamic diameter (MMAD), and geometric standard deviation of 49.5%, 2.06 μm, and 2.98 μm; respectively. Our results provide fundamental data for the

39 CFR 222.2 - Authority to administer oaths or function as notaries public.

Science.gov (United States)

2010-07-01

... 39 Postal Service 1 2010-07-01 2010-07-01 false Authority to administer oaths or function as notaries public. 222.2 Section 222.2 Postal Service UNITED STATES POSTAL SERVICE ORGANIZATION AND ADMINISTRATION DELEGATIONS OF AUTHORITY § 222.2 Authority to administer oaths or function as notaries public. (a...

Mucuna pruriens in Parkinson Disease: A Kinetic-Dynamic Comparison With Levodopa Standard Formulations.