Current Issue : January - March Volume : 2017 Issue Number : 1 Articles : 6 Articles
Objective: To assess the bioavailability of a formulation of metformin\nhydrochloride 850 mg coated tablets as test, compared to a reference\nproduct with the same dosage form, in healthy volunteers of both\ngenders.\nMethod: This clinical trial was designed as randomised, comparative,\nsingle-dose, open-label, two-period, two-sequence, crossover study\nunder fasting conditions. 28 healthy volunteers (fourteen men and\nfourteen women) took part in the study. The 850 mg coated tablets\nformulations were administered in a single dose orally. Blood samples\nwere obtained prior to dosing and at 30 min, 1, 1:20; 1:40, 2,\n2:20, 2:40; 3, 3:20, 3:40 4, 4:30, 5, 6, 8, 12, 16, 24 and 36 hours\nafter drug administration with an one week washout period. Plasmatic\nconcentrations of metformin were measured by specific and validated\nanalytical methods based on high-performance liquid chromatography\ncoupled to mass spectrometry (HPLC/MS). The pharmacokinetics parameter\nAUC0-36h, AUC0-âË?ž and Cmax were tested for bioequivalence\nafter log transformation of data and ratios of Tmax were evaluated\nnon parametrically.\nFindings: Data from this study showed that the test and the reference\nformulation presented similar results, within the acceptance range\n(80-125%) for AUC0-âË?ž (area under curve) and Cmax (maximum serum\nconcentration of the drug) parameters, satisfying the bioequivalence\ncriteria of the Brazilian Health Surveillance Agency and FDA.\nConclusion: These results indicate that the two formulations of\nmetformin hydrochloride 850 mg coated tablets are bioequivalent,\nthus, it will be possible to ensure interchangeability between them,\nwhich can generate market competition and better access to this\ntreatment....
Theobjective of this randomized, open-label, single-dose, two-phase crossover study was to determine the effect of ascorbic acid on\npharmacokinetics of ganoderic acid A, an important biologically active triterpenoid compound with anticancer activities, following\noral administration of water extract of fruiting bodies of Ling Zhi in 12 healthy male subjects. Each subject was randomized to receive\neither one of the two regimens: (1) a single dose of 3,000mg of the Ling Zhi preparation or (2) a single dose of 3,000mg of the Ling\nZhi preparation in combination with 2,500mg of ascorbic acid. After a washout period of at least two weeks, subjects were switched\nto receive the alternate regimen. Blood samples were collected in each phase immediately before dosing and at specific time points\nfor 8 hours after dosing. Plasma ganoderic acid A concentrations were quantified using liquid chromatography-mass spectrometry\n(LC-MS).The pharmacokinetic parameters analyzed were maximal plasma concentration (...
Background: More potent antitumor activity is desired in Interferon (IFN)-treated cancer patients. This could be\nachieved by combining IFN alpha and IFN gamma. The aim of this work was to characterize the pharmacokinetics\nand pharmacodynamics of a novel formulation containing a co-formulated combination of IFNs alpha-2b and\ngamma (CIGB-128-A).\nMethods: A group of nine healthy male subjects received intramuscularly 24.5 Ã?â?? 106 IU of CIGB-128-A. IFN\nconcentrations were evaluated for 48 h. Serum neopterin, beta2-microglobulin (Ã?²2M) and 2ââ?¬Â²Ã¢â?¬â??5ââ?¬Â² oligoadenylate\nsynthetase (2ââ?¬Â²Ã¢â?¬â??5ââ?¬Â² OAS), classical IFN-inducible serum markers, were measured during 192 h by enzyme\nimmunoassay and body temperature was used as pharmacodynamic variable as well.\nResults: Concerning pharmacokinetics, serum IFNsââ?¬â?¢ profiles were better fitted to a mono-compartmental model\nwith consecutive zero order and first order absorption, one bioavailability value. No interferences by simultaneous\nadministered IFNs were observed in their typical similar systemic profiles. Neopterin and Ã?²2M time profiles showed\na delay that was efficiently linked to pharmacokinetics by means of a zero order absorption rate constant. Neopterin\nlevel was nine-fold higher than initial values, 48 h post-administration, an increment not described before. At this time,\nmean serum Ã?²2M peaked around the double from baseline. Serum concentrations of the enzyme 2ââ?¬Â²Ã¢â?¬â??5ââ?¬Â² OAS was still\nelevated on the 8 day post-injection. The formulation was well tolerated. Most frequent adverse reactions were fever,\nheadache, arthralgia and lymphopenia, mostly mild.\nConclusions: The administration of co-formulated IFN alpha-2b and IFN gamma likely provides improved\npharmacodynamic properties that may be beneficial to treat several malignancies....
Background: Malaria remains a major public health problem, with half the world population at risk of contracting\nmalaria. The effects of Plasmodium vivax on prosperity and longevity have been highlighted in several recent clinical\ncase reports. The first line of vivax treatment drugs has seen no radical innovation for more than 60 years. This study\nintroduces a subtle incremental innovation to vivax treatment: a chloroquine and primaquine co-blister. The co-blister\nincludes a new chloroquine formulation incorporating coated tablets to mask the drugââ?¬â?¢s bitter taste and user-friendly\npackaging containing tablets of each drug, which may improve patient adherence and facilitate the appropriate use\nof the drugs. This new formulation will replace the non-coated chloroquine distributed in Brazil.\nMethods: Patients were orally treated with 150 mg coated chloroquine tablets for 3 days: an initial 450 mg dose,\nfollowed by two 300 mg doses. The patients were treated concomitantly with two 15 mg primaquine tablets for\n7ââ?¬â??9 days, according to their weight. The primary objective of this study was to prove parasitological and clinical cure\nrates above 90 % by day 28.\nResults: This single-arm open-label non-comparative trial was conducted according to the WHO recommended methodology\nfor the surveillance of anti-malarial drug efficacy in the Brazilian Amazon. On day 28, the parasitological and clinical\nresponse was adequate in 98.8 % of patients (CI 95 % 93.4ââ?¬â??100 %). The success rate on day 3 was 100 %, and the cumulative\nsuccess rate by day 28 was 98.8 % (CI 95 % 91.7ââ?¬â??99.8 %). There were no serious adverse events, with most adverse\nevents classified as mild. The pharmacokinetic parameters of chloroquine analysed in whole blood dry spot samples\nshowed mean (coefficient of variation) Cmax and AUC0ââ?¬â??t values of 374.44 (0.35) and 3700.43 (0.36) ng/mL, respectively.\nDiscussion: This study reports an appropriate safety and efficacy profile of a new formulation of coated chloroquine\ntablets for vivax malaria treatment in the Brazilian Amazon. The cure rates meet the WHO efficacy criteria, supporting\ncurrent Brazilian guidelines and the use of the formulation for vivax malaria treatment. Nevertheless, further studies\nshould be conducted to address adherence and the effectiveness of the formulation....
Background: The goal of this study was to develop an in vivo-in vitro (IVIV) correlation, both in men and\nwomen, which allows constructing a model to predict bioequivalence assessments for drugs with narrow\nabsorption windows. Besides, pharmacokinetic and pharmacodynamic equivalences were also investigated.\nFurosemide was chosen as a prototype.\nMethods: Twelve healthy Caucasian volunteers (8 women and 4 men) participated in a relative\nbioavailability study. Two oral formulations [Lasix�® (Reference, R) and Furosemide EFA�® (Test, T)] were\nadministered under fasting conditions. Urinary excretion of unchanged drug (PK), and of chloride, sodium\nand potassium (PD) wasmonitored throughout time. PK and PD parameters were calculated from each\nrespective excretion rate versus time curve. In vitro dissolution testing of both formulations was carried out\nusing the USP apparatus 2 and 4 with fixed and variable dissolution media.\nResults: T and R could be considered bioequivalent since the 90% confidence intervals for the T/R ratio of\ngeometric means for the area under the urinary drug excretion rate versus time curve and for the maximum\nexcretion rate were within the 0.80-1.25 bioequivalence interval. However, T had faster initial absorption\nand higher levels in women, while R displayed such characteristics in men. Closer IVIV correlations in\nwomen were obtained when apparatus 4 with variable biorelevant dissolution media were used [going\nfrom fasting state simulated gastric fluid to fasting state simulated intestinal fluid]. Since R had faster\ndisintegration time than T, a shorter stay of R under gastric conditions was required in order to obtain a\ngood IVIV correlation in men. Saluretic effect displayed a typical clockwise hysteresis loop for the PKPD\ncorrelation assessed through chloride-versus-furosemide urinary excretion rates. Even though a higher\namount of furosemide was excreted with the urine in men, differences in the excretion of electrolytes\nbetween sexes were almost negligible.\nConclusions: Sex-differences in the gastrointestinal transit of formulations, under fasting conditions,\ndetermined the extent and the rate of furosemide absorption. The prolongation of the absorption process\nby mean of slowing the gastric emptying would make the formulation more effective. The USP-4 apparatus\nwith variable dissolution media was able to discriminate the formulations even between sexes, becoming a\npromissory in vitro dissolution testing to predict bioequivalence....
Epothilones have demonstrated promising potential for oncology applications but suffer from a narrow therapeutic window.\nEpothilone D stabilizes microtubules leading to apoptosis, is active against multidrug-resistant cells, and is efficacious in animal\ntumor models despite lack of stability in rodent plasma. Clinical development was terminated in phase II due to dose limiting\ntoxicities near the efficacious dose. Taken together, this made epothilone D attractive for encapsulation in a stabilized polymer\nmicelle for improved safety and efficacy. We have designed a library of triblock copolymers to develop IT-147, a lead formulation\nof epothilone D that extends plasma circulation for accumulation in the tumor environment, and potentially decrease systemic\nexposure to reduce dose limiting toxicities. The drug loading efficiency for IT-147 exceeds 90%, is 75nm in diameter, and\ndemonstrates pH-dependent release of epothilone D without chemical conjugation or enzymatic activation. Administration of\nIT-147 at 20mg/kg increases exposure of epothilone D to the plasma compartment over 6-fold compared to free drug. At the same\ndose, 20mg/kg epothilone D fromIT-147 is considered the no observed adverse effect level (NOAEL) but is the maximum tolerated\ndose for free drug. Consequently, IT-147 is positioned to be a safer, more effective means to deliver epothilone D....
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