A Phase I clinical trial of lodenafil carbonate, a new phosphodiesterase Type 5 (PDE5) inhibitor, in healthy male volunteers.

UNLABELLED: Lodenafil carbonate is a new phosphodiesterase Type 5 (PDE5) inhibitor used in treatment of erectile dysfunction. OBJECTIVE: The present study was conducted to evaluate the safety, tolerability, and pharmacokinetics of lodenafil carbonate after administering ascending (1 - 100 mg) single oral doses to healthy male volunteers (n = 33). METHODS: The study was an open label, dose-escalation, Phase I clinical trial involving the administration of single oral doses of lodenafil carbonate. Lodenafil carbonate was administered sequentially, escalating in single doses of 1 mg - 100 mg with a washout period of at least 1 week between each dose. The progression to the next dose was allowed after clinical and laboratory exams, Ambulatory Monitoring of Arterial Pressure (AMAP) without relevant clinical modifications and adverse events without clinical relevancy. Blood samples were collected at pre-dose, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 10, 12, 14, 16, 20 and 24 h post-dosing. Plasma samples for measurement of lodenafil carbonate and lodenafil were analyzed by liquid chromatography coupled to tandem mass spectrometry. RESULTS: No serious adverse events were observed, and none of the subjects discontinued the study due to intolerance. The AMAP measurements, clinical and laboratory exams and ECG revealed no significant changes even at higher doses. Lodenafil carbonate was not detected in any samples, indicating that it acts as a prodrug. The mean lodenafil pharmacokinetic parameters for tmax and t1/2 were 1.6 ( ± 0.4) h and 3.3 ( ± 1.1) h, respectively. This study demonstrated that lodenafil carbonate was well tolerated and showed a good safety profile in healthy male volunteers.

Ciprofibrate quantification in human plasma by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry for pharmacokinetic studies.

A rapid, sensitive and specific method for quantifying ciprofibrate in human plasma using bezafibrate as the internal standard (IS) is described. The sample was acidified prior extraction with formic acid (88%). The analyte and the IS were extracted from plasma by liquid-liquid extraction using an organic solvent (diethyl ether/dichloromethane 70/30 (v/v)). The extracts were analyzed by high performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/MS). Chromatography was performed using Genesis C18 4 µm analytical column (4.6 × 150 mm i.d.) and a mobile phase consisting of acetonitrile/water (70/30, v/v) and 1mM acetic acid. The method had a chromatographic run time of 3.4 min and a linear calibration curve over the range 0.1-60 µg/mL (r>0.99). The limit of quantification was 0.1 µg/mL. The intra- and interday accuracy and precision values of the assay were less than 13.5%. The stability tests indicated no significant degradation. The recovery of ciprofibrate was 81.2%, 73.3% and 76.2% for the 0.3, 5.0 and 48.0 ng/mL standard concentrations, respectively. For ciprofibrate, the optimized parameters of the declustering potential, collision energy and collision exit potential were -51 V, -16 eV and -5 V, respectively. The method was also validated without the use of the internal standard. This HPLC-MS/MS procedure was used to assess the bioequivalence of two ciprofibrate 100mg tablet formulations in healthy volunteers of both sexes. The following pharmacokinetic parameters were obtained from the ciprofibrate plasma concentration vs. time curves: AUC(last), AUC(0-168 h), C(max) and T(max). The geometric mean with corresponding 90% confidence interval (CI) for test/reference percent ratios were 93.80% (90% CI=88.16-99.79%) for C(max,) 98.31% (90% CI=94.91-101.83%) for AUC(last) and 97.67% (90% CI=94.45-101.01%) for AUC(0-168 h). Since the 90% CI for AUC(last), AUC(0-168 h) and C(max) ratios were within the 80-125% interval proposed by the US FDA, it was concluded that ciprofibrate (Lipless 100mg tablet) formulation manufactured by Biolab Sanus Farmacêutica Ltda. is bioequivalent to the Oroxadin (100 mg tablet) formulation for both the rate and the extent of absorption.

Tratamento cirúrgico do paciente com síndrome de Barraquer-Simon: revisão bibliográfica e relato de caso / Surgical treatment of patient with Barraquer-Simon syndrome: review of literature and related case

Barraquer e Simon descreveram no começo do século uma doença caracterizada por progressiva atrofia da gordura do tecido subcutâneo, limitada à parte superior do corpo, incluindo face. É uma síndrome rara, de origem obscura, também conhecida como lipodistrofia céfalotorácica. Os pacientes com a síndrome perdem progressivamente sua gordura subcutânea em direção craniocaudal simetricamente, começando na face e progredindo até uma determinada área da coxa. Freqüentemente estes pacientes apresentam uma hipertrofia de tecido celular subcutâneo nas suas extremidades inferiores. A doença começa no final da primeira década de vida ou no começo da segunda década, e é rara em pacientes do sexo masculino. Os autores descrevem um caso da síndrome de Barraquer-Simon com envolvimento facial e torácico, sem outras anomalias. Durante o seguimento cirúrgico, foram realizadas lipoenxertias, cirurgia para colocação de bioimplantes malares e cirurgia ortognática. A síndrome de Barraquer-Simon, classificada como lipodistrofia parcial, ainda é pouco compreendida. Mais estudos serão necessários para confirmar a base genética.

Barraquer and Simon described at the beginning of the century a disease characterized by progressive atrophy of the fat tissue of the sub-cutaneous limited to upper body including face. It is a rare syndrome of obscure origin, also known as lipodystrophy cefalochest. The patients with the syndrome gradually lose their fat sub-cutaneous toward craniocaudal symmetrically, starting on the face and progresses to a certain area of the thigh. Often these patients have a hypertrophy of cellular sub-cutaneous tissue in their lower extremities. The disease begins at the end of the first decade of life or at the beginning of the second decade, and is rare in patients male. The authors describe a case of the syndrome Barraquer-Simon involvement with facial and chest with no other abnormalities. During the surgical follow up, was performed lipoenxertias, surgery for placement of bioimplantes malares and surgery orthognathic. The syndrome Barraquer-Simon, classified as partial lipodystrophy, is still little understood. More studies are needed to confirm the genetic basis.

Comparative bioavailability study with two pantoprazole delayed-released tablet formulations administered with and without food in healthy subjects.

OBJECTIVE: To assess the comparative bioavailability of two formulations (40 mg delayed-released [DR] tablet; test and reference) of pantoprazole (CAS 102625-70-7) in healthy volunteers of both sexes, with and without food. METHODS: The study was conducted using an open, randomized, two-period crossover design with a 1-week washout interval, in two groups, with and without food. Plasma samples were obtained for up to 24 h post dose. Plasma pantoprazole concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reactions monitoring (MRM). From the pantoprazole plasma concentration vs. time curves, the pharmacokinetic parameters AUC(last) and C(max) were obtained, with and without food. RESULTS: The limit of quantification was 5 ng/mL for plasma pantoprazole analysis. The geometric mean and 90% confidence interval CI of test/reference percent ratios were, without and with food, respectively: 104.6540% (90.8616%-120.5401%) and 99.9708% (90.9987%-109.8275%) for C(max), 95.6634% (85.2675%-107.3267%) and 89.3500% (83.6630%-95.4237%) for AUC(last). CONCLUSION: Since the 90% CI for AUC(last) and C(max) ratios were within the 80-125% interval proposed by the US FDA, it was concluded that pantoprazole 40 mg DR tablet (test formulation) with and without food was bioequivalent to the reference 40 mg DR tablet for both the rate and extent of absorption.

Comparative bioavailability study with two chlorpropamide tablet formulations in healthy volunteers.

OBJECTIVE: The aim of this study was the assessment of the bioequivalence of two formulations (250 mg tablet) of chlorpropamide (CAS 94-20-2) in 36 healthy volunteers of both sexes. METHODS: The study was conducted using an open, randomized, two-period crossover design with a 3-week washout interval. Plasma samples were obtained over a 72-h period. Plasma chlorpropamide concentrations were analyzed by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS) with positive ion electrospray ionization using multiple reaction monitoring (MRM). From the chlorpropamide plasma concentration vs time curves, the following pharmacokinetic parameters were obtained: AUC(0-72h), AUC(inf) and C(max). RESULTS: The limit of quantification was 0.1 microg/mL for plasma chlorpropamide analysis. The geometric mean and respective 90 % confidence interval (CI) of Test/ Reference percent ratios were 93.99% (87.11%-101.41%) for C(max), 92.45% (85.96%-99.44%) for AUC(0-72h) and 90.30% (83.35%-97.82%) for AUC(0-inf). CONCLUSION: Since the 90 % CI for AUC(0-72h), AUC(0-inf) and C(max) ratios were within the 80-125%interval proposed by the US FDA, it was concluded that chlorpropamide 250 mg tablet (test formulation) was bioequivalent to the reference 250 mg tablet for of both the rate and extent of absorption.

Clonazepam quantification in human plasma by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry in a bioequivalence study.

A rapid, sensitive and specific method for quantifying clonazepam in human plasma using diazepam as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by liquid-liquid extraction using a hexane/diethylether (20 : 80, v/v) solution. The extracts were analysed by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS-MS). Chromatography was performed on a Jones Genesis C8 4 microm analytical column (100 x 2.1 mm i.d.). The method had a chromatographic run time of 3.0 min and a linear calibration curve over the range 0.5-50 ng/ml (r2 > 0.9965). The limit of quantification was 0.5 ng/ml. This HPLC/MS/MS procedure was used to assess the bioequivalence of two clonazepam 2 mg tablet formulations (clonazepam test formulation from Ranbaxy Laboratories Ltd and Rivotril from Roche Laboratórios Ltda as standard reference formulation).