Rebamipide Does Not Protect Against Naproxen-induced Gastric Damage: A Randomized Double-blind Controlled Trial

Rebamipide is a gastroprotective agent with promising results against gastric damage induced by non-steroidal anti-inflammatory drugs. The present study evaluated if rebamipide protects against naproxen-induced gastric damage in healthy volunteers. Changes in gastric PGE2 tissue concentration were also evaluated. Methods: After a preliminary endoscopy to rule out previous gastric macroscopic damage, twenty-four healthy volunteers of both sexes were divided into 2 groups. One group received sodium naproxen 550 mg b.i.d. plus placebo for 7 days, while the other group received sodium naproxen 550 mg b.i.d. plus rebamipide 100 mg b.i.d. At the end of treatment, a new endoscopy was performed. Gastric macroscopic damage was evaluated by the Cryer score and by the modified Lanza score. The primary outcome measure of the trial was the macroscopic damage observed in each treatment group at the end of treatment. Biopsies were collected at both endoscopies for PGE2 quantification and histopathological analysis (secondary outcomes). Tissue PGE2 was quantified by ELISA. The randomization sequence was generated using 3 blocks of 8 subjects each. Volunteers and endoscopists were blind to whether they were receiving rebamipide or placebo. Results: All recruited volunteers completed the trial. Sodium naproxen induced gastric damage in both groups. At the end of the study, median Cryer score was 4 in both groups (Difference = 0; 95% CI = -1 to 0; p = 0.728). In the placebo group, the mean tissue PGE2 concentration was 1005 +/- 129 pg/mL before treatment and 241 +/- 41 pg/mL after treatment (p < 0.001). In the rebamipide group, the mean tissue PGE2 concentration was 999 +/- 109 pg/mL before treatment, and 168 +/- 13 pg/mL after treatment (p < 0.001). There was no difference in mean tissue PGE2 between the two groups (difference = 5; 95% CI from -334.870 to 345.650; p = 0.975). No significant change was observed at the histopathological evaluation, despite the evident macroscopic damage induced by naproxen. Conclusion: Rebamipide does not protect against naproxen-induced gastric damage in healthy volunteers.16Biolab Industria Farmaceutica Ltd

Rebamipide Does Not Protect Against Naproxen-induced Gastric Damage: A Randomized Double-blind Controlled Trial

Rebamipide is a gastroprotective agent with promising results against gastric damage induced by non-steroidal anti-inflammatory drugs. The present study evaluated if rebamipide protects against naproxen-induced gastric damage in healthy volunteers. Changes in gastric PGE2 tissue concentration were also evaluated. Methods: After a preliminary endoscopy to rule out previous gastric macroscopic damage, twenty-four healthy volunteers of both sexes were divided into 2 groups. One group received sodium naproxen 550 mg b.i.d. plus placebo for 7 days, while the other group received sodium naproxen 550 mg b.i.d. plus rebamipide 100 mg b.i.d. At the end of treatment, a new endoscopy was performed. Gastric macroscopic damage was evaluated by the Cryer score and by the modified Lanza score. The primary outcome measure of the trial was the macroscopic damage observed in each treatment group at the end of treatment. Biopsies were collected at both endoscopies for PGE2 quantification and histopathological analysis (secondary outcomes). Tissue PGE2 was quantified by ELISA. The randomization sequence was generated using 3 blocks of 8 subjects each. Volunteers and endoscopists were blind to whether they were receiving rebamipide or placebo. Results: All recruited volunteers completed the trial. Sodium naproxen induced gastric damage in both groups. At the end of the study, median Cryer score was 4 in both groups (Difference = 0; 95% CI = -1 to 0; p = 0.728). In the placebo group, the mean tissue PGE2 concentration was 1005 +/- 129 pg/mL before treatment and 241 +/- 41 pg/mL after treatment (p < 0.001). In the rebamipide group, the mean tissue PGE2 concentration was 999 +/- 109 pg/mL before treatment, and 168 +/- 13 pg/mL after treatment (p < 0.001). There was no difference in mean tissue PGE2 between the two groups (difference = 5; 95% CI from -334.870 to 345.650; p = 0.975). No significant change was observed at the histopathological evaluation, despite the evident macroscopic damage induced by naproxen. Conclusion: Rebamipide does not protect against naproxen-induced gastric damage in healthy volunteers.1658Biolab Industria Farmaceutica Ltd

Phase I study of the novel antifungal agent dapaconazole (zilt®) in healthy volunteers

The study aims to evaluate the tolerability of multiple-dose topical dapaconazole tosylate, a new imidazole antiftmgal drug, in healthy vohmteers. Twenty-four healthy vohmteers (12 men) with skin pigmentation classified as I-III in the Fitzpatrick scale emolled in this open-label, two-treatment study with daily application of 40 mg of dapaconazole for 14 consecutive days. Drug application was monitored by a physician and photographs were taken before and 1 h after application to evaluate possible dermatological reactions. Medical evaluations including physical examination, laboratory tests and electrocardiograms were performed to evaluate possible systemic adverse events. To evaluate systemic dapaconazole absorption blood samples were collected before and 2, 4 and 6 h after products application on the first day of treatment. The same occwred in days 7 and 13, but an extra 24 h sample was collected after application of the products. Dapaconazole plasma levels were measured by high-performance liquid chromatography coupled to tandem mass spectrometry. No vohmteers had dermatological reactions to the formulations. Only one blood sample had detectable levels of dapaconazole (0.23 ng mL-1). One volunteer presented hypertriglyceridemiaThe study aims to evaluate the tolerability of multiple-dose topical dapaconazole tosylate, a new imidazole antiftmgal drug, in healthy vohmteers. Twenty-four healthy vohmteers (12 men) with skin pigmentation classified as I-III in the Fitzpatrick scale emolled in this open-label, two-treatment study with daily application of 40 mg of dapaconazole for 14 consecutive days. Drug application was monitored by a physician and photographs were taken before and 1 h after application to evaluate possible dermatological reactions. Medical evaluations including physical examination, laboratory tests and electrocardiograms were performed to evaluate possible systemic adverse events. To evaluate systemic dapaconazole absorption blood samples were collected before and 2, 4 and 6 h after products application on the first day of treatment. The same occwred in days 7 and 13, but an extra 24 h sample was collected after application of the products. Dapaconazole plasma levels were measured by high-performance liquid chromatography coupled to tandem mass spectrometry. No vohmteers had dermatological reactions to the formulations. Only one blood sample had detectable levels of dapaconazole (0.23 ng mL-1). One volunteer presented hypertriglyceridemia10850751

Tolerability of 2.5% lidocaine/prilocaine hydrogel in children undergoing cryotherapy for molluscum contagiosum

The tolerability of a 2.5% lidocaine/prilocaine hydrogel ( Nanorap, Biolab Industria Farmace aceutica Ltd., Sao Paulo, Brazil) was evaluated in 20 children ages 2 to 11 years undergoing cryotherapy for molluscum contagiosum ( MC). The product was well tolerated, with only two children presenting with eczema at the application site. These adverse reactions were considered unlikely to be related to the test product, because a patch test was negative in one of the individuals and the other event occurred in only one of the two treated areas. Nanorap is an efficacious and well-tolerated option for topical anesthesia in children undergoing cryotherapy for MC333E214E215sem informaçã

Propylthiouracil Quantification In Human Plasma By High-performance Liquid Chromatography Coupled With Electrospray Tandem Mass Spectrometry: Application In A Bioequivalence Study

A rapid, sensitive and specific method for quantifying propylthiouracil in human plasma using methylthiouracil as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by liquid-liquid extraction using an organic solvent (ethyl acetate). The extracts were analyzed by high performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/MS) in negative mode (ES-). Chromatography was performed using a Phenomenex Gemini C18 5μm analytical column (4.6mm×150mm i.d.) and a mobile phase consisting of methanol/water/acetonitrile (40/40/20, v/v/v)+0.1% of formic acid. For propylthiouracil and I.S., the optimized parameters of the declustering potential, collision energy and collision exit potential were -60 (V), -26 (eV) and -5 (V), respectively. The method had a chromatographic run time of 2.5min and a linear calibration curve over the range 20-5000ng/mL. The limit of quantification was 20ng/mL. The stability tests indicated no significant degradation. This HPLC-MS/MS procedure was used to assess the bioequivalence of two propylthiouracil 100mg tablet formulations in healthy volunteers of both sexes in fasted and fed state. The geometric mean and 90% confidence interval CI of Test/Reference percent ratios were, without and with food, respectively: 109.28% (103.63-115.25%) and 115.60% (109.03-122.58%) for Cmax, 103.31% (100.74-105.96%) and 103.40% (101.03-105.84) for AUClast. Conclusion: This method offers advantages over those previously reported, in terms of both a simple liquid-liquid extraction without clean-up procedures, as well as a faster run time (2.5min). The LOQ of 20ng/mL is well suited for pharmacokinetic studies. The assay performance results indicate that the method is precise and accurate enough for the routine determination of the propylthiouracil in human plasma. The test formulation with and without food was bioequivalent to reference formulation. Food administration increased the Tmax and decreased the bioavailability (Cmax and AUC). © 2014 Elsevier B.V.9691928Glinoer, D., Cooper, D.S., (2012) Curr. Opin. Endocrinol. Diabetes Obes., 19, pp. 402-407Zakrzewski, R., (2008) Arch. Pharm. Res., 31, pp. 1622-1630Wei, Y., Zhang, Z.J., Zhang, Y.T., Sun, Y.H., (2007) J. Chromatogr. B: Analyt. Technol. Biomed. Life Sci., 854, pp. 239-244Okuno, A., Taguchi, T., Inyaku, F., Yano, K., Suzuki, Y., (1983) Pediatr. Pharmacol., 3, pp. 43-47Ringhand, H.P., Ritschel, W.A., Meyer, M.C., Straughn, A.B., Cabana, B.E., (1983) J. Pharm. Sci., 72, pp. 1409-1412Giles, H.G., Roberts, E.A., Orrego, H., Sellers, E.M., (1981) J. Clin. Pharmacol., 21, pp. 466-471Clark, S.M., Saade, G.R., Snodgrass, W.R., Hankins, G.D., (2006) Ther. Drug. Monit., 28, pp. 477-483Rosseel, M.T., Lefebvre, R.A., (1990) J. Chromatogr., 16, pp. 247-251Zakrzewski, R., (2008) J. Pharm. Biomed. Anal., 10, pp. 145-159Abdul-Fattah, A.M., Bhargava, H.N., (2001) Drug Dev. Ind. Pharm., 27, pp. 831-835Batjoens, P., De Brabander, H.F., De Wasch, K., (1996) J. Chromatogr., 25, pp. 127-132Giles, H.G., Miller, R., Sellers, E.M., (1979) J. Pharm. Sci., 68 (11), pp. 1459-1460Cannell, G.R., Williams, J.P., Yap, A.S., Mortimer, R.H., (1991) J. Chromatogr., 564, pp. 310-314Moretti, G., Betto, P., Cammarata, P., Fracassi, F., Giambenedetti, M., Borghese, A., (1993) J. Chromatogr., 616, pp. 291-296Pinel, G., Bichon, E., Pouponneau, K., Maume, D., André, F., Le Bizec, B., (2005) J. Chromatogr. A, 1085, pp. 247-252Lõhmus, M., Kallaste, K., Le Bizec, B., (2009) J. Chromatogr. A, 1216 (46), pp. 8080-8089(2013) J. Am. Med. Assoc., 310, pp. 2191-2194. , World Medical Association(2003) Bioavailability and Bioequivalence Studies for Orally Administered Drug Products - General Considerations, , Food and Drug Administratio

Pharmacokinetic And Pharmacodynamic Evaluation Of A Nanotechnological Topical Formulation Of Lidocaine/prilocaine (nanorap) In Healthy Volunteers

BACKGROUND:: Nanorap is a new nanotechnological formulation for topical anesthesia composed of lidocaine (2.5%) and prilocaine (2.5%). The present study evaluated the pharmacokinetics (PK) of Nanorap. For the determination of lidocaine and prilocaine in human plasma a new method using high-performance liquid-chromatography coupled to tandem mass spectrometry was developed. Nanorap pharmacodynamic (PD) and its physical proprieties were also evaluated.METHODS:: Nanorap was administered by topical application of 2g to healthy volunteers and blood samples were collected for the PK analysis. The drugs were extracted from plasma by liquid-liquid extraction with ether/hexane (80/20, v/v). The chromatography separation was performed on a Genesis C18 analytical column 4 µm (100 x 2.1 mm i.d.) with a mobile phase of methanol/acetonitrile/water (40/30/30, for lidocaine, and 50/30/20, for prilocaine, v/v/v) + 2 mM of ammonium acetate and ropivacaine as internal standard. The drugs were quantified using a mass spectrometer with an electrospray source in the ESI positive mode (ES+) configured for multiple reaction monitoring. The PD of Nanorap was evaluated with the use of a visual analogue scale. Nanorap was characterized by cryofracture.RESULTS:: The chromatography run time was 5.5 min for lidocaine and 3.3 min for prilocaine and the lower limit of quantification was 0.05 ng/mL for both drugs. Mean Cmax was 6.62 and 1.72 ng/mL for lidocaine and prilocaine, respectively. Median Tmax was 6.5 hours for both drugs. Nanocapsules had a mean size of 88nm and mean drug association of 92.5% and 89% for lidocaine and prilocaine, respectively. The PD study showed that Nanorap has a sufficient analgesic effect (>30% reduction in pain) after 10 minutes of application.CONCLUSIONS:: A new simple, selective and sensitive method for determination of lidocaine and prilocaine in human plasma was developed. Nanorap generated safe plasma levels of the drugs and satisfactory analgesic effect

Effects Of Testosterone Replacement On Electrocardiographic Parameters In Men: Findings From Two Randomized Trials

Context: Endogenous testosterone levels have been negatively associated with QTc interval in small case series; the effects of testosterone therapy on electrocardiographic parameters have not been evaluated in randomized trials. Objective: To evaluate the effects of testosterone replacement on corrected QT interval (QTcF) in two randomized controlled trials. Participants: Men with pre- and postrandomization electrocardiograms (ECGs) from the Testosterone and Pain (TAP) and the Testosterone Effects on Atherosclerosis in Aging Men (TEAAM) Trials. Interventions: Participants were randomized to either placebo or testosterone gel for 14 weeks (TAP) or 36 months (TEAAM). ECGs were performed at baseline and at the end of interventions in both trials; in the TEAAM trial ECGs were also obtained at 12 and 24 months. Outcomes: Difference in change in the QTcF between testosterone and placebo groups was assessed in each trial. Association of changes in testosterone levels with changes in QTcF was analyzed in men assigned to the testosterone group of each trial. Results: Mean total testosterone levels increased in the testosterone group of both trials. In the TAP trial, there was a nonsignificant reduction in mean QTcF in the testosterone group compared with placebo (effect size = -4.72 ms; P = 0.228) and the changes in QTcF were negatively associated to changes in circulating testosterone (P = 0.036). In the TEAAM trial, testosterone attenuated the age-related increase in QTcF seen in the placebo group (effect size = -6.30 ms; P < 0.001). Conclusion: Testosterone replacement attenuated the age-related increase in QTcF duration in men. The clinical implications of these findings require further investigation.WoSScopu