G. Di Girolamo

Dual effect of nitric oxide on uterine prostaglandin synthesis in a murine model of preterm labour

BACKGROUND AND PURPOSE Maternal infections are one of the main causes of adverse developmental outcomes including embryonic resorption and preterm labour. In this study a mouse model of inflammation‐associated preterm delivery was developed, and used to study the relationship between nitric oxide (NO) and prostaglandins (PGs).

Vitamin D3 seems more appropriate than D2 to sustain adequate levels of 25OHD: a pharmacokinetic approach

Background/Objectives:The superiority of cholecalciferol (D3) over ergocalciferol (D2) in sustaining serum 25-hydroxy vitamin D (25OHD) levels is controversial. To compare D2 with D3 we performed a single-blind, placebo-controlled randomized trial spanning 11 weeks.Subjects/Methods:Healthy volunteers (n=33, aged 33.4±6 years) were divided into three groups (n=11, each): D2, D3 and placebo. Treatment started with a loading dose (100 000 IU) followed by 4800 IU/day (d) between d7 and d20 and follow-up until d77. Serum samples were obtained at baseline and at days 3, 7, 14, 21, 35, 49, 63 and 77.Results:Baseline 25OHD values in the D2 group were lower than those in the D3 and placebo groups (P<0.01). Placebo 25OHD levels never changed. As after the loading dose both D2 and D3 groups had reached similar 25OHD levels, we tested equivalence of the area under the concentration × time curve (AUC) between d7 and d77. The AUC was 28.6% higher for D3 compared with D2, and both were higher with respect to placebo. At d77, D2 25OHD levels were higher than those at baseline, but similar to placebo; both were lower than D3 (P<0.04). According to raw data, the elimination half-life of 25OHD was 84 and 111 days under D2 and D3 supplementation, respectively; after subtracting the placebo values, the corresponding figures were 33 and 82 days.Conclusions:D2 and D3 were equally effective in elevating 25OHD levels after a loading dose. In the long term, D3 seems more appropriate for sustaining 25OHD, which could be relevant for classic and non-classic effects of vitamin D.

Effects of enoxaparin preparations on thrombin generation and their correlation with their anti-FXa activity.

Abstract Objective: Anticoagulant effect of LMWHs is monitored by anti-factor Xa (anti-FXa) activity assay. Since this test has several limitations, the aim of this study was to explore the activity of two LMWHs by thrombin generation assay (TG, which presents an overall picture of hemostatic balance) and its correlation with their anti-FXa activity. Methods: In an open-label, randomized cross-over study, 40 mg of two enoxaparins, the original branded formulation (R) and another one, also marketed in Argentina (T), were daily injected subcutaneously, for 7 days, to 20 healthy volunteers, with a 7-day washout interval. Blood samples were collected before treatment and 180 minutes after the injection on days 3 and 7. TG in platelet-poor plasma activated with tissue factor was assessed by lag time (LT), time to peak (TTP), peak (PTG), and endogenous thrombin potential (ETP). Anti-FXa and anti-FIIa activities, free tissue factor pathway inhibitor (free TFPI), tissue plasminogen activator (t-PA), plasminogen activator inhibitor type 1 (PAI-1), and euglobulin lysis time (ELT) were also assayed. Results: The mean (SD) anti-FXa (UI/ml) for T and R increased on days 3 and 7. LT and TTP were significantly prolonged by both LMWHs, with no differences between them. The mean ETP (nmol/L) for T and R at 3 and 7 days after treatment were significantly reduced when compared with basal values (p = 0.001 for all). On day 3, a significant correlation was shown between the variables describing TG and anti-FXa for T and R, without differences between them, for LT (r: 0.516 and 0486), ETP (r: 0.532 and 0.574), PEAK (r: 0.482 and 0.501), and TTP (r: 0.577 and 0.503), respectively. This correlation was also significant on day 7. Anti-FIIa activity and free TFPI increased significantly at 3 and 7 days for both LMWHs, without differences between them. R and T decreased ELT and PAI-1, but had no effect on t-PA. There were no differences between both LMWHs in routine hemostatic tests. No adverse events were reported. Conclusions: Correlation between TG and anti-FXa activity was good. Both enoxaparins induced similar change of coagulation parameters, with a significant increase in fibrinolytic activity.

Ex vivo effects of lysine clonixinate on cyclooxygenases in rat lung and stomach preparations

Abstract—Lysine clonixinate (LC) is an anti-inflammatory, anti-pyretic and analgesic drug with minor digestive side effects, which might suggest a weak COX-1 inhibitor. The aim of this study focused on ex vivo effects of LC 40 mg/kg ip and indomethacin (INDO) 10 mg/kg ip in lung and stomach preparations of control rats and LPS-treated rats (5 mg/kg ip). The non-steroidal antiinflammatory drugs were administered concomitantly, following three hours and before one, two or three hours of LPS treatment. Tissues were weighed and incubated in 2 ml of Kress Ringer Bicarbonate buffer containing glucose (11 mM) under an atmosphere of 95% oxygen and 5% CO2. Approximately 200 mg of tissue were used for each determination; 0.25 μCi of 14C-arachidonic acid was added to each tube and the tissues were incubated for 60 min. Prostanoids were extracted from the incubation medium and separated by TLC. Results were expressed as a percentage of the total radioactivity of the plates (% of cpm on plate/100 mg ww). It was found that LC animals that were not given LPS did not modify the synthesis of PGE2; in lung and stomach tissues showing that did not inhibit COX-1 activity. However, LC inhibited clearly the synthesis of PGE2 in both preparations obtained from LPS-treated animals. The inhibition was shown when the rats were treated concomitantly, 3 h after or 1 or 2 h before the injection of LPS.

Relative bioavailability of a 5 mg mosapride/10 mg rabeprazole fixed dose combination tablet versus separate single tablets in healthy volunteers: a single-dose randomized open-label crossover study

Abstract Objective: To evaluate the relative bioavailability of a new formulation containing 5 mg mosapride and 10 mg rabeprazole (T) and compare it with the branded formulations of both drugs co-administered in separate tablets (R) to meet the regulatory requirements of bioequivalence in Argentina. Methods: A randomized-sequence, open-label, two-period crossover study was conducted on 24 healthy Caucasian volunteers in a fasting state. A single oral dose of either T or R formulations was followed by a 7-day washout period. Blood samples for mosapride were collected before administration (baseline) and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 18, and 24 h after administration. Samples for rabeprazole were taken baseline and at 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8 and 10 h after dosing. Mosapride and rabeprazole concentrations were determined using a validated LC-MS/MS method. Adverse events were monitored based on clinical parameters and volunteer reports. Results: The geometric means (90% CI) Cmax for mosapride in T and R were 23.13 (20.05–39.45) and 23.09 (21.69–32.37) ng/mL, the AUC0–t were 70.80 (66.23–102.37) and 70.81 (66.35–93.26) ng h/mL and the AUC0–∞ were 74.05 (69.29–106.11) and 74.98 (70.43–97.77) ng h/mL. For rabeprazole T and R the Cmax were 197.42 (186.12–239.91) and 195.50 (186.08–250.07) ng/mL, the AUC0–t were 294.90 (275.13–374.15) and 296.96 (280.11–387.89) ng h/mL and the AUC0–∞ were 301.12 (280.78–380.82) and 304.07 (286.60–394.21), respectively. No differences were detected between the formulations. The T/R ratios (90% CI) for Cmax, AUC0–t and AUC0–∞ were 100.17% (82.35–121.84), 99.99% (87.58–114.16) and 98.77% (87.02–112.11) for mosapride, and 100.99% (85.14–119.77), 99.31% (84.74–116.38) and 99.03% (85.07–115.28) for rabeprazole. No subject complained of adverse events. Conclusions: In this single-dose study, the mosapride/rabeprazole tablets (test formulation) met the criterion for bioequivalence with the reference formulations. Study limitations include single-dose, open-label design, and a small sample of healthy volunteers.

Drug Induced — Hepatotoxicity

Drug Induced Hepatotoxicity is the most common cause of acute liver failure in developed countries. It represents approximately 10% of cases of acute liver failure worldwide and around the 40 50% of all cases of liver injury. The aim of this study is to expose the result about the incidence of drug induced hepatotoxicity obtained from a pharmacovigilance data base and which are the most frequently drugs associated. Study: To determinate the incidence of Drug induced hepatotoxicity was performed a retrospective study based on a pharmacovigilance data base from an Argentinian tertiary care hospital, Hospital General de Agudos Dr Cosme Argerich, During a five years’ period from June 2008 to February 2012. Results: From a pharmacovigilance base of 2993 Adverse Drug Reactions, we detected 428 events of drug induced hepatotoxicity, 14 of them were severe and two were lethal. The group of drugs most frequently associated were antibiotics, neuropsychiatric drugs and NSAIDs. Males were most frequently affected than women. Conclusions: Drug induced hepatotoxicity is the most frequently cause of acute liver failure in developed countries and one of the most frequent in developing countries and has been the leading cause of withdrawal of drugs from the market. It’s becoming a serious health problem that affects all the actors involved in the health system. The diagnosis and recognition are often difficult so the true incidence of this phenomenon is still unknown. In concordance with the international bibliography the most common association was seems with antibiotics and neuropsychiatric drugs.