An oral (gavage) control embryo-fetal development study in the Wistar Hannover rat

Many of the studies conducted to examine the developmental and reproductive toxicity potential of candidate pharmaceuticals use the Sprague-Dawley rat as the animal model. This is due in part to the large database for this outbred rat available for comparison of litter data, and the low incidence of fetal malformations and variations. The following study was conducted to generate information on potential embryo-fetal developmental defects and litter data in another outbred stock of rat, the Wistar Hannover. One hundred fifty pregnant female Wistar Hannover rats (Tac:Glx:WIfBR) were dosed orally once per day with distilled water from Gestation Days (GD) 6 through 17 covering the time from implantation to closure of the hard palate (GD0 = day of insemination). Caesarean sections were performed on Day 20 of gestation. All fetuses were examined for external, visceral and skeletal malformations and variations. Macroscopic and histomorphologic examinations were also completed for the F0 females at termination. The percent pregnant (88%) and litter size (average 10.6) were found to be lower than that commonly reported for the Sprague-Dawley rat (Crl:CD (SD)BR; 95.4% and 14.6, respectively). Pre-implantation loss (14.1%), post-implantation loss (7.4%) and percent resorptions (7.2%) occurred at a higher incidence than typically seen in the Sprague-Dawley rat (5.9, 5.6 and 5.1%, respectively). The average fetal body weights for both the female and male rats were lower than those typically seen in the Sprague-Dawley rat. External, visceral and skeletal examination of the F1 fetuses revealed numerous malformations and variations which also occurred at higher incidences than those reported for the Sprague-Dawley rat. Routine macroscopic and histomorphologic examination showed there were no changes that would be interpreted to have impaired mating performance, fertility or gestation. Thus, this study provides information on the reproductive effects and the background incidence of embryo-fetal development defects that could be used for comparison to those identified when using this outbred rat for developmental and reproductive toxicity studies, as well as for comparison to the more commonly used rat stock, the Sprague-Dawley rat. For the parameters evaluated, the Wistar Hannover rat had greater variability and an increased incidence of spontaneous malformations as compared to the Crl:CD (SD)BR Sprague-Dawley rat. These findings should be considered if this stock of rat is selected in the conduct of developmental and reproductive toxicity studies.     

Limited tolerability of levofloxacin and pyrazinamide for multidrug-resistant tuberculosis prophylaxis in a solid organ transplant population

STUDY OBJECTIVE: To determine the long-term tolerability of prophylactic administration of pyrazinamide and levofloxacin in patients possibly exposed to multidrug-resistant tuberculosis (MDRTB) after undergoing solid organ transplantation. DESIGN: Retrospective analysis. SETTING: Community outpatient clinic. PATIENTS: Forty-eight recipients of solid organ transplants beginning prophylaxis for MDRTB during August 1999 after possible exposure to a single index case of multidrug-resistant Mycobacterium tuberculosis within our community INTERVENTION: Prophylaxis consisted of pyrazinamide 30 mg/kg/day plus levofloxacin 500 mg/day, administered for 1 year. MEASUREMENTS AND MAIN RESULTS: Thirteen (27.1%) of the 48 patients completed therapy; 27 (56.3%) discontinued therapy within 4 months due to adverse drug events. Gastrointestinal intolerance was the major adverse event resulting in early discontinuation. CONCLUSION: Prophylaxis of MDRTB with levofloxacin and pyrazinamide was associated with limited tolerability due to the high frequency of adverse events. While we search for a better tolerated prophylactic regimen, close monitoring for adverse reactions is recommended.     

Antinociceptive action of captopril and transcutaneous electric nerve stimulation in Mus musculus mice

1. In the present study, the antinociceptive action of captopril was investigated, as well as its association with transcutaneous electric nerve stimulation (TENS), in mice under nociceptive stimulation. 2. The modulation of abdominal contortions (writhes) produced by acetic acid was observed in order to evaluate captopril pain stimuli blockade. 3. The administration of captopril produced a significant reduction of nociception, which was further reduced when captopril was associated with TENS. 4. Apparently this increase in the inhibition of nociception was produced by an indirect mechanism, involving opioid liberation by TENS and an enzymatic inhibition induced by captopril and this may lead to clinical applications of captopril and TENS association in pain relief.     

Didanosine extended-release matrix tablets: optimization of formulation variables using statistical experimental design

Statistical experimental design was applied to evaluate the influence of some process and formulation variables and possible interactions among such variables, on didanosine release from directly-compressed matrix tablets based on blends of two insoluble polymers, Eudragit RS-PM and Ethocel 100, with the final goal of drug release behavior optimization. The considered responses were the percent of drug released at three determined times, the dissolution efficiency at 6 h and the time to dissolve 10% of drug. Four independent variables were considered: tablet compression force, ratio between the polymers and their particle size, and drug content. The preliminary screening step, carried out by means of a 12-run asymmetric screening matrix according to a D-optimal design strategy, allowed evaluation of the effects of different levels of each variable. The drug content and the polymers ratio had the most important effect on drug release, which, moreover, was favored by greater polymers particle size; on the contrary the compression force did not have a significant effect. The Doehlert design was then applied for a response-surface study, in order to study in depth the effects of the most important variables. The desirability function was used to simultaneously optimize the five considered responses, each having a different target. This procedure allowed selection, in the studied experimental domain, of the best formulation conditions to optimize drug release rate. The experimental values obtained from the optimized formulation highly agreed with the predicted values. The results demonstrated the reliability of the model in the preparation of extended-release matrix tablets with predictable drug release profiles.     

Waterborne outbreak of Norwalk-like virus gastroenteritis at a tourist resort,Italy

In July 2000, an outbreak of gastroenteritis occurred at a tourist resort in the Gulf of Taranto in southern Italy. Illness in 344 people, 69 of whom were staff members, met the case definition. Norwalk-like virus (NLV) was found in 22 of 28 stool specimens tested. The source of illness was likely contaminated drinking water, as environmental inspection identified a breakdown in the resort water system and tap water samples were contaminated with fecal bacteria. Attack rates were increased (51.4%) in staff members involved in water sports. Relative risks were significant only for exposure to beach showers and consuming drinks with ice. Although Italy has no surveillance system for nonbacterial gastroenteritis, no outbreak caused by NLV has been described previously in the country.     

West Nile virus epidemic in horses,Tuscany region,Italy

During the late summer of 1998, veterinary authorities in Tuscany, Italy, received reports of cases of neurologic disease among horses residing in a large wetland area located in the provinces of Florence and Pistoia. West Nile virus was isolated from two of the six horses that died or were euthanized. A retrospective epidemiologic study identified 14 clinical neurologic cases that occurred from August 20 to October 6 (attack rate of 2.8%). A serologic survey conducted over a 700-km2 area in stables with and without apparent clinical cases confirmed a wider spread of the infection, with an overall seroprevalence rate of 38% in the affected area. No significant differences in age-specific prevalence were observed, suggesting that the horses residing in the area had not been exposed previously to West Nile virus and supporting the hypothesis of its introduction in the wetland area during the first half of 1998.     

International classification of functioning,disability and health (ICF) 2001

The approach which had been being employed to date for dealing with and classifying those aspects related to health and disability have been revised and updated thanks to the World Health Organization (WHO) having drafted the International Classification of Functioning, Disability and Health, which has now been accepted 191 countries after revamping the prior model and reaching a consensus regarding a new international model for describing and measuring health and disability. As background information, it must be recalled that the Classification of Impairments, Disabilities and Handicaps (CIDH) previously in effect was first published by the WHO in 1980. The process of revising this classification has resulted in some changes of far-reaching importance. The change in the name has been aimed at reflecting the wish to replace the negative perspective of impairments, disabilities and handicaps for a more neutral view of structure and function, considering the positive perspectives of activities and of participation. Another new aspect has been that of including a section related to environmental factors in recognition of their importance, given that by interacting with the health condition they may give rise to a disability, or, at the opposite end of the scale, may restore functioning. The data available has enabled the WHO make estimates including that of some 500 million years of life being lost annually due to disabilities related to health problems, which totals over one half of the years lost annually due to premature deaths. The main objective of this new classification is that of providing the conceptual framework by means of unified, standardized language with a view to of the underlying challenges, setting out a valuable instrument of practical use in public health.     

Different mechanism of LPS-induced vasodilation in resistance and conductance arteries from SHR and normotensive rats

1. The direct and endothelium-dependent effects of lipopolysaccharide (LPS) were investigated on resistance and conductance arteries from normotensive Wistar (NWR) and spontaneously hypertensive (SHR) rats. 2. In both NWR and SHR, LPS induced dose-dependent relaxations of the mesenteric vascular bed, which were inhibited by L-NNA in SHR but not in NWR. Iberiotoxin (IBTX) inhibited the responses to LPS in both groups, indicating the participation of high conductance Ca(2+)-dependent K(+) channels. 3. In mesenteric artery rings, the resting membrane potentials and the hyperpolarizing responses of NWR to LPS did not differ in endothelized and denuded preparations but L-NNA inhibited the responses only in endothelized rings. These responses were reduced by bosentan, suggesting that endothelin release may mask a possible hyperpolarizing response to LPS. The hyperpolarizing responses to LPS were blocked by IBTX in both endothelized and de-endothelized NWR rings. In the SHR only intact rings showed hyperpolarization to LPS, which was inhibited by IBTX and byL-NNA. 4. In SHR aortic endothelized or denuded rings, LPS induced hyperpolarizing responses which, in endothelized rings, were partially blocked by L-NNA, by IBTX or by glibenclamide, but totally abolished by IBTX plus glibenclamide. No response to LPS was observed in NWR aortic rings. 5. Our results indicate that LPS activates large conductance Ca(2+)-sensitive K(+) channels located in the smooth muscle cell membrane both directly and indirectly, through NO release from the endothelium in NWR, whereas NO is the major mediator of the LPS responses in SHR resistance vessels.     

Effects of levobupivacaine,ropivacaine and bupivacaine on HERG channels: stereoselective bupivacaine block

1 Levobupivacaine and ropivacaine are the pure S(-) enantiomers of N-butyl- and N-propyl-2',6'-pipecoloxylidide, developed as less cardiotoxic alternatives to bupivacaine. In the present study, we have analysed the effects of levobupivacaine, ropivacaine and bupivacaine on HERG channels stably expressed in CHO cells. 2 The three drugs blocked HERG channels in a concentration-, time- and state-dependent manner. Block measured at the end of 5 s pulses to -10 mV induced by 20 microM bupivacaine (52.7+/-2.0%, n=15) and ropivacaine (55.5+/-2.7%, n=13) was similar (P>0.05) and both lower than that induced by levobupivacaine (67.5+/-4.2%, n=11) (P<0.05). 3 Dextrobupivacaine (20 microM) was less potent (47.2+/-5.2%, n=10) than levobupivacaine (P<0.05), indicating stereoselective HERG channel block. 4. Block induced by the three local anaesthetics exhibited a steep voltage dependence in the range of channel activation. In all cases, block measured at the maximum peak current at a test potential of 0 mV after promoting recovery from inactivation (I-->O) was lower than that observed at the end of 5-s pulses (I+O). 5. Levobupivacaine, ropivacaine and bupivacaine accelerated HERG inactivation kinetics, slowed the recovery from inactivation and shifted the inactivation curve towards more negative membrane potentials. The three local anaesthetics induced a rapid time-dependent decline after using a protocol that quickly activates HERG channels. 6. All these results suggest that: (1) these drugs bind to the open and the inactivated states of HERG channels, (2) they stabilize HERG channels in the inactivated state, and (3) block induced by bupivacaine enantiomers is stereoselective.