Minimizing DILI risk in drug discovery - A screening tool for drug candidates.

Drug-induced liver injury (DILI) is a leading cause of acute hepatic failure and a major reason for market withdrawal of drugs. Idiosyncratic DILI is multifactorial, with unclear dose-dependency and poor predictability since the underlying patient-related susceptibilities are not sufficiently understood. Because of these limitations, a pharmaceutical research option would be to reduce the compound-related risk factors in the drug-discovery process. Here we describe the development and validation of a methodology for the assessment of DILI risk of drug candidates. As a training set, 81 marketed or withdrawn compounds with differing DILI rates - according to the FDA categorization - were tested in a combination of assays covering different mechanisms and endpoints contributing to human DILI. These include the generation of reactive metabolites (CYP3A4 time-dependent inhibition and glutathione adduct formation), inhibition of the human bile salt export pump (BSEP), mitochondrial toxicity and cytotoxicity (fibroblasts and human hepatocytes). Different approaches for dose- and exposure-based calibrations were assessed and the same parameters applied to a test set of 39 different compounds. We achieved a similar performance to the training set with an overall accuracy of 79% correctly predicted, a sensitivity of 76% and a specificity of 82%. This test system may be applied in a prospective manner to reduce the risk of idiosyncratic DILI of drug candidates.

High volume local infiltration analgesia compared to peripheral nerve block for hip and knee arthroplasty-what is the evidence?

Since being reported in 2008, high volume local infiltration analgesia (HVLIA) has rapidly gained popularity for patients undergoing hip and knee replacement. We undertook this review to investigate whether there was evidence for equivalence of HVLIA compared to peripheral nerve block techniques with respect to early postoperative analgesia and functional recovery, or for other outcomes such as cost and process efficiency, persistent postsurgical pain and arthroplasty revision rate. We found that despite the popularity of HVLIA, supporting evidence for its use is currently limited. HVLIA certainly provides postoperative analgesia, but it is not clear whether it is equivalent to contemporary peripheral nerve block techniques in terms of either analgesia or early or later functional outcome in the context of a modern, comprehensive enhanced recovery program. Nor is it possible to state whether HVLIA provides benefits in terms of persistent postsurgical pain or cost and process efficiency. Well designed trials directly comparing peripheral nerve block with a standardised HVLIA technique are urgently required.

Comparison of two intracranial self-stimulation (ICSS) paradigms in C57BL/6 mice: head-dipping and place-learning.

A variety of intracranial self-stimulation (ICSS) paradigms have been utilized for investigations of reward. Among them, nose-poking and spatial-preference paradigms are known to be relatively more resistant to the effects of drug-induced motor-deficits in rat studies, although these two ICSS paradigms have not been directly compared in previous studies. In the present study, head-dipping and place-learning (forms of nose-poking and spatial-preference tasks, respectively) paradigms with lateral hypothalamus stimulation were systematically analyzed using C57BL/6 mice in the presence and absence of two motor-deficit-inducing drugs: tolperisone and harmaline. Rapid acquisition and rapid extinction patterns of ICSS responding were observed in the head-dipping and place-learning paradigms. In contrast to these pre-drug similarities in responding, dramatic differences were noted after drug administration. Tolperisone significantly reduced head-dipping but not place-learning ICSS responding. Similarly, reduction of ICSS responding after harmaline was more pronounced in the head-dipping task. Therefore, the place-learning paradigm may be superior for the assessment of reward values under motor-deficit-inducing conditions in C57BL/6 mice. The relative benefits and disadvantages of both ICSS paradigms are discussed. Combinations of complementary ICSS paradigms using mice may be useful for further investigations of the molecular bases of reward.

An outbreak of hepatitis A associated with green onions.

Forty-three cases of serologically confirmed hepatitis A occurred among individuals who ate at restaurant A in Ohio in 1998. Serum samples from all restaurant A employees who worked during the exposure period were negative for IgM antibodies to hepatitis A virus (HAV). A matched case-control study determined that foods containing green onions, which were eaten by 38 (95%) of 40 case patients compared with 30 (50%) of 60 control subjects, were associated with illness (matched odds ratio, 12.7; 95% confidence interval, 2.6-60.8). Genetic sequences of viral isolates from 14 case patients were identical to each other and to those of viral isolates from 3 patients with cases of hepatitis A acquired in Mexico. Although the implicated green onions, which could have come from one of 2 Mexican farms or from a Californian farm, were widely distributed, no additional green onion-associated cases were detected. More sensitive methods are needed to detect foodborne hepatitis A. A better understanding of how HAV might contaminate raw produce would aid in developing prevention strategies.

Levels and trends of PCBs, chlorinated pesticides and petroleum hydrocarbons in mussels from the NW Mediterranean coast: comparison of concentrations in 1973/1974 and 1988/1989.

A mussel watch survey was conducted in 1988-1989 along the Mediterranean coast of France and Italy, between Sete and Genoa, in order to assess contamination by organochlorine pesticides, PCBs and petroleum hydrocarbons. Results show concentrations of DDTs (average 130 ng g-1 dry wt.) and PCBs (average 527 ng g-1 dry wt.) higher in coastal areas receiving river discharges and close to large cities. Concentrations of total aliphatics (average 470 micrograms g-1 dry wt.) and PAHs (average 233 micrograms g-1 dry wt.) were generally higher also near large harbours, namely Marseille, Toulon and Genoa. PAHs in mussel samples from Genoa and Monaco were mostly of pyrolytic sources, likely forest fires and exhaust gases from cars, whereas PAHs in other stations were mainly of petrogenic sources. Comparison of chlorinated hydrocarbon concentrations measured in 1988-1989 with those measured in a similar survey carried out at the same sites in 1973-1974, shows that DDTs and PCBs decreased by a factor of approximately 5 in 15 years. This decrease is in agreement with the ban on DDT implemented in 1975 in western Europe and gradual cessation of PCBs production in the 1970s and 1980s. Nevertheless, the residues of these compounds measured in mussels confirm the well-known long persistence of DDTs and PCBs, which are still present in relatively high concentrations in a few areas.

Oral famciclovir for suppression of recurrent genital herpes simplex virus infection in women. A multicenter, double-blind, placebo-controlled trial. Collaborative Famciclovir Genital Herpes Research Group.

OBJECTIVE: To evaluate the efficacy and safety of oral famciclovir in the suppression of genital herpes. METHODS: In this randomized, double-blind, placebo-controlled trial that was performed at 11 university and 9 private ambulatory care referral centers, 375 women who were 18 years of age or older and had a history of 6 or more episodes of genital herpes during 12 of the last 24 months in the absence of suppressive therapy were treated for 4 months with oral famciclovir, 125 mg once daily or twice daily, 250 mg once daily or twice daily, 500 mg once daily, or placebo. The primary outcome measures included the time to first clinically and virologically confirmed recurrences, and safety as measured by clinical laboratory tests and adverse experiences. RESULTS: The median time to first recurrence was 82 days in the placebo group, 114 days in those receiving famciclovir, 125 mg once daily, and more than 120 days in the other treatment groups. When compared with placebo recipients, the time to the first clinical recurrence was significantly prolonged in subjects who received famciclovir, 125 mg twice daily (hazard ratio, 1.8; 95% confidence interval, 1.0-3.0; P = .03), and in those who received famciclovir, 250 mg twice daily (hazard ratio, 3.6; 95% confidence interval, 1.9-6.9; P < .001). Treatment was well tolerated, and there was no evidence of emergence of resistance during or after suppressive famciclovir therapy. CONCLUSIONS: Oral famciclovir, 250 mg, given twice daily for 4 months is an effective, well-tolerated treatment for the suppression of genital herpes in women with frequent recurrences, but single daily doses produced less complete suppression of genital herpes.

Monomeric human cathepsin E.

Cathepsin E is a homodimer, consisting of two monomers linked by an inter-molecular disulphide bond. The cysteine residue involved is located near to the N-terminus of the mature proteinase. By mutating this residue to alanine, a monomeric form of human cathepsin E was engineered and purified. The activity of the resultant enzyme was not altered significantly (in terms of its ability to hydrolyse two chromogenic peptide substrates; and its susceptibility to inhibition by pepstatin). However, the stability of the mutant enzyme to alkaline pH and to temperature was markedly reduced.

Effects of alternative control procedures for electromyographic biofeedback relaxation training.

Twenty-four college students participated in a single session of electromyographic (EMG) biofeedback in a comparison of three experimental control procedures commonly employed in biofeedback relaxation training research. One group received contingent EMG biofeedback from the forehead area, and each subject in this group served as his or her own control. Subjects in a second group received noncontingent EMG feedback from a tape recorder but were instructed to use the feedback signal to relax their forehead muscles (single blind). Subjects in a third group received the same auditory feedback as those in the second group but were not told the purpose or source of the feedback stimulus (yoked control). The contingent feedback group showed significantly less EMG activity when compared to the other two groups. However, this group did not exhibit significant EMG level decrements from the beginning to end of the session. This seemingly contradictory finding may have been due to statistically capitalizing on the artifactually high EMG level of the experimental and control groups, although the single-blind and yoked-control groups showed nonsignificant increases across the session. The single-blind group's data had a variance several times larger than the other two groups' variance. Findings are discussed with respect to a "probing" hypothesis as opposed to the previously offered frustration hypothesis. Of the three control procedures, the data suggest the yoked control as the procedure of choice for EMG biofeedback relaxation research.