Structure-activity relationship of biaryl acylsulfonamide analogues on the human EP(3) prostanoid receptor.

Potent and selective ligands for the human EP3 prostanoid receptor are described. Biaryl compounds bearing a tethered ortho substituted acidic moiety were identified as potent EP3 antagonists based on the SAR described herein. The binding affinity of key compounds on all eight human prostanoid receptors is reported.

Assessing the emetic potential of PDE4 inhibitors in rats.

1. Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha(2)-adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine/ketamine-induced anaesthesia. We further characterized this latter effect since it appears to reflect the emetic potential of PDE4 inhibitors. 2. Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10 mg kg(-1), i.m.) and ketamine (10 mg kg(-1), i.m.). PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline) - PDE4 inhibitor: 0.01 - 3 mg kg(-1)), like MK-912 (alpha(2)-adrenoceptor antagonist: 0.01 - 3 mg kg(-1)), dose-dependently reduced the duration of anaesthesia. In contrast, vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor), milrinone (PDE3 inhibitor) and zaprinast (PDE5 inhibitor) had no significant effect at the doses tested (1 - 10 mg kg(-1)). Analysis of plasma and cerebrospinal fluid (CSF) of treated animals confirmed the absorption and distribution to the brain of the inactive inhibitors. 3. Neither MK-912 (3 mg kg(-1)) nor PMNPQ (0.1 - 1 mg kg(-1)) altered the duration of anaesthesia induced via a non-alpha(2)-adrenoceptor pathway (sodium pentobarbitone 50 mg kg(-1), i.p.). 4. Central NK(1) receptors are involved in PDE4 inhibitor-induced emesis. Consistently, [sar(9), Met(O(2))(11)]-substance P (NK(1) receptor agonist, 6 microg i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine. 5. In summary, this model is functionally coupled to PDE4, specific to alpha(2)-adrenoceptors and relevant to PDE4 inhibitor-induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats.

Prostaglandin receptor EP(4) mediates the bone anabolic effects of PGE(2).

Prostaglandin (PG) E(2) is a potent inducer of cortical and trabecular bone formation in humans and animals. Although the bone anabolic action of PGE(2) is well documented, the cellular and molecular mechanisms that mediate this effect remain unclear. This study was undertaken to examine the effect of pharmacological inactivation of the prostanoid receptor EP(4), one of the PGE(2) receptors, on PGE(2)-induced bone formation in vivo. We first determined the ability of EP(4)A, an EP(4)-selective ligand, to act as an antagonist. PGE(2) increases intracellular cAMP and suppresses apoptosis in the RP-1 periosteal cell line. Both effects were reversed by EP(4)A, suggesting that EP(4)A acts as an EP(4) antagonist in the cells at concentrations consistent with its in vitro binding to EP(4). We then examined the effect of EP(4) on bone formation induced by PGE(2) in young rats. Five- to 6-week-old rats were treated with PGE(2) (6 mg/kg/day) in the presence or absence of EP(4)A (10 mg/kg/day) for 12 days. We found that treatment with EP(4)A suppresses the increase in trabecular bone volume induced by PGE(2). This effect is accompanied by a suppression of bone formation indices: serum osteocalcin, extent of labeled surface, and extent of trabecular number, suggesting that the reduction in bone volume is due most likely to decreased bone formation. The pharmacological evidence presented here provides strong support for the hypothesis that the bone anabolic effect of PGE(2) in rats is mediated by the EP(4) receptor.

Sex-specific determinants of HIV infection among injection drug users in Montreal.

BACKGROUND: Sex-specific issues have not been extensively addressed in studies of HIV prevalence, despite the strong implications of differences between men and women in the risk of HIV transmission. The objective of this study was to examine sex-specific behaviours associated with HIV infection among injection drug users in Montreal. METHODS: A total of 2741 active drug users (2209 [80.6%] men) were recruited between 1988 and 1998. Information was sought on sociodemographic characteristics, drug-related behaviour and sexual behaviour, and participants were tested for HIV antibodies. Sex-specific independent predictors of HIV prevalence were assessed by stepwise logistic regression. RESULTS: The overall prevalence of HIV among study subjects was 11.1%; the prevalence was 12.0% among men and 7.5% among women. In multivariate models, a history of sharing syringes with a known seropositive partner (odds ratio [OR] for men 2.44, 95% confidence interval [CI] 1.72-3.46; OR for women 3.03, 95% CI 1.29-7.13) and of sharing syringes in the past 6 months (OR for men 0.61, 95% CI 0.44-0.85; OR for women 0.32, 95% CI 0.14-0.73) were independently associated with HIV infection. Other variables associated with HIV infection were homosexual or bisexual orientation, cocaine rather than heroin as drug of choice, frequency of injection drug use, and obtaining needles at a pharmacy or through needle exchange programs (for men only) and obtaining needles at shooting galleries and being out of treatment (for women only). INTERPRETATION: These results support the hypothesis that risk factors for HIV seropositivity differ between men and women. These sex-related differences should be taken into account in the development of preventive and clinical interventions.

Clindamycin resistance in the Bacteroides fragilis group: association with hospital-acquired infections.

A retrospective study was conducted to assess the relationships between clindamycin resistance in members of the Bacteroides fragilis group, previous antimicrobial therapy, and the context for the development of infection, whether in the community or during hospitalization. Eighty-five clindamycin-resistant clinical strains (one isolate per patient) isolated from January 1988 to October 1994 were matched (one to one) with clindamycin-susceptible isolates recovered during the same period, and the charts of the patients from whom the isolates were recovered were reviewed retrospectively. Of the clindamycin-resistant strains, 65% were recovered from patients with hospital-acquired infections compared with 40% of the clindamycin-susceptible strains (odds ratio [OR], 2.75; 95% confidence interval [CI], 1.41-5.38; P = .002). Prior antimicrobial therapy for > or = 48 hours was also associated with clindamycin resistance (OR, 2.33; 95% CI, 1.16-4.70; P = .02). However, clindamycin resistance remained associated with hospital-acquired infections independent of prior antimicrobial therapy (Mantel-Haenszel weighted average OR, 2.22; 95% CI, 1.03-4.89; P = .04). Clinicians should consider the risks for clindamycin resistance when treating hospital-acquired infections caused by members of the B. fragilis group.

High rates of HIV infection among injection drug users participating in needle exchange programs in Montreal: results of a cohort study.

Needle exchange programs (NEPs) are designed to prevent human immunodeficiency virus (HIV) transmission among injection drug users. Although most studies report beneficial effects in terms of behavior modification, a direct assessment of the effectiveness of NEPs in preventing HIV infection has been lacking. A cohort study was conducted to assess the association between risk behaviors and HIV seroprevalence and seroincidence among injection drug users in Montreal, Canada. The association between NEP use and HIV infection was examined in three risk assessment scenarios using intensive covariate adjustment for empirical confounders: a cross-sectional analysis of NEP use at entry as a determinant of seroprevalence, a cohort analysis of NEP use at entry as a predictor of subsequent seroconversion, and a nested case-control analysis of NEP participation during follow-up as a predictor of seroconversion. From September 1988 to January 1995, 1,599 subjects were enrolled with a baseline seroprevalence of 10.7%. The mean follow-up period was 21.7 months. The adjusted odds ratio for HIV seroprevalence in injection drug users reporting recent NEP use was 2.2 (95% confidence interval 1.5-3.2). In the cohort study, there were 89 incident cases of HIV infection with a cumulative probability of HIV seroconversion of 33% for NEP users and 13% for nonusers (p < 0.0001). In the nested case-control study, consistent NEP use was associated with HIV seroconversion during follow-up (odds ratio = 10.5, 95% confidence interval 2.7-41.0). Risk elevations for HIV infection associated with NEP attendance were substantial and consistent in all three risk assessment scenarios in our cohort of injection drug users, despite extensive adjustment for confounders. In summary, in Montreal, NEP users appear to have higher seroconversion rates then NEP nonusers.

Illicit use of methadone among i.v. drug users in Montreal.

Few studies have been done on the prevalence of illicit methadone use. Five hundred fifty-nine IV drug users recruited in various ways in Montreal were interviewed concerning their drug use as part of a longitudinal study on HIV infection. Of this number, 133 had heroin as their drug of preference and 426 cocaine. Among the cocaine group, 202 also used heroin. The lifetime prevalence of any illicit methadone use was 59.4% in the heroin group, 26.7% in the cocaine/heroin group, and 3.6% in the cocaine-only group. The 6-month (preceding the interview) prevalence of any illicit use was 42.1%, 6.9%, and 1.3%, respectively, and the prevalence of at least weekly illicit use during that period was 6.3%, 2.0%, and 0%, respectively. The prevalence of illicit methadone use is significant in the population studied. Whether this level of use will be affected by more stringent control on methadone prescription and dispensation remains to be demonstrated.

Susceptibilities of beta-lactamase-positive and -negative strains of Campylobacter coli to beta-lactam agents.

The percentages of susceptibility of 28 strains of Campylobacter coli to beta-lactam agents were 96% for amoxicillin and ampicillin, 57% for ticarcillin, 4% for cefoxitin and cefuroxime, 61% for cefotaxime, and 11% for ceftazidime. None of the strains were susceptible to penicillin G, piperacillin, cefazolin, cephalothin, cefamandole, and cefoperazone. All strains were susceptible to imipenem and ciprofloxacin, and 21% were susceptible to erythromycin. A beta-lactamase was detected in 68% of the strains by cefinase disks and by the nitrocefin method. The beta-lactamase-positive strains were significantly less susceptible to amoxicillin, ampicillin, and ticarcillin than the beta-lactamase-negative strains (P < or = 0.003). Clavulanic acid (0.25 microgram/ml) but not sulbactam and tazobactam (2 micrograms/ml) lowered to susceptible levels the amoxicillin and ampicillin MICs of the only strain of C. coli resistant to amoxicillin, ampicillin, and ticarcillin.

Role of the beta-lactamase of Campylobacter jejuni in resistance to beta-lactam agents.

We studied the role of the beta-lactamase of Campylobacter jejuni in resistance to beta-lactam agents. beta-Lactamase-positive strains were more resistant than beta-lactamase-negative strains to amoxicillin, ampicillin, and ticarcillin (P less than 0.05). With penicillin G, piperacillin, imipenem, and six cephalosporins, the susceptibility levels were similar for both beta-lactamase-positive and -negative strains. By using spectrophotometric and microbiological assays, the beta-lactamase from three strains hydrolyzed ampicillin, amoxicillin, penicillin G, cloxacillin, and, partially, cephalothin. Ticarcillin and piperacillin were partially hydrolyzed in the microbiological assay. There was no activity against five other cephalosporins or imipenem. Isoelectric focusing of the enzyme showed a pI of 8.8. Tazobactam was the best inhibitor of the enzyme, followed by clavulanic acid, sulbactam, and cefoxitin, while EDTA and p-chloromercuribenzoate had no activity. All beta-lactamase-positive strains became susceptible to amoxicillin and ampicillin with 1 micrograms of clavulanic acid per ml. With the same inhibitor, there was a reduced but significant effect for ticarcillin but no effect for penicillin G or piperacillin. Sulbactam had no effect and tazobactam was effective only at 2 micrograms/ml on amoxicillin and ampicillin. The beta-lactamase of C. jejuni seems to be a penicillinase with a role in resistance for only amoxicillin, ampicillin, and ticarcillin.

Ecological validity of laboratory studies of videopoker gaming.

This study compared the cognitive and behavioral components of videopoker players under laboratory and natural settings. Twenty regular gamblers (19 men and 1 woman) were matched into two groups on age and on frequency of gambling. Irrational verbalizations during gambling, monetary risk (number of bets doubled and number of tokens bet), and motivation served as dependent variables. Results showed no significant differences between laboratory and natural settings for the number of inadequate verbalizations, bets doubled, and motivation. The amount of money gambled was greater in the laboratory than in the natural setting. The practical and theoretical implications of these results are discussed according to the ecological validity of gambling studies conducted in laboratory settings.