Dipeptidyl peptidase-4 inhibitors administered in combination with metformin result in an additive increase in the plasma concentration of active GLP-1.

The aim of the study was to investigate the effects of a dipeptidyl peptidase-4 (DPP-4) inhibitor, of metformin, and of the combination of the two agents, on incretin hormone concentrations. Active and inactive (or total) incretin plasma concentrations, plasma DPP-4 activity, and preproglucagon (GCG) gene expression were determined after administration of each agent alone or in combination to mice with diet-induced obesity (DIO) and to healthy human subjects. In mice, metformin increased Gcg expression in the large intestine and elevated the plasma concentrations of inactive glucagon-like peptide 1 (GLP-1) (9-36) and glucagon. In healthy subjects, a DPP-4 inhibitor elevated both active GLP-1 and glucose dependent insulinotropic polypeptide (GIP), metformin increased total GLP-1 (but not GIP), and the combination resulted in additive increases in active GLP-1 plasma concentrations. Metformin did not inhibit plasma DPP-4 activity either in vitro or in vivo. The study results show that metformin is not a DPP-4 inhibitor but rather enhances precursor GCG expression in the large intestine, resulting in increased total GLP-1 concentrations. DPP-4 inhibitors and metformin have complementary mechanisms of action and additive effects with respect to increasing the concentrations of active GLP-1 in plasma.

Pharmacokinetics, pharmacodynamics, and safety of a prostaglandin D2 receptor antagonist.

Laropiprant is a selective antagonist of the prostaglandin D(2) (PGD(2)) receptor subtype 1 (DP1). Three double-blind, randomized, placebo-controlled studies evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple oral doses of laropiprant in healthy male volunteers. Single doses up to 900 mg and multiple doses up to 450 mg were generally well tolerated. Laropiprant exhibited dose-proportional pharmacokinetics. Oral absorption is rapid (T(max)=0.8-2.0 h) and the terminal half-life is approximately 12-18 h. The pharmacokinetics of laropiprant was not affected by food. Single doses of 6 mg and higher were effective in suppressing PGD(2)-induced cyclic AMP accumulation in platelets, demonstrating laropiprant target engagement with DP1. Laropiprant has detectable off-target antagonist effects at the thromboxane A(2) receptor but no clinically significant effect on collagen-induced platelet aggregation or bleeding times with multiple doses up to 200 mg.

Exploring the relationship between cultural values, beliefs, and practices and patient falls: a Middle Eastern study.

Patient falls have been a concern in North American healthcare for many years. Studies have examined environmental, clinical, and patient variables for purposes of risk identification and fall reduction, primarily in the context of Western societies. An investigation at King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia, began in 1993 to determine whether commonly reported risk factors apply to the Saudi patient population and whether cultural values, beliefs, and practices such as the performance of ablution before prayer, fasting during the holy month of Ramadan, and the need for socialization influence the rate of patient falls. The study included all inpatients (N = 379) who fell during a 3-year period.

Sydney Anglicans and homosexuality.

The city of Sydney in Australia has one of the largest gay and lesbian communities in the English-speaking world, while the Anglican Church in Sydney is proud of its reputation as a strong-hold and guardian of conservative evangelicalism. Since the early 1970s the Anglican diocese, in its official statements and pastoral policies, has been strongly opposed to homosexuality and the organized gay movement. In 1973 a report on homosexuality by its Ethics and Social Questions Committee was unusual at the time because it recommended the continuance of legal sanctions against male homosexual behavior. There have been many confrontations between Anglican institutions and Sydney's increasingly confident gay community. This paper examines these tensions, the reasons for the stance of the diocese, and the responses of gay Christian groups such as Cross+Section and AngGays.

Massage for the seriously mentally ill.

1. Some seriously mentally ill clients have unfulfilled needs for safe touch. 2. Flashbacks or provocative behavior have not been triggered by the use of massage in a structured setting. 3. The blending psychiatric skills and therapeutic massage can be an effective stress reducer for inpatients or outpatients who seek safe touch.

The effect of MK-0591, a novel 5-lipoxygenase activating protein inhibitor, on leukotriene biosynthesis and allergen-induced airway responses in asthmatic subjects in vivo.

BACKGROUND: The 5-lipoxygenase metabolites of arachidonic acid are likely to be involved in the pathophysiology of atopic asthma. We investigated the effect of pretreatment with MK-0591, a novel 5-lipoxygenase activating protein inhibitor, on allergen-induced early asthmatic reactions (EARs) and late asthmatic reactions (LARs), and subsequent airway hyperresponsiveness to histamine. METHODS: Eight atopic men with mild to moderate asthma aged 19 to 31 years, (forced expiratory volume in 1 second [FEV1] > or = 67% of predicted value, histamine provocative concentration causing a 20% fall in FEV1 [PC20] < 4 mg/ml) and documented EAR and LAR to house dust mite extract participated in a two-period, double-blind, placebo-controlled, crossover study. During each study period histamine PC20 was measured 2 days before and 1 day after a standardized allergen inhalation challenge test. MK-0591 was administered in 3 oral doses of 250 mg each at 24, 12, and 1.5 hours before inhalation of allergen. Biochemical activity of MK-0591 was determined by calcium ionophore A-23187-stimulated leukotriene (LT)B4 biosynthesis in whole blood ex vivo and by urinary LTE4 excretion. Airway response to allergen was measured by FEV1 (percent fall from baseline). The EAR (0 to 3 hours) and the LAR (3 to 8 hours) were expressed as corresponding areas under the time-response curves. RESULTS: MK-0591 and placebo did not differ in their effects on prechallenge FEV1 (p = 0.10). As compared with the value before pretreatment, MK-0591 blocked LTB4 biosynthesis and LTE4 excretion by a mean of 98% (range, 96% to 99%; p < 0.002) and 87% (range, 84% to 96%; p < 0.046), respectively, from 0 to 24 hours after allergen challenge. Both the EAR and the LAR were significantly reduced after administration of MK-0591 as compared with placebo, with a mean inhibition of 79% (p = 0.011) and 39% (p = 0.040), respectively. Allergen-induced airway hyperresponsiveness was not significantly different between the two pretreatment periods (p = 0.37). CONCLUSIONS: In this study oral MK-0591 prevented leukotriene biosynthesis after allergen challenge in patients with mild to moderate asthma. The results of our study indicate that 5-lipoxygenase products play an important role during the EAR, whereas their contribution to the pathophysiology of the LAR seems to be of less importance.

Redundant clothing: a readily observable marker for schizophrenia in the psychiatric emergency room population.

Most mental health workers have seen bizarrely dressed patients who wear multiple pieces of some item of clothing. Since many of these patients carried a schizophrenic diagnosis, we devised a study to test whether redundant clothing is a reliable indicator of schizophrenia. Of 25 patients who presented at the city psychiatric emergency room wearing redundant clothes, 18 received schizophrenic diagnoses. A Chi square analysis comparing proportions attained significance at the P < .0001 level. Although not a particularly sensitive measure, wearing redundant clothes appears to be a readily observable behavior associated with schizophrenia in the psychiatric emergency room.

Chemotherapy of non-small cell lung carcinoma guided by an in vitro drug resistance assay measuring total tumour cell kill.

Specimens from 45 patients with previously-untreated non-small cell lung cancer (NSCLC) were tested for in vitro chemosensitivity to ten drugs utilising the DiSC assay, which measures cell kill in the total (largely non-dividing) tumour cell population. Thirty-five assays were successful and 25 patients with advanced disease subsequently received chemotherapy with the 'best' three drugs selected by the assay. Six patients were Karnofsky performance status 60 or less and the median pretreatment weight loss was 8.5%. Nine patients had a partial response (response rate = 36%; 95% confidence interval = 17-55%) and the median survival of all patients was 202 days. Specimens from responding patients were significantly more sensitive in the assay to drugs in general (especially to etoposide and to 'natural product' drugs) and to the drugs used in treatment than were specimens from non-responding patients. In vitro drug resistance differences between responding and non-responding patients were of greater significance than were differences between other clinical and laboratory measurements. Assay results classified patients into two cohorts, having relatively high and low probabilities of responding to chemotherapy. Assay results also identified patient cohorts with above average and below average durations of survival. Five patients (20%) were found to have tumours with extreme drug resistance (EDR), defined as assay results for the average of all ten tested drugs falling greater than one standard deviation more resistant than the median for all tumours assayed, and none of these patients with EDR responded to chemotherapy.

Randomized trial of the addition of cis-platin (DDP) and/or BCG to cyclophosphamide (CTX) chemotherapy for ovarian carcinoma.

A prospective randomized trial has compared cyclophosphamide (CTX) with CTX plus cis-diamminodichloroplatinum (DDP) as the initial chemotherapy for advanced ovarian carcinoma. A secondary randomization compared the addition of BCG treatment to either chemotherapy. The addition of DDP had no measurable impact on survival, but a small survival trend favoring BCG-treated patients was noted (P less than 0.08). Toxicity from BCG treatment was insignificant, but the addition of DDP increased both early nausea and vomiting and later hematologic toxicity. There were three long-term complete remission patients, and these all came from the group of six patients with pretreatment residual disease less than 2 cm. A univariate analysis of pretreatment prognostic factors indicated significantly better prognosis (P less than 0.02) for patients with no palpable tumor, platelet count less than 400,000/mm3, residual tumor less than 2 cm, resting pulse less than 91/min. and LDH less than 250 U/L. The authors conclude that for patients with large (greater than 2 cm) residual disease, there is no compelling evidence that initial combination therapy is superior to aggressive single alkylating agent treatment.

Adjuvant methotrexate escalated to toxicity for resectable stage III and IV squamous head and neck carcinomas--a prospective, randomized study.

To determine if adjuvant methotrexate (MTX), escalated weekly to toxicity, could improve disease-free survival (DFS) and overall survival by preventing recurrent disease, 60 patients with potentially resectable stage III or IV squamous head and neck carcinomas were stratified by primary site, stage, and nutritional status, then randomized by pairs to receive or not receive adjuvant MTX. All received standard surgery and postoperative radiation therapy. Five patients were taken off study because of unresectability at the time of surgery, leaving 55 evaluable patients. There were no statistically significant imbalances in known prognostic factors between the two treatment arms. MTX was begun at 40 mg/m2 and escalated 10 mg/m2 weekly (four doses preoperatively; four doses postoperatively, preradiation therapy; eight doses postradiation therapy) to mucosal or hematologic toxicity. The median peak MTX dose achieved was 80 mg/m2. Although three patients were hospitalized with MTX toxicity, none died of MTX toxicity. No patient receiving MTX had disease progression during treatment, and there was no increase in postoperative complications. Thirty-two patients died (median survival, 19 months); 23 patients are alive with median follow-up of 43 months. There was no statistically significant difference in actuarial DFS (P = 1.0) or overall survival (P = .61). Although patients on the MTX arm appeared to have less local and regional recurrences at first recurrence (thus more distant metastases), this did not reach statistical significance (P = .06). There was no significant difference between the sites of recurrence at death or last follow-up (P = .38).

Tamoxifen response following no response to orchiectomy in metastatic male breast cancer: a case report.

A male patient with advanced breast cancer had no response to orchiectomy but subsequently enjoyed a 17-month partial response to tamoxifen 10 mg B.I.D. His tumor estrogen receptor (ER) protein was 555 fmol protein/ml cytosol. The potential role of ER determinations in the selection of therapy for advanced male breast cancer is discussed.

Unplanned pregnancies in a midwestern community.

Despite widespread birth control availability and increasing emphasis on sex education, a large proportion of childbearing continues to be unplanned. Using an anonymous questionnaire, unplanned pregnancies were studied in Cedar Rapids, Iowa. Of 1,002 women who completed questionnaires, 56 percent had had one or more unplanned pregnancies, and 44 percent of all pregnancies were found to be unplanned. This study confirms the findings of other studies which have shown a similar proportion of unplanned pregnancies. More unplanned pregnancies occur in the younger, lower socioeconomic population. Women generally consider their lives unchanged or improved because of these unplanned births. However, unhealthy aspects of some unplanned pregnancies include self-blame and negative feelings toward both the father and baby. Furthermore, a considerable number of young women lack adequate birth control knowledge, and they desire more family planning information from their physicians.

Documentation of change in problem behaviors among anxious and hostile-aggressive children enrolled in a therapeutic preschool program.

A relatively simple, straightforward procedure is utilized to identify and document changes in problem behaviors among children enrolled in a therapeutic preschool program. Results of two outcome measures indicated a significant overall reduction in problem behaviors for the total group. When subgroups of anxious and hostile/aggressive children were considered, however, there was a significantly greater probability that anxious children would benefit more from the program than hostile/aggressive children. The need to consider subgroups of patients when documented treatment effectiveness is emphasized, and the advantage of building documentation techniques into the record-keeping system is discussed.