Metabolic disposition of 14C-bromfenac in healthy male volunteers

The metabolic disposition of 14C-bromfenac, an orally active, potent, nonsteroidal, nonnarcotic, analgesic agent was investigated in six healthy male subjects after a single oral 50-mg dose. The absorption of radioactivity was rapid, producing a mean maximum plasma concentration (Cmax) of 4.9 +/- 1.8 microg x equiv/mL, which was reached 1.0 +/- 0.5 hours after administration. Unchanged drug was the major component found in plasma, and no major metabolites were detected in the plasma. Total radioactivity recovered over a 4-day period from four of the six subjects averaged 82.5% and 13.2% of the dose in the urine and feces, respectively. Excretion into urine was rapid; most of the radioactivity was excreted during the first 8 hours. Five radioactive chromatographic peaks, a cyclic amide and four polar metabolites, were detected in 0- to 24-hour urine samples. Similarity of metabolite profiles between humans and cynomolgus monkeys permitted use of this animal model to generate samples after a high dose for structure elucidation. Liquid chromatography/mass spectrometry (LC/MS) analysis of monkey urine samples indicated that the four polar metabolites were two pairs of diastereoisomeric glucuronides whose molecular weight differed by two daltons. Enzyme hydrolysis, cochromatography, and LC/MS experiments resulted in the identification of a hydroxylated cyclic amide as one of the aglycones, which formed a pair of diastereoisomeric glucuronides after conjugation. Data also suggested that a dihydroxycyclic amide formed by the reduction of the ketone group that joins the phenyl rings formed the second pair of diastereoisomeric glucuronides. Further, incubation of various reference standards in control (blank) urine and buffer with and without creatinine indicated that the hydroxy cyclic amide released from enzyme hydrolysis can undergo ex vivo transformations to a condensation product between creatinine and an alpha-keto acid derivative of the hydroxy cyclic amide that is formed by oxidation and ring opening. Further experiments with a dihydroxylated cyclic amide after reduction of the keto function indicated that it too can form a creatinine conjugate.     

A dose proportionality study of eprosartan in healthy male volunteers

BACKGROUND: Previous investigations in BALB/c strain mice have revealed that, after skin sensitization, draining lymph node cells (LNC) produce high levels of interleukin 6 (IL-6) and that the secretion of this cytokine correlates closely with the proliferative activity of LNC. The main source of IL-6 within draining lymph nodes was found to be dendritic cells (DC), most of which derive from epidermal Langerhans cells. OBJECTIVE: To explore further the relationship between DC-derived IL-6 production in lymph nodes, LNC proliferative activity, and the development of contact sensitization, comparisons between BALB/c and C3H/HeN strains of mice have been conducted. METHODS: Contact sensitizing potential was measured in both strains of mice as a function of lymphocyte proliferative responses (assessed by the incorporation of radiolabelled thymidine) and challenge-induced increases in ear thickness. The concentration of IL-6 in skin homogenates and the production of IL-6 by allergen-activated LNC were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: In both strains of mouse, topical exposure to oxazolone, a potent contact allergen, induced a vigorous proliferative response by draining LNC and the development of skin sensitization. However, under these conditions of exposure, activated LNC prepared from mice of C3H/HeN strain failed to secrete substantial amounts of IL-6, the levels of this cytokine being on average some 20- to 40-fold less than those measured in BALB/c mice. The failure of LNC from C3H/HeN mice to secrete comparable levels of IL-6 was not attributable to a reduced ability of DC to accumulate in draining lymph nodes after skin sensitization. Nor did reduced IL-6 secretion by C3H/HeN LNC reflect a systemic inability to elaborate this cytokine. Epicutaneous exposure of C3H/HeN mice to oxazolone resulted in the induction of cutaneous IL-6 at levels similar to, or greater than, those observed after identical treatment of BALB/c strain mice. CONCLUSIONS: The conclusion drawn is that there does not exist a universal association between IL-6 production in draining lymph nodes and the vigor of proliferative responses by LNC. Further, cutaneous immune responses and skin sensitization may proceed apparently normally in the absence of high levels of IL-6 production by lymph node cells.     

Factors determining compliance with tuberculosis treatment in an urban environment, Tamatave, Madagascar

SETTING: Patient compliance remains one of the main obstacles that need to be overcome by tuberculosis control programmes, in the developing world as well as in industrialised countries. A better understanding of the various factors accounting for treatment default could help to achieve better compliance from patients. OBJECTIVES: To increase the understanding of the determining factors of default in an urban environment where medical facilities are accessible. Different kinds of determinants were studied: objective socio-demographic factors, subjective psychological factors, attitudes and behaviour of patients in relation to chemotherapy, quality of relationships with the medical staff, knowledge and attitudes regarding tuberculosis. DESIGN: Risk factors for default were assessed by a retrospective case-control study in a sample of 38 patients who had not completed treatment for pulmonary tuberculosis, compared with 111 controls who had completed treatment under comparable conditions. RESULTS: Default appears to be significantly linked to transportation time, the sex of the patient, patient information and the quality of communication between patients and health workers. False addresses given by patients are both a methodological bias and a risk factor for future default. CONCLUSION: Improved communication skills and attention from the medical staff could encourage more patients to complete their TB treatment.     

Leptospirosis in an urban setting: case report and review of an emerging infectious disease

Leptospiosis is a common zoonosis affecting most mammals. Leptospirosis has protean manifestations ranging from a flu-like illness to fulminant hepatic and renal failure culminating in death. Although the diagnosis is often not considered upon presentation, the literature suggests that leptospirosis is a reemerging infectious disease in urban centers throughout the industrialized world. It will be incumbent upon Emergency Physicians to include this spirochetal disease in the differential diagnosis of febrile patients with appropriate risk factors and symptomatology. We present the case of a 36 year-old woman who presented to the Emergency Department with fever and hypotension. We review the literature on leptospirosis with specific focus on risk factors and pathogenesis, clinical manifestations, diagnosis, treatment, and outcome.     

Increased aggressive responding in male volunteers following the administration of gradually increasing doses of testosterone cypionate

Traumatic vertebral artery injuries are relatively rare. Until recently, insufficient neurodiagnostic technology and a lack of normative data for the population of USAF aviators prevented recommending flying waivers following such vascular injuries. We report the case of an aviator who experienced a traumatic right vertebral artery occlusion with distal embolization. Timely access to a state-of-the-art neurodiagnostic evaluation, which included time-of-flight magnetic resonance angiography (MRA), and standard contrast angiography, provided anatomic imaging at the time of injury and during the recuperative period. Sophisticated neurologic testing protocols at the Armstrong Laboratory's Aeromedical Clinical Sciences Division, Brooks Air Force Base, TX, assessed in-depth this individual's functional status. Consult Service evaluators then compared his performance data with current data in the Head Injury Study in Aviators (HISA) data base. MRA, in comparison with standard contrast angiography, demonstrated anatomic stability of his vascular and neurologic lesions. He demonstrated a functional capacity consistent with normal neurologic functioning in aviators which permitted recommending an occupational (flying) waiver. This case exemplified application of sophisticated ACS neurologic testing protocols to aeromedical evaluations and the use of MRA technology as a vascular screening tool during medical followup.     

Shaping of isodose curves in intracavitary irradiation using the afterloading method. A feasibility study involving mathematical simulation

The possibility of adjusting the irradiation scheme to shape the isodose curve around an intracavitary source arrangement was studied mathematically. The total number of millicurie hours of irradiation for each source position was derived by a linear programming approach, taking into account the shape of the tumor in three different cases. The practical isodose curves obtainable with the source arrangement chosen were compared with the shape desired.     

Screening for breast cancer in Ghent, Belgium: first results of a programme involving the existing health services

In 1992, a population-based breast cancer screening programme was initiated in the municipality of Ghent: all women aged 40-69 years were personally invited to attend a local radiology unit for a mammogram, after being examined by a general practitioner or gynaecologist of their choice. The results of history taking, clinical breast examination, first and second reading, further investigation and primary treatment were registered. In total, 24.3% of the eligible population was screened in the period 1992-1994. The recall and biopsy rates were 2.9% and 1.4%, respectively. The cancer detection rate was 8.1 per 1000 women screened. Of all cancers detected, 88.0% (66/75) were invasive. Of these, 35.9% (23/64) measured 10 mm or less in diameter. The benign to malignant biopsy ratio was 0.7. Apart from the low participation, these results suggest that the programme is effective, compared with reference standards and the results of other studies.     

Inhibition of gastric emptying and intestinal transit by amphetamine through a mechanism involving an increased secretion of CCK in male rats

1. The effect of amphetamine on gastrointestinal (GI) transit and the plasma levels of cholecystokinin (CCK) were studied in male rats. 2. Gastric emptying was inhibited both acutely and chronically by the administration of amphetamine. GI transit was decreased by the acute administration of amphetamine but not affected by the chronic administration of amphetamine. 3. Plasma CCK levels were increased dose-dependently by amphetamine. 4. Proglumide, a CCK receptor antagonist, prevented amphetamine-induced inhibition of gastric emptying and the decrease in GI transit in male rats. 5. The selective CCK(A) receptor antagonist, lorglumide, dose-dependently attenuated the amphetamine-induced inhibition of gastric emptying in male rats. In contrast, the selective CCK(B) receptor antagonist, PD 135,158, did not reverse the effect of amphetamine on gastric emptying. 6. Both lorglumide and PD 135,158 reversed the inhibitory effect of amphetamine on GI transit in male rats. 7. These results suggest that amphetamine-induced inhibition of gastric emptying and intestinal transit is due in part to a mechanism associated with the hypersecretion of endogenous CCK.     

Aetiologies and outcomes of wounds in an outpatient programme

This study reviewed the records of all new patients seen in an outpatient wound-care programme during a six-month period. Most of the 115 patients were referred by physicians in internal medicine or family practice (48%) or surgeons (39%); 101 had a wound (88%). Of the 92 who had their wound measured at the time of their first clinic visit, 72 (78%) had their largest wound located on a lower extremity and 40% of all lower extremity wounds were on the feet. Wounds were most frequently due to pressure (36%), venous insufficiency (16%), diabetic neuropathy (16%), or arterial insufficiency (13%). Within 12 months of their initial presentation, wound closure was documented in 35 of the 92 patients (38%). Of the four most common aetiologies, the healing rate was highest in wounds attributable to venous insufficiency (67%) (p < 0.02).     

Dimensions of assertiveness in an Asian-American student population.

The components of assertiveness assessed by the College Self-Expression Scale were analyzed in 150 Asian-American and 135 Caucasian college student populations. A significant difference in full-scale assertion scores indicated lower levels of overall assertion in the former sample, although sampling differences could have augmented the difference. Sources of the difference in mean scores were examined by the factor analyses and post hoc comparisons of derived subscales. Results are consistent with value differences between Asian-American and Caucasian college students. Limitations, counseling implications, and strategies for developing culturally relevant assertion training are discussed. (18 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Volume kinetics of Ringer solution, dextran 70, and hypertonic saline in male volunteers

We asked patients to assess their functional health status by completing the SF-36. Over 2 years, we studied 1,000 patients (average age, 58 years; 50% male; 25% white; 36% diabetic) in three outpatient, staff-assisted hemodialysis units. We used both the eight-scale scores and two-component summary scores to study the relationship between baseline functional health status and clinical outcomes. The physical component summary (PCS) score was as significant a predictor of mortality as was the normalized protein catabolic rate or the delivered Kt/V. Patients with a PCS score below the median for our patients (< 34) were twice as likely to die and 1.5 times more likely to be hospitalized as patients with PCS scores at or above the median score. Either a low PCS score or a low mental component summary (MCS) score correlated with the number of days of hospitalization. While the average dialysis patient has a relatively normal (47 v 50) MCS score and a low (37 v 50) PCS score compared with the normal population, patients who skipped more than two treatments per month tended to have a relatively higher PCS score (judged themselves physically healthier) and a relatively lower MCS score (judged themselves less mentally healthy) than patients who did not skip two or more treatments per month. The prevalence of depression as defined by an MCS score of < or = 42 was approximately 25%. The SF-36 provided a good screening tool for patients at high risk for death, hospitalization, poor attendance, and depression.     

Cohort analyses of the treatment of smear-positive pulmonary tuberculosis patients under programme conditions in Korea, 1983-1994

The authors previously reported that male offspring of mothers rats given alkaline ionized water (AKW) showed a significantly higher body weight by day 14 after birth than did offspring of mother rats given tap water (TPW); furthermore, marked myocardial necrosis and fibrosis were observed particularly in the former male offspring at the age of 15 weeks. In the present experiment we looked for differences in bioparameters, namely the milk yield of mothers and suckled milk volume of the offspring, between the AKW- and the TPW-treated groups in order to reveal the factors which cause the unusual body weight gain in the offspring. Even though we were able to repeat our previous observation (the body weight of the male offspring of the AKW group increased significantly more by day 14 and 20 after birth and of the female by day 20 after birth than did that of the TPW group (p < 0.05), no significant difference was noted in any of the bioparameters, including those related to milk production and consumption. It is thus suspected that the water-hydrated cation, which was transferred either to the fetus through the placenta or to the offspring through the milk, might be the cause of the unusual body weight increase. Since calcium plays an important role in skeletal formation, it is tentatively concluded that the higher calcium concentration of AKW enriched the mother, serum calcium which was transferred to the fetus through the placenta and to the offspring through the milk.     

Comparison of the single-dose pharmacokinetics and tolerability of modafinil and dextroamphetamine administered alone or in combination in healthy male volunteers

An open-label, randomized, crossover study was performed in healthy male volunteers to evaluate the potential pharmacokinetic and pharmacodynamic interactions and tolerability of single oral doses of modafinil (200 mg) and dextroamphetamine (10 mg). Blood samples were collected for determination of plasma levels of modafinil, the acid and sulfone metabolites of modafinil, and dextroamphetamine at intervals through 48 hours after administration for each treatment. Vital signs (blood pressure and pulse rate) were measured through 48 hours, and electrocardiograms were measured through 24 hours after administration. Pharmacokinetic parameters were determined using noncompartmental methods. The data collected in this study of 24 healthy volunteers suggest that concomitant administration of single oral doses of modafinil and dextroamphetamine has no clinically significant effects on the pharmacokinetic profile of either agent. Although there was a slightly greater incidence of adverse events when modafinil and dextroamphetamine were administered together, the concomitant administration of the two drugs was well tolerated.