Benzbromarone disposition and uricosuric action; evidence for hydroxilation instead of debromination to benzarone

Summary Benzbromarone is one of the main uricosuric drugs currently used. We determined plasma concentrations of benzbromarone, bromobenzarone, and benzarone and 24 hour uric acid excretion in ten healthy individuals following fasting application of two different non-micronised benzbromarone brands. In addition we explored the influence of adjusting urinary pH to near neutral values and of concomitant food intake. Benzbromarone was more rapidly absorbed from the test preparation than from the reference preparation; the extent of systemic availability did not differ significantly. Urinary pH adjustment had no clearcut effect, whereas food intake retarded drug absorption (even though not significant because of the variability of the data). Binding of benzbromarone to plasma proteins exceeded 99%. Bromobenzarone and benzarone were not detectable and are unlikely to be major metabolites of benzbromarone. Instead we found two other compounds suggestive of metabolites, one of them being monohydroxilated benzbromarone. The plasma concentrations of the parent compound in one subject exceeded those of the rest of the group, possibly indicating genetic differences in drug metabolism. The uricosuric effect was not related to benzbromarone plasma concentrations.Abbreviations AUC area under the (plasma concentration time) curve - GC-MS gas chromatography-mass spectrometry - HPLC high performance liquid chromatography - t1/2 plasma elimination half life Dedicated to Professor Dr. N. Zöllner on the occasion of his 65th anniversary     

Effect of aerobic capacity on sweat rate and fluid intake during outdoor exercise in the heat

We measured the aerobic capacity, sweat rate and fluid intake of trained athletes during outdoor exercise and examined the relationship between aerobic capacity and thermoregulatory responses at high ambient temperatures. The maximal aerobic capacity ( ) of the subjects, nine male baseball players of college age, was determined by maximal exercise tests on a cycle ergometer. The subjects practised baseball regularly without drinking fluids from 1330 to 1530 hours. After 30 min rest, they played a baseball game with free access to a sports drink at 15°C from 1600 to 1830 hours. At a mean ambient temperature of 36.7 (SEM 0.2)°C, the mean percentage of body mass loss (m _b) and increase of oral temperature (T _o) from 1330 to 1530 hours was 3.47 (SEM 0.12)% and 0.81 (SEM 0.14)°C, respectively. The sweat loss from 1330 to 1830 hours was 56.53 (SEM 1.56)ml · kg^–1 of body mass (M _b) while the mean fluid consumption was 44.78 (SEM 2.39)ml · kg^–1 ofm _b, with recovery of 76.08 (SEM 2.81)% of sweat loss. The was significantly inversely correlated withm _b, fluid intake and rehydration amount, but showed no correlation withT _o. These results would suggest that at a given exercise intensity in subjects with a higher aerobic capacity body temperature is maintained with a lower sweating rate than that in subjects with a lower aerobic capacity.     

Psychosocial correlates of alcohol intake among women aged 45 to 64 years: The Framingham Study

This study of 749 women, aged 45 to 64 years, investigates the psychological, behavioral, and social correlates of alcohol intake. These data from the Framingham Study are uniquely based on a community sample of women, which results in a normative study of drinking behavior in women. Two measures of alcohol intake were utilized in these analyses: (1) the frequency of alcohol intake over 1 week and (2) drinking vs abstaining from alcohol. Among this sample of women, increased socioeconomic status, worrying about aging, and being easily upset were positively associated with frequency of alcohol intake. The rigid attitude scale was the strongest discriminating variable for drinkers vs nondrinkers. Older women were more likely to be nondrinkers compared to younger women, however, among older women, being a homemaker was significantly associated with increased alcohol intake. Contrarily, younger women who were homemakers were more likely to be abstainers than women employed outside the home. As would be expected, cigarette smoking was associated with drinking alcohol.This research is dedicated in fond remembrance to our friend and colleague Joseph Stokes III, M.D.     

Hyperdipsia produced by severing ventral septal fiber systems.

The septum of male hooded rats (N = 59) was completely isolated from the rest of the brain (ISS) or was partially isolated by severing dorsal (DP), ventral (VP), anterior (AP), or posterior (PP) fiber tracts using a knife-cut technique. Daily water intakes and intakes following hypertonic NaCl and polyethylene glycol (PG) injections were measured. The septum totally degenerated for the ISS group and these rats had normal or hypodipsic daily intakes, likewise for intakes following NaCl and PG. Rats of the VP group sustained little septal damage, yet these cuts yielded the highest percentage (55 percent) of hyperdipsic daily drinkers of any group. The daily hyperdipsic rats drank normally in response to NaCl and PG, demonstrating a dissociation between daily drinking and drinking in response to specific thirst stimuli. The results indicate the importance of ventral fiber systems in the production of Septal Hyperdipsia, and support the notion that the septum has multiple effects upon water regulation.     

Effect of insulin on sex differences in the intake of glucose solutions in rats

Adult male and female Wistar rats maintained on ad lib diet were given a choice between tap water and a solution of glucose in the concentration of either 5 or 12%. Both sexes exhibited a marked preference for glucose solutions. With the 5% solution the volume intake was similar in both sexes and the total calorie intake was normal. With the 12% solution the volume intake was higher in females than in males, while in both sexes the total calorie intake was increased to a similar (maximum acceptable) level. Treatment with Protamine Zinc Insulin (PZI) in a daily dose of 40 U/kg b.w. markedly increased the intake of the 5% solution in both sexes, but significantly more in females than in males, thus revealing sex differences which were not manifest in untreated rats. PZI treatment had little effect on 12% glucose solution intake, presumably because with this solution the total calorie intake was increased to a maximum already in untreated rats.     

Dietary selection for lysine by the chick

Broiler chicks were provided choices of synthetic diets (a) adequate or low in lysine, and (b) adequate in or devoid of lysine. In each case, chicks consumed some of each diet offered, but preference was shown for the adequate lysine diet. Growth rates of chicks given choices ranged from 80% of that of chicks fed an adequate lysine diet with no choice for two weeks, then growth rates fell to about 60% of those fed adequate lysine. In another study, chicks were fed a diet devoid of lysine but were offered pure L-lysine HCl in a separate feeder. These chicks selected some of the supplementary lysine, but their body weights were only 68% of the body weight of chicks fed an adequate lysine diet after 21 days. Chicks given a choice of diets prepared with an adequate quantity of either L- or D-lysine preferred with L-lysine diet but did not select sufficient quantity to reach normal growth. These observations indicate that chicks can discern the presence of L-lysine in diets or separately, but will not select sufficient quantity for maximum growth potential. A diet prepared with D-lysine was more acceptable than one completely devoid of lysine, suggesting some sensory recognition for lysine.     

Energy cost and mechanical efficiency of riding a four-wheeled, human-powered, recumbent vehicle

Oxygen consumption at steady state (V˙O ₂, l · min⁻¹) and mechanical power (W˙, W) were measured in five subjects riding a human-powered vehicle (HPV, the Karbyk, a four-wheeled recumbent cycle) on a flat concrete road at constant sub-maximal speeds. The external mechanical work spent per unit of distance (W, J · m⁻¹), as calculated from the ratio of W˙ to the speed (v, m · s⁻¹), was found to increase with the square of v: W˙=8.12+(0.262 ·v ²) (r=0.986, n=31), where the first term represents the mechanical energy wasted, over a unit of distance, against frictional forces (rolling resistance, R_r), and the second term (k · v ²) is the work performed, per unit distance, to overcome the air drag. The rolling coefficient (C_r, obtained dividing R_r by m · g, where m is the overall mass and g is the acceleration of gravity) amounted to [mean (SD)] 0.0084 (0.0008), that is about 60% higher than that of a racing bicycle. The drag coefficient was calculated from the measured values of k, air density (ρ) and frontal area (A) [C_x=k · (0.5 · A · ρ)⁻¹], and amounted to 1.067 (0.029), that is about 20% higher than that of a racing bicycle. The energy cost of riding the HPV (C_k, J · m⁻¹) was measured from the ratio of metabolic power above rest (net V˙O ₂, expressed in J · s⁻¹) to the speed (v, m · s⁻¹); the value of this parameter increased with the square of v, as described by: C_k=61.45 + (0.675 · v ²) (r=0.711, n=23). The net mechanical efficiency (η) was calculated from the ratio of W to C_k: over the investigated speed range this turned out to be 0.22 (0.021). Best performance times (BPTs) of a “typical”élite athlete riding the Karbyk were calculated over the distances of 1, 5 and 10 km: these were about 8% longer than the BPTs calculated, on the same subjects, when riding a conventional racing bicycle. Accepted: 7 August 2000     

Increase of food intake induced by glucagon in the rat

The effect of intraperitoneal administration of saline, glucose (25 mg/100 g b.w.), insulin (0.025 U/100 g b.w.) and glucagon (50 micrograms/kg b.w.) on glycemia, liver glycogen concentration and food intake was studied on 104 male adult Wistar rats. When saline was injected the amount of food ingested was similar to that expected at the metabolic moment selected for the tests. Glucose administration did not reduce food intake but both insulin and glucagon provoked a threefold increase during the 60 minutes ensuing the injection. The overall ingestion of food during the 24 hours after the injection of the hormones was significantly higher (about 10%) than the control values during the preceding or the succeeding 24 hours. A hyperphagic, rather than a hypophagic effect of glucagon administration is possibly related to the small dose used in the experiments. The mechanisms involved in the increase of food intake due to glucagon are discussed in terms of acceleration of the metabolic reactions that normally prevent large drops of glycemia as glucose utilization proceeds during the inter-meal periods and that in physiological conditions build up until the need for food arises.     

Interaction between the septal area and the subfornical organ in the control of water intake induced by thirst-eliciting procedures

Rats bearing lesions in the septal area followed by lesions in the subfornical organ were submitted to various thirst-eliciting procedures. The rats with hyperdipsia induced by lesions of the septal area drank more water than either during the control period or after lesion of the subfornical organ under the same thirst-eliciting or angiotensin-liberating stimuli (polyethyleneglycol, isoproterenol, water deprivation and ligation of the inferior vena cava). The overdrinking elicited by lesions in the septal area was blocked after lesion of the subfornical organ. Neither hypovolemia, nor hypotension or water deprivation could elicit increased water intake in animals whose subfornical organ had been destroyed. Animals with lesions in the subfornical organ showed decreased water intake after cellular dehydration. The results obtained suggest that the subfornical organ acts as a more important structure than the septal area in the regulation of water intake elicited by angiotensin, with two opposite effects: a direct one facilitating water intake, and an indirect one inhibiting the septal area. The septal area has an inhibitory effect on the subfornical organ and on water intake.     

Psychotropic drug utilization patterns in a metropolitan population

Summary Psychotropic drug intake by a random sample of citizens of the city of Munich aged 30–69 years has been assessed. A 1-week prevalence of 9.3% for all psychotropic drug users was found, benzodiazepines accounting for approximately two-thirds (6.6%) of the users. Two-thirds of drug users were women. Drug use in both sexes increased with age. The doses of benzodiazepines prescribed in most cases were less than 10 mg diazepam equivalent per day. Intake of benzodiazepines in combination with analgesics or alcohol (40 g/day) did not appear to represent a major problem. Multiple logistic regression analysis showed that the number of chronic diseases was the strongest predictor of benzodiazepine intake in men, whereas stress and age determined intake in women. Long-term use seemed to be relatively rare at 11% of all benzodiazepine users, so it was not considered to be a severe public health problem.