A randomized three-way cross-over study in healthy pituitary-suppressed women to compare the bioavailability of human chorionic gonadotrophin (Pregnyl) after intramuscular and subcutaneous administration.

The objective of this study was to compare the bioavailability of s.c. and i.m. administration of human chorionic gonadotrophin (HCG; Pregnyl). In a randomized, single-centre, three-way cross-over study, 18 healthy pituitary-suppressed volunteers were assigned to single HCG injections of 5000 and 10,000 IU i.m. and 10,000 IU s.c. Rate (Cmax, t(max)) and extent [area under curve from zero to infinity (AUC(0-infinity))] of absorption of HCG were determined. Serum immunoactive HCG increased from 0.4-0.5 IU/l at baseline to mean peak concentrations, which were reached 20 h after injection of 156 IU/l with 5000 IU i.m., of 307 IU/l with 10,000 IU i.m. and of 339 IU/l with 10,000 IU s.c. Eight days after administration, < 10% of the maximum HCG activity was found for each regimen. The elimination half-life (t(1/2)) was on average 32-33 h, irrespective of the treatment regimen. Intramuscular and s.c. injections of 10,000 IU HCG were bioequivalent with respect to AUC(0-infinity). The Cmax and t(max) were also similar between the two administration routes but bioequivalence could not be proven due to intersubject variability. Intramuscular doses of 5000 IU and 10,000 IU HCG were dose-proportional. Since s.c. HCG is bioequivalent to i.m. HCG with respect to extent of absorption (its major pharmacokinetic variable) and is well tolerated, the s.c. administration route may be effectively and safely used in assisted reproduction. Moreover, since s.c. injection can be performed by the patients themselves, acceptability may be enhanced.

The interaction of the lipase inhibitor orlistat with ethanol in healthy volunteers.

OBJECTIVES: The primary objective was to investigate the possible interference of ethanol on the orlistat effect on inhibition of dietary fat absorption and the possible interference of orlistat on the pharmacokinetics of ethanol. Secondary objectives were to assess the tolerability during concomitant dosing of orlistat and ethanol and to determine the ethanol effect on plasma levels of orlistat. METHODS: This was a double-blind, placebo-controlled, parallel, randomized study performed in 30 (three parallel groups of ten subjects each) healthy normal weight male subjects between the ages of 20 and 30 years. A 5-day run-in period to accustom subjects to a standardized diet of 2500 kcal/day (30% fat) and to establish baseline fecal fat excretion was followed by a 6-day treatment period. Subjects were randomly assigned to one of three treatment groups (A = orlistat 120 mg t.i.d. and ethanol placebo, B = orlistat 120 mg t.i.d. and 40 g ethanol qd on days -1 and 6, and 40 g bid on days 1-5, and C = orlistat placebo tid and 40 g ethanol qd on days -1 and 6, and 40 g b.i.d. on days 1 5). Serial blood samples were collected for determination of ethanol serum concentrations at specified times over 5 h after each dose of ethanol on days -1 and 6, and for determination of orlistat plasma concentrations on days 1, 3, 5, and 6. Feces were collected quantitatively on days -5 through 8 for analysis of fecal fat. RESULTS: The means of baseline-corrected fecal fat excretion values were comparable: 23.7 g for group A (orlistat) and 22.7 g for group B (orlistat and ethanol). No significant difference was found regarding ethanol pharmacokinetic parameters between treatments with orlistat and placebo. No apparent differences existed between the number of plasma samples with measurable orlistat concentrations in groups A and B. CONCLUSION: Concomitant ingestion of social amounts of ethanol did not alter the inhibitory effect of orlistat on dietary fat absorption during short-term treatment (6 days) with orlistat. Short-term treatment with orlistat had no significant influence on ethanol pharmacokinetics.

Assessment of bioequivalence after subcutaneous and intramuscular administration of urinary gonadotrophins.

The objective was to demonstrate bioequivalence between s.c. and i.m. administration of Humegon (FSH/LH ratio 1:1) and Normegon (FSH/LH ratio 3:1). In two randomized, single-centre, cross-over studies, 18 healthy volunteers on each formulation were assigned to one of the two administration sequences. Subjects were given single doses of one of the above gonadotrophins after endogenous gonadotrophin production had first been suppressed using high-dose oral contraceptive. Subsequently, rate (Cmax, tmax) and extent (AUC) of absorption of follicle stimulating hormone (FSH) and luteinizing hormone (LH) were determined for 14 days. For Cmax and AUC, analysis of variance (ANOVA) was performed on log-transformed data and for tmax ANOVA was performed on ranks. Intramuscular and s.c. injections of Humegon were bioequivalent with respect to the main pharmacokinetic parameters, being AUC and Cmax of FSH absorption. Intramuscular and s.c. injections of Normegon were bioequivalent with respect to the AUC of FSH and not bioequivalent with respect to the Cmax of FSH. For tmax of FSH as well as for most LH variables of both preparations, bioequivalence could not be proven due to the high intra- and interindividual variability and/or concentrations being close to the detection limit. Thus, the main pharmacokinetic FSH variables after i.m. and s.c. administration of Humegon and Normegon were bioequivalent.

Lack of interaction between orlistat and oral contraceptives.

OBJECTIVES: Orlistat, a potent and selective inhibitor of gastrointestinal lipases, is designed for the treatment of obesity. A double-blind, randomised, placebo-controlled, 2-way crossover study investigated the possible influence of orlistat on the ovulation-suppressing action of combination oral contraceptives (OC). METHODS: After an 8-day run-in prior to the first of two consecutive menstrual cycles (Day 1 was the first day of menstruation), two groups of 10 healthy women, 20-27 years of age and on a stable regimen with OCs, received either 120 mg orlistat t.i.d. or placebo t.i.d. on Days 1-23 of the first cycle, and, separated by a placebo washout period on Days 24-28, the alternative treatment on Days 1-23 of the second cycle. In both cycles, serum luteinizing hormone (LH) was measured on Days 12-16 and progesterone on Days 12, 16, 19-23. RESULTS: The geometric means of time averaged concentrations (Days 12-16 for LH and Days 19-23 for progesterone) in the cycles with orlistat and placebo, respectively, and the one-sided 95% confidence region for the mean in the cycle with orlistat were 1.92, 2.03 and < 2.23 IU 1-1 for LH and 0.147, 0.145 and < 0.176 micrograms 1-1 for progesterone. The one-sided 95% confidence region for the ratio (orlistat/placebo) of geometric means was < 1.06 for LH and < 1.11 for progesterone. CONCLUSION: During normal ovulation the peak serum concentration of LH is above 30 IU 1-1 around Day 14 of the cycle, and that of progesterone exceeds 3 micrograms 1-1 around Day 21. The 95% confidence regions for the means, as well as all individual concentrations, were below these limits. It was concluded that orlistat did not influence the ovulation suppressing action of oral contraceptives.

PIP: In the Netherlands, a double-blind, randomized, placebo-controlled, two-way crossover study was conducted to determine whether administration of the inhibitor of gastrointestinal lipases, Orlistat, concomitantly with combined oral contraceptives (OCs) inhibits the ovulation-suppressing action of OCs. The 20 subjects, 20-27 years old, were healthy and had a body mass index between 22 and 27 kg m-2. All subjects completed the study. Most adverse events were mild and related to the pharmacological effect of Orlistat (fatty or oily stool, flatus with discharge, or abdominal pain). The geometric means of time-averaged serum concentrations in the cycles with Orlistat and the placebo and the 1-sided 95% confidence region for the mean in the cycle with Orlistat were 0.147, 0.145, and less than 0.176 mcg l-1 for progesterone and 1.92, 2.03, and less than 2.23 IU l-1 for luteinizing hormone (LH), respectively. These figures were well below the peak concentrations during normal ovulation (3 mcg l-1 for progesterone and 30 IU l-1 for LH). The plasma concentration of Orlistat was either close to the limit of quantification (1 mcg l-1) or below this limit. These findings suggest that Orlistat had no effect on the ovulation-suppression capabilities of the OCs.

Pharmacokinetics and pharmacodynamics of Ro 41-3696, a novel nonbenzodiazepine hypnotic.

This report describes the first evaluation in humans of Ro 41-3696. Based on its preclinical profile, Ro 41-3696, a nonbenzodiazepine partial agonist at the benzodiazepine receptor, offers promising perspectives as an innovative hypnotic drug in that it does not exhibit most of the disadvantages associated with full agonists. Single oral doses of 0.1, 0.3, 1.0, 3.0, 10, and 30 mg were administered sequentially to six groups of six healthy male volunteers in a placebo-controlled, double-blind design. Tolerability was assessed and pharmacokinetic and pharmacodynamic measurements were conducted during a period of 28 hours after drug intake. Ro 41-3696 was well tolerated at all doses, causing no clinically relevant changes in vital signs or laboratory parameters. At doses of 10 and 30 mg there were signs of unsteady gait, indicating a central nervous system depressant effect. Pharmacokinetic analyses revealed that Ro 41-3696 was absorbed and eliminated rapidly (tmax = approximately 1 hour; t1/2 = approximately 4 hours). At all times plasma levels of Ro 41-3290, the desethylated derivative of Ro 41-3696, were higher than those of the parent drug (tmax and t1/2 values = approximately 2 and 8 hours, respectively). Area under the curve (AUC) data indicated dose-proportional pharmacokinetics for both Ro 41-3696 and Ro 41-3290. Performance in both a tracking and a memory search test was significantly affected by doses of 10 and 30 mg, and long-term memory, as assessed by a word learning and recall test, was slightly impaired at these doses. The results of this study support the initiation of therapeutic efficacy studies with Ro 41-3696 in doses up to approximately 5 mg and further exploration of the characteristics of Ro 41-3290.

A prospective, double-blind, split-subject study on local skin reactions after administration of human menopausal gonadotrophin preparations to healthy female volunteers.

This study was designed to investigate local reactions after the intracutaneous (i.c.) administration of two human menopausal gonadotrophin preparations. For this purpose, 20 healthy female volunteers received six i.c. injections simultaneously, viz. three different batches of both Humegon (Organon, Oss, The Netherlands) and Pergonal (Serono, Geneva, Switzerland) at six different sites on their bodies. Local pain, induration and erythema were registered at 2, 4 and 24 h after administration. No pain was observed. At 4 h after administration, Pergonal-treated sites showed more induration (P = 0.008) and greater surfaces of erythema (P < 0.001) than Humegon-treated sites. Batches of Pergonal showed variation in the surface of erythema induced (P < 0.001), indicating heterogeneity of the batches tested.

Comparison of the inhibition of dietary fat absorption by full versus divided doses of orlistat.

Orlistat is a potent and selective inhibitor of gastrointestinal lipases. The drug is designed for the treatment of obesity. The effect on dietary fat absorption of orlistat after administration of divided doses spread over 2 hours from mid-meal, in comparison with that after administration of a full dose mid-meal, was investigated in a randomized, single-blind study including 16 hospitalized healthy males. After a 5-day run-in, to accustom the subjects to a diet of 2350 kcal and 76 g fat per day and to establish baseline fecal fat excretion, subjects received, in two parallel groups of eight over 8 days, three times a day 80 mg orlistat at mid-meal, and placebo at mid-meal and 0.5, 1, and 2 hr after mid-meal (group A), or placebo at mid-meal, and 20 mg orlistat at mid-meal and 0.5, 1, and 2 hr after mid-meal (group B). Feces were collected to measure total fat excretion. The mean (SD) of fecal fat in percent of dietary fat, after deduction of pretreatment fecal fat, was (%) 36.1 (4.2) and 37.0 (9.3) in groups A and B, respectively. Changing the mode of administration of orlistat, within the dose regimens investigated, does not affect its pharmacologic efficacy.

Influence of dietary composition on the inhibition of fat absorption by orlistat.

Orlistat, a potent and selective inhibitor of gastrointestinal lipases, is designed for the treatment of obesity. The effect of orlistat on dietary fat absorption, when it was administered with diets differing in fibre content (high and low) and accessibility of fat (intra- and extracellular fat), was investigated in 32 hospitalized healthy males, according to an open, two-factorial study design. The subjects were randomly allocated to one of four parallel groups of equal size: A = intracellular fat, high fibre (28 g/day); B = extracellular fat, high fibre; C = extracellular fat, low fibre (9 g/day); or D = intracellular fat, low fibre. After a 5-day run-in period to accustom the volunteers to the standardized diet (2500 kcal and 84 g fat per day) and to establish baseline faecal fat parameters, they received 80 mg orlistat, three times daily mid-way through each meal for 8 days. Faeces were collected to measure total fat and free fatty acid excretions. The mean baseline-corrected excretion (% of dietary fat) in groups A, B, C and D, respectively, was 37.0, 30.4, 30.3 and 34.5 for total fat, and 6.5, 4.3, 2.6 and 3.9 for free fatty acids. The 95% confidence intervals for the difference between the means for high fibre and low fibre groups and for intracellular fat and extracellular fat groups, respectively, were 1.4 +/- 4.9 and 5.5 +/- 4.9 for total fat, and 2.2 +/- 3.1 and 1.9 +/- 3.1 for free fatty acids. The statistically significant difference (P < 0.05) in total faecal fat between intracellular fat and extracellular fat groups, in absolute terms < 5 g fat/day, was not regarded as clinically relevant. Under the conditions of this study, dietary fibre content and accessibility of fat had no relevant effect on the inhibition of fat absorption by orlistat.

Effect on dietary fat absorption of orlistat, administered at different times relative to meal intake.

Orlistat (O) is a potent and selective inhibitor of gastrointestinal lipases. The effect on dietary fat absorption following dosing of O at different times relative to meals was investigated in a placebo (P) controlled study in 24 hospitalized healthy males. After a 5-day run-in, to accustom the subjects to a diet of 2400 kcal and 77 g fat per day and to establish baseline faecal fat excretion, subjects received, in four parallel groups of 6. over 8 days three times daily doses of 80 mg O.P.P (group A) or P. 80 mg O.P (group B) or P.P. 80 mg O (group C) or P.P.P (group D) at mid-meal. 1 h and 2 h after mid-meal respectively. Faeces were collected to measure total fat excretion. The mean (s.d.) of faecal fat in percent of dietary fat, after deduction of pre-treatment faecal fat, was (%) 32.8 (8.1), 34.0 (8.8), 26.9 (4.0) and -1.4 (1.7) in groups A. B. C and D respectively. It was concluded that, within the time period investigated, the pharmacological effect of O is not critically dependent on the time of dosing relative to meals.

Marginal nutritional status among institutionalized elderly women as compared to those living more independently (Dutch Nutrition Surveillance System).

The nutritional status (assessed by anthropometric indices, and biochemical and hematological variables in blood) of three groups of elderly women (aged > or = 65 years) was evaluated within the framework of the Dutch Nutrition Surveillance System. The groups were composed of women living in a nursing home (n = 51), women living in service flats and receiving their dinners from the nursing home kitchen (n = 29), and women living independently (n = 52). Mean blood levels of folate, pyridoxal 5'-phosphate, 25-hydroxyvitamin D, alpha-tocopherol, vitamin C, albumin, selenium and total cholesterol were significantly (p < 0.05) lower among nursing home women. Among these women a biochemical deficiency was frequently found for 25-hydroxyvitamin D (73%), pyridoxal 5'-phosphate (57%), vitamin C (38%), selenium (30%) and folate (28%). These nutritional risks were largely independent of each other. Since folate and pyridoxal 5'-phosphate were associated with several clinicochemical indicators, health status may be an important determining factor for this unfavorable situation. Low 25-hydroxyvitamin D concentrations were associated with limited exposure to ultraviolet radiation and nonusage of vitamin D supplements. We conclude that dietary intake variables are not the only determinants of a marginal nutritional status among nursing home women. Use of foods with a high nutrient density should be encouraged, whereas other preventive measures are needed to improve vitamin D status.

Iodide excretion before and after revision of goiter prophylaxis (Dutch Nutrition Surveillance System).

To assess the iodine supply in The Netherlands after the revision of the goiter prophylaxis measures (Bread Act of 1982, with an increase of iodine content of bread salt) the data of a nationwide survey among Dutch elderly people conducted in 1984/1985 were analysed. Iodide excretion in 24 h urine samples was used as the main iodine status indicator. The data were compared with data on iodine nutriture obtained among an elderly population in The Netherlands before the revision of goiter prophylaxis. High prevalences (greater than or equal to 37%) of low iodine excretion (less than 0.78 mumol/24 h; 100 micrograms/24 h) were found for Dutch elderly people. Mean urinary iodide excretion was 0.95 mumol/24 h (121 micrograms/24 h) for men and 0.79 mumol/24 h (100 micrograms/24 h) for women which is low, especially among women, in comparison with the United States recommended dietary allowance (118 mumol/day = 150 micrograms/day). Consistent positive associations of iodide excretion were found with urinary potassium and sodium excretion, bread consumption and total iodine intake. Bread, as the iodine carrier chosen for goiter prophylaxis in The Netherlands, was found to be the main dietary iodine source. No improvement in iodine nutrition was found among the elderly studied in 1984/1985 in comparison with an elderly population seen in 1981. Therefore, it is concluded that the present measures regarding goiter prophylaxis in The Netherlands might be of limited effectiveness.

[Comparison of antibody titers against Aujeszky's disease virus in pig blood collected on the farm and in the slaughterhouse]. / De vergelijking van antistoftiters tegen het virus van de ziekte van Aujeszky in bloed verzameld bij vleesvarkens op de boerderij en in het slachthuis.

Antibody titres against Aujeszky's disease virus (ADV) in the plasma of slaughter pigs were compared with respect to the site of sampling, namely on the farm (one day before delivery to the slaughterhouse) and in the slaughterhouse during slaughter. No significant differences were noted in the antibody titres against ADV with respect to the different sampling sites. Blood samples collected at the slaughterhouse can be used for monitoring and surveillance systems within the framework of organised pig health care.

Amino acids and glucose in human cerebrospinal fluid after acute ischaemic brain damage.

In the search for potential biochemical markers of value for prognosis after acute hypoxic brain damage, amino acids and glucose were assessed in the cerebrospinal fluid (CSF) and glucose in blood. Samples were taken by lumbar puncture 4, 28, 76 and 172 h after resuscitation from 20 patients and once from 10 control patients. Eight of the resuscitated patients recovered neurologically but 12 remained comatose. The concentrations of alanine (P less than 0.001) and phenylalanine (P less than 0.035) differed most in 4-h samples between the groups. The concentration of alanine was higher in all patient groups with hypoxic brain damage as compared to the controls, the concentrations in patients dying within 76 h (disabled-s group) being higher than in the recovered patients. Phenylalanine in the disabled-s group was significantly higher than the control value. Furthermore, there were significant differences between various patient groups in the concentrations of glutamine, isoleucine, leucine, lysine, serine, tyrosine and valine. When taking into account the permeability of the BBB to these amino acids, alanine, valine and isoleucine most clearly represent brain amino acid metabolism. CSF glucose in the control group and in the recovered patients was lower than in patients dying within 76 h.

Relationship between pathological findings and values of haematological and blood-chemistry variables in apparently healthy finishing pigs at slaughter.

The present study was performed to study possibilities of early decision making for appropriate conveyor-line at future slaughtering of normal, clinically healthy finishing pigs. Blood was collected at slaughter from barrows (n = 112). A meticulous examination for subclinical pathological lesions was performed, revealing 5 groups of subjects listed in order of increasing disease-activity: 1--no real disease-activity; 2--with mild subchronic lesions; 3--with subacute lesions; 4--with abscesses; and 5--with fibrinous-necrotic lesions. Significant differences for values of erythrocyte sedimentation rate (ESR), protein, albumin, globulins, and plasma viscosity appeared to occur in this series. It is suggested that measuring acute phase reactants in blood of slaughtered pigs in the near future may reveal appropriate modern tools for meat inspection and predicting slaughtered animal quality.

Blood flow velocities in the vertebrobasilar system during migraine attacks--a transcranial Doppler study.

In this study, blood flow velocity in the basilar artery and both vertebral and middle cerebral arteries was measured with a transcranial Doppler device in 23 migraineurs during and outside a migraine attack. The aim of the study was to compare blood flow velocities during and outside an attack and to examine vascular reactivity to voluntary hyperventilation during both conditions. No differences in blood flow velocity were found. Although blood pressure was increased and end-expiratory CO2 decreased during the attack, this exerted no influence on blood flow velocity. Neither was a difference in vascular reactivity to voluntary hyperventilation detected between the two conditions. These findings support the notion of functional integrity of the examined large arteries during migraine attacks without aura.

Hematocrit and cardiovascular risk factors among elderly men and women (Dutch Nutrition Surveillance System).

Changes in whole blood viscosity associated with hematocrit could be one of the pathways along which the cardiovascular disease (CVD) risk factors affect these diseases. Therefore, we studied in a nationwide survey comprising 514 apparently healthy Dutch elderly men and women aged 65-79 the possibility of any association between hematocrit and CVD risk factors (tobacco smoking, serum cholesterol, body mass index and blood pressure). Among men, diastolic blood pressure and total serum cholesterol were positively associated with hematocrit in both bivariate and multivariate regression analysis, whereas positive associations of hematocrit with body mass index and smoking were only significant (p < 0.05) in bivariate analysis. Among women, hematocrit was positively associated with body mass index and smoking. Except for smoking, which was associated with the mean corpuscular volume of the erythrocytes, hematocrit was positively correlated with hemoglobin and the number of erythrocytes. It is concluded that hemorrheological aspects should be considered when studying CVD among elderly people.

Indicators of iodine status among adults. Dutch Nutrition Surveillance System.

To evaluate the iodine status of Dutch adults we used three different iodine status indicators, namely urinary 24-hour iodide excretion (I/24 h), iodide/creatinine ratio in 24-hour urine samples (I/Cr) and 24-hour iodide excretion per kilogram body weight (I/kg). Additionally, the habitual daily iodine intake was calculated. Men had higher mean I/24 h and mean iodine intake than women. No differences between men and women were found for mean I/Cr and mean I/kg. Relatively high (greater than or equal to 18%) prevalences of low values for the different iodine status indicators were found, especially for I/24 h. The intraindividual variance for all three indicators was high. Risk assessment regarding iodine supply, based on urinary iodide excretion, depends on the indicator used, and therefore caution is called for when drawing conclusions. Our results do not argue against the usage of I/24 h as iodine status indicator. More research is needed to solve the question whether iodine requirement depends on such factors as body size, body composition and physical activity.

Haematological and clinico-chemical profiles of barrows at the farm and at slaughter.

Haematological and clinico-chemical profiles of blood of healthy stress-resistant swine collected at the farm and at slaughter were determined to investigate whether values of blood variables can be used to establish stress. The values of most variables investigated showed highly significant changes. It is concluded that haematological and clinico-chemical values may be useful in studies to detect, quantify and reduce stress-provoking conditions in stress-resistant swine.

Vascular reactivity during migraine attacks: a transcranial Doppler study.

We measured vascular reactivity--expressed i) as decrease in blood flow velocity (cm/sec) per vol% CO2 decrease due to voluntary hyperventilation and ii) as increase of blood flow velocity during the first minute after resuming normal ventilation, per vol% CO2 increase--in the middle cerebral and basilar artery of 48 migraineurs with attacks without aura, and 17 normal controls. We found no differences for both determinants of vascular reactivity between migraineurs during and outside an attack, and between migraineurs and healthy volunteers. We conclude that the vasomotor reactivity is normal during migraine attacks without aura.

Biogenic amines in anorexia nervosa: circadian rhythm in urinary excretion and influence of posture and physical task load on plasma catecholamines.

To investigate the sympathetic response in anorexia nervosa (AN) patients to stimuli occurring in normal life, biogenic amines were studied in 10 female outpatients. As control groups 10 lean and 10 normal weight healthy female subjects were included. It was hypothesized that the lean control group would have intermediate values between the AN patients and the normal weight controls. The AN patients and the lean controls had a mean underweight of 33.1% and 13.7%, respectively. For the excretion in 24-hr urine, differences among the groups were observed for several compounds, unexpectedly the values being lowest for the patients and highest for the lean controls. Furthermore, the lean controls had a higher excretion of a number of compounds in diurnal than in nocturnal urine, whereas this effect was absent or reversed for the AN patients and intermediate for the normal weight controls. Plasma norepinephrine was highest in the patients and lowest in the lean controls. The catecholamine response to postural changes and physical exercise did not differ among the groups. The results obtained indicate neither a (linear) relationship between underweight and the metabolism of biogenic amines nor a disturbed response to sympathetic stimulation in AN, but suggest an altered metabolism of biogenic amines in patients suffering from AN.