Dieter Hartmann

Initial studies in humans with the novel gastrointestinal lipase inhibitor Ro 18–0647 (tetrahydrolipstatin)

Excessive intake of dietary fat contributes to the development and maintenance of both obesity and hyperlipidemia. Inhibition of gastrointestinal lipases could decrease the amount of ingested fat that is absorbed systemically by preventing the hydrolysis of triglycerides. Ro 18-0647, a chemically synthesized derivative of the natural product lipstatin, inhibits the action of gastrointestinal lipases. Initial studies in humans have shown that Ro 18-0647 can reliably increase fecal fat excretion. Ro 18-0647 has also been shown to be well tolerated in the majority of normal volunteers and obese patients studied. Further research must be conducted to determine whether clinical endpoints of weight loss or cholesterol lowering can be produced by using this new pharmacologic principle.

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 l−1 for LH and 0.147, 0.145 and < 0.176 μg l−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 l−1 around Day 14 of the cycle, and that of progesterone exceeds 3 μg l−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.

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.

Lack of effect of the benzodiazepine antagonist flumazenil (Ro 15-1788) on the performance of healthy subjects during experimentally induced ethanol intoxication.

SummaryFlumazenil is a specific benzodiazepine antagonist. This study was designed to determine whether it also reverses CNS depression due to acute alcohol intoxication.Intoxication was experimentally induced in 6 healthy volunteers by intravenous infusion of ethanol. Individual constant ethanol plasma concentrations in the range 1.47±0.04 g · l−1 to 1.71±0.03 g · l−1 were maintained over 6 h. Two doses of flumazenil (0.1 or 0.2 mg · kg−1) and placebo were administered intravenously in a randomized, double-blind, two-way cross-over fashion. A battery of psychometric tests and subjective ratings of mood and performance were performed at baseline and at regular intervals during the study.Before the administration of flumazenil the characteristic symptoms and signs of ethanol intoxication were present in all subjects. Performance (measured by visual analogue scales), reaction time, digit symbol substitution test, and a tracing test, were markedly impaired by ethanol. After the injection of flumazenil three volunteers reported some subjective improvement in performance. However, in none of the subjects was there a difference between either dose of flumazenil and placebo in terms of an improvement in the objective psychometric variables.

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

AbstractObjectives: 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.

Exposure to Retinyl Esters, Retinol, and Retinoic Acids in Non-Pregnant Women following Increasing Single and Repeated Oral Doses of Vitamin A

Background: High intakes of vitamin A cause congenital malformations in experimental animals with elevated generation of retinoic acids (RA). Results in humans are conflicting. Objective: To evaluate plasma concentration-time curves of retinyl esters, retinol and their metabolites at increasing doses of vitamin A. Methods: An open-label dose-response study. Non-pregnant females (3 groups with n = 12; 18–40 years) received once daily oral doses of vitamin A palmitate up to 30,000 IU/day over 21 days. The area under the plasma concentration-time curve (AUC24h) served as indicator for exposure. Results: AUC24h of retinyl esters increased linearly with dose. Retinol concentrations were unaffected. All-trans RA exhibited a diurnal-like concentration-time profile (Cmax at 3 h; Cmin at 8 h), concentrations decreasing below pre-dose levels at 5 h and regaining pre-dose levels at 16 h. The maximum temporary increase in exposure was 33% (single dose) and 19% (repeated doses) above baseline, but AUC24h remained unaltered. AUC24h increased linearly with dose for 13-cis RA and 13-cis-4-oxo RA. Repeated doses caused a 25% increase in exposure with the highest vitamin A intake. Accumulation of 13-cis- 4-oxo RA at 30,000 IU/day doubled compared to the 4,000 IU/day intake. Conclusion: Repeated oral doses of up to 30,000 IU of vitamin A in addition to dietary vitamin A were without safety concern. Safe doses are probably higher, since plasma concentrations and exposure to RA remained at levels earlier shown to be without increased risk of teratogenicity in pregnant women.

Exposure to retinoic acids in non-pregnant women following high vitamin A intake with a liver meal.

Animal liver is a rich source of vitamin A. Due to retinoic acid (RA) metabolites, vitamin A has a teratogenic potential and women are generally advised to avoid or to limit the consumption of liver during pregnancy. In a recent study in non-pregnant female volunteers following single and repeated doses of up to 30,000 IU/day of vitamin A as a supplement, the plasma concentration time curve of all-trans RA acid showed a diurnal-like profile. But, the overall exposure (AUC24h) remained essentially unaltered whereas AUC24h increased linearly with dose for 13-cis and 13-cis-4-oxo RA. The current study in non-pregnant female volunteers showed that a single high vitamin A intake with a liver meal (up to 120,000 IU) exhibited a similar diurnal-like plasma concentration time curve for all-trans RA and its overall exposure remained also unaltered, despite a temporary two-fold increase in peak plasma concentration. Concentrations of 13-cis and 13-cis-4-oxo RA increased several-fold after a liver meal, and exposure (AUC24h) increased three- to five-fold. Pooling our results with data in the literature revealed a linear relation between the mean AUC24h of 13-cis and 13-cis-4-oxo RA and vitamin A intake with liver. Metabolism to all-trans RA of vitamin A with liver seems not to be of safety concern. However, the observed increase of plasma concentrations and the dose-dependent increase in exposure to 13-cis and 13-cis-4-oxo RA support the current safety recommendations on vitamin A intake and suggest that women should be cautious regarding their consumption of liver-containing meals during pregnancy.

Comparison of Galenic Formulations of Orlistat (Tetrahydrolipstatin)

SummaryOrlistat (tetrahydrolipstatin) reduces absorption of dietary fat by inhibiting lipases in the gastrointestinal tract. Since conventional bioavailability testing by pharmacokinetic methods is meaningless, 2 capsule formulations [containing orlistat as micronised powder (A) or granules (B)] were compared using the following pharmacological end-points: faecal fat excretion after multiple 3-times-daily doses, and 14C-recovery in breath (breath test) and in faeces after single doses administered with 14C-triolein. The study was conducted in 12 hospitalised healthy male subjects at dose levels of 50 and 150mg according to a balanced 4-way crossover scheme. The diet was standardised with an intake of 76g fat per day.Orlistat was generally well tolerated. The few adverse events of moderate intensity were limited to the gastrointestinal tract and were consequences of the pharmacological action of the drug. At the 50 and 150mg doses, respectively, mean faecal fat excretion (% of dietary fat intake) was 29.6 and 35.4% for capsule A, and 30.4 and 37.4% for capsule B. Mean 14C-recovery in faeces (% of 14C-dose) was 52.5 and 56.2% for A, and 50.5 and 62.9% for B. Mean cumulative 14C-excretion in breath after 24 hours (% of 14C-dose) was 17.6 and 13.6% for A and 16.7 and 11.2% for B. At the 50mg dose both capsules were pharmacologically equivalent. At the 150mg dose B showed a trend towards superior efficacy compared with A (p = 0.09). The 150mg doses were significantly more effective (p < 0.05) than the 50mg doses. There were no significant carry-over effects.All investigated end-points yielded consistent results. The 14C-breath test proved to be a reliable and convenient method to assess fat absorption in relative terms and thus to compare galenic formulations of orlistat.

Effect of acitretin on the response to an intravenous glucose tolerance test in healthy volunteers

SummaryThe effect of the synthetic retinoid acitretin (A) on the disposition of blood glucose and on the serum insulin response following the IV infusion of 139 mmol glucose over 10 min (IGTT) has been investigated in six healthy subjects. The IGTT was performed on Days 1, 10 and 24. On Days 3 to 10 A 50 mg/d was administered. Several parameters of glucose disposition and insulin response (K-values, AUC) were assessed. As a methodological variant, the profiles over time of blood glucose and serum insulin were evaluated by model calculations using the ‘minimal model’. Acitretin did not influence any parameter of glucose disposition. The area under the insulin-time curve (baseline corrected) was significantly decreased from 1.20 mU·min·l−1 on Day 1 to 0.89 mU·min·l−1 on Day 10, and was 0.91 mU·min·l−1 on Day 24. The model-derived ‘insulin sensitivity’ increased from 13·10−4 l·mU−1·min−1 on Day 1 to 20·10−4 l·mU−1·min−1 on Day 10 and was 18·10−4 l·mU−1·min−1 on Day 24. The results suggest that A increased sensitivity to endogenous insulin. It supports a recent report showing greater insulin sensitivity in patients treated with the synthetic retinoid etretinate.

SOME KINETIC ASPECTS OF ASCORBIC ACID IN MAN

Publisher Summary This chapter discusses some kinetic aspects of ascorbic acid in man. Data on the turnover and requirements of ascorbatic acid have been based on depletion studies on volunteers. These studies have been of fundamental importance for the estimation of human requirements of vitamin C. However, it can be assumed that they lead to an underestimation of the requirement because the turnover and the pool sizes are calculated in a depleted status of the subjects. Therefore, a kinetic experiment was designed that allows the calculation of these parameters while the subject is in a steady state with regard to ascorbate intake. In this study, several volunteers were equilibrated on different ascorbate intakes by restrictions of the diet and supplementation with subnormal, normal, and increased amounts of ascorbate. The kinetic study revealed a saturation process in the renal handling of ascorbate and indicated that this threshold occurs at a plasma level of about 60–80 mg/100 ml. A low but significant amount of unchanged ascorbate was also recovered from urine at daily turnovers in the range of 30 mg/day.