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A HPLC method with automated column switching and UV detection is described for the simultaneous determination of retinol and major retinyl esters (retinyl palmitate, retinyl stearate, retinyl oleate and retinyl linoleate) in human plasma. Plasma (0.2 ml) was deproteinized by adding ethanol (1.5 ml) containing the internal standard retinyl propionate. Following centrifugation the supernatant was directly injected onto the pre-column packed with LiChrospher 100 RP-18 using 1.2% ammonium acetate-acetic acid-ethanol (80:1:20, v/v) as mobile phase. The elution strength of the ethanol containing sample solution was reduced by on-line supply of 1% ammonium acetate-acetic acid-ethanol (100:2:4, v/v). The retained retinol and retinyl esters were then transferred to the analytical column (Superspher 100 RP-18, endcapped) in the backflush mode and chromatographed under isocratic conditions using acetonitrile-methanol-ethanol-2-propanol (1:1:1:1, v/v) as mobile phase. Compounds of interest were detected at 325 nm. The method was linear in the range 2.5-2000 ng/ml with a limit of quantification for retinol and retinyl esters of 2.5 ng/ml. Mean recoveries from plasma were 93.4-96.5% for retinol (range 100-1000 ng/ml) and 92.7-96.0% for retinyl palmitate (range 5-1000 ng/ml). Inter-assay precision was < or =5.1% and < or =6.3% for retinol and retinyl palmitate, respectively. The method was successfully applied to more than 2000 human plasma samples from clinical studies. Endogenous levels of retinol and retinyl esters determined in female volunteers were in good accordance with published data.

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A still unresolved public health concern is that excessive vitamin A intake, like vitamin A deficiency, possibly causes birth defects not only in animals but also in man. Due to the low incidence of possibly vitamin A-related malformations in man, available data cannot convincingly define the upper safe limit of periconceptional vitamin A intake. Direct human intervention studies are not feasible for ethical reasons. Therefore, a novel approach in addressing this issue was chosen by combining teratogenicity data from a validated animal model with data on systemic exposure to vitamin A and its major metabolites in female volunteers. In a study in pregnant women endogenous plasma concentrations of vitamin A metabolites during early pregnancy ranged from 0.26 to 7.72 ng/ml. Since they did not cause any foetal malformations, retinoid plasma levels in this range can be considered non-teratogenic. Results of a trial in non-pregnant women document that daily oral vitamin A supplements of 4000, 10,000 and 30,000 IU given for 3 weeks were in the range or slightly above the range of endogenous plasma levels seen in early pregnancy. Even after a 3-week treatment with 30,000 IU/day, peak plasma levels of retinoic acid and isotretinoin were within or just slightly above the range of their physiological levels. In cynomolgus monkeys (average weight: 3-4 kg), a NOAEL (no observed adverse effect level) of 7500 IU per kg body weight and a LOAEL (lowest observed adverse effect level) for developmental toxicity of 20,000 IU/kg was found. Considering these results in the cynomolgus monkey, a dose of 30,000 IU/day should also be considered as non-teratogenic in man.

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The objective of the review is to determine whether preformed vitamin A (retinol and retinyl esters) is teratogenic at dosages commonly used by women living in industrialized countries. Published human and animal data and research developed by the authors are reviewed. It is well known that vitamin A is essential for normal reproduction and development. Although doses of 10,000 IU/d or less of preformed vitamin A (retinyl esters and retinol) are considered safe, doses > 10,000 IU/d as supplements have been reported to cause malformations in a single epidemiologic study. Nonhuman primate data show no teratogenicity at doses of 30,000 IU/d. Daily periconceptional exposures greater than 25,000 IU/d of preformed vitamin A have not been sufficiently studied to establish specific risk. Because no study reports adverse effects of 10,000 IU/d preformed vitamin A supplements and this dose is more than the Recommended Dietary Allowance for pregnant women (2670 IU or 800 RE/d), we recommend that women living in industrialized countries or who otherwise have nutritionally adequate diets may not need to ingest more than the Recommended Dietary Allowance of preformed vitamin A as supplements. If periconceptional vitamin A exposures to levels up to 30,000 IU/d (9,000 micrograms RE/d) do occur unintentionally, multiple animal studies do support only very low risk. Human epidemiologic studies do not establish at what level vitamin A becomes teratogenic; however, pharmacokinetic data presented in this paper indicate that blood levels of retinoids from women taking 30,000 IU/d of preformed vitamin A are not greater than retinoid blood levels in pregnant women during the first trimester who delivered healthy babies. Interestingly, neither teratogenicity nor vitamin A toxicity has been observed in multiple species exposed to high doses of beta-carotene.

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1. The acidic retinoid, acitretin, was esterified to etretinate (ethyl ester) by rat and human liver 12,000 g supernatant. The amount of etretinate formed was increased by adding ethanol to the rat preparation. 2. This esterification almost certainly involves enzymic catalysis, and the amounts of etretinate formed were increased by the use of fresh rat liver. 3. Co-administration of acitretin and ethanol to rats resulted in a maximum plasma concentration of etretinate at approximately 1 h after dosing. Secondary maxima were induced by administering ethanol alone at 5 and 8 h after dosing with acitretin. 4. Comparison of acitretin and etretinate concentrations in rat portal and jugular vein plasma after ethanol administration indicated that the ester was formed mainly systematically, rather than during absorption. 5. The results of our study in the rat could indicate that the presence of etretinate in plasma of some patients being treated with acitretin may result from the intake of alcohol.

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Formation of etretinate, ethyl ester of acitretin, can be confirmed in vitro and in vivo using acitretin as the substrate. Etretinate was identified by LC/MS. The in vitro incubation was performed using rat and human liver 12,000 g supernatant, and the in vivo experiment was conducted in rats after oral dosing of acitretin. The ethyl ester formation was greatly enhanced by addition of or dosing with ethanol.

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In clinical pharmacology studies, cilazapril, after its bioactivation to cilazaprilat, was characterised as a potent, reversible angiotensin converting enzyme (ACE) inhibitor with a terminal half-life of 30 to 50 hours, which is consistent with saturable binding to ACE. Despite the arterial vasodilatation, only slight increases in heart rate occurred during cilazapril administration. Cilazapril had no acute effect on cardiovascular reflexes, and increased effective renal plasma flow slightly. Glomerular filtration rate remained unaltered. A close positive correlation was found between the cilazaprilat plasma concentration and degree of ACE inhibition. The potency of cilazaprit, defined as the concentration of cilazaprilat causing 50% inhibition of ACE, was approximately 1 microgram/L plasma. In short term studies in patients with hypertension, it appeared that more than 90% inhibition of plasma ACE was needed to obtain blood pressure reduction. Results of various dose-response studies established the indirect relationship between dose, the plasma concentration of the drug, and the blood pressure response, and identified the dose producing the maximal effect to be 5mg. Cilazapril inhibited ACE for a relatively long period which was extended in patients with severe chronic renal impairment or hepatic failure. In these patients a reduction of the dose and/or less frequent administration is recommended. There was no clinically relevant interaction of cilazapril with food, furosemide (frusemide), digoxin or coumarins. The effects of hydrochlorothiazide on sodium and chloride excretion were potentiated by cilazapril, and an additive effect of propranolol and nitrendipine on the blood pressure response to cilazapril was observed. An interaction with indomethacin and cilazapril might occur, potentially reducing the blood pressure-lowering effect of cilazapril. In general, cilazapril was well tolerated.

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In clinical pharmacology studies cilazapril, after its bioactivation to cilazaprilat, was characterized as a potent, reversible angiotensin-converting enzyme (ACE) inhibitor with a terminal half-life of 30 to 50 hours consistent with saturable binding to ACE. Despite the arterial vasodilation, only slight increases in heart rate were found. Cilazapril had no acute effect on cardiovascular reflexes. Cilazapril increased effective renal plasma flow slightly. Glomerular filtration rate remained unaltered. A close and steep correlation between cilazaprilat plasma concentration and ACE inhibition was found. The potency of cilazaprilat, defined as the concentration of cilazaprilat causing 50 percent ACE inhibition, was approximately 1 ng/ml plasma. In short-term studies in hypertensive patients, it appeared that more than 90 percent of plasma ACE inhibition is needed to obtain blood pressure reduction. The result of various dose-response studies established the indirect relationship between dose, plasma concentration of the drug, and the blood pressure response and identified the dose producing maximal effect (i.e., 5 mg). Cilazapril had relatively long-lasting effects on ACE inhibition. In patients with severe chronic renal impairment or hepatic failure, the duration of ACE inhibition of cilazapril was prolonged. In these patients a reduction of the dose and/or less frequent dosing is recommended. There was no clinically relevant interaction of cilazapril with food or furosemide. The effects of hydrochlorothiazide on sodium and chloride excretion were potentiated by cilazapril. An additive effect of propranolol and nitrendipine on the blood pressure response to cilazapril was observed. An interaction with nonsteroidal anti-inflammatory drugs and cilazapril might occur, potentially reducing the blood pressure lowering effect. In general cilazapril was well tolerated.

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1. The pharmacokinetics, hormonal and haemodynamic responses at rest and during challenges with angiotensin I (blood pressure), isoprenaline (heart rate), and noradrenaline (blood pressure) were investigated in six healthy male volunteers following a 1 week treatment with placebo, propranolol (120 mg day-1), cilazapril (2, 5 mg day-1), and a combination of both in a double-blind cross-over design. 2. Both drugs reduced systolic and diastolic blood pressure by about 7 mm Hg as compared with placebo. After coadministration, this drop in blood pressure was doubled and lasted longer than after the administration of the individual components. 3. Following cilazapril, a pronounced increase in plasma renin activity (PRA) was found (factor approximately 10 at drug peak concentrations). Coadministration of both drugs resulted only in a moderate increase in the PRA (factor approximately 3). Significant changes in plasma catecholamines were not observed. 4. Propranolol shifted the isoprenaline dose-effect curve to the right, and cilazapril that of angiotensin I, irrespective of the presence of the other drug. Cilazapril tended to shift the noradrenaline dose-effect curve somewhat to the right. 5. The gain of the baroreceptor reflex (angiotensin-stimulation) was not influenced by cilazapril but was lowered by propranolol, irrespective of the presence of the ACE inhibitor. 6. Except for a statistically not significant decrease in the peak concentrations of each drug during the combined therapy, a pharmacokinetic interaction between the two drugs was not found.

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Plasma concentrations of free fatty acids (FFApl) can be used as a parameter to measure stress. The present study aimed to evaluate the changes in the concentration of FFA during perioperative stress caused by minor elective surgery under a standard anaesthetic technique using enflurane. The premedication administered included heptabarbital on the preoperative night and morphine with promethazine prior to the transfer of the patient to the theatre. Blood samples for the analysis of FFA were obtained from 12 patients at the following times: 1 day preoperatively (control, c), prior to induction of anaesthesia (s1), following the administration of thiopentone (s2), following tracheal intubation (s3), 10 min after the commencement of enflurane administration (s4), following surgical incision (s5), intraoperatively (s6), following extubation (s7), 1 h after extubation (s8), and on the 1st postoperative day (s9). FFA were extracted from plasma with hexane and analysed in duplicate by a specific and sensitive gas-chromatographic assay with flame ionisation detection using pentadecanoic acid as the internal standard. All FFApl from the preoperative day (c) were within normal range. FFA concentrations at s1, s2, s3 and (to a lesser extent) at s4 were statistically significantly increased compared to control values. The maximum concentration of FFA in plasma occurred at s2. A decrease from this maximum was found in samples s4, s5 and s6 (the latter was the minimum intraoperative FFApl). The FFApl levels at s7, s8 and s9 were similar to control. A different response was found for each individual free fatty acid. The maximum increase ranged from 40% (stearic acid) to 300% (oleic acid).(ABSTRACT TRUNCATED AT 250 WORDS)

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Hepatic extraction of organic nitrates, including that of isosorbide dinitrate (ISDN), has been thought to be nearly complete in man but has never been directly measured. We examined the time course of plasma ISDN and metabolite concentrations in arterial and hepatic venous blood in four cardiac patients receiving an intravenous ISDN infusion. Apparent hepatic extraction of ISDN was high (90%) at the beginning of infusion but fell to about 44% 1 hr after termination of infusion. The decrease in ISDN concentration gradient across the liver correlates with an increase in plasma isosorbide-5-mononitrate concentration, but a cause-and-effect relationship resulting from metabolite inhibition cannot be established. The time-averaged hepatic extraction of ISDN, at about 70%, agreed with its oral bioavailability in patients.

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Isosorbide dinitrate (ISDN) kinetics and dynamics were examined after various routes of administration for angina. Given intravenously, ISDN kinetics were apparently linear over the range of infusion rate (0.083 and 0.133 mg/min) and duration (15 min and 1 and 2 hr) studied. Mean +/- SD systemic clearance of ISDN was 3.4 +/- 1.4 l/min and volume of distribution (VdSS or Vdarea) about 100 l. These data are consistent with the presence of extensive extrahepatic metabolism. In six patients, sublingual ISDN (5 mg) was also given and mean bioavailability of 59% (19% to 93%) for this route was determined. For this group, sublingual absorption of intact ISDN was incomplete and variable. The presence of a longer disappearance t 1/2 after sublingual dosing suggested that the input process may be rate limiting. After percutaneous application of a topical formulation (100 mg over an area of 400 cm2), steady-state plasma concentrations at about 7 ng/ml were maintained from 6 to 24 hr. The bioavailability of the topical application was estimated at 30%. At the doses given, intravenous ISDN had no apparent effect on heart rate but induced significant reduction in standing systolic blood pressure. The effect vs the ISDN concentration profile was described by a hysteresis loop, indicating that changes in blood pressure response lag behind changes in plasma ISDN concentration. After intravenous dosing, peak plasma ISDN concentration and peak effect (maximum change in standing systolic blood pressure). At the doses used, both sublingual and percutaneous ISDN induced less distinct circulatory changes than the intravenous infusion.

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The elimination kinetics of alinidine and the changes in heart rate and blood pressure were determined in five health subjects following intravenous and oral administration of single doses of 40 mg alinidine. The plasma concentration after the intravenous injection declined at least biexponentially with time, with mean half-lives of 0.6 +/- 0.15 h and 3.9 +/- 0.28 h for the distribution and the elimination phase, respectively. The mean total clearance amounted to 40.3 +/- 8.9 L/h and the renal clearance to 33.6 +/- 12.3 L/h. The bioavailability following oral administration was nearly complete (0.92 +/- 0.06). Alinidine produced a modest bradycardia effect in healthy subjects. The maximal decrease in the heart rate was 19.2 +/- 7.7% (p less than 0.05) and 14.2 +/- 8.1% (p less than 0.05) following intravenous and oral administration, respectively. Time intervals in surface electrocardiogram (duration of the P- wave, PG time, QRS duration, and QTc) were not significantly altered by alinidine after both routes of administration. There was also a slight but consistent decrease in the systolic blood pressure (3-8%) after both routes of administration, whereas the diastolic blood pressure remained unchanged.

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The purpose of this investigation was to determine the effect of heparin-induced endogenous inhibitors of plasma protein binding on the plasma concentrations of total (free plus bound) and free bilirubin in rats with experimental hyperbilirubinemia. Adult male rats received constant-rate intravenous infusions of bilirubin and, after attaining steady state, were given either an intravenous injection of heparin, 500 units/kg, or this injection plus a maintenance infusion of hepatin. Control animals received normal saline solution instead of heparin. The free fraction of bilirubin in plasma increased substantially within 2 min after heparin injection and remained elevated when heparin concentrations were sustained by infusion of the anticoagulant. Despite the decreased plasma protein binding of bilirubin, the plasma concentration of total bilirubin did not decrease (as it does, consistent with pharmacokinetic theory, following injection or infusion of certain other inhibitors of bilirubin binding) and the plasma concentration of free bilirubin did not return to normal (as observed previously after administration of other binding inhibitors) but remained elevated. These results are consistent with the recently demonstrated rapid and extensive hepatic extraction of heparin-induced endogenous inhibitors of plasma protein binding. The heparin interaction with bilirubin may be particularly serious because of the sustained elevation of free bilirubin concentrations in plasma and the potential neurotoxicity of free bilirubin.

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