Pharmacokinetics, pharmacodynamics and bioavailability of the ACE inhibitor ramipril.

The pharmacokinetics and pharmacodynamics of the prodrug ramipril and its active ACE-inhibiting metabolite ramiprilat were investigated in an open, randomised, three-way cross-over study in 12 healthy male volunteers. Subjects received 2.5 mg ramipril orally, 2.5 mg ramipril intravenously and 2.5 mg ramiprilat intravenously. The absolute bioavailability as judged by ramipril plasma AUC was 15%, by ramiprilat plasma AUC, 44%. Ramiprilat formation from intravenous ramipril was 53% and from oral ramipril 28%. Urinary recovery of oral ramipril was 23%, i.v. ramipril 49%, and i.v. ramiprilat 68% of the given dose. Maximum ACE inhibition was highest (100%) after i.v. ramiprilat; it was 99% after i.v. ramipril and 84% following oral ramipril. ACE inhibition over 24 h was highest after i.v. ramipril, 2% less with i.v. ramiprilat and 34% less with oral ramipril. Ramiprilat renal clearance was concentration dependent. The biological availability of ramipril can best be judged by ramiprilat AUC, urinary recovery of ramipril and metabolites, or ACE inhibition over 24 h. It is concluded that the bioavailability of oral ramipril seems to be in the range of 44-66%.

Clinical trials of gene/biotechnology products.

Gene/biotechnology products can be either physiological peptides for the purpose of substitution of deficiencies or for therapeutic purposes in superphysiological concentrations, or nonphysiological peptides, or newer biotechnology products like monoclonal antibodies. The rules for clinical trials developed so far are also valid for clinical trials with gene/biotechnology products. Nevertheless, a major challenge for the clinical pharmacologist is the species specificity of many reactions induced by gene/biotechnology products in man. In general, animal experiments may be less predictive, so there is a greater demand for human pharmacology studies. Gene/biotechnology products offer more chances for treatment of many diseases, but during the clinical trials the clinician has to always be aware of unexpected side effects. Several newer gene technology products offer superior safety as compared to older biological products like Factor VIII preparations and human growth hormone. More than 19 therapeutics produced by gene/biotechnology have already been approved by health authorities all over the world. Major clinical benefit could be shown with hepatitis B vaccine, insulin, human growth hormone, TPA, erythropoietin, GM-CSF, G-CSF, and monoclonal antibodies for immune suppression. There is also good evidence of efficacy of interferon alpha in chronic hepatitis. So far, our knowledge about cytokines is still limited. In several cancer diseases, interferons show efficacy as well as in several autoimmune diseases. Well designed clinical pharmacology studies will be important to elaborate the therapeutic potential of drugs arising from gene/biotechnology.

Recombinant hirudin, a new anticoagulant, has no effect on faecal blood loss.

Hirudin is a selective thrombin inhibitor with strong anticoagulant properties which could elicit gastro-intestinal bleeding. A double-blind cross-over study of the effects of hirudin on gastro-intestinal bleeding was therefore conducted on 12 healthy, consenting males. After labelling erythrocytes with 51Cr and returning them intravenously, stools were collected for 2 days to measure radioactivity and hence baseline faecal blood loss. After injection of hirudin or placebo stools were collected for 3 days. Partial thromboplastin time was measured sequentially after medication with hirudin or placebo. This procedure was repeated after injection of the alternate medication 1 week later. Hirudin was tolerated well. Mean faecal blood loss associated with hirudin was slightly higher than with placebo (1.63 ml vs 1.15 ml over 3 days; 95% confidence interval for the difference between hirudin and placebo was -0.68 to 1.63) but these differences are clinically irrelevant. After hirudin injection PTT was elevated to about twice the baseline values but returned to baseline within 12 h after the last hirudin injection.

The effects of felodipine on the pharmacokinetics of diazepam.

Twelve consenting, caucasian male volunteers participated in a double-blind, randomized, crossover study of the effects of felodipine, a calcium antagonist, on the pharmacokinetics of diazepam. There were two trial periods of 12 days each with a wash-out period of 9 days between them (total duration: 12 + 12 + 9 = 33 days). During the 12-day periods they received either felodipine or placebo each morning under fasting conditions. On day 6 of each of the two 12-day periods, diazepam, 10 mg was injected i.v. 30 minutes after the felodipine/placebo. Diazepam and desmethyldiazepam concentrations were measured in plasma up to 168 hours after the injection. Diazepam plasma concentrations and pharmacokinetic parameters were not affected by the concomitant medication with felodipine. However, the co-administration of felodipine increased desmethyldiazepam plasma concentrations relative to placebo: mean area under the plasma concentration-time curve of 4,910 vs 5,581 ng.h/ml and mean peak concentrations of 40 vs 47 ng/ml. Felodipine might cause a retarded elimination of desmethyldiazepam, possibly by obtruding the formation of oxazepam. The clinical relevance of these findings remains to be elucidated.

Safety, tolerance and pharmacokinetics of cefpirome administered intramuscularly to healthy subjects.

The pharmacokinetics of cefpirome were studied in healthy male subjects following single (0.5, 1.0 and 2.0 g) and multiple (1.0 g every 12 h for 3.5 days) intramuscular injections. High pressure liquid chromatography was used to determine cefpirome concentrations in plasma and urine. Cefpirome was absorbed rapidly, mean peak times were 1.6-2.3 h. Pharmacokinetics were linear over the 0.5 to 2.0 g range with mean total body clearance ranging from 148 to 154 mL/min. The peak plasma concentration and area under the curve increased in a dose proportional manner. The terminal half-life (2 h) was not influenced by dose or duration of dosing. There was no drug accumulation after multiple in administrations. About 70-80% of an administered dose was excreted in the urine as unchanged cefpirome. Cefpirome was well tolerated, slight to moderate pain being reported in less than 30% of the injections.

Pharmacodynamics of methylprednisolone phosphate after single intravenous administration to healthy volunteers.

The pharmacokinetics and pharmacodynamics of methylprednisolone were investigated after intravenous administration of methylprednisolone phosphate to healthy subjects at seven different doses (16 to 1000 mg). Forty different pharmacodynamic parameters were followed for 1 week. The pharmacodynamic data were analyzed as a function of time as well as cumulative effects in form of the areas under the effect-time curves. Statistically significant dose-dependent effects of methylprednisolone were observed for 15 pharmacodynamic parameters. Highly significant (P less than or equal to 0.0001) effects were increases in glucose levels, number of white blood cells, and segmented granulocytes as well as a decrease in the number of lymphocytes. For these pharmacodynamic effects an integrated pharmacokinetic/pharmacodynamic model was derived that translates the methylprednisolone plasma concentration-time profiles into effect-time profiles. This model allows prediction of pharmacodynamic effects for any single dose in the range studied at any time point.

The pharmacology of recombinant hirudin, a new anticoagulant.

A new anticoagulant, recombinant hirudin, was given to healthy volunteers (5 per test dose) in single intravenous doses of 0.01, 0.02, 0.04, 0.07 and 0.1 mg/kg to study its anticoagulant effects, how it was tolerated and its pharmacokinetics. Hirudin proved to be a potent anticoagulant with important effects on thrombin (increase in thrombin time and partial thromboplastin time). The maximum pharmacodynamic effect was achieved with the 0.07 mg/kg dose, and upwards. All doses of the compound were tolerated without side-effects. The mean elimination half-life is about 1 hour. Mean total clearance and volume of distribution are approximately 190 ml/min and 14 l, respectively. Hirudin obeys first-order pharmacokinetics.

Aclarubicin: experimental and clinical experience.

Aclarubicin, discovered by Umezawa in 1975, is a new cytostatic anthracycline antibiotic. It is one of the anthracyclines with the lowest cardiotoxicity, it is not mutagenic and it stimulates differentiation of tumour cells. The therapeutic index of aclarubicin (efficacy related to toxicity) is higher than that of doxorubicin and daunorubicin, using a proper dose schedule. Single dose therapy of aclarubicin shows only marginal efficacy, whereas multiple divided dose therapy exhibits efficacy comparable to that of doxorubicin and daunorubicin. Thus for clinical trials two dose schedules were designed: 25 mg/m2/day, days 1-7 for acute leukaemia; and 30 mg/m2/day, days 1-4 for solid tumours. Aclarubicin was shown to be highly active in acute leukaemia with 58% complete remissions in first relapse of AML. Good results were also seen in acute leukaemia in combination with cytosine arabinoside and thioguanine. In clinical trials with breast cancer and thyroid cancer the efficacy was in the same range as would be expected for doxorubicin, but side-effects were markedly reduced. Anorexia, mild nausea and infrequent vomiting were observed. Myelosuppression was common but dose reduction was not necessary. There was no alopecia and no congestive heart failure.

Interferon-beta in patients with low-grade astrocytomas--a phase I study.

In 3 patients with low-grade astrocytomas clinical pharmacology of interferon-beta (10(7) U/mg protein) was investigated. Interferon-beta with escalating dosage (2.3, 6.9, 23, 69 X 10(6) U/patient) was given to each patient in 4 infusions at weekly time intervals. In these patients dose-dependent plasma-levels of interferon-beta of up to 5800 IU/ml were achieved. Plasma concentrations showed a biphasic decline (T1 1/2:0.095-0.49 hrs and T2 1/2: 5-14.5 hrs). Side effects were: mild fatigue, myalgia, tachycardia, hypertension, and fever; the latter was well controlled by pretreatment application of paracetamol. Hematological changes included lymphopenia (2-6 hrs after infusion) and granulocytosis (3-6 hrs after infusion). Natural Killer cell activity was also monitored: 6 hours after infusion a drop of activity - not clearly dose dependent - was observed to a minimum of 1% pretreatment activity; 24 hrs after infusion activity increased up to a maximum of 400%. In this phase I study high biological activity of interferon-beta could be detected in plasma of astrocytoma patients - clinical tolerance was good and only mild toxicity was observed.

Excretion of total and muscular N tau-methylhistidine and creatinine in muscle diseases.

The daily urinary excretions of N tau-methylhistidine and creatinine from 52 adult patients were measured under standardized conditions. The ratio of N tau-methylhistidine to creatinine excretion was calculated on the basis of the total and muscle-specific excretion rates and correlated to the clinical status of the patients. In patients with muscular diseases and in those with diseases of the central nervous system, the total daily excretion of both metabolites was about 30% lower than in controls. The muscle-specific ratio in patients with diseases of the central nervous system and patients with muscular diseases was not different from that observed in controls. Only in patients with neurogenic atrophies was the ratio elevated, so that it was more than twice the control value. The ratio of excreted N tau-methylhistidine/creatinine is only valid as an indicator of myofibrillar protein breakdown after correction for the contribution of nonskeletal muscle tissues to the urinary excretion.

Quantitative importance of non-skeletal-muscle N tau-methylhistidine and creatine in human urine.

The excretion of N tau-methylhistidine and creatinine was determined in a totally paralysed patient wih neither macroscopic nor microscopic detectable skeletal-muscle tissue. In this subject, it was possible for the first time to measure the basal non-skeletal-muscle-dependent excretion of N tau-methylhistidine and creatinine per 24 h and per kg of non-muscular body weight, 1.15 mumol (N tau-methylhistidine) and 35 mumol (creatinine) respectively. For the calculation of myofibrillar protein breakdown and skeletal-muscle mass on the basis of N tau-methylhistidine and creatinine excretion, the values have to be corrected for non-muscular sources. Our data show that skeletal-muscle tissue is the major contributor of N tau-methylhistidine in urine, since it contributes as much as 75% to the urinary excretion.

[Diabetic amyotrophy--a polygenetic syndrome (author's transl)]. / Die diabetische Amyotrophie--ein polygenetisches Syndrom.

Detailed clinical and biochemical investigations were done in 14 patients with the syndrome of diabetic amyotrophy. Three patients suffered from manifest insulin-dependent diabetes, five had only diminished glucose tolerance. Simultaneously, excretion of creatinine was reduced indicating reduction of healthy muscle mass. In these cases disturbance of glucose tolerance must be considered symptom and not cause of amyotrophy. Further investigations revealed neoplasia (n = 2), generalised amyloidosis (n = 3), polycythaemia vera (n = 1), chronic infectious disease (n = 3), and motor neuron degeneration (n = 3). The attribute "diabetic" must not bea considered representing a single cause in this connection. With treatment aimed at more than one factor, satisfactory results of therapy may be expected in the majority of cases.

Insulin effect on proteolytic activities in rat skeletal muscle.

Proteolytic activity has been measure in rat skeletal muscle by use of [14C]-hemoglobin as substrate. The activity of the alkaline proteinases increases during starvation and in diabetic state. In streptozotocin-diabetic animals the activity of alkaline proteases increases to 300% over a time of 21 days. Insulin treatment reverses the enhanced enzyme activity to normal level.