[Serum digitoxin in concomitant use of antiepileptics in routine therapy]. / Serum-digitoksin ved samtidig bruk av antiepileptika i rutinebehandling.

Concomitant use of digitoxin and enzyme-inducing antiepileptics may lower serum levels, and accordingly the effect of digitoxin, unless the higher metabolic clearance is compensated for by higher dosage. Use of digitoxin is almost always guided by serum concentration measurements. Information on a possible enzyme-inducing effect of phenobarbital, phenytoin and carbamazepine is easily accessible. Compilation of serum level measurements for digitoxin showed that serum levels shifted towards lower values during concomitant use of phenytoin or carbamazepine than when digitoxin was used alone. As a consequence, the fraction of patients with serum levels below the therapeutic range was doubled. Concomitant use of phenobarbital did not cause a shift in the levels of digitoxin. In fact, in this group, a larger fraction of the serum level measurements were within the therapeutic range. Thus, the dosage of digitoxin appears to be fully compensated during concomitant use of phenobarbital, but obviously deserves attention during concomitant use of phenytoin or carbamazepine.

Ex vivo ras peptide vaccination in patients with advanced pancreatic cancer: results of a phase I/II study.

In a pilot I/II study we have tested synthetic ras peptides used as a cancer vaccine in 5 patients with advanced pancreatic carcinoma. The treatment principle used was based on loading professional antigen-presenting cells (APCs) from peripheral blood with a synthetic ras peptide corresponding to the ras mutation found in tumour tissue from the patient. Peptide loading was performed ex vivo and the next day APCs were re-injected into the patients after washing to remove unbound peptide. Patients were vaccinated in the first and second week and thereafter every 4-6 weeks. In 2 of the 5 patients treated, an immune response against the immunising ras peptide could be induced. None of the patients showed evidence of a T-cell response against any of the ras peptides before vaccination. The treatment was well tolerated and could be repeated multiple times in the same patient. Side effects were not observed even if an immunological response against the ras peptide was evident. We conclude that ras peptide vaccination according to the present protocol is safe and may result in a potentially beneficial immune response even in patients with advanced malignant disease.

Dietary supplement of omega-3 fatty acids has no effect on acute collagen-induced thrombus formation in flowing native blood.

We have studied the effect of a daily supplement of 2.4 omega-3 fatty acids (omega 3 FAs) to 16 healthy men on acute collagen-induced thrombus formation in flowing non-anticoagulated blood. The supplement was formulated as Triomar capsules, containing 60% omega-3 FAs with an eicosapentaenoic/docosahexaenoic acid ratio of 3/2. A parallel-plate perfusion chamber device was used to study thrombus formation prior to and after 3 months of omega-3 FAs supplement. The wall shear rates at the thrombogenic surface were 650, 2,600 and 10,500 s-1, which are typical for small arteries, slightly stenosed arteries and severely stenosed arteries, respectively. For the latter situation a parallel-plate perfusion chamber with an eccentric stenosis occluding 80% of the cross-sectional area of the blood flow channel was used. The dietary supplement of omega-3 FAs did not cause significant changes in platelet adhesion to collagen or in thrombus volume. However, fibrin deposition was reduced by 34% (P < 0.03) at the highest shear condition (stenosis). Plasma fibrinogen was reduced by 18% (P < 0.0006). Changes in serum concentration of triglycerides, total-cholesterol, LDL- and HDL-cholesterol were not significant. Our data suggest that a moderate intake of omega-3 FAs provides virtually no protection against acute platelet-dependent thrombus formation, irrespective of the shear conditions. However, the significant reduction in plasma levels of fibrinogen following dietary supplementation of omega-3 FAs may be important, since high levels of fibrinogen is associated with cardiovascular disease and thrombosis.

Triiodothyronine and brain excitability.

We investigated mechanisms involved in thyroid hormone action on brain excitability. The effect of acute exposure of triiodothyronine (T3) to rat hippocampal slices in vitro was studied. No significant changes could be detected in prevolley, field excitatory postsynaptic potentials (fEPSP) and population spike amplitude, while there was a minor, nonsignificant trend toward shortening of the population spike latency time. T3 had no effect on penicillin-induced epileptiform activity. There was, however, an active accumulation of radioactively labeled T3 in the slices. A rat cervaux-isolé preparation was used to determine focal seizure thresholds in the visual cortex, and no acute (2-4 h) effects were demonstrated. No significant acute effects of T3 on brain excitability in the hippocampus and visual cortex was observed, despite an active accumulation of T3. Thus, the effect of T3 on brain excitability most likely is due to delayed effects.

Follicle-stimulating hormone as a prognostic indicator in clomiphene citrate/human menopausal gonadotrophin-stimulated cycles for in-vitro fertilization.

Follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestradiol and prolactin levels were studied in a sequential clomiphene citrate/human menopausal gonadotrophin (CC/HMG) regimen for in-vitro fertilization. At completion of CC administration, the median FSH level in 44 cancelled cycles was elevated compared to a control group of 65 completed cycles, 29 IU/l versus 15 IU/l, P less than 0.01. Also the median FSH/LH ratio was higher in the cancelled cycles than in the control group, 1.08 versus 0.71, P less than 0.05. Conversely, the median oestradiol level was lower in the cancelled cycles than in the completed cycles, 0.27 nmol/l versus 0.59 nmol/l, P less than 0.01. No difference was seen in the median LH and prolactin levels. An FSH value above the 95% confidence limit was found in 24 of the cancelled cycles, but in only two of the completed cycles. Based on this study, an elevated FSH value following CC administration predicts a poor response to further stimulation with an accuracy of 92.3% and should result in cancellation of the cycle.

CQP 201-403, a new dopamine agonist in the treatment of hyperprolactinemia.

Current drugs used for hyperprolactinemia may have severe side effects. Effects and side effects of a new propylergoline derivate (CQP 201-403 SANDOZ) have been evaluated. Twenty-four otherwise healthy women (21-44 years) with hyperprolactinemia (35-318 micrograms/l) without extrasellar extension of pituitary adenomas took part in a randomized, double-blind study. Fasting prolactin levels measured on day 7 was significantly decreased when compared with day 1 (P less than 0.05) in all CQP groups, to 78% with 0.005 mg daily, to 40% with 0.015 mg daily, and to 27% with 0.025 mg CQP per day for one week. The levels in the control group did not change (96%). The area under the curve of the prolactin day curve (1-8 h after drug administration) decreased significantly (P less than 0.05) at all doses when day 7 was compared with day 1, to 77% with 0.005 mg, to 51% with 0.015 mg, and to 37% with 0.025 mg CQP. No change was seen in the control group (96%). Four patients (one on 0.005 mg, one on 0.015 mg, and two on 0.025 mg) experienced orthostatic hypotension while standing blood pressure was to be measured on the first day of treatment, and they had to lie down. CQP 201-403 lowers prolactin levels in hyperprolactinemic women at all doses employed. The effect was seen after the first dose of treatment, and lasted for at least 24 h. The adverse reactions are few and tolerable, and might be less than with current bromocriptine therapy.

Effects of electroconvulsive therapy (ECT) on thyroid function parameters.

Serum concentrations of thyroxine, triiodothyronine, TSH and prolactin were measured in 10 patients with affective disorders receiving ECT. Samples were drawn at -15 min, 0, +30 min, +60 min and +3 hr after ECT. A significant increase in both prolactin and TSH was observed 30 min after ECT. A small but significant decrease in triiodothyronine but no change in thyroxine was found in all post-ECT samples. The increase in TSH may be caused by an anti-dopaminergic effect of ECT at either the pituitary or the hypothalamic level.

Association between regularly occurring complex partial seizures and thyroid function parameters.

A 28-year-old man with regularly occurring clusters of complex partial seizures was studied over a total of 224 days. His seizure periods lasted 2-4 days and occurred at intervals of 5-6 weeks. Several parameters were studied. The most striking finding was an increase in the serum concentration of thyroxine prior to and during the seizure periods. The concentrations of urine catecholamines and serum cortisol also varied with the seizure periods, but these hormones increased after the seizure periods had begun. To determine if there is a general 4-6-week rhythm in thyroid hormone concentrations, 12 weekly blood samples from 10 healthy male students were analyzed. No rhythmicity was found.

No monthly variations in serum levels of thyroid hormones in human males.

There have been very few reports on rhythmic variation in thyroid hormone concentrations with a periodicity of 4-6 weeks. In an attempt to evaluate whether such a rhythm is a general phenomenon we studied ten healthy male students with weekly blood samples over 12 weeks for T4, T3 and TSH. No rhythmicity could be demonstrated.

Formation of prostanoids in human umbilical vessels perfused in vitro.

Four major prostanoids (6-keto-PGF1 alpha, PGE2, PGF2 alpha and TXB2) were measured by specific radioimmunoassays in the outputs from human umbilical vessels perfused in vitro. As evaluated by scanning electron microscopy (SEM) only few blood platelets were attached to the vessel wall. After an initial flush with decreasing concentrations of all four prostanoids, a stable stage was reached, lasting for 4-5 hours. During this stage the production could be inhibited by indomethacin and only slightly stimulated with arachidonic acid. The TXA2 synthetase inhibitor UK 38485 depressed the TXB2 production, while only slightly affecting the other three prostanoids at very high concentrations. The arteries produced relatively more 6-keto-PGF1 alpha than did the vein.

Changes in plasma and red cell volumes during exposure to high altitude.

Training at moderate altitude has been used by athletes to improve the performance at sea level. Not all athletes benefit from altitude training, and there also has been some doubt as to whether red cell volume increases in all subjects. Ten members of the Norwegian Everest Expedition 1985 took part in the present study. Plasma volume was determined by isotope dilution, using 125I-albumin. By simultaneous measurement of hematocrit the total blood volume and red cell volume were calculated. Measurements were done in Oslo (sea level) before departure, and in Base Camp (5300 m) four weeks later. The mean altitude during these four weeks was 4100 m. Red cell volume increased in all participants, and excessively in two of them. Since plasma volume decreased in four subjects, the change in total blood volume was less consistent. In one climber dehydration led to a decrease in total blood volume. While a significant correlation was found between maximal oxygen uptake and red cell volume at sea level, the hematologic response to altitude seemed independent on physical fitness. In one climber the erythropoietic response was so excessive (more than 50% increase in red cell volume), that he had to be hemodiluted.

Altered angiotensin-prostanoid interactions in umbilical arteries in pregnancy-induced hypertension.

The production rate of four prostanoids (PGE2, PGF2 alpha, 6-keto-PGF1 alpha and TXB2) in human umbilical cords from normal pregnancies (control) and cases with pregnancy-induced hypertension (PIH) were compared. The cords in the PIH-group produced significantly less 6-keto-PGF1 alpha and more TXB2 than did those in the control-group. Production rates of PGE2 and PGF2 alpha were almost equal in the two groups. After stimulation with angiotensin II the PIH-cords displayed a far smaller increase in 6-keto-PGF1 alpha production compared to the control cords. The responses in PGE2 and PGF2 alpha production were again equal in the two groups. The present results indicate that the angiotensin-prostanoid interactions are disturbed in fetal as well as in maternal vessels. Such a disturbance may explain the observed relative hypersensitivity to angiotensin II observed in gravidae prone to develop pregnancy-induced hypertension.

Reduced cerebral blood flow in high altitude climbers.

Cerebral blood flow (CBF) was studied by 133Xe inhalation dynamic single photon emission computer tomography in 8 members of a climbing expedition to the Himalayas. With one exception they had all previously climbed at high altitudes. All stayed above 6,500 m for approximately 3 weeks, and 5 reached the summit of Mt. Everest. CBF was measured in Oslo before, immediately after, and one year after the completion of the expedition. Measurements were made at rest and following the injection of 1 g acetazolamide intravenously. As reference group was used 13 healthy male subjects of similar age from the hospital staff. Ten age-matched male diving instructors formed a second control group. In the climbers a small, but not significant reduction in CBF was seen after the expedition. On the other hand, they had significantly lower CBF than reference subjects already before the expedition. The flow difference was most pronounced corresponding to the perfusion territory of the middle cerebral artery. One year after the completion of the expedition the average CBF in climbers was still more than 15% lower than in the reference group. The climbers had higher relative flow increase after acetazolamide injection than the reference subjects, showing that the functional capacity of the microvascular system of the brain was intact. Whether neuronal activity or number of neurones is reduced in climbers proportional to the decrease in flow, or maintained at normal level by increased oxygen and glucose extraction, cannot be answered by the present data.

Plasma HDL cholesterol and the in vitro esterification of cholesterol.

In vitro esterification of plasma cholesterol was measured in twelve healthy subjects, six of whom had high plasma concentrations of high density lipoprotein (HDL) cholesterol, whereas the other six had low concentrations. Irrespective of the method used no difference between the groups with the respect to cholesterol esterification could be demonstrated. This may indicate that the beneficial effect of HDL on the development of atherosclerotic disease works thorugh other mechanisms than by facilitating the transport of cholesterol from peripheral tissues to the liver.