Clinical experience with Repotin, a locally produced recombinant human erythropoietin, in the treatment of anaemia of chronic renal failure in South Africa.

OBJECTIVE: To evaluate the efficacy and safety of Repotin, a locally produced recombinant human erythropoietin (rHuEPO), in the treatment of the anaemia of chronic renal failure (ACRF). DESIGN: The study consisted of two multicentre non-randomised open stages. SETTING: Renal units at several teaching hospitals in South Africa. PARTICIPANTS: Haemodialysis patients with haemoglobin (Hb) levels less than 8.0 g/dl were recruited. The first stage examined 26 patients during a 12-week period in which the dose of intravenous rHuEPO was adjusted according to haematological response. In the second stage 27 patients were stabilised with intravenous rHuEPO and then maintained at a Hb level above 8.0 g/dl by subcutaneous administration for up to 1 year. OUTCOME MEASURES: In both stages, outcome was measured by clinical examination, blood pressure, full haematological parameters and blood chemistry. RESULTS: In stage 1, all patients responded to therapy with a statistically significant increase in Hb from geometric means of 6.28 g/dl to 8.50 g/dl (geometric SDs of 1.17 and 1.20 respectively). The doses used ranged from 25 IU to 125 IU/kg (average 47.1). In the second stage, Hb levels reached a mean of 8.06 g/dl (SD 0.9) and were maintained at target range with an average dose of 55.5 IU/kg three times a week. Apart from changes in serum iron, ferritin (associated with increased haematopoiesis) and potassium, there were no significant alterations in blood chemistry. The incidence of adverse events reported during the 12-month second stage was no greater than that reported for other forms of rHuEPO therapy. CONCLUSION: Repotin is a safe and effective rHuEPO preparation for the treatment of ACRF.

Wild rodents as laboratory models and their part in the study of diseases.

The paper describes the use of 14 South African wild rodent species as experimental models and demonstrates the proven value of many of these as laboratory animals in research on bacterial infections (plague, relapsing fever), rickettsial infections (tickbite fever, louse typhus), viral infections (poliomyelitis. Rift-Valley fever and other arbovirus infections, Lassa fever), fungal infections (histoplasmosis), parasitic infections (schistosomiasis) and in diabetes mellitus and cancer research.

Growth hormone and prolactin response to bromocriptine in patients with Huntington's chorea.

The growth hormone (hGH) and prolactin (hPRL) responses to oral bromocriptine were studied in two groups of patients with Huntington's chorea and in seven healthy control subjects. The patients included six patients who had previously been treated with phenothiazines and six patients who had not received phenothiazine treatment. All medication was stopped 72 hours before the investigation which involved taking blood samples for up to 210 minutes after taking bromocriptine (2.5 mg). Plasma samples were analysed for hGH and hPRL. There was no significant difference in basal hGH concentrations between the patients and control subjects. The hGH response to bromocriptine varied in the individual patients but the concentrations were significantly lower in the patients compared with the controls between 160 and 210 minutes. The basal concentrations of hPRL were also not different, apart from the findings of elevated hPRL concentrations in three patients previously treated with phenothiazines. The patients and control subjects showed a consistent fall in hPRL concentrations after taking bromocriptine. The lower peak hGH response to bromocriptine found in the patients suggests that there may be an alteration of dopaminergic neurones mediating hGH release.

Metabolic changes during glucose tolerance tests in migraine attacks.

(1) Intravenous glucose tolerance tests have been carried out on 6 migraine sufferers on two occasions. The first study was carried out during a migraine attack and the second was performed in an attack-free period. The patients had fasted overnight and the investigations were carried out in the morning. Samples of venous blood were taken for measurement of concentrations of glucose, lactate, pyruvate, free fatty acids (FFA), glycerol, ketone-bodies, insulin and growth hormone. (2) an impaired tolerance to glucose was found during the migraine attacks compared with the control studies. Elevated ketone and FFA levels were found during the attacks and may have accounted for the glucose intolerance. The elevation of plasma FFA levels during the migraine attacks paralleled changes in blood glycerol concentrations suggesting increased lipolysis during the attacks. Growth hormone and cortisol were raised and insulin was depressed during attacks. (3) Our observations, in which the patients acted as their own controls, imply increased lipolysis during migraine attacks and are in contrast to previously reported studies. The patterns of metabolic and hormonal changes are consistent with a stress response during the attacks and the significance in relation to the causation of the attacks is discussed.

Treatment of epilepsy with clonazepam and its effect on other anticonvulsants.

Clonazepam was added to the treatment of patients with poorly controlled epilepsy in a double-blind trial and an open trial. Considerable improvement occurred with patients with myoclonic jerks and tonic-clonic convulsions, and with photosensitive epilepsy. Patients with atypical petit mal and focal epilepsies also improved. Drowsiness was initially common but lasted only a short time. No evidence was found for an action of clonazepam on the metabolism of other drugs, but treatment with phenobarbitone lowered serum concentrations of clonazepam. We conclude that clonazepam is particularly valuable in epilepsy with associated myoclonsu and in photosensitive epilepsy.

Idiopathic orthostatic hypotension from failure of noradrenaline release in a patient with vasomotor innervation.

A 26 year old man is described with life-long orthostatic hypotension unrelated to autonomic nerve degeneration and apparently due to failure of peripheral noradrenaline realese. Tests of parasympathetic and sympathetic cholinergic nerve function were normal, but sympathetic adrenergic activity was defective. Thus blood pressure regulation was abnoraml. There was no pressor response to tyramine, an indirect sympathomimetic drug, but a marked pressor response to the directly acting sympathomimetic drugs phenylephrine and noradrenaline. On standing there was a progressive fall rather than a rise in circulating noradrenaline concentrations, although adrenaline levels rose normally. The pupils showed diminished responses to ephedrine and cocaine, and a normal response to phenylephrine. Fluorescence microscopy of blood bessels showed that they were innervated with adrenergic nerves. His orthostatic hypotenstion responded well to oral phenylephrine (50 mg five times daily) but not to other forms of therapy. It is suggested that this patient's symptoms were due to failure of noradrenaline release even though sympathetic adrenergic nerves were present. We therfore wish to draw attention to a further cause of orthostatic hypotension, failure of peripheral noradrenaline release without autonomic neuropathy.

Treatment of neurogenic orthostatic hypotension with a monoamine oxidase inhibitor and tyramine.

Six patients with neurogenic orthostatic hypotension were treated with a chemical preparation of tyramine and tranylcypromine ("Parnate"), a monoamine oxidase inhibitor (M.A.O.I.). Four had autonomic failure with no other neurological deficit (idiopathic orthostatic hypotension), and in two patients other neuronal systems were also involved (Shy-Drager syndrome). Previous therapy with fludrocortisone, ephedrine, elastic garments, postural training, and, in one patient, an anti-G suit was unsatisfactory. Tyramine given orally with tranylcypromine produced a moderate rise in blood-pressure which was sustained for 2-4 hours, enabling patients to walk about without symptoms of orthostatic hypotension. Measurement of circulating adrenaline and noradrenaline during therapy suggested that release of noradrenaline caused the pressor response. In three patients there has been a pronounced improvement for 8, 20 and 30 months. In a further patient, therapy has been successful in treating the orthostatic hypotension, although his mobility has been restricted by cerebellar ataxia. In one patient a confusional state developed during treatment and therapy was stopped. The only patient in whom the drugs did not produce a pressor response had orthostatic hypotension with failure of noradrenaline release. It is suggested that the pressor response to a M.A.O.I. and tyramine should be examined in patients with neurogenic orthostatic hypotension and that this treatment should be tried in those who respond.

Altered growth hormone release in Huntington's chorea.

Glucose tolerance tests have been performed on five patients with Huntington's chorea and no difference in response has been observed compared with seven controls. Insulin tolerance tests have been performed on 12 patients with Huntington's chorea and 10 controls. Blood samples were taken at regular intervals for 75 minutes and analysed for blood glucose, insulin, and growth hormone (HGH). There was no difference between the groups in the hypoglycaemia which developed. The patients, however, had an earlier elevation of HGH than the controls. The difference was highly significant (P less than 0.001, P less than 0.02) 30 and 35 minutes after the intravenous injection of insulin. The patients, although awake, ceased to have choreiform movements for at least the last 60 minutes of the insulin tolerance tests. Our observations of HGH release imply that hypothalamic activity is altered in Huntington's chorea. Further observations of HGH release may therefore be of value in its diagnosis.

Treatment of neurogenic orthostatic hypotension with a monoamine oxidase inhibitor and tyramine.

The clinical response of treatment with a chemical preparation of tyramine and tranylcypromine, a monoamine oxidase inhibitor, is described in six patients wit neurogenic orthostatic hypotension. Previous therapy with fluorocortisone, ephedrine, elastic garments, postural training and, in one patient, an anti-G suit was unsuccessful. Oral and intravenous tyramine produced no pressor response. However, after treatment with tranylcypromine five of the patients when supine showed a marked rise of blood pressure to intravenous tyramine which was sustained for over two hours when they stood up. Tyramine given orally with tranylcypromine produced a moderate rise of blood pressure in the supine position which was sustained for over 3-4 hours in the erect position enabling patients to walk about without symptoms of orthostatic hypotension. Measurement of circulating adrenaline and noradrenaline during therapy suggested that the pressor response was due to release of noradrenaline. Three patients have had marked improvement for four, fifteen and twenty-four months respectively. In a further patient, therapy has been successful in treating his orthostatic hypotension although his mobility has been restricted due to cerebellar ataxia. One patient developed a confusional state during treatment and the therapy was stopped. The only patient in whom the drugs produced no pressor response had orthostatic hypotension with evidence of adrenergic innervation of blood vessels, but failure of noradrenaline release. It is suggested that the pressor response to a monoamine oxidase inhibitor and tyramine should be examined in patients to a monoamine oxidase inhibitor and tyramine should be examined in patients with neurogenic orthostatic hypotension in whom conventional therapy is unsatisfactory and those who respond should receive a trial of this treatment.