Roy Spector

Pharmacokinetics of intravenous glibenclamide investigated by a high performance liquid chromatographic assay.

SummaryA simple high performance liquid Chromatographic assay for the determination of plasma glibenclamide concentrations is described. This resolved glibenclamide from normal plasma constituents. The calibration curve of the assay was linear over the range 10–500 μg/1 and the minimum level of detection was 2 μg/1. Within-assay coefficients of variation were 11.6% (20 μg/1); 5.3% (50 μg/1); 6.8% (100 μg/1); between-assay coefficients of variation were 8.4% (20 μg/1); 4.7% (50 μg/1) and 7.4% (100 μg/1). The assay was used to study the pharmacokinetics of a 1 mg intravenous dose of glibenclamide in eight normal subjects. The mean half-life was found to be 1.47±0.42 h (SD) and no evidence for a non-linear β-phase or slowly equilibrating ‘deep’ compartment was found although this could not be rigorously excluded. The mean systemic drug clearance was 78±29 ml·h-1·kg-1 and the apparent volume of distribution in the β-phase was 155±44 ml/kg. The median time of maximum response of plasma immunoreactive insulin was 25 min and the median time of maximum blood glucose response was 53 min. No correlation could be found between the pharmacokinetics of glibenclamide and these responses in fasted normal individuals.

Plasma mexiletine concentrations following combined oral and intramuscular administration

SummaryMexiletine in doses of 50, 100 and 400 mg was administered by intramuscular injection to a healthy subject and the resulting plasma concentrations were compared with those after 100 mg given intravenously. The bioavailability of mexiletine given by this route is complete and the kinetics are linear with dose. Plasma mexiletine concentrations resulting from 200 mg given orally with either two 4-ml intramuscular injections each containing 100 mg (Mexitil® — for intravenous use) or one 2-ml intramuscular injection of an experimental preparation containing 200 mg were compared in 3 and 6 normal subjects respectively. Plasma levels within the therapeutic range of 0.75–2 µg/ml were attained at mean times of 28.7 and 42.5 min respectively. Apart from raised plasma creatine phosphokinase levels (as would be expected following an intramuscular injection) the tolerability of intramuscular mexiletine injections was satisfactory. Further studies in patients will be required to determine whether the combined oral and intramuscular administration of mexiletine is of value in acute myocardial infarction.

Bencyclan: A new drug with unusual membrane stabilizing properties in erythrocytes

Bencyclan, a drug recently introduced to treat peripheral circulatory disease, has been shown to stabilise human erythrocytes in hypotonic saline. Two peaks of maximum stabilisation are present: at 10(-5)--10(-4) M and at 10(-3) M drug concentration.

Study of Repeated Administration of Fenbufen in Patients with Chronic Rheumatic Disorders and Renal Impairment

Male and female patients suffering from rheumatoid arthritis with normal renal function or with renal impairment were treated in hospital with 300 mg of fenbufen 8 hourly for fourteen days. Concentrations of fenbufen and its principal metabolites were measured by high pressure liquid chromatography on days 0, 7, 10 and 14 and also four days after discontinuation of the drug. Renal impairment does not produce cumulation of either fenbufen or its major metabolites in the plasma. The metabolite profile of the drug was similar to that observed in patients with normal renal function.

ABNORMAL SPERMATOZOA AND PERINATAL DISEASE.

Vomiting and diarrhoea also occur. There is sometimes a history of loss of consciousness during the attacks but it can still be difficult to know if this is due to syncope or epilepsy. A particularly suggestive feature is a prolonged period of sleep, occurring immediately after the pain. A family history of epilepsy is strong supporting evidence. Precipitating factors include hyperventilation, exercise, emotional upsets and minor head injuries. The possibility of this symptom complex being due to epilepsy is well recognised4* ’* *, ’, but in view of the social implications of the diagnosis of epilepsy, suspicion is not enough. However suggestive the symptoms may be, the final diagnosis may have to await developments such as the occurrence of convulsions. It is important to make a full study of the patient’s emotional and environmental background to eliminate disorders from these causes. The EEG of children with recurrent abdominal pain may contain no significant abnormalities2 but may show generalised discharges of slow waves or spike and wave complexes. The latter are particularly suggestive of epilepsy. The most frequent EEG finding to correlate with this syndrome is the 14 and 6 per second positive spike pattern seen in the record during sleep3. 5, lo, ll. It has been suggested that this type of discharge arises from the hypothalamus but this is not yet proven. Its value as a diagnostic criterion is also reduced as it occurs in the recordings of about 10 to 15 per cent of normal adolescents. Where an exact diagnosis is impossible, a trial of treatment can be given with drugs such as phenobarbitone or phenytoin sodium. A failure to respond to such treatment will be an indication for further psychological or other investigation. NEIL GORDON

EFFECTS OF MATERNAL IRRADIATION ON THE EMBRYO AND FOETUS

These recent reports confirm that the hormone treatment of massive spasms often has a beneficial effect on the incidence of the seizures and on the EEG abnormalities but that the chances of preventing mental deficiency are poor. This may not be surprising in a group of such varied causation, where the clinical and EEG findings seem to be related more to the patient’s age than to any other factor. Pathological studies of these cases have been few and no consistent abnormalities have been reported. TUCKER and SOLITAIRE^^ have lately described the case of a 4-months-old child who died after having infantile spasms for 3 months. Much of the brain seemed normal for the patient’s age but there were changes in the cytoarchitecture of the Betz cells, a general increase in microglia and astrocytes, and several foci of neuronophagia in the frontal cortex, with minimal demyelination in the subjacent white matter. There was also a malformed gyrus in the right parietal lobe. Whatever the underlying cause of the patient’s fits, the brain damage is likely rapidly to become irreversible, so that even if the recorded cases of complete recovery are few it is still an urgent matter to begin treatment as soon as possible. If brain damage is prevented by treatment with steroids, this may be related to the cause of the particular case, rather than to the control of the fits. For instance, if the fits are due to an encephalomyelitis following inoculation,2 early treatment could well be of vital impor tan~e .~ Likewise, if in some cases an enzyme defect is revealed by the tryptophan load test which can be influenced by hormone treatment,’ the sooner this is given the better. Bower and Jeavons demonstrate (p. 577) the value of hormone treatment in phenylketonuria. If the clinical picture is associated with undoubted mental deficiency or neurological disease before the onset of fits, it would seem reasonable to try anticonvulsants first, only resorting to steroids if they fail; but the sudden onset of massive spasms in an otherwise healthy baby should be treated as an emergency. NEIL S. GORDON REFERENCES 1 . Bower, B. D., Jeavons, P. M. (1959) ‘Prognosis of infantile spasms.’ Arch. Dis. Childh., 341, 357. 2. Cox, P. J. N., Martin, E. (1959) ‘Infantile spasms and hypsarhythmia.’ Lancet, i, 1099. 3. Degen, R. (1963) ‘Uber blitz-, nickund salaamkrampfe und ihre ~ c ~ ~ b e h a n d l u n g . ’ Z . Kinderheilk.,

PHARMACOLOGY AND THE CENTRAL NERVOUS SYSTEM

STUDIES on the sites and mechanisms of drug action in the brain are illuminating the physiological processes by which the brain affects the body as a whole. Feldberg and his co-workers have studied intensively the effects of intraventricular drug administration on the cat. They showed that substances penetrate from this site into the brain substance by an active process (it did not occur in dead animals) and that the depth and anatomical localisation depend on the particular chemical which was tested. Regional perfusion of the ventricular system was performed by the use of multiple inflow and outflow cannulae. Infusion of tubocurarine into each lateral ventricle produced autonomic effects (raised blood pressure, piloerection, mydriasis), increased muscular excitability and abnormal electroencephalographic activity. Using regional perfusion it was possible to localise the site of action leading to the autonomic and motor effects to the wall of the ventral half of the third ventricle. On the other hand, the abnormal electrical activity resulted from action of the drug on the wall of the lateral ventricle. Some components of the abnormal EEG arose in the anterior horn and other patterns were due to the drug in the inferior horn. Insertion of needle electrodes revealed the sensitive structure in the inferior horn to be the hippocampus. Intraventricular injections of adrenalin or noradrenalin produced a prolonged drop in body temperature of normal cats and those with a fever produced by bacterial pyrogens. 5-hydroxytryptamine7 administered intraventricularly, gave a rise in temperature which was brought back to normal by adrenalin or noradrenalin via the same route. Both the hypothermic and hyperthermic effects were due to the drugs acting on the anterior hypothalamus and unilateral administration of these amines gave similar temperature effects to panventricular perfusion. Although FELDBI~RG and FLEISCHHAUER (1965)l point out that it is impossible to extrapolate from these pharmacological experiments to human disease, this work has led to a working hypothesis of how the brain could influence body temperature. Noradrenalin, adrenalin and 5-hydroxytryptamine occur naturally in the walls of ventral half of the third ventricle, and chemical or other influences could alter the rate of synthesis of one of these amines and thus alter the body temperature. The role of the nervous system in oestrus has been investigated by MICHAEL (1965).2 In the ovariectomised cat, subcutaneous injections of oestrogen produced reversal of the atrophy of the genital tract, and the females showed the behavioural and anatomical changes of oestrus. Michael implanted small solid pellets of aliphatic diesters of stilboestrol into the brains of spayed cats. No significant absorption into the blood stream occurred-as evidenced by the atrophic genital tract and the anoestrus appearance of the vaginal epithelial cells. Implants into the cerebellum, pre-optic area, caudate nucleus, white matter, amygdaloid area and dorsomedial nucleus of the thalamus were accompanied by little change in behaviour. However, when the drug was placed in the hypothalamus the full

Periventricular Leukomalacia and Listeriosis in the Newborn

Periventricular Leukornalacia This is the term used by Banker and Larroche (1962) for a disease affecting the cerebral white matter of liveborn premature infants, most of whom have suffered from severe asphyxia after delivery. These workers found that approximately 19 per cent of 117 premature infants who died under the age of one month suffered from this disease. Macroscopically the lesions were found only in formalin-fixed brain and had the appearance of white spots, streaks and areas of softening, usually surrounded by congestion, in the white matter adjacent to the lateral ventricles. The microscopical changes were those of coagulation necrosis, microglial proliferation and gliosis. Similar appearances have been observed over the past two years in necropsy material at Guys Hospital i n approximately one-sixth of prematurc infants who died in the first week of life, but the diseasc has also been seen in stillborn infants and in non-premature liveborn infants. For many years it has been known that an important danger of prematurity is brain damage. Recently McDonald ( 1 962) found neurological or ophthalmic disorders in 22 per cent of over a hundred children whose birth-weight was not more than 4 Ib. (1,810 g.); 6 .5 per cent had cerebral palsy and four-fifths of these had spastic diplegia. McDonald (1964) has commented on the similar association with prematurity of spastic diplegia and periventricular leukomalacia and has suggested that some cases of diplegia in premature children could arise from this typc of white matter lesion.