Mechanisms of seizures and coma in hypoglycemia. Evidence for a direct effect of insulin on electrolyte transport in brain.

The mechanisms involved in the production of hypoglycemic coma were studied in rabbits. Measurements were made in brain, cerebrospinal fluid (CSF), and plasma of osmolality, Na(+), K(+), Cl(-), water content, exogenous insulin, glucose, lactate, and glutamate, while pH, Pco(2), Po(2), and bicarbonate were evaluated in arterial blood, 35 min after i.v. injection of insulin (50 U/kg), plasma glucose did not change, but brain K(+) content increased significantly. Grand mal seizures were observed in unanesthetized animals (+/-SD) 133+/-37 min after administration of insulin, at a time when brain glucose was normal, but brain tissue content of Na(+), K(+), osmoles, and water was significantly greater than normal. Coma supervened 212+/-54 min after insulin injection, at which time brain glucose, lactate, and glutamate were significantly decreased. At both 35 and 146 min after insulin administration, exogenous insulin was present in brain, but not in the CSF. After 208 min of insulin administration, animals were given i.v. glucose and sacrificed 35 min later. Most changes in the brain produced by hypoglycemia were reversed by the administration of glucose. Hypoxia (Po(2) = 23 mm Hg) was produced and maintained for 35 min in another group of animals. Hypoxia caused brain edema but did not affect brain electrolyte content. However, brain lactate concentration was significantly greater than normal. The data indicate that the seizures noted early in the course of insulin-induced hypoglycemia are temporally related to a rise in brain osmolality secondary to an increased net transport into brain of Na(+) and K(+), probably caused by insulin, per se. As hypoglycemia persists, there is also depletion of energy-supplying substrates (glucose, lactate, glutamate) in the brain, an event which coincides with the onset of coma. The brain edema observed during hypoxia is largely due to an increase in brain osmolality secondary to accumulation of lactate.

[Beta-interferon for labial and genital herpes virus infection].

19 women and 9 men, aged 15-59 (mean, 35.1), who had had recurrent lip or genital infections with herpes virus (HSV) for from 1-38 years, were treated with beta-interferon gel (100,000 IU/g), self-administered 4 times daily to the affected areas. In half the patients the drug and a placebo were given in a double-blind, cross-over study. The trial lasted 30 months. Frequency of attacks, length of each attack and its severity, and the presence of itching were noted. If there was improvement in at least 2 parameters treatment was considered successful. This was the case in about 75% of the patients. The mean number of attacks per year before and during treatment with interferon was 6.8 and 3.0, respectively (p less than 0.003) and the mean length of attacks 8.2 and 4.7 days, respectively (p less than 0.001). Results of the double-blind, cross-over test were also significant, and were similar to those for the total group. These results clearly indicate that local interferon is effective treatment for genital and labial HSV infections.

Topical application of human fibroblast interferon (IFN) in cutaneous leishmaniasis.

Fifteen patients with single or multiple lesions of cutaneous leishmaniasis were randomly assigned to apply either IFN-beta-containing cream or a placebo cream base. Despite 8 weeks of therapy no significant improvement of the lesions was achieved. Although topical IFN-beta was not effective in this study, several laboratory studies suggest that IFN, particularly IFN-gamma, may be of therapeutic value in cutaneous leishmaniasis.

Placebo-controlled trial of topical interferon in labial and genital herpes.

The efficacy of topical interferon-beta (IFN-beta) treatment was assessed in 25 patients with herpes of the lips or genitals who completed a 2-year follow-up in a double-blind placebo-controlled trial. IFN-beta gel (10(5) U/g) 4 times daily (about 2 x 10(4) U) applied locally during eruptions (about 10 days) reduced the mean number of recurrences (p less than 0.007) and the duration of eruptions (p less than 0.007): in the placebo group these indices did not change significantly. Reduction of symptoms and severity was noted in 11 of 12 patients on IFN-beta and in only 1 on placebo. No important side-effects were recorded. Topical IFN-beta may therefore be advantageous as a time-limited local treatment of recurrent herpes simplex virus infections of the genitals and lips.

Sensitivity in vitro of herpes simplex virus isolates to human fibroblast interferon.

Sensitivity of herpes simplex virus (HSV) isolates, from patients with recurrent infections, to human fibroblast beta interferon (IFN), was tested in vitro. Among 25 HSV strains, 12 were HSV-1, isolated from facial and labial lesions, and 13 were HSV-2 isolated from genital lesions. Viral sensitivity to IFN was examined on epithelial MB cell line by yield reduction and plaque reduction and close correspondence between the two methods was observed. Most of HSV-1 isolates were in the same range of sensitivity to IFN, while HSV-2 isolates varied in sensitivity and differences approached statistical significance (P = 0.14). No correlation was found between various biological properties, such as plaque size, virulence in baby mice, growth at different temperatures, thymidine kinase activity in the presence or absence of IFN and sensitivity to IFN. Application of beta IFN containing cream reduced clinical symptoms in most of the patients. However, larger numbers of patients should be evaluated in order to conclude whether in vitro sensitivity correlates to clinical improvement.

Rapid improvement in a terminal case of hairy cell leukemia treated with a new human recombinant interferon, IFN-alpha-C.

A new type of human interferon (IFN), IFN-alpha-C, produced in Escherichia coli and purified on monoclonal antibodies, was given at a dose of 3 X 10(6) u (3 micrograms)/day to a terminally ill unsplenectomized patient with hairy cell leukemia, who had had severe recurrent infections and pancytopenia. There was marked reduction in the size of the spleen after 2 weeks, and platelet counts returned to normal after 1 month of treatment. The IFN treatment also raised the granulocyte counts and hemoglobin levels, improved the normal repopulation of the bone marrow, and restored resistance to infections. IFN-alpha-C was well tolerated, without serious side effects, and treatment has been continued for 10 months.

Intramuscular human interferon-beta injections in treatment of condylomata acuminata.

A two-part study was done to assess the value of human fibroblast interferon (IFN-beta) in the treatment of condylomata acuminata. The first part was an open study of different IFN-beta preparations, which showed that intramuscular injection was the most suitable mode of administration of IFN-beta. In the double-blind placebo section 22 patients were given injections of 2 X 10(6) units IFN-beta or placebo for 10 consecutive days and followed up for 3 months. In 9 of the 11 in the IFN-beta group and 2 in the placebo group lesions disappeared from about 5 weeks after completion of the course of injections. After 3 months 8 of the non-responders were given a course of IFN-beta and all responded to treatment. None of those who had responded has had a recurrence, the disease-free period now being 12 months. Changes in (2'-5')oligo A synthetase levels in white blood cells confirm that intramuscular injections of IFN-beta produce a systemic response.