Lessons to be learned: a case study approach. Severe hypoglycaemia in insulin-dependent diabetes mellitus (IDDM)--living to tell the tale.

The case is presented of a 62 year old doctor with insulin-dependent diabetes mellitus (IDDM) who experienced severe nocturnal hypoglycaemia following a total intake for the day of fruit and yoghurt (providing 230 kcal) for breakfast, four pints of beer (providing 540 kcal-which included the energy from 37.0 g carbohydrate) later in the day and an evening meal containing approximately 123 g of carbohydrate (providing 1050 kcal). He had taken insulin, as was his custom, just before breakfast, half-an-hour prior to the evening meal and again two-and-a-half hours afterwards. He felt entirely well when he retired to bed at 2100 h. He awoke later, having dreamt that he was practically immobile-but then found to his horror that the dream was true. He soon realised that he was severely hypoglycaemic and, as he had no glucose immediately available, had no alternative but in some way to attempt the journey to the kitchen where there was non-diet mandarin drink available in tin cans inside a refrigerator. He was able later to recall and, in consequence, describe the whole terrifying experience in great detail, on account of the remarkable preservation of mental clarity. The clinical features of the episode are viewed in terms of the relationships between alcohol intake, carbohydrate ingested and the insulin administered. Exercise was minimal on this day.

Assessment of tolerance to immunosuppressive activity of delta 9-tetrahydrocannabinol in rats.

Immunosuppression evoked by delta 9-tetrahydrocannabinol (delta 9-THC) has been a consistent finding in rats but the development of tolerance to this phenomenon has not been explored. Therefore, Fischer rats of both sexes were orally given delta 9-THC at 6 or 12 mg/kg or sesame oil as vehicle control for 5-26 days before and after I.P. antigenic stimulation with sheep red blood cells (SRBC). delta 9-THC doses were relevant to those of man and produced mild CNS-inhibition followed by CNS-stimulation, tolerance developing to both behavioral phases. The primary immune response was evaluated by determining splenic antibody-forming cells (AFC), hemagglutinin (HT) and/or hemolysin (HS) titers. Simultaneous administration of delta 9-THC and SE induced dose-related splenic atrophy and reduced AFC proliferation as well as HT and HS responses. These changes were not elicited by sesame oil. Tolerance did not develop to immunosuppression during 26 days of cannabinoid treatment. delta 9-THC given 3 days post SRBC inoculation induced immunosuppression at 12 but not 6 mg/kg. Immunosuppression was directly related to delta 9-THC rather than to non-specific debilitating factors since body weights are stable. The inductive phase of the primary immune response was most sensitive to impairment although the reproductive phase was also affected at the high dose level.

The dosing schedule dependent toxicities of adriamycin in beagle dogs and rhesus monkeys.

The toxic effects of Adriamycin were studied following i.v. administration of from 10.0 mg/kg to 0.039 mg/kg (200--0.780 mg/m2) to beagle dogs, and from 5.83 mg/kg to 0.625 mg/kg (49.9--7.5 mg/m2) in rhesus monkeys by a variety of short and long term treatment schedules. 5 daily doses and 1 dose every 3 weeks were given for both species and, only in dogs, as single injections, 10 daily treatments and 5 daily doses followed by 9 days rest, repeated 3 times. In both species, short term administration of toxic doses caused weight losses, anorexia, diarrhea, atypical oesophageal and intestinal mucosa, bone marrow hypoplasia, lymphoid atrophy and alopecia. Specific adverse responses seen only in monkeys were hypocalcemia, hypomagnesemia, atypical buccal mucosa and reddish urinary pigmentation. Testicular degeneration and prostatic atrophy were produced in dogs. The triweekly treatment schedule caused an additional toxicity at lower doses. In both species a cardiotoxicity syndrome developed with pulmonary oedema and centrolobular hepatic necrosis, plus focal necrosis and vacuolization in cardiac myocytes. Clinical signs of cardiac dysfunction were EKG arrhythmias in dogs, and peripheral oedema, ascites and hydrothorax in monkeys.

Toxicology studies in mice, beagle dogs and rhesus monkeys given chlorozotocin (NSC 178, 248).

Chlorozotocin was studied for toxic effects in beagle dogs and rhesus monkeys. The results are the subject of this report. The compound was administered i.v. as single and 5 daily doses in dogs and monkeys; and, in dogs, as 10 consecutive daily doses, once weekly for 6 weeks and for 5 daily doses followed by 9 days rest repeated 3 times. The most prominent toxicities in both species were dose-related renal tubular lesions. These appeared as a necrosis at the most toxic levels and a nephrosis at lower doses. The latter change was also seen in animals surviving higher doses but only after a 6-week posttreatment period. Bone marrow hypoplasia and lymphoid atrophy were other common findings at the highest doses in both species. The same general pattern of toxicity appeared in extended treatment studies in dogs, but also included aspermatogenesis. Signs of hepatotoxicity were seen in dogs at the highest dose levels, while monkeys receiving lethal doses also evidenced a toxic gastroenteritis. A single monkey had a diabetic response following 1 treatment with a high non-lethal dose. Renal lesions found in mice following acute, single dose administration were similar to those described for the larger laboratory animals.

Methyl-CCNU: preclinical toxicologic evaluation of a single iv infusion in dogs and monkeys.

Methyl-CCNU, a compound with marked antitumor activity against the solid Lewis lung tumor in mice, was submitted to a preclinical pharmacologic evaluation. The toxicity of a single iv infusion was tested in 37 beagle dogs and 21 rhesus monkeys. The minimum lethal dose (LD) in dogs was 14 mg/kg and five of six dogs died within 7-10 days after treatment from hematopoietic toxicity with neutropenia, lymphopenia, anemia, and concomitant sepsis. Metaplasia of the intestinal epithelium also occurred. Thrombocytopenia was not observed. Dogs treated with 9.27-1.56 mg/kg exhibited reversible neutropenia and lymphopenia but survived without severe morbidity or histopathologic lesions. In monkeys, interstitial nephritis was the treatment-limiting toxicity and three of six monkeys treated with 45 or 30 mg/kg died, became moribund, or exhibited severe renal histopathologic lesions. One monkey treated with 45 mg/kg had degeneration of the testes. Survivors exhibited reversible toxicity and no histopathologic lesions. Treatment with doses as low as 7.5 mg/kg caused reversible neutropenia, lymphopenia, and anemia. The largest nontoxic dose for a single iv infusion was 3.12 mg/kg (62.40 mg/m2) for the dog and 3.75 mg/kg (45 mg/m2) for the monkey. These and earlier observations showed that methyl-CCNU had approximately one third the toxicity of CCNU. Methyl-CCNU also did not cause the delayed hepatic toxicity which is characteristic of CCNU treatment in the dog.