Toxicity of a novel HMG-CoA reductase inhibitor in the common marmoset (Callithrix jacchus).

1. GR95030X, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, was administered daily to marmosets by gavage. In a Maximum Repeatable Dose (MRD) study, doses of up to 30 mg kg-1 day-1 were administered for 49 days. In a chronic study, animals received dosages equivalent to 0, 1, 2.5, 7.5 and 20 mg kg-1 day-1 for 204 or 205 days. Some animals were maintained without treatment for a recovery period of 29 or 30 days. 2. Clinical signs included poor coat condition, weakness with impaired coordination, lethargy and other behavioural changes. There was also alimentary disturbance, and some deaths occurred at doses of 20 mg kg-1 day-1 and above. 3. Adverse effects upon body weight were seen although some recovery was apparent after the cessation of treatment. 4. Serum cholesterol concentrations were reduced. Very large increases in serum ALT, AST and CK activities were recorded with CK-MM isoenzymes accounting for 80% or more of the total CK enzyme activity. 5. Treatment was associated with muscle fibre atrophy and a sarcolemmal response with little evidence of regeneration. Histological examination revealed vascular changes, glial proliferation and cell death in the brain, with no consistent distribution. Alveolar capillary congestion and alveolar proteinosis indicated that there may have been a reduction in cardiac function. 6. HMG-CoA reductase inhibitors have evident potential to cause myopathy in marmosets. This is believed to be the first report of such an effect.

Association of long lasting unsurmountable histamine H2 blockade and gastric carcinoid tumours in the rat.

The oral administration of loxtidine, a potent histamine H2-antagonist, to a total of 378 rats at doses of 50, 185, or 685 mg/kg/day for 116 weeks resulted in the late formation of carcinoid tumours of the gastric fundus. The first such tumour was detected after 712 days of treatment. There was no dose related response; 11 rats at the low level of treatment were affected, 12 at the intermediate and 11 at the high. Twenty seven females but only seven males were affected. No gastric tumours were found in the 228 controls. There is no evidence that loxtidine acts as a direct carcinogen and it is suggested that the tumours were the result of prolonged achlorhydria produced by a potent unsurmountable histamine H2 receptor antagonist.

Suppression of rat adjuvant disease by cyclophosphamide pretreatment: evidence for an antibody mediated component in the pathogenesis of the disease.

Cyclophosphamide (Cy), given intraperitoneally at a dose of 100 mg per kg body weight 3 days before adjuvant, was found to abolish the development of adjuvant disease in the PVG/c rat. This treatment, however, enhanced the delayed hypersensitivity responses to purified protein derivative of tuberculin (PPD) developed by these animals. Lower doses of Cy caused a partial inhibition of arthritis which was dose-related. When the time between giving Cy and the injection of adjuvant was increased, a gradual time-dependent recovery of the response was observed. The arthritic response was restored by the passive transfer of 7.6 x 10(7) to 1.5 x 10(8) normal syngeneic spleen cells, although the development of secondary lesions was delayed by 7-14 days. The response could also be restored by the transfer of small amounts of serum from arthritic, but not normal, rats. Large amounts of serum failed to restore the response. Additional evidence that pretreatment with Cy preferentially depleted the B lymphocytes was obtained by the histological examination of the lymphoid tissue. It was also shown that the primary antibody response to sheep erythrocytes was abolished by Cy, but that skin allograft rejection was unaffected. A partial inhibition of the acute inflammatory reaction to carrageenan was observed 3 days after giving Cy. It is suggested that the pathogenesis of adjuvant arthritis involves an immune complex-mediated phase, whihc initiates the joint lesions. Once these lesions have formed, cell-mediated immune mechanisms predominate in the development of the disease. It is not known whether the persistence of immune complexes is necessary to maintain the lesions.

The histological appearance of tumours derived from rat embryo cells transformed in vitro spontaneously and after treatment with nitrosomethylurea.

Wistar rat embryo cells were treated in vitro with either 25 µg/ml of nitrosomethylurea (NMU) or phosphate buffered saline. Both groups showed morphological transformation by the 13th passage but their ability to grow in soft agar did not occur until at least passage 23; plating efficiencies indicated that NMU had reduced transformation. However, both control and treated cells gave rise to fibrosarcomata after similar latent periods following inoculation into syngeneic recipients. The fibrosarcomata had "myxoid" and "leiomyomatous" areas, and two resembled haemangiopericytomata; for the most part the tumours were transplantable. Inoculation of cloned NMU-treated cells produced fibrosarcomata with a high proportion of giant cells but only after a very long latent period. No virus particles were detected in tumour samples by electron microscopy.