Pharmacology of cyclosporine (sandimmune). VII. Pathophysiology and toxicology of cyclosporine in humans and animals.
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Biomedical subjects
Publications and source records attributed to J Mason.
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A method of performing endoscopic cholangiopancreatography using a mobile intensifier in a theatre or endoscopy unit setting is described. A total of 140 ERCPs were attempted in 132 patients. The examination was diagnostically successful in 114 (85%) of patients and endoscopic sphincterotomy was performed in 54 (38.5%). There were 10 (18%) complications after sphincterotomy and one postoperative death after a retroperitoneal leak. With increasing expertise, it is hoped to match the figures from specialist centres, and this method is suggested as an alternative way to expand this service where X-ray department facilities are not readily available.
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104 patients suffering from neurotic or reactive depression were treated with either alprazolam or amitriptyline in randomised, double-blind fashion. Seventeen patients were either lost to follow-up or withdrawn before week 2 (13 due to side effects and 1 because she was feeling better). A further 7 patients did not comply with the protocol, giving a total of 24 patients whose data were not considered suitable for inclusion in the analysis of therapeutic assessments. Evaluation of the 80 patients (40 in each group) who completed at least 2 weeks of the 4-week study demonstrate that both treatments produced a statistically significant response rate. There was a more rapid effect in those patients who received amitriptyline, but there was no significant difference in response between the treatment groups after 4 weeks treatment. Analysis of safety and side effect data on 101 patients (50 treated with alprazolam and 51 with amitriptyline) shows no statistically significant difference in the overall number of side effects experienced in each group, although 11 of those patients who received amitriptyline withdrew because of adverse reactions before completing the study compared to 6 in the alprazolam group. These results suggest that alprazolam may be a useful treatment for patients with neurotic or reactive depression not requiring hospitalisation.
[185W]trithio- and tetrathiotungstates (0.5 mg W) were injected intravenously into sheep. The compounds circulated in plasma bound reversibly to plasma proteins, particularly to albumin. After the first few minutes, levels declined exponentially with a T 1/2 of 12-14 hr. The initial movement of [185W]trithiotungstate from the plasma compartment was delayed transiently by the immediate injection of copper (2-6 mg); the longer-term metabolism was unaffected. The final fate of the compounds appeared to be hydrolysis and excretion in urine as [185W]tungstate. 185W from [185W]trithiotungstate appeared more rapidly than from [185W]tetrathiotungstate, but in both the rate was unaffected by copper injections. Since the appearance in urine did not correspond to the disappearance from plasma, it was suggested that the hydrolysis occurred in extravascular tissues and that the liver might be the site. A control experiment showed that [185W]tungstate in plasma was very rapidly cleared (and appeared in urine). At higher W levels (25-50 mg W per sheep per day), systematic copper metabolism was perturbed since plasma copper levels rose. The experiments demonstrated that in sheep the behavior and the effects of thiotungstates and thiomolybdates are sufficiently similar for 185W to be used as a more convenient alternative to 99Mo for longer-term studies on the interaction of the compounds with copper metabolism in animals.
Approximately 3% of patients undergoing hip arthroplasty develop postoperative sciatic neuropathy. The factors associated with changes in somatosensory evoked potentials (SSEP) and sciatic neuropathy were examined in patients undergoing hip arthroplasty, to evaluate whether the use of intraoperative SSEP could help reduce the incidence of postoperative sciatic neuropathy. Eighty-eight patients were assigned to either monitored or unmonitored groups. SSEP were recorded following peroneal nerve stimulation, using contralateral stimulation to detect systemic influences on SSEP. Amplitude reduction of less than 50% of control and/or latency increase of greater than 10% of control was considered significant, and surgical intervention was attempted to restore SSEP. Previous surgery and a lateral incision approach tended to be associated with sciatic neuropathy (p less than 0.053). The incidence of sciatic neuropathy in the monitored group (4.3%) was not different from the unmonitored group (2.4%). Isolated reduction in amplitude or prolongation in latency of the SSEP was not predictive of postoperative neurologic function of the sciatic nerve. Six patients, two of whom developed sciatic neuropathy, demonstrated complete flattening of the SSEP. Both of these patients had flattened SSEP for two or more surgical events (p less than 0.01) and flattened SSEP were present at the end of the surgical procedure. There were no false-negative SSEP changes. Simultaneous amplitude and latency changes appear to be predictive of sciatic nerve function following hip arthroplasty.
Levels of circulating total thyroxine (TT4), free thyroxine (FT4), total triiodothyronine TT3 and thyrotropin (TSH) were determined in 27 men with unipolar major depressive disorder ages 24-50, mean +/- SEM 36.9 +/- 2.9 years, and 38 healthy controls (HC) ages 20-50, mean +/- SEM 34.2 +/- 3.1 years. No significant differences were observed between HC and depressed men with regard to TT4 and FT4. Mean TT3 levels were lower, and mean TSH levels higher in depressed patients than in HC, p less than 0.05 for both, compatible with possible subclinical primary hypothyroidism in depressed patients. Consistent with this, an inverse correlation between basal TSH values and TT3 (r = -0.38, p less than 0.05) was noted in depressed but not in HC subjects.
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Experiments were performed on rats to examine the cause of the vascular congestion that accompanies renal ischemia, and the potential role of cell swelling in its generation. Renal function and gross morphology were examined after reflow, whereas tissue morphometry was performed both before and after reflow in kidneys. Small doses of mannitol applied into the renal artery just before ischemia greatly reduced the incidence of vascular congestion and the depression of renal function. During ischemia the outwardly directed swelling of the proximal tubule depleted the interstitial and vascular space of the cortex and outer medullary outer stripe and the inwardly directed swelling of the thick ascending limb occluded the lumen. Mannitol reduced cell swelling, lessened the depletion of the interstitial and vascular space and eliminated the occlusion of the thick ascending limb. It is proposed that the loss of interstitial and vascular fluid during ischemia is the cause of the vascular congestion, which, in turn, is responsible for the poor perfusion and impaired renal function seen after ischemia.
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[185W] thiotungstates were synthesized in-vitro and purified by techniques developed for thiomolybdates. [185W] trithiotungstate (15 mg W) injected intravenously into cattle was mainly associated with albumin albumin. The presence of the compound in plasma when injected in larger amounts (0.2 to 1 gW) caused an increase in albumin-bound copper and transiently depressed ceruloplasmin diamine oxidase activity. It is suggested that the long-lived, less costly 185W could prove a convenient alternative to 99Mo for tracer studies with labelled thio-compounds in animals.
[35S]trithiomolybdate (20 micrograms Mo) was readily absorbed from intestinal sacs in anesthetized rats, and radioactivity was subsequently detectable in all the subcellular fractions examined in the organs sampled. The compound was bound reversibly to proteins in patterns similar to those observed in liver in cattle and sheep. Absorption was depressed by the presence of copper in the sacs. At higher levels of trithiomolybdate (1 mg Mo per rat), the characteristic copper peak of metallothionein disappeared from the liver, kidney, and intestine cytosol fractions in most animals, while the concentration of copper in plasma increased by about 50%. It is suggested that the changes in copper distribution are relevant to the clinical syndromes produced by increased dietary Mo in ruminants.
Fatty acids were determined in erthrocytes in 49 patients with colorectal cancer and compared with age and sex-matched controls. Marginally increased levels of stearic acid (P = 0.057) and oleic acid (P = 0.064) and decreased arachidonic acid (P = 0.043) occurred in cancer patients. There was no difference in the stearic to oleic acid ratio between the two groups. Dietary intake, assessed by dietary recall and adipose tissue analysis was also not different. In control subjects the polyunsaturated:saturated (P:S) fatty acid ratio correlated between diet and adipose tissue (P less than 0.01, at least). In contrast cancer patients showed different correlations; in particular dietary and erythrocyte P:S fatty acid ratios correlated (P less than 0.01). These findings may indicate disturbed fat metabolism in cancer patients. The erythrocyte stearic to oleic acid ratio is of no diagnostic value.
1. The effects of intravenous trithiomolybdate administration on the fate of 64Cu and on stable Cu metabolism were examined in sheep held in metabolism cages and fed on a low-Cu diet supplying 2.95 mg Cu/animal per d. 2. In Expt 1 the injection of trithiomolybdate, 30 mg molybdenum/sheep per d for 5 d, greatly increased plasma Cu levels and more than doubled the faecal Cu excretion. Urinary Cu excretion was unaffected. The disappearance from plasma of 64Cu injected during the trithiomolybdate administration was slowed although faecal 64Cu excretion was increased more than threefold. 3. In Expt 2 trithiomolybdate, 10 and 30 mg Mo/sheep per d for 3 d, was administered 22 h after the injection of 64Cu. Radioactivity reappeared immediately in plasma and faecal 64Cu excretion was increased. 4. In both experiments the 64Cu and the increased stable Cu in plasma were associated with albumin. 5. The experiments explain the effectiveness of thiomolybdates as 'decoppering' agents and provide a model for some of the systemic effects seen in ruminants exposed to increased dietary Mo. The experiments support the view that the thiomolybdates, by causing the appearance of new ligands, alter the distribution of Cu in tissues and cause an overall depletion.
Efficiency of ground-applied naled (Dibrom 14), based on caged mosquito bioassays in a moderately vegetated coastal southeastern Florida citrus grove, proved to be significantly associated with downwind distance. However, association analysis between wind speed, temperature or relative humidity revealed no correlation between these meteorological factors and mosquito mortality. Tests conducted with 3 of the commonly used ULV machines demonstrated no significant differences in efficiency. Equipment modifications to simulate aerial application by elevating the spray release point proved ineffective. Increasing the dosage of naled to 3 times the labeled rate for ground treatment resulted in greater than 95% mortality.
The comparative efficacy of propranolol and amitriptyline in the prophylaxis of migraine headache was studied in 30 patients in a double-blind, placebo-controlled, crossover design. Headache response to medication was measured monthly by compilation of headache scores derived from quantitative data recorded by patients in a daily diary; at each visit, Zung and Hamilton tests for depression and the Spielberger state test for anxiety were performed. In the absence of clinical toxicity at monthly visits, the decision to maintain the current dose or raise it was made by a computer, which compared current headache score with that of the previous month. Both drugs were superior to placebo. Neither drug was superior to the other. The effectiveness of neither drug correlated with a decrease in anxiety or depression demonstrated by psychological testing.
Among 56 persons who were acutely bereaved or threatened with a loss, a group with worsening separation anxiety over a period of a month early after the event had higher urinary free cortisol output than a group experiencing improvement in grief. Although not tested in this study, both these psychological and physiological measures may have potential for serving as early predictors of poor outcome in bereavement for the 15%-20% of exposed persons who are at risk for unresolved grief or persistent depressive syndromes.