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Ten patients with severe intractable psoriasis were treated with cyclosporin (CyA) at an average dose of 3 mg/kg/day for a period of 12 weeks. At the end of the study, 5 patients had a greater than 90% reduction in their PASI (psoriasis area severity index) score, 3 an 80%, one a 69% and one a 52% reduction. In a long term study, 13 patients with severe psoriasis were treated with CyA for an average duration of 2.5 years. The average dose of CyA was 3 mg/kg/day, with a range of 1 - 5 mg/kg/day. The average reduction in mean PASI score throughout the study was 70 - 80%. Seven of the 13 patients developed a rise in blood pressure, 3 of whom required antihypertensive therapy. Studies on possible nephrotoxicity showed that 4 of the 13 had a greater than 30% rise in their serum creatinine compared to their baseline value. 6 of the 13 patients had a low glomerular filtration rate (GFR) at the end of the study, but this rose in all 6 when CyA was discontinued, and to normal levels in 5 patients. In the sixth, a renal biopsy was performed which showed no structural damage due to CyA. In a further 11 patients, the mean GFR was shown to fall significantly after 9 weeks of CyA. Thus, CyA causes impairment of renal function with a dose of 3 mg/kg/day, but this impairment appears to be reversible when CyA is stopped. Six patients with plaque psoriasis were treated with topical CyA, and a further 10 with intralesional CyA. Topical CyA was ineffective, but intralesional CyA was effective in clearing psoriasis, implying that failure of topical preparations is probably due to lack of penetration. T cell and dendritic cell subsets in psoriasis were studied during oral CyA, and at the end of intralesional CyA treatment. After oral CyA, total CD4 and CD8, and DR+CD8 cells were decreased in the epidermis and dermis. However, DR+CD4 cells were decreased in the dermis but not the epidermis. After intralesional CyA, total and DR+CD4 and CD8 cells were decreased in both dermis and epidermis. The most significant effect of both intralesional and oral CyA on the dendritic cells was the decrease of the DR+CD1-subset.

The thesis examines the pathogenesis and treatment of acute intermittent porphyria (AIP), an inherited disorder of haem biosynthesis characterised biochemically by overproduction and increased excretion of porphyrin precursors, and clinically by neurovisceral crises which can be life-threatening. Both prevention and treatment of porphyric crises are considered. Acute attacks can be triggered by either endogenous or exogenous precipitants. A trial of hormonal suppression, using the luteinizing hormone releasing hormone analogue buserelin, in 7 patients suffering premenstrual attacks of AIP, suggested a trend towards clinical improvement on buserelin although response to treatment varied widely between patients. The relationship between endogenous steroids and disease activity in AIP was further examined by measuring urinary steroid metabolite excretion in patients with active, latent, and quiescent disease. In patients with active AIP the ratio of 5α to 5β urinary steroid metabolites was reduced, as was total steroid metabolite excretion. The finding of elevated plasma sex hormone-binding globulin concentrations in patients with active AIP is also reported. Drug porphyrinogenicity is discussed with reference to antidepressants and anticonvulsants. Preliminary anecdotal experience of the use of the haem derivative haem arginate in the treatment of 37 acute attacks of porphyria is described, and the first double-blind controlled trial of haem derivative treatment reported. This studied 21 attacks in 12 patients. While haem arginate invariably produced a marked fall in porphyrin precursor excretion, it did not significantly affect clinical outcome, although there was a trend in favour of haem treatment. In 7 attacks of AIP, haem arginate corrected the impaired hepatic mixed function oxygenase activity which is a recognised feature of AIP : antipyrine clearance was increased. The finding of raised blood lactate levels after glucose loading suggested that cytochrome deficiency affecting the terminal respiratory chain also occurs in AIP. It is postulated that the genetic, metabolic, endocrine and hepatic abnormalities of AIP may be inter-related through haem deficiency.

Rats with streptozotocin-induced diabetes exhibit both a reduction in nerve conduction velocity (NCV) and an impaired regenerative response after nerve injury. Nerve blood flow is also reduced in diabetic rats. Vasodilator treatment normalized the deficit in maximum regeneration distance after nerve injury. This strongly suggests a role for endoneurial hypoxia in the impaired regenerative response associated with diabetes. Inhibition of polyol pathway hyperactivity in diabetic rats corrects the deficit in nerve regeneration. Compensation for impaired essential fatty acid metabolism with evening primrose oil treatment had no significant effect on nerve regeneration, but corrected NCV. These findings implicate these two hyperglycemia-related metabolic disturbances in the development of diabetic nerve dysfunction. Levels of oxidative stress are increased in diabetic rats. It was demonstrated that various treatments which act to decrease levels of oxidative stress corrected both the deficit in nerve regeneration and the reduction in NCV found in diabetic rats. It is suggested that an increase in oxidative stress contributes towards nerve dysfunction in diabetes. Feeding non-diabetic rats a 40% galactose diet causes an increase in polyol pathway activity. These animals exhibited similar deficits in nerve regeneration and NCV to those seen in diabetic rats. Anti-oxidant treatment improved both nerve regeneration and NCV in galactose-fed animals. These studies give support to the suggestion that nerve dysfunction due to the diabetes-induced increase in polyol pathway activity involves an increase in levels of oxidative stress. Levels of certain growth factors are reduced in diabetic rats. Treatment of diabetic animals with ciliary neurotrophic factor normalized both nerve regeneration and NCV. Brain-derived neurotropic factor treatment improved nerve regeneration but had no significant effect on NCV.

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No description available.

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No description available.