Pharmacokinetics of low doses of methotrexate in patients with psoriasis over the early period of treatment.

OBJECTIVE: The aim of the present study was to investigate the pharmacokinetics and pharmacodynamics of low-dose methotrexate (MTX) in the early phase (3 months) after the start of antipsoriatic therapy. METHODS: Ten male and female psoriatic patients who failed to respond to previous conventional therapy were treated with 15 mg oral MTX once per week. The pharmacokinetics in plasma and the urinary excretion of MTX and 7-hydroxymethotrexate (7-OH MTX) were investigated after doses 1, 5 and 13 (corresponding to phases I, II and III, respectively). On the same occasions, MTX accumulation in erythrocytes obtained before MTX administration was investigated. Pharmacodynamics of MTX were evaluated using the psoriasis area and severity index (PASI) score. RESULTS: There were marked intersubject differences (range of coefficients of variation 34.9-76.3%) in the area under the curve (AUC), peak concentration (Cmax) and clearance (CL) of MTX. Total CL was proportional to renal clearance (CLR) (r2 = 0.735, P < 0.0001) which accounted for 73 (19)% of the former. There was a strong linear relationship (r2 = 0.819, P < 0.0001) between CL of MTX and creatinine clearance. Within 48 h of drug administration, the urinary excretion of MTX was 46-99% of the dose, while that of 7-OH MTX was 1.5-8.6%. In 8 of 10 patients, more than 70% of the MTX dose was recovered. No intraindividual variations of MTX kinetic parameters during treatment were observed. MTX concentrations in erythrocytes reached the steady-state concentration in the range 40.7-170 nmol.l(-1) after 2 months of therapy. Pharmacodynamic measurement versus pharmacokinetics revealed a significant inverse relationship between PASI score and MTX AUC (rs = -0.912, P < 0.002) and between PASI score and erythrocytic MTX (rs = -0.988, P < 0.002). CONCLUSION: The relationship between MTX pharmacokinetics (AUC or erythrocytic MTX) and pharmacodynamics (PASI score) may exist. It is likely that the efficacy of psoriasis therapy with MTX could be improved by adjusting the dose according to plasma concentrations obtained after the first MTX administration.

Biological skin covers in treatment of two cases of the Lyell's syndrome.

The treatment of two cases of toxic epidermal necrolysis (Lyell's syndrome) is described. Although some features were common for both ones (young men practically of the same age, reaction after using the same drug) the clinical course of illness was very different. Spontaneous epithelisation of partial-thickness lesions and definitive healing under the xenografts in one patient and full-thickness skin-loss on 12% of body surface with severe septic complications requiring application of cultured keratinocytes and/or skin autografting in the other patient were the main differences. The interdisciplinary approach using a burns treatment protocol in non-burned patient including the close co-operation with the tissue bank in preparing different types of biological covers has been applied.

The effect of combination therapy with cyclosporine A and hydrocortisone on glucose metabolism in diabetic rats following pancreatic islet transplantation.

Glucose tolerance, insulin secretion and in vitro insulin action were examined in streptozotocin-induced diabetic rats following pancreatic islet allotransplantation treated with combination of oral cyclosporine A (10 mg/kg) and hydrocortisone (1.5 mg/kg) intramuscularly. 1400 pure islets from multiple donors were implanted either into the portal vein (n = 10) or under the renal capsule (n = 11). Ten sham-operated non-diabetic animals receiving the same immunosuppressive therapy, 8 healthy animals without any treatment and 10 diabetic animals without immunosuppression following islet transplantation were used as controls. In all transplanted animals blood glucose was normalized by day 3 after transplantation with lower levels in those transplanted intraportally (p < 0.05). Non-immunosuppressed animals rejected the graft after 6.5 +/- 1.2 days after transplantation, immunosuppressed animals in both groups remained normoglycaemic till the end of the experiment on day 28. Oral glucose tolerance tests and insulin levels on days 10 and 28 improved dramatically. No differences in glucose and insulin levels between intraportal and subcapsular groups were found. Post-load glucose levels in immunosuppressed non-transplanted animals were higher on day 28 than before treatment and were also higher than in the healthy non-treated group (p < 0.05). In vitro insulin action determined by the incorporation of labelled glucose into adipose tissue was impaired only in animals in which islets were transplanted into the liver (p < 0.05 vs other groups). In conclusion, therapy with cyclosporine A and hydrocortisone prevents allogeneic islet rejection in rats during a short-term experiment. Although glucose tolerance is not completely normalized following transplantation, slight impairment is also demonstrable in healthy animals on the same drug therapy.

Screening for biotinidase deficiency in some skin diseases.

Biotinidase deficiency is an inherited, autosomal recessive disorder involving gluconeogenesis, synthesis of fatty acids and catabolism of branched chain amino acids. As the cutaneous manifestations have been described to be a prominent part of the clinical picture, we tested a group of children and adults with various skin lesions. The blood-spot screening test was repeatedly (new disc and new card) positive in some patients suffering from psoriasis and atopic eczema. The quantitative assay does not confirm the decrease of serum biotinidase activity. Some alternative explanations of these results are put forward.

Morphometrical histochemical and biochemical parameters in the dog alloxan diabetes.

Changes of morphometrical, biochemical, histochemical and immunohistochemical parameters were investigated in the alloxan diabetes in the dog. Samplings of material for electron microscopical and histochemical examinations were performed in 3 month period (4 times). A significant thickening of capillary basement membranes in the striated muscle (vastus lateralis) was ascertained even in the dog with glucose intolerance only. In this mentioned case a decrease of glucoso-6-phosphatase activity was observed. Evaluation of different types of muscle fibres assigned an increase of slow twitch fibres or intermediate ones respectively.

[Skin diseases in computer terminal operators]. / Kozní obtíze u obsluhy terminálu pocítace.

Authors describe two cases of computer operators (female subjects) which experienced face skin disorders in connection with computer's terminal staffing. The first case was concerned with acute worsening of seborrheic dermatitis, the second one with photosensitive reaction complicated partially by psychogenic erythema.

Polymorphous light eruption: PUVA-induced skin hyporeactivity.

Eight patients with polymorphous light eruption (PLE) were treated with the 8-methoxypsoralen (0.6 mg/kg) and UV-A given in an ordinary PUVA cabin. Excellent or good results were observed in 4 and moderate in others remained patients. It is concluded that PUVA treatment is a safe form of therapy which exercises its beneficial effect in the patients with PLE. Various theories concerning the mode of action of photochemotherapy in PLE are discussed in this paper.

[The effect of cytomegalovirus and Epstein-Barr virus infection on immunologic signs]. / Vliv infekce cytomegalovirem a virem Epsteina a Barrové na nekteré imunologické znaky.

Patients with active CMV or EBV infection characterized by the presence of specific serum IgM and/or high immunofluorescence in IgG, have higher levels of circulating immune complexes and a lower phagocytic activity of leucocytes than patients with latent CMV/EBV infections or not infected patients. In active infections at the same time the absolute number of lymphocytes with the surface sign CD8 increases. The amount of lymphocytes with differential antigens CD3 and CD4 does not change substantially. Also the levels of the third and fourth component of complement and C-reactive protein remain within the normal range.

The effect of intravenous administration of fat emulsion on the flow rate and composition of thoracic duct lymph in the dog.

In seven dogs weighing 17-25 kg, the terminal segment of the thoracic duct was isolated, under total pentobarbital anesthesia, so as to collect lymph continuously before, during and after infusion of a 20% fat emulsion Intralipid (Vitrum). Arterial blood and lymph were withdrawn simultaneously for analysis of total protein, amylase, cholesterol, triglycerides, urea and AST. The lymph flow rate was calculated in ml/min. Compared with the control period, during which a 5% glucose solution was administered, a two-hour infusion of the fat emulsion did not change the lymph flow rate nor the levels of biochemical parameters monitored in lymph. These results distinguish intravenous administration of a fat emulsion from a situation, in which fat is administered orally. The unchanged lymph amylase levels following fat administration suggest that no significant stimulation of external pancreatic secretion occurs after this route of fat administration.

Photoprotective adaptation in polymorphic light eruption.

Six patients with polymorphic light eruption were treated with ultraviolet light A (UV-A) for 1-2 months during the spring of 1984 and a follow-up study was carried-out in September 1984. The PLE patients with an UVA - induced skin pigmentation became clearly better or got rid of their symptoms more often than those with "non-adapted" pale skin condition. The good results achieved during and after UV-A phototherapy held during the summer but were lost during the winter. Therefore it became necessary to repeat the photoprotective adaptation each spring.

Progressive pigmented purpuric dermatosis: effect of psoralens and ultraviolet A irradiation.

The administration of 8 - methoxypsoralen combined with UV-A exposure (PUVA) was found to be effective in a case of progressive pigmented purpuric dermatosis (PPPD). After one month (16 therapeutical sessions), favourable cleaning occurred in the skin areas clinically affected by purpuric lesions. Histological examination after the intensive phase of PUVA therapy showed decreased masses of the extravasated erythrocytes formerly situated around the dermal capillaries, and diminution of hemosiderin deposits. In addition, the inflammatory infiltrates were less intense following the maintenance phase of therapy. Various theories concerning the mode of action of oral photochemotherapy in PPPD are discussed in the light of these observations. This is the first report of a case of PPPD which was successfully treated by PUVA.

Natural killer cells and cytomegalovirus and Epstein-Barr virus infection in cardiac graft recipients.

The serum of 10 male patients undergoing heart transplantation was found to contain anamnestic antibodies (IgG) against cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Patients with decreased natural killer (NK) cell activity displayed specific IgM against these viruses, a fact suggesting their activation and reproduction. Patients whose NK activity was within the range of that of healthy blood donors did not have serum IgM against CMV and EBV. Decreased NK activity and presence of specific IgM are associated with an increased number of LGL and monocytes, determined both by a monoclonal antibody (MEM-18) against their surface antigen, and morphologically.

Problems in experimental pancreatic segment transplantation with open duct.

Using in-situ "autotransplantation model" and dogs with allotransplant of pancreatic segment with the open duct, we confirmed the capacity of the canine peritoneum to tolerate the presence of inactive pancreatic juice and to resorb it. However, non-living tissue surrounding the graft may induce activation of pancreatic juice and lead to acute pancreatitis. Diffuse interstitial fibrosis, unaffecting endocrine parenchyma, develops in all autologous and allogenic pancreatic grafts. Reduction of acinose parenchyma probably accounts for the gradual normalization of serum amylase levels. We assume that graft fibrosis is caused by a gradual closure of the pancreatic duct. Diffuse interstitial fibrosis cannot be classified as a rejection change. It antiplatelet drugs are not administered, graft necrosis is caused by splenic artery thrombosis at a low flow rate. In diabetic recipients with antiplatelet therapy both the animal and the graft survivals averaged 22.5 days. All dogs died of complications at a normal glucose metabolism. We hold that at present research should concentrate on vascular complications of pancreatic segment transplantation.

Indications and experimental preparatory studies for pancreas transplantation.

Clinical and experimental evidence support the metabolic aetiology of diabetic microangiopathy. This paves the way for its management by transplantation of endocrine pancreas. In an informative article, the authors attempts to conceptualize their position concerning indications for pancreas transplantation and offer a review of their own experimental studies, a prerequisite before actual clinical application.