Biomedical subjects

C G Groth

Publications and source records attributed to C G Groth.

At least 127 records · Page 7Linked to original sources

PubMed1992

Toxicology of FK506 in the cynomolgus monkey: a clinical, biochemical, and histopathological study.

We investigated clinical, biochemical, and histopathological parameters in FK506-treated cynomolgus monkeys. Eight monkeys given oral FK506, 1 (n = 4) or 10 (n = 4) mg/kg daily, survived the 90 days of treatment apparently in good health and without significant changes in biochemical and histopathological parameters, as did 2 control monkeys except one monkey on 10 mg/kg/day FK506 orally, who was found to have a malignant lymphoma. In contrast, monkeys given intramuscular FK506 1 mg/kg daily (n = 4) had to be sacrificed at day 20, 25, 32, and 47 because of severe illness. They showed abnormal biochemical parameters (increased serum urea and aspartate aminotransferase activity) and major histopathological changes in the kidney (mesangial cell proliferation and acute tubular necrosis), pancreas (depletion of beta cells), liver (steatosis), and heart (cardiomyopathy). Intramuscular administration of 1 mg/kg daily resulted in serum levels ranging from 10 to 15 ng/ml, while oral administration at a dose of 1 or 10 mg/kg daily resulted in equal or even higher serum levels (range 2-70 ng/ml). Thus, the height of the serum trough level of FK506 using the enzyme immunoassay is not related to the toxicity of FK506 in cynomolgus monkeys.

Administration, Oral↗

PubMed1992

A randomized pilot study of cyclosporin G in renal transplantation.

Animal studies have suggested that the analogue cyclosporin G (CyG) may be less nephrotoxic than cyclosporin A (CyA). A pilot study was therefore performed in 10 primary cadaveric renal allograft recipients who were randomized to receive posttransplant immunosuppression with either CyA or CyG. The follow-up time was a minimum of 1 year. One graft was lost in each group. All patients in both groups experienced at least one acute rejection episode. Episodes of acute nephrotoxicity were observed in both groups. Renal function, as assessed by determinations of the serum creatinine level and chromium-ethylene diamine tetra-acetic acid (Cr-EDTA) clearance, did not differ between the two groups. Renal allograft biopsies showed a significantly higher degree of fibrosis in the CyG group than in the CyA group. All CyG-treated patients evidenced laboratory signs of acute liver toxicity, which was dose-dependent and reversible. Today, all CyG-treated patients have been switched to CyA. This study shows that immunosuppression after renal transplantation in man is possible with CyG; however, it does not seem to have any advantages over CyA.

Adult↗

PubMed1992

Rejection associated with early appearance of donor-reactive antibodies after kidney transplantation treated with plasmapheresis and administration of 15-deoxyspergualin. A report of two cases.

In two kidney transplant patients, one of whom had panel-reactive antibodies (PRA) before transplantation, a pretransplant negative donor-recipient crossmatch became positive within the 1st week after transplantation. Simultaneously, good graft function deteriorated to a state of anuria. One patient graft biopsy showed a vascular rejection, whilst the other patient biopsy was unrevealing. Both patients were treated with plasmapheresis and a new immunosuppressive drug, 15-deoxyspergualin (DSG). Plasmapheresis was performed for 6 and 9 days, respectively, and DSG was given for 5 days in a dosage of 6 mg/kg body weight per day. One of the patients received methylprednisolone i.v. in addition. During treatment the cross-match became negative and has since remained that way. In both patients the graft function was restored. No adverse effects were seen from the treatment, except for a slight leukocytopenia and thrombocytopenia.

Adult↗

PubMed1992

Pancreatic juice cytology for monitoring pancreatic grafts in the early postoperative period.

Thirty-one pancreas transplant recipients were monitored by pancreatic juice cytology in the early postoperative period. An increase in the total amount of cells and, in particular, signs of immunoactivation with the appearance of two or more blast-transformed cells per specimen were taken as evidence of acute rejection. According to these criteria a total of 38 rejection episodes were diagnosed. The first positive cytology appeared after 9 days (mean) and lasted for 2 days (mean). Immunocytochemical analysis of the juice showed increased amounts of CD3+ cells during rejection. When rejection occurred during prophylaxis with antithymocyte globulin, neutrophils were preponderant in the pancreatic juice while during OKT-3 prophylaxis a high percentage of monocytes was a characteristic finding. Antirejection treatment was started when the cytology became positive and all rejection episodes except one were reversed. A decrease in the pancreatic juice amylase activity occurred in 66% of the rejection episodes, but in only 5 of the 38 episodes was the decrease highly significant. No correlation was found between graft rejection and volume excretion of pancreatic juice. There were no persistent or characteristic changes in serum amylase or peripheral white blood cell count at the time of rejection. Graft pancreatitis was diagnosed cytologically in 7 patients, in 5 of whom the grafts were eventually lost.

Adolescent↗

PubMed1992

Effect of reduced cyclosporin dosage on long-term renal allograft histology.

The effect of different doses of cyclosporin (CyA) on the occurrence of histological lesions in renal allograft biopsies was investigated 2 years after transplantation. Biopsy findings were compared in three different groups of patients. In group 1, patients were immunosuppressed with CyA and prednisolone according to an early, high-dosage schedule (initial CyA dose 15-17.5 g/kg body weight); in group 2, they were treated with a medium CyA dose (initial dose 12 mg/kg), together with prednisolone; and in group 3, patients were given triple drug therapy consisting of low doses of CyA (initial dose 8 mg/kg), together with both azathioprine and prednisolone. Interstitial fibrosis and tubular atrophy were common findings in all groups, and on the basis of all biopsies, no difference could be found between the groups with respect to the relative volume of the renal cortical interstitium, which was used as a quantitative parameter for interstitial fibrosis. Likewise, no difference was found with respect to serum creatinine levels. When grafts that showed signs of rejection (usually vascular rejection) in the biopsy were excluded (two in group 1, six in group 2, and ten in group 3), the mean interstitial volume was significantly lower in group 3 (triple drug therapy) than in the other groups. The serum creatinine levels were also significantly lower in group 3 than in group 1. Thus, chronic renal lesions could be ameliorated when CyA doses were lowered, but this appeared to entail an increased risk of acute or chronic vascular rejection.

Adult↗

PubMed1992

Injection of xenogeneic endocrine pancreatic tissue into the portal vein--effects on coagulation, liver function, and hepatic hemodynamics. A study in the pig-to-dog model.

The safety of injecting discordant xenogeneic fetal endocrine pancreatic tissue into the portal vein was studied in a pig-to-dog system. It was found that minced fetal porcine pancreas and fetal porcine isletlike cell clusters prepared by collagenase digestion and culture could be injected with only minor or no hepatic hemodynamic disturbances. Coagulation studies revealed a small increase in plasma fibrinopeptide A, but this increase could be prevented by heparinization of the recipient. There was no consumption of fibrinogen or platelets. In contrast, injection of minced adult porcine pancreas caused pronounced hepatic hemodynamic changes and marked coagulation abnormalities, indicating consumption coagulopathy. The present finding that fetal porcine pancreas can be injected intraportally without deleterious effects in dogs provides a foundation for the eventual clinical use of such material as treatment for insulin-dependent diabetes mellitus.

Animals↗

PubMed1992

The effect of FK506 treatment on pancreaticoduodenal allotransplantation in the primate.

The effect of FK506 monotherapy on pancreaticoduodenal allotransplantation was studied in a primate model. The recipients were made diabetic by total pancreatectomy, thus glycemic control depended on the graft. In control animals hyperglycemia occurred after 14 +/- 3 days and the animals died after 36 +/- 15 days. For FK506-treated animals, the time until development of hyperglycemia was 60 +/- 12 days (P less than 0.05). The animals were then sacrificed by day 90 (P less than 0.05). All three control animals lost their graft function because of severe rejection, as verified by postmortem examination. Only one of the five treated animals showed evidence of a moderate-to-severe rejection at 90 days, one animal having a mild rejection as judged by the histological findings. The drug was clinically well tolerated in all except one animal that became apathetic and refused to eat. Hyperglycemia and an elevated serum creatinine level, which were probably related to the FK506 treatment, occurred in one animal each. Both of these side-effects were reversed by reducing the dose. Thus the use of FK506 permits successful single pancreatic transplantation in primates.

Amylases↗

PubMed1992

FK506-induced impairment of glucose metabolism in the primate--studies in pancreatic transplant recipients and in nontransplanted animals.

The effect of FK506 on glucose metabolism was studied in five cynomolgus monkeys after pancreatic transplantation and in 10 nontransplanted cynomolgus monkeys. We have clearly demonstrated that FK506 can induce hyperglycemia in these animals. In the orally treated nontransplanted animals the hyperglycemia was usually very mild (4.5-6.0 mmol/L). In one of the five transplanted animals, hyperglycemia was induced by the FK506 treatment, since histological signs of rejection were absent and since plasma glucose levels normalized on dose reduction. The glucose disappearance rates, as indicated by the K-values, decreased from a mean of 3.0 +/- 0.5%/min before FK506 treatment to 2.4 +/- 0.6%/min at one month and 1.5 +/- 0.4%/min at three months in the nontransplanted animals. In the transplant group, the K values decreased significantly from 4.2 +/- 0.6%/min in the donor animals to 1.4 +/- 0.4%/min at day 10 posttransplantation (P < 0.02). At one and three months postoperatively, the mean K-values were 1.4 +/- 0.2%/min and 1.2 +/- 0.6%/min, respectively. We conclude that FK506 is diabetogenic in the cynomolgus monkey. This side effect, however, was found to be reversible on dose reduction.

Animals↗

PubMed1992

A randomized trial of cyclosporine and prednisolone versus cyclosporine, azathioprine, and prednisolone in primary cadaveric renal transplantation.

A randomized trial was performed with the aim to compare two immunosuppressive treatment schedules in adult recipients of first cadaveric renal transplants. A total of 229 patients were randomized to double therapy with cyclosporine and prednisolone and 234 patients were randomized to triple therapy with cyclosporine, azathioprine, and prednisolone. Minimum follow-up was 4 years. The actuarial 5-year patient survival was 79.8% in the double therapy group and 82.3% in the triple therapy group (n.s.). The corresponding graft survival figures were 54.4% and 59.6% in the two groups, respectively (n.s.). There were no differences between the groups regarding cause of death or cause of graft loss. Renal function as determined by serum creatinine did not differ between the groups and was stable throughout the observation period. Azathioprine was instituted in a total of 51 patients randomized to double therapy. This subgroup of patients had a patient and graft survival not different from the remaining patients randomized to double therapy or from the patients randomized to triple therapy. There were no differences between the double and triple therapy groups regarding incidence and timing of acute rejection or infections. The incidence of other medical diseases and adverse events such as nephrotoxicity or malignancy did not differ between the groups. Azathioprine-induced leukopenia was uncommon (19 episodes in the triple therapy group). In a multivariate analysis of the whole series the only covariates that significantly influenced graft survival were age of recipient and occurrence of acute rejection, while among other factors treatment schedule did not. Thus this prospective study, in accordance with previous such studies, failed to find support for the use of triple therapy as first choice immunosuppression in first cadaveric renal transplantation. However, the study could not rule out the possibility that some patients at risk for the development of irreversible rejection or nephrotoxicity of CsA might benefit from the addition of azathioprine to the treatment schedule.

Adult↗

PubMed1992

Liver transplantation in a boy with acute porphyria due to aminolaevulinate dehydratase deficiency.

The clinical and biochemical outcome of a liver transplantation in a seven-year-old boy with acute porphyria due to aminolaevulinate dehydratase deficiency is described. Before transplantation standard liver function tests were normal and the rationale for transplantation was that the new liver would reduce the metabolic disturbance and thus avert the porphyric symptoms. During the year after the transplantation, the functioning of the new liver has been excellent. Basal excretion of porphyrin and porphyrin precursors has remained unchanged but, with the new liver transplant the patient has been able to withstand several porphyrinogenic challenges without increasing the excretion. Episodes of neurological and respiratory crises may have been due to persistent porphyric vulnerability. Alternatively, two early attacks may have been caused by neurotoxic effects of cyclosporin in combination with the existing damage to nervous tissue.

Acute Disease↗

PubMed1992

Improvement of nerve conduction in diabetic neuropathy. A follow-up study 4 yr after combined pancreatic and renal transplantation.

Eighteen patients with long-standing insulin-dependent (type 1) diabetes mellitus and polyneuropathy were studied after combined pancreatic and renal transplantation. Repeated tests were performed on peripheral nerve function (electroneurography) and on autonomic function (R-R test) 6 mo and 1, 2, and 4 yr after the transplantation. Eighteen diabetic patients with only a kidney graft served as controls. After initial improvement of nerve conduction in both groups, probably caused by the elimination of uremia, further improvement was seen only in the euglycemic pancreas-graft recipients. Improvement of autonomic (parasympathetic) function was slight after 48 mo and was similar in both groups.

Adult↗

PubMed1992

Effects of FK506 and cyclosporin A on cytokine production studied in vitro at a single-cell level.

Mononuclear cells obtained from human blood were mitogen or antigen activated in vitro in the presence or absence of FK506 or cyclosporin A (CsA). Cytokine production was studied at a single-cell level by ultraviolet (UV) microscopy of fixed permeabilized cells using cytokine-specific monoclonal antibodies (mAb). Phenotypic characterization of the monokine-producing cells was achieved by two-colour immunofluorescent staining. Cytokine production after antigen activation with Staphylococcus aureus enterotoxin A (SEA) was significantly reduced. FK506 or CsA inhibited SEA-induced tumour necrosis factor-alpha (TNF-alpha) production both in monocytes (P less than 0.01) and in lymphocytes (P less than 0.001), at a drug concentration of 1-25 ng/ml for FK506 and 100-500 ng/ml for CsA. Lymphocyte synthesis of interleukin-2 (IL-2), interferon-gamma (IFN-gamma) and TNF-beta after SEA activation was also significantly reduced by either of the drugs. In contrast, endotoxin-induced monokine production (TNF-alpha and IL-6) after lipopolysaccharide (LPS) stimulation was unaffected by FK506 or CsA even when added in concentrations as high as 1000 ng/ml. When the cells were stimulated by phorbol ester (phorbol 12-myristate 13-acetate, PMA) plus calcium ionophore (ionomycin), FK506 and CsA inhibited, in a dose-dependent manner, the production of IL-2, IL-4, IL-5, IFN-gamma and TNF-alpha. The 50% inhibitory concentration (IC50) for FK506 or CsA on the cellular synthesis of the various cytokines varied between 0.6 and 1.0 ng/ml and 20 and 60 ng/ml, respectively. Further stimulation by addition of anti-CD28 mAb to the cultures resulted in an augmented IL-2 and IFN-gamma production which was resistant to both FK506 and CsA. This report delineates extensive similarities between the two drugs in mechanisms of immunosuppression by blockade of identical interleukin production. Depending on the mode of cell activation the two drugs inhibited not only cytokine production in lymphocytes but also antigen-induced monokine (TNF-alpha) production in macrophages, although the optimal immunomodulatory effect of FK506 was achieved at a concentration approximately 50-fold lower than that of CsA.

Antigens, CD↗

PubMed1992