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Biomedical subjects

S A Gruber

Publications and source records attributed to S A Gruber.

At least 37 records · Page 2Linked to original sources
PubMed1998

Long-term composite tissue allograft survival in a porcine model with cyclosporine/mycophenolate mofetil therapy.

BACKGROUND: Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly reduced the frequency of rejection and drug-induced side effects in rat hindlimb allograft recipients. With an eye toward direct clinical application, we developed a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination CsA/MMF treatment. METHODS: Radial forelimb osteomyocutaneous flap transplants were performed between size-matched, outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression, and 10 pigs received a once-daily oral CsA/MMF/prednisone regimen. Rejection was assessed by visual inspection of flap skin and correlated with serial histopathologic examination of skin biopsies. RESULTS: In all control pigs, the flap was completely rejected on day 7. Of the 10 pigs receiving treatment, one died from pneumonia and an another from an anesthetic complication on days 19 and 30, respectively, without signs of rejection. Two flaps were lost on days 25 and 29 from severe rejection. Three pigs were free of rejection at the end of the 90-day follow-up period, and three had stable mild-to-moderate rejection at 90 days (P= 0.0007 vs. controls). White blood cell and platelet counts, serum creatinine values, and liver function tests remained normal in all animals receiving immunosuppressive therapy. CONCLUSIONS: Our results, to our knowledge, demonstrate for the first time that rejection can be significantly delayed in a large-animal composite tissue allograft model including skin using only orally administered agents dosed according to clinically relevant strategies without significant drug-specific systemic side effects.

Animals↗
PubMed1998

Decreased protein binding of mycophenolic acid associated with leukopenia in a pancreas transplant recipient with renal failure.

BACKGROUND: Mycophenolate mofetil (MMF) is rapidly hydrolyzed to its active metabolite mycophenolic acid (MPA), which is excreted by the kidney after undergoing glucuronidation to MPAG. MPAG has been shown to accumulate in patients with renal failure. MPA is extensively and avidly bound to human serum albumin. In vitro inhibition of the pharmacologic target, inosine monophosphate dehydrogenase, is dependent on free MPA. It has been demonstrated that high MPAG concentrations decrease MPA protein binding in vitro. In addition, the uremic state is associated with altered protein binding of many drugs. METHODS: We assessed free MPA, total MPA, and MPAG kinetics in a patient with renal failure receiving MMF for a pancreas transplant, who presented with signs of MMF toxicity. MPA, MPAG, and free MPA were measured by high performance liquid chromatography and a validated 14C-MPA ultrafiltration methodology. RESULTS: The MPAG area under the concentration curve (AUC) in this patient was extremely high (5899 microg x hr/ml). The total MPA AUC of 36.8 microg x hr/ml was within the range usually obtained in stable renal patients. The free fraction of MPA and the free MPA AUC were markedly elevated (13.8% and 5.07 microg x hr/ml, respectively). CONCLUSIONS: Patients with severe renal insufficiency may have markedly increased free MPA levels that may not be reflected in total MPA concentrations. These patients may be at increased risk for MMF-related toxicity.

Adult↗
PubMed1997

Comparative pharmacokinetics and renal effects of cyclosporin A and cyclosporin G in renal allograft recipients.

Cyclosporin G (CSG) has produced less nephrotoxicity than cyclosporin A (CSA) at equivalent doses in animal models. Conflicting results have been reported concerning differences in the pharmacokinetics of CSA and CSG in preclinical studies, and no data exist regarding the effect of steady-state oral administration of CSG on renal function in transplant patients or CSG-induced release of endothelin and nitric oxide (NO) in vivo. The objective of the study was to examine steady-state pharmacokinetic profiles of adult renal allograft recipients receiving CSA and CSG in relation to concentrations of endothelin-1 and NO2/NO3 in urine and plasma, creatinine clearance (Clcr), and urinary excretion of N-acetyl-beta-D-glucosaminidase (NAG) 9 months after transplantation. Concentrations of CSA and CSG were measured in whole blood over a 12-hour dose interval by both a monoclonal and polyclonal fluorescence polarization radioimmunoassay for CSA. A metabolite fraction was defined as the numerical difference between the levels obtained at each time point by both assays. Patient groups were defined as follows: group 1: initial CSA (n = 6); group 2: initial CSG (n = 7); group 3: five of the seven patients in group 2 taking CSG subsequently undergoing conversion to CSA; group 4: the same five patients in group 3 restudied 1 month after 1:1 dosage conversion to CSA; and group 5: CSA groups 1 and 4 combined (n = 11). In group 1, the metabolite fraction accounted for 32% to 54% of the total measurable drug concentration at each time point, whereas in group 2, the metabolite fraction accounted for at most 10% to 15% of the total drug levels measurable by polyclonal fluorescence polarization radioimmunoassay. Although there were no significant differences in any of the mean pharmacokinetic parameters between groups using monoclonal fluorescence polarization radioimmunoassay, the normalized area under the concentration-time curve (NAUC) value was less in four of five patients after conversion from CSG to CSA, with a more variable and delayed time to reach peak concentration (tmax) but equivalent apparent oral clearance (Clpa) values. Clcr was found to change significantly with time in groups 1 and 5 but not in group 2, with CSA producing a more profound and sustained decrease than CSG. Endothelin-1 and NO2/NO3 levels in plasma and urine remained relatively constant after administration of both CSA and CSG, and there were no significant differences between groups 3 and 4 regarding mean endothelin-1 and NO2/NO3 concentrations in plasma, urinary release of endothelin-1 and NO2/NO3, and mean AUC of endothelin-1 and AUC of NO2/NO3. However, monoclonal NAUC correlated significantly with total urinary endothelin-1 within CSA groups 1 and 5 but not within CSG group 2. Metabolite NAUC correlated significantly with total urinary NAG within CSA group 1. Although limited by the small number of patients, this study suggests that 1) CSG may produce less of a reduction in Clcr over time after oral administration at steady state than does CSA, and 2) this beneficial effect of CSG may be in part due to decreased intrarenal release of endothelin-1, as urinary excretion of endothelin-1 seemed to correlate better with CSA than with CSG exposure.

Acetylglucosaminidase↗
PubMed1997

Pharmacokinetics and pharmacodynamics of 15-deoxyspergualin in a canine renal allograft model of local immunosuppression.

Local immunosuppression is based on the rationale that one can simultaneously prevent rejection and reduce systemic side effects by administering appropriately chosen immunosuppressive agents directly into the allograft. We utilized a mongrel canine renal transplant model with a programmable, implantable pump/catheter system to estimate the first-pass extraction of 15-deoxyspergualin (DSG) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (ia) versus intravenous (iv) DSG delivery. Six autotransplanted dogs were given DSG by both iv bolus (1 mg/kg) and ia infusion (1.0 mg/kg/d). DSG was administered to allograft recipients by continuous ia infusion at 0.5 (n = 11) and 0.75 (n = 8) mg/kg/day and by continuous iv infusion at 0.5 (n = 12) and 0.75 (n = 6) mg/kg/day. Mean +/- SD elimination half-life was 0.6 +/- 0.1 hr, and the transplanted kidney removed as much as 55-88% (mean 66%) of locally infused DSG. When compared with untreated controls [mean survival time (MST) = 8 days], low-dose (0. 5 mg/kg/day) DSG produced a significant antirejection effect when given ia (MST = 12 days; P = 0.04) but not iv (MST = 9 days; P = 0. 09), with equivalent overall mean drug levels during normal renal function. However, two of the four longest-surviving animals in the ia group died from severe systemic toxicity, manifested by anorexia, diarrhea, leukopenia, and sepsis. High-dose (0.75 mg/kg/day) DSG significantly prolonged survival via both local (MST = 12 days; P = 0.04) and systemic (MST = 11 days; P = 0.02) routes, but half of the iv-treated dogs died from, and four of the longer-surviving ia-treated animals manifested signs of, systemic toxicity, with significantly higher mean drug levels in the iv group. DSG significantly suppressed vascular rejection at both doses when administered locally and systemically, dose-dependently affected the severity of tubulointerstitial rejection and graft edema, and was not nephrotoxic. Our autotransplant pharmacokinetic data overestimated the allografted kidney's ability to extract DSG during local infusion of slightly lower, but immunosuppressive, doses, so that death from systemic toxicity was not prevented and a direct survival benefit of ia vs iv therapy was not realized. Local DSG administration might be combined with other immunosuppressants to therapeutic advantage.

Animals↗
PubMed1996

Renal transplantation exposes patients with previous Kaposi's sarcoma to a high risk of recurrence.

It is currently estimated that about 0.5% of patients will develop Kaposi's sarcoma (KS) after kidney transplantation. Tapering of immunosuppression often leads to KS remission, but also results in graft loss in more than 50% of cases. Whether retransplantation is safe in these patients is unknown. We here report on eight patients who developed KS recurrence after kidney transplantation-(A) Patients with previously treated KS: There were 4 patients who had clinical remission of KS (including three posttransplantation) for periods ranging from 5 months up to 19 years before transplantation. All 4 developed KS recurrence within months after transplantation. In 3 patients, KS regressed only when all immunosuppression was discontinued, at the price of allograft removal. Partial remission occurred in the fourth patient following reduction of immunosuppression and gancyclovir administration; (B) Patients with recurrent KS during a single transplant: 4 patients developed KS after transplantation that regressed following reduction of immunosuppressive therapy. Increased immunosuppression, in the form of steroid pulses in 3 patients was associated with recurrence of KS. Subsequent reduction of immunosuppression caused regression of KS in all 4 patients, but 2 recipients lost their allografts. These data emphasize the high risk of recurrence of KS after renal transplantation. If physicians decide to transplant patients with a history of KS, they should inform the future recipient of the possibility of KS recurrence.

Adult↗
PubMed1996

New immunosuppressive drugs in organ transplantation.

An examination of the mechanisms by which four new immunosuppressive drugs--rapamycin, mizoribine, mycophenolate mofetil, and 15-deoxyspergualin--exert their effects reveals three major categories. Rapamycin binds to an intracellular immunophilin. The resulting drug-immunophilin complex inhibits the action of cytokines, thus blocking the activation and proliferation of T cells. Mizoribine and mycophenolate mofetil are antimetabolites that inhibit a key enzyme in the de novo purine biosynthetic pathway. As a result, the proliferation of T cells and B cells is inhibited selectively compared with that of nonlymphoid cells because the salvage pathway is unavailable to lymphocytes. Finally, 15-deoxyspergualin has a unique mechanism of action, which includes suppressive effects on macrophage function, the induction of cytolytic T cells, B-cell reactivity, and antibody responses. The demonstrated synergism among certain immunosuppressants allows reduction in the dose of each agent to minimize the individual toxicities. As more of these new agents become available, it is likely that azathioprine will be replaced, and it may be possible to eliminate the need for long-term maintenance steroid therapy.

Animals↗
PubMed1996

Proton magnetic resonance spectroscopy of the temporal lobes in schizophrenics and normal controls.

Previous research has found structural and functional abnormalities in the temporal lobes of schizophrenic patients, often with greater impairment on the left side. This study applied proton MRS to both right and left temporal lobes of schizophrenic patients and normal control subjects. Reductions in the NAA/Cr ratio were found bilaterally for schizophrenic patients as compared to normal controls, and may be associated with reduced neuronal integrity. These results strengthen the evidence for biochemical abnormalities in the temporal lobes in schizophrenia.

Adult↗
PubMed1996

Functional magnetic resonance imaging of schizophrenic patients and comparison subjects during word production.

OBJECTIVE: This study was undertaken to test the feasibility of using functional magnetic resonance imaging (MRI) to examine changes in cortical activation in response to verbal tasks in two brain regions. METHOD: Twelve schizophrenic patients and 11 comparison subjects underwent functional MRI of the frontal and temporal lobes. Stimulus sequences were divided into five 30-second segments by using a task-activation paradigm that alternated between resting and stimulated states. Functional images were collected every 30 seconds by using a gradient echo pulse sequence. RESULTS: Schizophrenic subjects demonstrated significantly less left frontal activation and greater left temporal activation than comparison subjects during a word fluency task. CONCLUSIONS: These preliminary data suggest that functional MRI has the sensitivity to detect differences in activation between comparison subjects and schizophrenic patients during higher cortical functions. These findings are in agreement with PET studies that reported reduced left frontal activation during challenge paradigms for the schizophrenic patients.

Adult↗
PubMed1995

Preemptive ganciclovir therapy in cytomegalovirus-seropositive renal transplants recipients.

OBJECTIVE: To evaluate the efficacy, safety, and cost of preemptive ganciclovir therapy in cytomegalovirus (CMV)-seropositive renal transplant recipients treated with antilymphocyte antibody (ALA) preparations. DESIGN AND SETTING: A prospective, randomized trial at a 650-bed tertiary medical center hospital. PATIENTS: Forty consecutive CMV-seropositive renal allograft recipients who underwent transplantation between January 1992 and January 1994 and were treated with ALA for induction immunosuppression or acute rejection therapy. MAIN OUTCOME MEASURES: The incidence and severity of CMV disease, length of hospitalization, and patient and allograft survival. INTERVENTION: Cytomegalovirus infection prophylaxis by use of intravenous ganciclovir during ALA therapy was administered to 22 patients (group 1) and the results were compared with those obtained in 18 control patients who did not receive prophylaxis for CMV disease (group 2). RESULTS: Preemptive ganciclovir therapy significantly reduced the incidence of CMV disease (P < .05) in CMV-seropositive renal transplant patients who were treated with ALA and was well tolerated. In addition, the cost of prophylactic therapy was offset by the decreased length of hospitalization observed in patients in group 1. CONCLUSION: Preemptive ganciclovir therapy provides a cost-effective approach toward significantly improving the outcome of renal transplantation in CMV-seropositive patients treated with ALA.

Adult↗
PubMed1995

Elevated serum antibody response to toxin A following splenic abscess due to Clostridium difficile.

Splenic abscess and segmental small-bowel infarction were documented in a patient from whose splenic culture Clostridium difficile was isolated. A week and a half after splenectomy and partial bowel resection, diarrhea developed and stool cultures yielded an isolate of C. difficile that was identical to the abscess isolate when subjected to restriction endonuclease analysis. The level of IgG antibody to toxin A was markedly higher in serum from this patient than in sera from patients with C. difficile diarrhea alone. This case illustrates a rare but serious extraintestinal manifestation of infection with C. difficile and suggests a correlation between serum levels of IgG antibody to toxin A and systemic exposure to C. difficile, a typically noninvasive enteric pathogen.

Abscess↗
PubMed1994

Prophylaxis of primary cytomegalovirus disease in renal transplant recipients. A trial of ganciclovir vs immunoglobulin.

OBJECTIVE: To compare the efficacy, safety, and cost of prophylactic low-dose ganciclovir with that of immunoglobulin in renal transplant recipients at risk for primary cytomegalovirus (CMV) disease. DESIGN AND SETTING: A prospective, randomized trial at a 650-bed tertiary medical center hospital. PATIENTS: Fifty-one consecutive CMV-seronegative patients who received renal allografts from seropositive donors between March 1990 and April 1992. MAIN OUTCOME MEASURES: Patient and allograft survival, and the incidence and severity of CMV disease. INTERVENTION: Cytomegalovirus prophylaxis with seven doses of intravenous immunoglobulin for 6-week periods (group 1, n = 27) or low-dose intravenous ganciclovir for 3 weeks (group 2, n = 24). Results were compared with those obtained in 23 CMV-seronegative historical controls who received renal allografts from CMV-seropositive donors between 1987 and 1989, and who did not receive prophylaxis for CMV (group 3). RESULTS: Both prophylactic regimens significantly reduced the incidence of invasive CMV infection (P < .05) and were well tolerated. However, the cost of ganciclovir ($350 per patient) was substantially less than that of immunoglobulin ($4000 per patient). CONCLUSIONS: These data suggest that prophylactic ganciclovir therapy provides a cost-effective approach toward significantly improving the outcome of renal transplantation in recipients at risk for primary CMV disease.

Adult↗
PubMed1994

Pharmacokinetics of FK506 after intravenous and oral administration in patients awaiting renal transplantation.

The authors examined the safety and pharmacokinetics of FK506, a new hepatically metabolized immunosuppressant, after single-dose intravenous (i.v.) infusion (20 micrograms.kg(-1) x 4 hours-1) and oral (80 micrograms/kg) administration in six nondialysis patients, aged 27 to 53 years, with chronic renal failure awaiting transplantation. A two-period, randomized, crossover study protocol was used with blood samples drawn for 72 hours after each dose and a washout period of 4 days. Whole-blood FK506 levels were determined using a standard, two-step, nonspecific enzyme immunoassay. There were no significant changes in vital signs, EKG, or complete laboratory test battery for any patient during the entire study period. No side effects were noted after i.v. or oral FK506 dosing. Mean +/- SD distribution half life was 0.9 +/- 0.2 hours, elimination half life (t1/2 beta) 33 +/- 8 hours, total body clearance (CL) 2.4 +/- 1.1 L/hour, and bioavailability 14 +/- 12%. There was no significant correlation between serum creatinine (Cr) and CL (r = 0.36) or between Cr and t1/2 beta (r = -0.30). It was found that FK506 is incompletely and erratically absorbed after oral administration and is rapidly distributed outside the blood compartment after IV dosing. An extended sampling period seems necessary to accurately characterize the slow elimination phase of FK506.

Administration, Oral↗