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Biomedical subjects

M R First

Publications and source records attributed to M R First.

At least 127 records · Page 7Linked to original sources
PubMed1993

Antibody response to OKT3 and methods for monitoring.

Monitoring the antibody response to OKT3 is essential. Retreatment with OKT3 can be accomplished successfully in the great majority of patients. It is important to know the patient's peak antibody status before and during retreatment. Patients with no anti-OKT3 antibodies, or with low-titer (< or = 1:100) antibodies, especially if these do not include anti-idiotypic antibodies, have retreatment success similar to that of patients undergoing primary treatment with OKT3. In contrast, patients with high-titer (> or = 1:1000) antibodies should be treated with immunosuppression other than OKT3. Methods for monitoring the OKT3 antibody response have progressed, allowing one to estimate the titer and specificity (anti-idiotype and/or anti-isotype) in a timely fashion. Improvements still must be made in the area of standardization, so that results between various transplant centers can be more accurately compared.

Animals↗
PubMed1993

Cyclosporine-ketoconazole interaction. Long-term follow-up and preliminary results of a randomized trial.

Forty-three renal transplant recipients receiving cyclosporine were started on 200 mg/day of oral ketoconazole 10 days to 75 months posttransplant. The cyclosporine dose was reduced by 70% when ketoconazole was started. The mean cyclosporine dose was 5.6 mg/kg/day preketoconazole, and 0.9, 0.8, and 0.7 mg/kg/day at one, two, and three years after addition of ketoconazole (cyclosporine dose reduction 84%, 86%, and 88% at one, two, and three years, respectively). Two patients died after two years of combination therapy, six patients returned to dialysis, and ketoconazole was discontinued in four. Renal function in patients on ketoconazole remained stable (serum creatinine 1.8, 1.7, 1.7, and 1.8 mg/dl preketoconazole and at one, two, and three years, respectively). In a second study, 52 patients were randomized to standard doses of cyclosporine (n = 28), or reduced doses of cyclosporine with ketoconazole (n = 24); seven of the patients were not started on ketoconazole. In 28 patients on standard-dose cyclosporine, there were two deaths and one graft loss. In 17 patients receiving ketoconazole there were two deaths and no graft losses. Renal function and the frequency of rejection episodes was similar in the two groups. In the ketoconazole group, the cyclosporine dose was < 20% of that in the patients on standard doses. In both studies addition of ketoconazole to cyclosporine-treated patients resulted in significant inhibition of cyclosporine metabolism and decrease in dosage in patients followed for up to four years. This drug interaction provides a significant reduction in cost of immunosuppressive therapy in organ transplant recipient.

Adult↗
PubMed1992

Efficacy of a single pretransplant donor-specific transfusion and cyclosporin A administered 24 to 48 hours before one-haplotype-mismatched living related donor kidney transplant.

During the 7-year period from March 1984 to June 1991, 86 haploidentical living related kidney recipients were entered into one of three donor-specific transfusion (DST) and cyclosporine treatment protocols: (1) Multiple pretransplant DSTs with cyclosporine begun after transplant, n = 34; (2) Multiple pretransplant DSTs with cyclosporine begun pretransplant, n = 31; and (3) a single DST 24 to 48 hours before transplant with intravenous cyclosporine initiated after the transfusion, n = 21. Triple immunosuppression (prednisone, azathioprine, and cyclosporine) was continued in all groups after transplant. The 1-year patient (97%, 97%, and 93%, p = not significant) and graft (91%, 90%, and 87%, p = not significant) survival were similar for the three groups. No differences were seen in the incidence of rejection at 1 year (61%, 45%, and 60%, p = not significant) or in the incidence of infectious complications (26%, 42%, and 47%, p = not significant). It is concluded that a single DST given 24 to 48 hours before operation followed by pretransplant cyclosporine is as effective as classic DST conditioning of recipients using either pretransplant or post-transplant cyclosporine. The single DST protocol has the advantage of not eliminating any donors because of sensitization and was less costly and easier to administer.

Adult↗
PubMed1992

The effect of indomethacin on the febrile response following OKT3 therapy.

Fifty renal transplant recipients with histologically documented acute allograft rejection were treated with OKT3 monoclonal antibody therapy. Group 1 (n = 25) received standard premedication with steroids, acetaminophen, and diphenhydramine. Group 2 (n = 25) received these agents plus indomethacin in an attempt to minimize the early adverse effects associated with OKT3. At 1 hr prior to the first dose of OKT3, 50 mg of indomethacin was administered orally followed by 25 mg every 6 hr for the next 48 hr. Demographics were similar in the two groups. Reversal of rejection occurred in 23 of 25 (92%) in group 1, and in 22 of 25 (88%) in group 2. Graft survival rates at six months after the rejection were 88% in group 1 and 80% in group 2. There was a single patient death in group 2, due to a suicide in a patient with a functioning kidney and pancreas graft. The maximum temperature was significantly diminished in the group receiving indomethacin during the first three days of OKT3 therapy. The percentage of patients with a maximum temperature less than 100 degrees F was significantly higher in group 2: day 1--16% vs. 36%, day 2--12% vs. 48%, day 3--52% vs. 68% for group 1 and group 2, respectively. No serious side effects occurred in either group--however, subjective side effects were less common in group 2. Serum creatinine levels were similar in the two groups prior to rejection, at the start of OKT3 therapy, at the peak during OKT3 therapy, at the end of OKT3 therapy, and 30 days and 180 days post OKT3. The data indicate that the concurrent use of indomethacin with OKT3 appears to significantly decrease the initial febrile response without compromising renal function or the efficacy of OKT3 therapy.

Adolescent↗
PubMed1992

The induction of immunologic hyporesponsiveness by preoperative donor-specific transfusions and cyclosporine in human cadaveric transplants. A preliminary trial.

A prospective randomized preliminary trial was performed in patients undergoing cadaveric renal transplantation to determine the potential benefits, disadvantages, and logistic problems associated with the administration of donor-specific transfusions and cyclosporine initiated 24 hr before transplantation. Ten patients received DST followed by continuous intravenous CsA approximately 24 hr before cadaveric renal transplantation from the same donor. Twelve patients receiving sequential therapy with Minnesota antilymphoblast globulin, azathioprine, and steroids with subsequent conversion to CsA served as controls. Patient demographics and the donor characteristics were evenly matched in the two groups. While the study group had longer cold ischemia time and more evidence of renal dysfunction within the first two weeks, subsequent renal function was identical in the groups and there were fewer episodes of severe rejection requiring treatment with OKT3 within the first six months in the DST group (5 vs. 0, P less than 0.05), which also had less reactivity in mixed lymphocyte cultures against preserved donor-specific lymphocytes than did the control group (stimulation index 9.0 +/- 3.0 vs. 25.3 +/- 6.0, respectively, P less than 0.05). The need for dialysis, incidence of infections and other complications, and subsequent immunosuppressive therapy were not different in the two groups. It is concluded that DSTs and intravenous CsA initiated 24 hr prior to transplantation are capable of inducing reduced immunologic responsiveness against the specific donor. Patients treated with this therapy should receive organs from "ideal" donors without risk factors and cold ischemia time should not exceed 30 hr. Further clinical studies of this approach are warranted.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Evaluation of flowcytometric crossmatching in renal allograft recipients.

Forty-four cadaver renal allograft recipients who had flowcytometric cross-match (FCXM) testing and sequential quadruple immunosuppression were studied with respect to the number of rejection episodes and the functional viability of the graft in the first year after transplantation. Fourteen of these patients had antibodies to donor T cells by FCXM. All were negative by conventional crossmatch. Multiple-regression analysis with HLA mismatches, panel-reactive antibody (PRA) percentage, flowcytometric channel shifts and transplant number as independent variables revealed that transplant number and high PRA (> 50%) impacted (p < 0.05) on serum creatinine at 1 month and 1 year, and graft survival at 1 year. In first transplants, a positive FCXM had no impact on 1-year graft survival rates; however, in retransplants, a positive FCXM and/or high PRA had a significant negative impact on 1-year graft survival. This study indicates that the FCXM should be utilized for retransplant patients, and in patients with a high PRA, in an attempt to improve graft survival for these high-risk recipients.

Antilymphocyte Serum↗
PubMed1992

Flow cytometric evaluation of cytotoxic peripheral blood lymphocytes in acute renal graft rejection.

The presence of the S6F1+ epitope on the surface of CD8+ lymphocytes is believed to be uniquely representative of cytotoxic subpopulations. A preliminary study was conducted to evaluate the CD8+ S6F1+ peripheral lymphocytes by flow cytometry in patients undergoing renal allograft biopsy for allograft dysfunction. Lymphocytes, obtained at the time of biopsy, were analyzed by flow cytometry with CD8-FITC/S6F1-RD1 as the test monoclonal antibody and MsIgG-RD1/MsIgG-FITC as internal control. A 100% increase in S6F1+ cells over internal control was considered to be positive result. The results were correlated with the histopathologic findings in 14 instances of allograft dysfunction occurring 26.5 +/- 11.6 days posttransplantation. The histopathologic diagnosis was acute cellular rejection in eight cases, acute tubular necrosis in four, and cyclosporine nephrotoxicity in two. Flow cytometric detection of an increase in S6F1+ cells yielded a sensitivity of 87.5% and a specificity of 83.3% for the diagnosis of acute rejection. It would appear that the use of a monoclonal antibody to detect increases in the number of CD8+ S6F1+ peripheral lymphocytes is a valuable test for the detection of acute allograft rejection in the initial period after transplantation.

Acute Disease↗
PubMed1992

A multicenter study to evaluate a novel assay for quantitation of soluble interleukin 2 receptor in renal transplant recipients.

The clinical utility of monitoring soluble interleukin 2 receptor (sIL-2R) as an indicator of immune stimulation in renal transplant patients was evaluated in a retrospective study at 3 centers. Serum samples (n = 2360) were obtained from 86 (17 living related donor, 69 cadaver) transplant recipients. The patients had received either triple therapy (n = 35) or antilymphocyte antibody induction therapy followed by triple therapy (n = 51). The mean period of postoperative observation was 118 days (range, 6-349 days). Serum sIL-2R concentrations were quantitated by an automated microparticle enzyme immunoassay (MEIA) (Abbott Diagnostics) in which sIL-2R was captured by 7G7/B6 monoclonal antibody-coated microparticles and detected by an immunospecific rabbit antihuman sIL-2R-alkaline phosphatase conjugate. A distinct advantage of the technique was rapid turn-around time: 1-24 results were obtained in less than 50 min. Cyclosporine trough concentrations were determined by radioimmunoassay or high-performance liquid chromatography. Diagnosis of rejection was established by clinical and histological criteria. The mean sIL-2R concentration in patients receiving antilymphocyte antibody induction therapy increased from 3486 +/- 1729 U/ml (+/- SD) at the time of transplant to a maximum of 7395 +/- 7101 U/ml on the third day posttransplant; this increase was not observed in patients receiving triple therapy (P less than 0.0001). By the sixth day of posttransplant, there were no differences in sIL-2R levels in the two groups. Fifty rejection episodes were observed in 29 patients on triple therapy. The mean sIL-2R concentration rose from 3022 U/ml at the data point prior to rejection to 3524 U/ml at the time of rejection. Thirty-four rejection episodes were observed in 26 patients receiving induction therapy. The mean sIL-2R concentration was 3015 U/ml at the data point prior to rejection and 4815 U/ml at the time of rejection. The sIL-2R concentrations began increasing earlier and rose higher in rejecting patients who received induction therapy than in those receiving triple therapy. Early posttransplant sIL-2R levels increased significantly more in cadaver recipients than in LRD recipients, reaching a maximum on day 2 posttransplant (P less than 0.001). Prerejection sIL-2R concentrations were significantly lower in LRD recipients than in cadaver recipients (2248 U/ml vs. 4290 U/ml, P less than 0.02), as were sIL-2R levels at the time of diagnosis of rejection (2800 U/ml vs. 4832 U/ml, P = 0.01). The mean sIL-2R level in stable long-term graft recipients was 2110 U/ml, with approximately 90% of values less than 3000 U/ml.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1991

Disseminated histoplasmosis in a renal transplant patient: a cause of renal failure several years following transplantation.

A 49-year-old man developed disseminated histoplasmosis 6 1/2 years after transplantation. The organism was initially present in the urine and in a tongue lesion. Treatment with itraconazole was instituted. However, there was further dissemination of the disease and worsening of renal function. Allograft biopsy showed extensive involvement with the organism. Amphotericin B was started, resulting in a rapid resolution of the disease. However, renal function deteriorated, leading to permanent hemodialysis.

Biopsy↗
PubMed1991

The efficacy of OKT3 in vascular rejection.

Sixty-six consecutive biopsies of renal allograft recipients treated with OKT3 monoclonal antibody were reviewed and placed into one of two groups. Group I (29 patients) had evidence of acute vascular and cellular rejection, while group II (32 patients) had cellular rejection but no vascular rejection. In 5 cases, the sample was inadequate to determine if vascular rejection was present or not. The severity of the cellular rejection was graded histologically as mild, moderate, or severe. The severity was equivalent when comparing group I with group II (mild, 17% vs. 10%; moderate, 52% vs. 59%; and severe, 31% vs. 31%). There was no difference in the rejection reversal rate between the two groups (86% vs. 91%). However, at 6 and 12 months there was a higher graft loss in the group with vascular rejection (graft survival 64% vs. 81%, P = 0.13, and 58% vs. 75%, P = 0.08, respectively). The poorest outcome was in those patients with both severe acute cellular rejection and acute vascular rejection (4/9, or 44%). The serum creatinine level was higher both pre- and post-OKT3 therapy and at 1, 6, and 12 months in the group with vascular rejection. In conclusion, OKT3 was equally successful in reversing acute cellular rejection and acute vascular rejection. However, increased graft loss occurred at 6 and 12 months in the group with vascular rejection.

Adult↗
PubMed1991

Cyclosporine dose reduction by ketoconazole administration in renal transplant recipients.

Cyclosporine metabolism occurs in the liver via hepatic cytochrome P-450 microsomal enzymes. Ketoconazole, an imidazole derivative, has been shown to inhibit the cytochrome P-450 enzyme system. Thirty-six renal transplant recipients receiving cyclosporine as part of a triple immunosuppressive drug regimen were started on 200 mg/day of oral ketoconazole. The dose of cyclosporine was reduced by 70% at the start of ketoconazole; this dose reduction was based on our previous experience with concomitant cyclosporine-ketoconazole therapy. Ketoconazole was started in patients who had been on cyclosporine for between 10 days and 74 months. The mean cyclosporine dose was 420 mg/day (5.9 mg/kg/day) before starting ketoconazole and 66 mg/day (0.9 mg/kg/day) one year after the addition of ketoconazole; this represents a cyclosporine dose reduction of 84.7% (P less than 0.0001). The mean trough whole-blood cyclosporine concentrations measured by HPLC, were 130 ng/mL preketoconazole and 149 ng/mL after 1 year of combination therapy. Mean serum creatinine and BUN levels were unchanged before and during ketoconazole administration, and no changes in liver function tests were noted. Cyclosporine pharmacokinetics were performed before and after at least three weeks of ketoconazole. Hourly whole-blood samples were measured by HPLC (parent cyclosporine only) and TDX (parent + metabolites). Combination therapy resulted in decreases in the maximum blood concentration and the steady-state volume of distribution divided by the fractional absorption, and increases in mean residence time and the parent-to-parent plus metabolite ratio (calculated by dividing the HPLC by the TDX value). The addition of ketoconazole to cyclosporine-treated patients resulted in a significant inhibition of cyclosporine metabolism and decrease in the dosage. There was minimal nephrotoxicity, and only four rejection episodes occurred on combined therapy. The concomitant administration of the two drugs was well tolerated, and there was no deleterious effect on the immunosuppressive activity of cyclosporine. This drug interaction provides a significant reduction in the costs associated with organ transplantation.

Adult↗
PubMed1991

Critical ketoconazole dosage range for ciclosporin clearance inhibition in the dog.

Ciclosporin (CsA) is metabolized exclusively by the hepatic cytochrome P-450 mixed function oxidase system. Ketoconazole (KC) is a potent inhibitor of this enzyme system. CsA was administered alone and in combination with five different doses of KC (1.25, 2.5, 5.0, 10.0, 20.0 mg/kg/day) under steady-state conditions to 7 adult mongrel dogs. KC produced a highly significant (p = 0.0001), dose-dependent decrease in CsA total body clearance [Cl(T)]. The critical KC dosage range for this to occur was found to be between 2.5 and 10 mg/kg/day. The reduction of CsA CL(T) was insignificant (p greater than 0.05) at a KC dose of less than 2.5 mg/kg/day, and the 92% reduction observed using 20 mg/kg/day KC was not significantly greater than the 85% reduction occurring after only 10 mg/kg/day KC (p greater than 0.05). The dose of concomitant KC was also highly correlated with a reduction in the whole blood CsA parent/parent + metabolite ratio as determined using high-performance liquid chromatography and polyclonal fluorescent polarization immunoassay for CsA measurement (r = 0.998, p less than 0.0001). The absolute oral bioavailability of CsA as well as the time required to reach its maximum concentration in the blood following oral administration did not change significantly over the course of the study (p greater than 0.05). We conclude from these new observations that the KC-induced decrease in CsA Cl(T) in the dog in vivo is dose-dependent and maximized within the KC dosage range of 2.5-10 mg/kg/day. The effect does not appear to involve a decrease in the rate of CsA oral absorption, and may be compensated for by an appropriate reduction in the concomitantly administered dose of CsA.

Administration, Oral↗
PubMed1991

Solid-organ transplantation in the pediatric population.

The results of solid-organ transplantation in children have improved dramatically in recent years with advances in surgical technique and immunosuppressive therapy regimens. Donor organ availability continues to be a limiting factor in the pediatric age-group, and it has been estimated that 20-30% of children waiting for a heart or liver transplant die before a suitable donor can be found. A number of problems remain for the long-term pediatric graft recipient, and these will need to be vigorously pursued so that optimal rehabilitation and longevity can be achieved for the transplanted child.

Adolescent↗
PubMed1991

Recent contributions to transplantation at the University of Cincinnati.

1. Clinical investigations at the University of Cincinnati have focused primarily on infection control, methods to increase donor-specific unresponsiveness, improvement in immunosuppression, donor maintenance and evaluation, posttransplant monitoring, and reduced-size livers for children. 2. Donor specific unresponsiveness (DSU) can be achieved frequently in recipients of both cadaver donor and living related donor kidneys by giving a single donor specific transfusion and CsA only 24 hours preoperatively with continuing triple immunosuppressive therapy. 3. Prednisone can be withdrawn from almost all patients with no rejection by 1 year with significant improvement in blood pressure, daily insulin requirement in diabetics, total blood cholesterol, and low density lipoproteins (LDL). 4. Oral ketoconazole 200 mg/day can be used safely to block the hepatic metabolism of CsA and reduce the amount of CsA administered by an average of 77-88%. This is of great economic consequence to lower income patients and patients with poor drug absorption. 5. Eighteen patients with SLE who received 23 kidney transplantations had an increase in graft loss in the first 6 months but the rate of graft loss after 6 months was almost identical to other ESRD patients. 6. The Cincinnati Transplant Tumor Registry has data on about 8,000 patients. Except for those with CNS tumors, patients with active cancers should not be used as donors. However, donors with previous curative procedures should not be excluded automatically. Cancers arising in immunosuppressed transplant recipients that have a higher incidence than the general population (expressed as percentage of treated cancers) are: lymphomas (22% vs 5%), lip cancers (7% vs 0.3%), Kaposi's sarcoma (6% vs less than 0.1%), vulva and perineal cancers (4% vs 0.6%), hepatobiliary cancers (2.5% vs 1.0%) and sarcomas (1.8% vs 0.5%). Other cancers have about the same-distribution. 7. Immunologic monitoring during OKT3 therapy is particularly useful in re-treatment and treatment of pediatric liver patients when increased doses of the drug may be necessary. 8. The MEGX test has been found to be a major predictor of primary non-function of the transplanted liver, and it is also useful in predicting the risks of dying from liver disease. 9. Reduced-size livers have been used in 37 patients, representing almost half of all pediatric liver transplants. Survival with reduced-size grafts (91% at 1 year) compared favorably with survival of whole organs (79% at 1 year). The benefit is particularly dramatic in infants with biliary atresia (100% 1-year graft survival in 24 patients, median age 11 months).(ABSTRACT TRUNCATED AT 400 WORDS)

Actuarial Analysis↗