Biomedical subjects

M D Pescovitz

Publications and source records attributed to M D Pescovitz.

At least 37 records · Page 2Linked to original sources

PubMed2001

Immunosuppressive therapy and post-transplantation diarrhea.

Gastrointestinal complications, including diarrhea, are among the anticipated adverse events secondary to immunosuppression. The reported overall rate of diarrhea may be affected by drug-specific effects, dose-response effects, interactions with other medications, drug formulation, the length of study follow-up, reporting bias and population characteristics such as ethnicity and baseline disease, including transplant organ type. The true incidence of diarrhea is often difficult to assess from the numerous published clinical trials. A number of deficiencies, including self-reporting, interstudy comparisons, lack of blinding, concomitant medications and a general lack of standardization and quantification of diarrhea may greatly obscure comparisons among the different immunosuppressive medications. This review considers each of these factors in assessing the overall incidence of post-transplantation diarrhea for the various immunosuppressive medications currently in use.

Clinical Trials as Topic↗

PubMed2000

Intravenous mycophenolate mofetil: safety, tolerability, and pharmacokinetics.

An intravenous (i.v.) formulation of mycophenolate mofetil (MMF; CellCept, Roche Pharmaceuticals, Inc., Palo Alto, CA) that will enable its administration to patients unable to tolerate oral medication is available. Two separate studies, an open-labeled pharmacokinetic (PK) study and a double-blind safety study, were performed. Within 24 h after transplant, 153 (safety study) and 45 (PK study) first or second renal transplant recipients were started on i.v. MMF 1 g Q12h or placebo (used in the safety study only, 2:1 MMF:placebo), given over 2 h via a dedicated peripheral venous catheter. In the safety study, per os (p.o.) MMF (1g Q12h) or placebo was administered, starting within 72 h after transplant, whereas in the PK study, p.o. MMF was started on the evening of day 5. Sequential blood samples obtained on study days 5 (i.v. MMF) and 6 (p.o. MMF) before and up to 12 h after the AM dose were analyzed for mycophenolic acid (MPA) and MPA glucuronide (MPAG) concentrations by high-performance liquid chromatography. The area under the concentration curve (AUC) was calculated using the linear trapezoidal rule. The MPA AUC(0-12) was higher for i.v. MMF than p.o. MMF (40.8 +/- 11.4 microg x h/ mL vs. 32.9 +/- 15, p < 0.001). There were no other significant PK differences for plasma MPA or MPAG. In the safety study (n = 98 i.v. MMF vs. n = 55 placebo), 11 patients (11%, i.v. MMF) and 4 patients (7%, placebo) discontinued their use of the drug because of an adverse event (AE). Overall, AEs were similar between i.v. MMF and placebo. Injection site phlebitis (4%) and thrombosis (4%) were observed only with i.v. MMF. MMF i.v. 1 g twice daily (b.i.d.) should provide efficacy at least equivalent to p.o. MMF without increased toxicity, and it provides an acceptable alternative dose form in the immediate period after transplant.

Administration, Oral↗

PubMed2000

Valganciclovir results in improved oral absorption of ganciclovir in liver transplant recipients.

The pharmacokinetics of an orally administered valine ester of ganciclovir (GCV), valganciclovir (VGC), were studied. These were compared to the pharmacokinetics of oral and intravenous GCV. Twenty-eight liver transplant recipients received, in an open-label random order with a 3- to 7-day washout, each of the following: 1 g of oral GCV three times a day; 450 mg of VGC per os (p.o.) once a day (q.d.); 900 mg of VGC p.o. q.d.; and 5 mg of intravenous (i.v.) GCV per kg of body weight q.d., given over 1 h. GCV and VGC concentrations were measured in blood over 24 h. One-sided equivalence testing was performed to test for noninferiority of 450 mg of VGC relative to oral GCV (two-sided 90% confidence interval [CI] > 80%) and nonsuperiority of 900 mg of VGC relative to i.v. GCV (two-sided 90% CI < 125%). The exposure of 450 mg of VGC (20.56 microg. h/ml) was found to be noninferior to that of oral GCV (20.15 microg. h/ml; 90% CI for relative bioavailability of 95 to 109%), and the exposure of 900 mg of VGC (42.69 microg. h/ml) was found to be nonsuperior to that of i.v. GCV (47.61 microg. h/ml; 90% CI = 83 to 97%). Oral VGC delivers systemic GCV exposure equivalent to that of standard oral GCV (at 450 mg) or i.v. GCV (at 900 mg of VGC). VGC has promise for effective CMV prophylaxis or treatment with once-daily oral dosing in transplant recipients.

Antiviral Agents↗

PubMed1999

Sirolimus reduces the incidence of acute rejection episodes despite lower cyclosporine doses in caucasian recipients of mismatched primary renal allografts: a phase II trial. Rapamune Study Group.

BACKGROUND: The novel agent sirolimus (SRL; Rapamune; rapamycin) inhibits the immune response by a mechanism distinct from those of calcineurin antagonists or antimetabolites. This randomized, controlled, multicenter, single blind, phase II trial examined the combination of SRL, steroids, and full versus reduced doses of cyclosporine (CsA) for prophylaxis of acute renal allograft rejection. METHODS: A total of 149 recipients of mismatched cadaveric- or living-donor primary renal allografts were randomized into six groups. Three groups received placebo or 1 or 3 mg/m2/day SRL, as well as steroids and full-dose CsA (Sandimmune). Three groups received steroids, reduced-dose CsA (target trough level 50% of full-dose range), and 1, 3, or 5 mg/m2/day SRL. RESULTS: The incidence of biopsy-proven acute rejection episodes within the first 6 months after transplant was reduced from 32.0% in the control group to 8.5% in patients receiving SRL (1 or 3 mg/m2/day) and full-dose Sandimmune CsA (P=0.018). Similar low rates of acute rejection episodes were observed among non-African-Americans, but not African-Americans, treated with SRL and reduced-dose Sandimmune CsA. Despite the augmented immunosuppression, 1-year patient and graft survival rates did not differ significantly across groups. Adverse effects attributable to CsA, including hypertension and new-onset diabetes mellitus, were not exacerbated by SRL. Except for an increased incidence of pneumonia among patients receiving full-dose CsA and 3 mg/m2/day SRL, the incidences of opportunistic infections were similar in all treatment groups. Although SRL produced more frequent, but reversible, hematological and lipid abnormalities, it had no apparent nephrotoxic effects to exacerbate CsA-induced renal dysfunction. CONCLUSIONS: SRL in combination with CsA and steroids not only lowers the incidence of biopsy-proven acute renal allograft rejection episodes, but also may permit CsA sparing, at least among Caucasian patients, without an increased risk of rejection.

Adult↗

PubMed1999

Cytomegalovirus infections after treatment with daclizumab, an anti IL-2 receptor antibody, for prevention of renal allograft rejection. Roche Study Group.

Daclizumab is a newly developed humanized anti-IL-2 receptor monoclonal antibody. We describe the effect of adding daclizumab to conventional dual or triple cyclosporine A immunosuppressive therapy on the incidence and nature of cytomegalovirus (CMV) infections in patients receiving a first cadaveric renal graft. In the triple therapy study there was no evidence of any difference in CMV rate or course of disease between the two treatment arms, although in the dual therapy study a decrease in the incidence of CMV infection was observed in the patients treated with daclizumab. The onset of CMV disease was markedly delayed in the daclizumab groups in both studies. Daclizumab can effectively reduce the risk of acute rejection without causing a concomitant increase in opportunistic infections, and by decreasing the need for antirejection therapy may also have a beneficial effect on CMV infection rates.

Adult↗

PubMed1999

Absence of teratogenicity of oral ganciclovir used during early pregnancy in a liver transplant recipient.

BACKGROUND: Ganciclovir (GCV) is effective for prevention of cytomegalovirus (CMV) disease. In animals it may cause some teratogenicity. There is little information on the effect of GCV on a human fetus. METHODS: The chart of a liver transplant recipient who received oral GCV during the first trimester was reviewed as was the published literature. RESULTS: There was no evidence of teratogenicity in the baby or in a case reported elsewhere. CONCLUSIONS: GCV has been used in a few female transplant recipients without untoward effects. The still uncertain risk of short term and long term teratogenicity, however, must be weighed against the risk of CMV disease in the recipient and the development of congenital CMV in the baby.

Administration, Oral↗

PubMed1999

Bacillary angiomatosis in a renal transplant recipient.

A case of bacillary angiomatosis infection presenting as a skin nodule in a renal transplant recipient was found. The patient was taking cyclosporine, prednisone, and mycophenolate mofetil at the time of presentation. The bacillary angiomatosis responded to 6 months of therapy with oral erythromycin.

Adult↗

PubMed1999

Oral ganciclovir and pharmacokinetics of valganciclovir in liver transplant recipients.

The pivotal trial demonstrating efficacy of oral ganciclovir in preventing cytomegalovirus (CMV) disease following organ transplantation was conducted in liver transplant recipients, in whom the rate of CMV disease was reduced from 19% to 5%. Pharmacokinetic analyses have indicated that oral ganciclovir dosing should be adjusted, based on renal function, to achieve adequate drug levels. With normal renal function, 1 g t.i.d. of oral ganciclovir is required to achieve such adequate systemic levels. Children require proportionally more drug than adults do: in the range 600-800 mg/m2 to achieve adequate dosing. The development of an oral prodrug, valganciclovir, may help to obviate some of the drug exposure issues raised with oral ganciclovir. The ester linkage of the amino acid valine to ganciclovir results in ten-fold higher bioavailability of ganciclovir: 450 mg of valganciclovir given once daily produces drug exposure similar to that achieved with 3 g of oral ganciclovir; 900 mg of valganciclovir given once daily produces drug exposures equivalent to that of 5 mg/kg of IV ganciclovir. This drug may improve prophylactic efficacy in the high-risk CMV seropositive donor/seronegative negative recipient transplant groups and may also allow treatment of established CMV disease with an oral formulation.

Administration, Oral↗

PubMed1998

Oral ganciclovir dosing in transplant recipients and dialysis patients based on renal function.

BACKGROUND: An oral formulation of ganciclovir (GCV) was recently approved for the prevention of cytomegalovirus disease in solid organ transplant recipients. This study was designed to determine the bioavailability of GCV and to test a dosing algorithm in transplant and dialysis patients with different levels of renal function. METHODS: Pharmacokinetic studies were carried out in 23 patients who were either a recipient of an organ transplant or on hemodialysis. Drug dosing was established by the following algorithm based on calculated creatinine clearance (CrCl): CrCl = [(140-age) x body weight]/(72 x Cr) x 0.85 for women that is, CrCl >50 ml/min, 1000 mg every 8 hr; CrCl of 25-50 ml/min, 1000 mg every 24 hr; CrCl of 10-24 ml/ min, 500 mg every day; CrCl < 10 ml/min (or on dialysis), 500 mg every other day after dialysis. GCV was taken within 30 min after a meal. The patients received oral GCV for between 12 days and 14 weeks. Serum specimens (or plasma from patients on hemodialysis) obtained at steady state were analyzed for GCV concentrations by high-performance liquid chromatography. In nine of the transplant recipients, absolute bioavailability was determined by comparing GCV levels after single oral and intravenous doses of GCV. RESULTS: The following GCV concentrations (mean +/-SD) were determined: with CrCl of > or =70 ml/min, the minimum steady-state concentration (Cmin) and maximum concentration (Cmax) were 0.78+/-0.46 microg/ml and 1.42+/-0.37 microg/ml, respectively, with a 24-hr area under the concentration time curve (AUC0-24) of 24.7+/-7.8 microg x hr/ml; with CrCl of 50-69 ml/min, the Cmin and Cmax were 1.93+/-0.48 and 2.57+/-0.39 microg/ml, respectively, with an AUC0-24 of 52.1+/-10.1 microg x hr/ml; with CrCl of 25-50 ml/min, the Cmin and Cmax were 0.41+/-0.27 and 1.17+/-0.32 microg/ml, respectively, with an AUC0-24 of 14.6+/-7.4 microg x hr/ml. For one patient with a CrCl of 23.8 ml/min, the Cmin and Cmax were 0.32 and 0.7 microg/ml, respectively, with an AUC0-24 of 10.7 microg x hr/ml. With CrCl of <10 ml/min, the mean Cmin and Cmax were 0.75+/-0.42 and 1.59+/-0.55 microg/ml, respectively, with a mean AUC0-24 of 64.6+/-18.8 microg x hr/ml. Absolute bioavailability, for the nine patients so analyzed, was 7.2+/-2.4%. For those patients with end-stage renal failure, GCV concentrations fell during dialysis from a mean of 1.47+/-0.48 microg/ml before dialysis to 0.69+/-0.38 microg/ml after dialysis. CONCLUSIONS: The bioavailability of oral GCV in transplant patients was similar to that observed in human immunodeficiency virus-infected patients. However, levels between 0.5 and 1 microg/ml (within the IC50 of most cytomegalovirus isolates) could be achieved with tolerable oral doses. The proposed dosing algorithm resulted in adequate levels for patients with CrCl greater than 50 ml/min and for patients on dialysis. For patients with CrCl between 10 and 50 ml/min, the levels achieved were low and these patients would likely benefit from increased doses.

Administration, Oral↗

PubMed1998

Summary of the first round analyses of the Second International Swine CD Workshop.

The reactivity of 176 monoclonal antibodies (mAb) submitted to the Second International Swine CD Workshop, together with 19 internal standards, was analyzed by flow cytometry on 16 different cell types as a means of establishing the proper cell subset for later detailed clustering analyses. The exact CD subset reactivity of the 19 internal standard mAb had been characterized in the First International Swine CD Workshop. The flow cytometric analyses resulted in 40 data sets which were then subjected to statistical clustering using the Leukocyte Typing Database IV (LTDB4) software. As result of this work, 22 clusters were defined. After review of these results, panels of mAb from the defined first round clusters were assigned to cell subsets. The respective mAb in those first round clusters were then distributed to subset group researchers for further examination during the second round of the workshop.

Animals↗

PubMed1998

Summary of workshop findings for antibodies reacting with porcine T-cells and activation antigens: results from the Second International Swine CD Workshop.

After initial evaluation of the 176 new and 19 control monoclonal antibodies (mAb) submitted to the Second International Swine CD Workshop, 57 were assigned to the T-cell/activation marker subgroup. These 57 mAb were further analyzed using flow cytometry on whole blood lymphocytes, splenocytes, Peyer's patch lymphocytes, in vitro cell lines, broncho-alveolar lavage cells, Con A and PHA blasts, fetal cell populations, and by 2-color flow cytometry against mAb to porcine CD2, CD4, and CD8. Finally, the molecular weights of the target antigens were characterized when possible. As a result of these analyses, 23 mAb were distributed into 7 CD clusters. Newly confirmed mAb assignments included: two CD2; one CD4; two CD5; one wCD6; and one wCD25. Three new mAb were found that reacted with wCD8, one of which defined a new epitope, wCD8c. For the first time, mAb against porcine CD3 were identified, including 6 mAb that reacted with three different epitopes. Several new mAb reacted with antigens whose expression varied depending on the activation state of the test cell. These will require further characterization in order to assign a CD number.

Animals↗

PubMed1998

Analyses of monoclonal antibodies reacting with porcine CD3: results from the Second International Swine CD Workshop.

Among the 57 monoclonal antibodies (mAb) analyzed within the T-cell group from the Second Swine CD Workshop, six mAb fell within clusters T10 and T11 (No. 088, STH164; No. 148, FY1A3; No. 149, FY2C1; No. 150, FY1H2; No. 151, FY2A11; No. 169, BB23-8E6). The mAb within these two groups gave a similar appearance on flow cytometry and stained all peripheral blood T-cells as defined by CD4 and wCD8 staining. All six mAb precipitated a 24 kDa protein. On the basis of inhibition analyses performed as part of the workshop and from published data, the mAb define at least three epitopes. There is only minimal stimulation of resting peripheral lymphocytes, but four of the mAb produce strong stimulation in the presence of PMA. With the exception of STH164, all have been shown to react with CD3 epsilon-transfected COS cells. The new mAb, therefore, react with three epitopes on porcine CD3 epsilon designated CD3a (BB23-8E6, FY2A11), CD3b (FY1A3, FY2C1), and CD3c (FY1H2). mAb STH164 appears to be reactive with another epitope, however, since its reactivity with CD3 has not been confirmed it is designated as wCD3.

Animals↗

PubMed1998

Analyses of monoclonal antibodies reacting with porcine CD5: results from the Second International Swine CD Workshop.

Among the 57 monoclonal antibodies analyzed within the T-cell group, three mAbs fell within cluster T13 including the CD5a standard b53b7 (No. 174). The two new mAbs 1H6/8 (No. 058) and BB6-9G12 (No. 166) both precipitated 55 and 60 kDa proteins that were of similar molecular weights as the standard. Staining patterns on the various cell types were similar. Both new antibodies inhibited the binding of the CD5a reference mAbs b53b7 to peripheral lymphocytes. These mAbs, therefore both react with the CD5a epitope bringing the number of anti-porcine CD5 mAbs to eight, all of which appear to recognize the same epitope.

Animals↗

PubMed1998

Analyses of monoclonal antibodies reacting with porcine wCD6: results from the Second International Swine CD Workshop.

Among the 57 monoclonal antibodies analyzed within the T-cell group of the Second International Swine CD Workshop, one mAb fell within cluster T14a that included the CD6 standard a38b2 (No. 175). The new mAb MIL8 (No. 082) and a38b2 both precipitated from activated T-cells a 150 kDa monomeric protein. Staining patterns on the various cell types were similar. There was no inhibition of binding of either mAb to peripheral blood T-cells with the opposite mAb. The new mAb, MIL8, reacts with a separate epitope on porcine wCD6.

Animals↗

PubMed1998

Report on the analyses of mAb reactive with porcine CD8 for the second international swine CD workshop.

Based on an analysis of their reactivity with porcine peripheral blood lymphocytes (PBL), only three of the 57 mAbs assigned to the T cell/activation marker group were grouped into cluster T9 along with the two wCD8 workshop standard mAbs 76-2-11 (CD8a) and 11/295/33 (CD8b). Their placement was verified through the use of two-color cytofluorometry which established that all three mAbs (STH101, #090; UCP1H12-2, #139; and PG164A, #051) bind exclusively to CD8+ cells. Moreover, like the CD8 standard mAbs, these three mAbs reacted with two proteins with a MW of 33 and 35 kDa from lymphocyte lysates and were, thus, given the wCD8 designation. Because the mAb STH101 inhibited the binding of mAb 76-2-11 but not of 11/295/33, it was given the wCD8a designation. The reactivity of the other two new mAbs in the T9 cluster with the various subsets of CD8+ lymphocytes were distinct from that of the other members in this cluster including the standards. Although the characteristic porcine CD8 staining pattern consisting of CD8low and CD8high cells was obtained with the mAb UCP1H12-2, a wider gap between the fluorescence intensity of the CD8low and CD8high lymphocytes was observed. In contrast, the mAb PG164A, not only exclusively reacted with CD4-/CD8high lymphocytes, but it also failed to recognize CD4/CD8 double positive lymphocytes. It was concluded that this mAb is specific for a previously unrecognized CD8 epitope, and was, thus, given the wCD8c designation. A very similar reactivity pattern to that of PG164A was observed for two other mAbs (STH106, #094; and SwNL554.1, #009). Although these two mAbs were not originally positioned in the T cell subgroup because of their reactivity and their ability to inhibit the binding of PG164A, they were given the wCD8c designation. Overall, five new wCD8 mAbs were identified. Although the molecular basis for the differences in PBL recognition by these mAbs is not yet understood, they will be important in defining the role of CD8+ lymphocyte subsets in health and disease.

Animals↗

PubMed1998

Improved cyclosporine pharmacokinetics in maintenance renal transplant recipients converted to cyclosporine for microemulsion.

BACKGROUND: Variability in cyclosporine drug exposure of > or = 20% has been shown to be a risk factor for the development of chronic renal allograft rejection. We tested the hypothesis that a cyclosporine microemulsion (CsA-ME) would result in reduced variability in stable maintenance renal transplant patients when compared with the original formulation of cyclosporine (CsA). METHODS: The 31 maintenance renal transplant recipients were part of a multicenter, randomized, double-blind, prospective study comparing the CsA formulation with the CsA-ME formulation. Pharmacokinetics analyses were performed at two centers 1, 4, 12, and 52 weeks after patients were randomized to continue receiving CsA or to convert to CsA-ME. RESULTS: The means of the week 1-, 4-, and 12-week areas under the concentration-time curves (AUC), and Cmax were significantly higher and the Tmax was significantly shorter in those patients converted to CsA-ME than in those remaining on CsA. There was no correlation between change in AUC after conversion and change in serum creatinine. The coefficient of variation values for dose-adjusted AUC, expressed as a percentage (%CVAUC), were lower in CsA-ME patients than CsA patients after both 12 and 52 weeks. Over the initial 12 weeks. %CVAUC values of < or = 20% were seen in a significantly greater proportion of CsA-ME patients than CsA patients. CONCLUSIONS: Conversion of maintenance renal transplant recipients from CsA to CsA-ME resulted in improved absorption of cyclosporine. The CsA-ME formulation resulted in long-term reduction in the variability of cyclosporine exposure and more consistent pharmacokinetics.

Adult↗

PubMed1998

Mesocaval shunt inhibits primary and metastatic hepatoma growth and enhances apoptosis.

BACKGROUND: Previous reports indicate that hepatocyte growth factor and other hepatic trophic factors reach the liver presumably by portal venous inflow and stimulate experimental hepatic tumor growth, invasion, and metastasis. This study tests this hypothesis by evaluating whether a mesocaval shunt (MCS) alters hepatic tumor growth, the mitotic rate, apoptosis, and incidence and growth of lung metastasis in rats with implanted hepatoma. METHODS: Morris hepatoma (1 x 10(5)) cells were implanted intrahepatically in 19 ACI rats. One week after implantation, 10 rats underwent MCS operation and nine controls a sham operation. Rats were killed 21 days after the operation to assess tumor volume, tumor cell mitosis, apoptosis, area of tumor necrosis, pulmonary metastases and percentage of lung tumor area. RESULTS: Mesocaval shunt induced a significant increase in the rate of tumor apoptosis (25 +/- 5 v 14 +/- 6, P < .01) and the percentage of area of tumor necrosis (29% +/- 17% v 13% +/- 8%, P < .05), a decreased tumor volume (839 +/- 1,195 v 2,909 +/- 2,572, P < .05), a reduction in tumor mitosis (70 +/- 28 v 93 +/- 11, P < .05) and decreased percentage area of pulmonary metastatic tumor (9.8 +/- 6.8 v 18.8 +/- 14, P < .05). CONCLUSION: These observations show that growth of intrahepatic tumor is influenced by portal venous inflow and suggest that MCS or other methods of regulating portal vein flow may be useful as adjunctive therapy in the treatment of advanced hepatoma.

Animals↗

PubMed1998

Prostate-specific antigen values and their clinical significance in renal transplant recipients.

BACKGROUND: In the diagnosis of prostate cancer, prostate-specific antigen (PSA) is the most clinically useful tumor marker. Its utility in renal transplant patients is unclear. We hypothesized that PSA values might be affected by the renal function, immunosuppression, or proteinuria. METHODS: Three hundred four PSA values were measured in 166 patients >40 years (53.5 +/- 7.2 years, mean +/- SD, range 44.4 to 76.2). Charts were reviewed for 24-hour creatinine clearance, 24-hour urinary protein, cyclosporine use, age at the time of each PSA test, and evaluation done in response to the PSA result. Analyses used the Mann-Whitney U test and simple regression model. RESULTS: Twenty-five values in 13 patients were >4.0 ng/mL. Of these, 6 patients (6 values) had normal repeat PSA values; 3 patients (11 values) had negative evaluations for prostate cancer; and 4 patients (8 values) were diagnosed with prostate cancer. The latter 4 patients were excluded from the denoted normal group leaving 294 PSA values in 162 patients. The mean normal PSA was 1.3 +/- 1.8 ng/mL, range 0.1 to 20.2. The pretreatment mean PSA for recipients with prostate cancer was 302 +/- 800, range 8.0 to 2,281. An elevated PSA value was associated with a 31% incidence of prostate cancer. There was no association of PSA levels with cyclosporine use, 24-hour creatinine clearance, or 24-hour urinary protein, but there was with age. CONCLUSIONS: Prostate-specific antigen values in renal transplant recipients are similar to those in the general population and are not influenced by cyclosporine or by renal function. We recommend routine measurement of PSA in male transplant recipients.

Adult↗