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D V Cramer

Publications and source records attributed to D V Cramer.

At least 73 records · Page 4Linked to original sources
PubMed1993

Prevention of vascularized allograft and xenograft rejection in rodents by brequinar sodium.

The data that has been obtained from preclinical studies in rodents demonstrate that BQR is an effective primary immunosuppressive agent with important advantages for use in transplantation immunotherapy. The drug is highly effective when used as a single agent to prevent the rejection of a variety of vascularized allografts and xenografts. BQR is easily administered orally, the drug displays a high level of bioavailability, and drug plasma levels and immunosuppressive activity can be directly measured. The adverse side effects seen with the drug are those normally associated with antiproliferative drugs and are predictable and easily reversed by treatment withdrawal. Most importantly, perhaps, is the broad range of synergistic activity when used in combination with new immunosuppressive drugs. We believe that the combination of these attributes separate BQR from many of the new drugs now under study. Some, for example, do not exhibit synergism (CsA and FK 506), others have may have problems with inadequate oral bioavailability (MPM and rapamycin), and some exhibit the potential for substantial toxicity (15-DSG, myzorbine). The data derived from the use of BQR in combination with other immunosuppressive drugs, such as the studies described above, are important. They provide direct evidence to support the concept that the next important advances in immunosuppressive therapy will involve the use of an effective multidrug approach to preventing organ graft rejection. Combination therapies with immunosuppressive drugs that exhibit different modes of action improve graft survival, widen therapeutic windows, and reduce the risk of toxic side effects. The experimental evidence that several of these combinations are potentially useful is solid, consistent, and exciting. It is our expectation from the rodent experiments described in this symposium that the treatment of allograft (and perhaps xenograft) rejection will consist of the use of CsA (or FK 506), BQR, and a third drug such as rapamycin or mycophenolate mofetil, the choice of which will be heavily influenced by the development of either analogues of these drugs or perhaps new compounds with improved bioavailability and effective monitoring techniques.

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PubMed1993

Brequinar sodium: monitoring immunosuppressive activity.

There has been remarkable consistency in our laboratory for the experimental results derived from a variety of allogeneic and xenogeneic models of organ transplantation using BQR, a primary immunosuppressive agent, to prevent graft rejection. Considerable knowledge exists in a number of species with respect to the dose-response immunosuppressive efficacy, organ specificity, peripheral drug measurements, toxic side-effects, species sensitivity, and synergistic drug interactions. Despite the complexity of transferring experimental results to the clinical setting, the cumulative experience with this new immunosuppressive compound suggests that it may be highly effective when used for clinical transplantation. The identification of a predictive monitoring technique(s) would provide clinicians with a highly sensitive marker to effectively regulate BQR posttransplantation immunosuppressive therapies. Although the maintenance of a "therapeutic window" of immunosuppressive efficacy did not necessarily prevent the rejection of allografts or xenografts in the rat models tested, there was an important correlation between elevated BQR levels and the onset of recipient toxicity. Increased morbidity and mortality was noted when BQR blood levels were elevated above 16 micrograms/mL. The measurement of pyrimidine biosynthetic pathway metabolites provided a direct correlation between graft viability, global depletion of nucleotides (UTP, CTP, ATP, GTP), and suppression of PHA-mitogenic lymphocyte proliferative responses when different doses of BQR were tested. The analysis of these parameters were less informative following combination therapy with CsA. As with other immunosuppressive agents, the difficulty in relying exclusively on plasma trough drug levels as an accurate means to project graft viability may be influenced by individual differences in absorption, metabolism, and excretion of the compound. Additional parameters that may provide valuable information for the posttransplant therapeutic course include drug bioavailability, peak levels, drug clearance, or inhibition of immune response. It is anticipated that these studies will provide important baseline information for further refinement of these monitoring techniques to aid in posttransplant patient management.

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PubMed1992

The effect of a new immunosuppressive drug, brequinar sodium, on heart, liver, and kidney allograft rejection in the rat.

Brequinar sodium (BQR) prevents cell proliferation by virtue of its inhibition of de novo pyrimidine biosynthesis. BQR is capable of inhibiting immune responses in vitro and is effective in suppressing the development of contact sensitivity and adjuvant arthritis in rodent models. Based on the antiproliferative and immunosuppressive capacity of BQR, we have evaluated the efficacy of BQR in preventing allograft rejection utilizing experimental models of heterotopic heart and kidney and orthotopic liver transplantation in an MHC and non-MHC mismatched ACI----LEW rat strain combination. The immunosuppressive activity of BQR is illustrated by its ability to inhibit the development of delayed-type hypersensitivity to DNFB in mice. When BQR was administered orally throughout the sensitization and elicitation phases of the DNFB contact sensitivity response, it was found to be a potent immunosuppressant with an ED50 value of 0.5 mg/kg. This immunosuppressive activity is also seen in vitro, where BQR is capable of inhibiting the mixed lymphocyte response between allogeneic ACI and LEW rat strains with an IC50 of 150 ng/ml. The immunosuppressive activity of BQR is highly effective in prolonging heart, liver, and kidney allograft survival in the rat. Cardiac allografts are not rejected during the period of drug treatment at dosage levels of 12 to 24 mg/kg orally three times weekly. The grafts survive until the drug is discontinued (30 days posttransplantation), and the grafts are then rejected approximately 14 days later. Liver and kidney allografts are permanently accepted by approximately 50 to 90% of the recipient rats following 30 days of treatment with BQR at 12 mg/kg. The tolerance that is induced to the liver grafts extends in the majority of animals to greater than 250 days and is specific for the donor ACI strain. Challenge of long-term liver graft survivors with donor cardiac grafts is associated with permanent survival of donor, but not third-party, heart grafts. Combination therapy consisting of suboptimal doses of BQR and CsA demonstrates that the combination of these two immunosuppressive drugs results in an increased efficacy in prolonging graft survival. The results of these allograft experiments demonstrate that this new immunosuppressive agent is highly effective in preventing allograft rejection in the rat. The antiproliferative activity of BQR is effective for inhibiting T-lymphocyte-mediated immune responses, and Brequinar sodium should be an important addition to a polytherapeutic approach in the treatment of organ graft rejection.

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PubMed1992

The prolongation of concordant hamster-to-rat cardiac xenografts by brequinar sodium.

Brequinar sodium (BQR) prevents cell proliferation by virtue of its inhibition of de novo pyrimidine biosynthesis. The immunosuppressive activity of BQR is highly effective in prolonging heart, liver, and kidney allograft survival in the rat. In these experiments, we have tested the ability of BQR to prevent the rejection of concordant cardiac xenografts. LEW inbred rats transplanted with heterotopic hamster hearts were treated orally with brequinar sodium as a single agent. The survival of the cardiac xenografts was significantly prolonged with a variety of treatment regimens. The most effective treatment was the daily oral administration of BQR at 3 mg/kg. At this level, the median graft survival was approximately 25 days. Four animals had hamster heart xenografts that functioned for more than 90 days. The prolonged survival of the xenografts was associated with relatively constant plasma drug levels of approximately 1 to 3 micrograms/ml and a marked suppression of IgM production. At rejection, there was a significant rise in IgM levels compared with those of recipients with stable xenografts. In vitro MLR responses were effectively inhibited by BQR, with an IC50 of 0.08 microgram/ml. The results of these experiments demonstrate that BQR is a new immunosuppressive agent that is highly effective as a single agent in prolonging the survival of hamster-to-rat cardiac xenografts. The prolonged xenograft survival is associated with effective suppression of rat antihamster antibody production, suggesting that brequinar sodium may be an important addition to multidrug immunosuppressive regimes designed to prevent B and T lymphocyte-mediated immune responses.

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