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D M Canafax

Publications and source records attributed to D M Canafax.

At least 73 records · Page 4Linked to original sources
PubMed1989

Liposomal formulation eliminates acute toxicity and pump incompatibility of parenteral cyclosporine.

The currently available intravenous dosage form of cyclosporine (CSA), Sandimmune I.V., contains the vehicle, Cremophor EL, which has been implicated in producing anaphylactic reactions in man and animals. This formulation also leaches through silicone tubing, an important component of some automatic drug delivery devices, causing pump dysfunction. In an attempt to develop a less toxic and pump-compatible formulation of CSA, suitable for intrarenal infusion in a canine transplant model, we compared the acute toxicity, pharmacokinetics, and pump compatibility of emulsified (CSA/emulsion) and liposomal (CSA/liposomes) CSA preparations with those of Sandimmune I.V. and CSA dissolved in ethanol vehicle (CSA/alcohol) in healthy, unoperated dogs. Animals receiving Sandimmune I.V. demonstrated marked acute toxicity despite progressive 10-fold dose reduction and greater than 50-fold prolongation of infusion duration. One of two animals receiving CSA/emulsion and both dogs receiving emulsion vehicle alone exhibited a moderately severe reaction, while five of seven dogs receiving CSA/alcohol demonstrated immediate, mild reactions. No discernible adverse reactions occurred in any animal receiving CSA/liposomes. Systemic disposition of CSA/alcohol and CSA/liposomes was similar. In contrast to the liposomal vehicle, the emulsion vehicle produced a marked, early weight gain and substantial decrease in tensile strength of the pump tubing, both of which would adversely affect pump function. These results provide the first description of liposomal CSA toxicology and pharmacokinetics in a large animal model and may lead to the successful development of a less toxic parenteral CSA formulation for systemic and local pump-based administration.

Alcohols↗
PubMed1989

Experimental animal models for studying antimicrobial pharmacokinetics in otitis media.

Antimicrobial treatment of otitis media, especially drug dosing considerations, is largely empiric, with few reported pharmacologic studies of drug distribution into the middle ear. A chinchilla animal model of serous and purulent otitis media has been used for some time to investigate mechanisms of disease pathogenesis. This model was adapted to investigate the penetration of amoxicillin, trimethoprim, and sulfamethoxazole into middle ear effusion. Purulent otitis media was produced by direct middle ear inoculation with type 7F Streptococcus pneumoniae. Serous otitis media was produced by eustachian tube obstruction using silastic sponge or Coeflex cement, but the Coeflex caused an undesirable local inflammatory response. The three antibiotics were administered to chinchillas with serous and purulent middle ear effusion. Plasma and ear fluid drug concentrations were measured by liquid chromatography and demonstrated the value of this model in assessing antibiotic penetration.

Amoxicillin↗
PubMed1989

Allograft renal vascular thrombosis--lack of increase with cyclosporine immunosuppression.

Several recent reports have demonstrated an increased incidence of allograft renal vascular thrombosis in patients receiving cyclosporine alone or as part of multiple drug regimens when compared with patients receiving azathioprine (AZA) and prednisone (P). To determine whether CsA therapy is indeed a risk factor for renal artery or vein thrombosis, we examined the incidence of these complications in 224 adult renal allograft recipients who were prospectively randomized and stratified by risk to treatment with either CsA-P (n = 117) or AZA-P-antilymphocyte globulin (n = 107) between September 1980 and October 1983, and in 452 adult and 87 pediatric patients on triple (AZA-P-CsA) or quadruple (AZA-P-CsA-ALG) therapy protocols between July 1984 and November 1987. In the randomized trial, one of 107 AZA-P-ALG patients (0.9%) and two of 117 CsA-P patients (1.7%) developed renal vein thrombosis (P = 0.94), and there were no cases of arterial thrombosis. Though CsA levels were elevated in one of the two CsA-treated patients at the time of their events, and both these patients demonstrated other predisposing factors for thrombosis. In the triple/quadruple therapy era, there were no cases of renal vein thrombosis, and the only case of renal artery thrombosis occurred in a pediatric recipient who was not receiving CsA at the time. These data, when taken together with a critical review of the conflicting literature, strongly suggest that factors other than immunosuppression with CsA, including surgical technique, allograft rejection, use of multiple artery and/or pediatric donor kidneys, and postoperative hypotension, are important in the pathogenesis of allograft renal vascular thrombosis. It seems possible, however, that high initial dosing of CsA might trigger this complication in the early posttransplant period when other predisposing factors are present.

Antilymphocyte Serum↗
PubMed1989

The pharmacokinetic advantage of local 6-mercaptopurine infusion in a canine renal transplant model.

In light of recent technologic advances, we developed a canine renal allograft model utilizing implantable, programmable infusion pumps and biocompatible catheters to reexplore the concept of local immunosuppression. Thirteen mongrel dogs underwent bilateral nephrectomy and autotransplantation of 1 kidney via end-to-end renal-iliac artery and end-to-side renal-iliac vein anastomoses. The proximal end of an infusion catheter directed into the iliac artery was tunneled to a subcutaneously placed programmable pump. A second, sampling catheter was placed with its tip in the iliac vein just proximal to the venous anastomosis. During a period of i.a. infusion of heparinized saline ranging from 19 to 63 days, serum creatinine remained normal in all but 1 animal, which developed pyelonephritis and catheter-tip perforation of the iliac artery. No cases of arterial thrombosis or catheter migration were observed at necropsy. In 7 additional autotransplanted dogs, simultaneous iliac vein and systemic (jugular vein) concentrations of 6-mercaptopurine (6-MP), the major immunosuppressive metabolite of azathioprine, were determined during a continuous 24-hr i.a. infusion (10 mg/kg/24 hr). Following termination of the infusion, 10 mg/kg 6-MP was administered to the same 7 dogs as an i.v. bolus, and systemic drug concentrations were determined over a 4-hr period. Mean +/- SE total-body clearance and elimination half-life were 887 +/- 159 ml/min and 1.4 +/- 0.2 hr, respectively, in the i.v. bolus study, indicating that 6-MP is rapidly cleared from the systemic circulation. Unexpectedly, the kidney removed as much as 60-95% of locally infused 6-MP, reducing the amount of active drug entering the systemic circulation to 5-40% of that which would be present during an i.v. infusion of the same dose. According to the principles governing the advantages of i.a. infusions, these data demonstrate that 6-MP can be infused intrarenally to produce both a 4-fold increase in drug concentration within the kidney and an 80% decrease in systemic drug delivery when compared to same-dose i.v. administration. The overall result is the presence of a 30-fold gradient between local and systemic drug concentrations during intrarenal 6-MP infusion. We conclude that i.a. infusion of an immunosuppressive agent is technically feasible with preservation of renal function, and that 6-MP can be delivered locally in a canine model with great pharmacokinetic and potential therapeutic advantage.

Animals↗
PubMed1989

Reversible pancytopenia following OKT3. Use in the context of multidrug immunosuppression for kidney allografting.

We present two instances of pancytopenia in kidney transplant patients associated with a course of OKT3 therapy. In one case, OKT3 was used prophylactically, in the other therapeutically to treat biopsy-proved rejection. They both occurred in the setting of multi-drug immunosuppression, including Minnesota anti-lymphocyte globulin, and recovered with supportive therapy. Previous antihypertensive medication, antibiotics, and azathioprine were restarted without hematologic sequelae. Evidence implicating OKT3, and resultant gamma-interferon-induced marrow suppression is discussed.

Adult↗
PubMed1988

High-performance liquid chromatographic analysis of trimethoprim and sulfamethoxazole in microliter volumes of chinchilla middle ear effusion and serum.

A reversed-phase high-performance liquid chromatographic procedure was developed to analyze 25-microliters volumes of chinchilla middle ear effusion and 50-microliters volumes of serum for trimethoprim and sulfamethoxazole. The small sample volumes were dictated by the chinchilla model of otitis media and our need to collect multiple samples over a 12-h drug dosing interval. The drugs were separated on a cyanopropylsilane column using acetonitrile-40 mM sodium phosphate, (16:84, v/v), pH 4.8. Trimethoprim and the internal standard were detected at 230 nm while sulfamethoxazole was detected at 250 nm. Middle ear effusion and serum samples were extracted with ethyl acetate-dichloromethane (25:75, v/v). The limit of quantitation was 0.5 micrograms/ml for sulfamethoxazole and 0.1 micrograms/ml for trimethoprim (coefficient of variation less than 20%), the limit of detection 0.25 and 0.05 micrograms/ml, respectively. Middle ear and serum samples of chinchilla with experimentally induced otitis media receiving 10 mg/kg trimethoprim and 50 mg/kg sulfamethoxazole intramuscularly were collected over a 12-h period and analyzed. All statistics that validate the analytic method are reported.

Animals↗
PubMed1988

Time-dependent disposition of cyclosporine after pancreas transplantation, and application of chronopharmacokinetics to improve immunosuppression.

We studied the circadian influences on cyclosporine pharmacokinetics in five recipients of pancreatic allografts. Results from these patients demonstrate a slightly increased area under the concentration-time curve (p = 0.156) resulting from decreased apparent clearance during the resting (PM) versus activity (AM) period (p = 0.199). A significant delay in mean residence time was observed after the PM dose (p = 0.039), and the PM area under the moment curve was larger than the AM value (p = 0.063). We propose three chronopharmacokinetic dosing methods that alter either the PM dose administration time or redistribute the daily dose to produce equal exposure to cyclosporine during the active and resting periods. These trends and differences suggest that more sophisticated time-dependent cyclosporine dosing methods are needed to balance AM and PM drug exposure and thereby improve immunosuppression.

Administration, Oral↗
PubMed1988

An implantable pump for intrarenal infusion of immunosuppressants in a canine autotransplant model.

We developed a canine renal allograft model utilizing implantable infusion pumps and biocompatible catheters to investigate the pharmacokinetics of local immunosuppressive drug administration. Seven mongrel dogs underwent bilateral nephrectomy and autotransplantation of one kidney to the iliac vessels. The proximal end of an infusion catheter directed into the iliac artery was tunneled to a subcutaneously placed programmable pump. A second, sampling catheter was placed with its tip in the iliac vein. Simultaneous regional (iliac vein) and systemic (jugular vein) venous concentrations of 6-mercaptopurine (6-MP), the immunosuppressive metabolite of azathioprine, were determined during a continuous 24-h intraarterial infusion (10 mg/kg/24 hr). The gradient between regional and systemic 6-MP concentrations was maximal initially when the pump was turned on, continuously decreased until steady state was reached, and disappeared immediately after the pump was turned off. The mean ratio of steady-state iliac vein to systemic 6-MP concentrations was 5.0 +/- 1.4, demonstrating a pharmacokinetic advantage of continuous intraarterial 6-MP infusion to the autotransplanted kidney. The novel canine renal allograft model described herein overcomes the technical limitations of earlier models and represents a foundational step in the design of intrarenal infusion patterns of immunosuppressive agents which we expect to prolong survival of the allotransplanted kidney with minimal systemic drug exposure and side effects.

Animals↗
PubMed1988

A randomized trial comparing cyclosporine with antilymphoblast-globulin-azathioprine for renal allograft recipients. Results at 2 1/2-6 years.

Between September 1980 and June 1984, 246 splenectomized, transfused renal allograft recipients were stratified according to presence of diabetes and donor source, and randomized to treatment with either cyclosporine (CsA)-prednisone (pred) or antilymphoblast-globulin (ALG--azathioprine (AZA)--prednisone. As of August 1986, mean follow-up is 47 months. Over all, actuarial patient survival is 84% and 83%, respectively at 4 years. Corresponding graft survival is 70% and 63% for CsA-treated and ALG-AZA-treated patients (NS). Within the subgroup of diabetic recipients of cadaver grafts, graft survival is 70% for CsA-treated and 53% for ALG-AZA-treated recipients (P = .035). In the CsA group, 71% required either a significant reduction in CsA dosage with the addition of azathioprine or a complete switch to azathioprine, mainly because of CsA-associated nephrotoxicity. Of those CsA patients switched at a mean time of 21.3 +/- 16.4 months posttransplant with mean serum creatinine of 2.40 +/- .67, current serum creatinine is 1.79 +/- .63. Current mean serum creatinine values are significantly greater for patients randomized to CsA-pred (1.73 +/- .60) vs. ALG-AZA-pred (1.49 +/- .59), P = .014, even though most CsA-treated patients were eventually switched. The causes of graft loss are not different between CsA and ALG-AZA randomized patients. In nondiabetics, rejection is the most common cause of graft loss (17/33), whereas in diabetics loss due to complications from overimmunosuppression or death from cardiovascular events is significantly more common (27/44) than corresponding losses in nondiabetics (6/33, P less than .05). Switching does not seem to influence the incidence or cause of graft loss. Since most patients started on CsA-prednisone are ultimately switched to triple drug therapy, the latter is now the preferred initial treatment modality.

Adolescent↗
PubMed1988

A comparison of two cyclosporine protocols at the University of Minnesota.

1. There have been 1,426 renal transplants performed at the University of Minnesota from January 1, 1980 through August 31, 1988. CsA+P was used by 260 adult recipients, CsA+P+AZA(+ALG) by 536. 2. In general, there are no significant differences in actuarial graft or patient survival rates between the 2 CsA protocols. This is true for all adults, for all adult CAD recipients, and for a matched control group of adult CAD recipients. 3. Cox's proportional hazards regression model also indicates that there is no significant difference between the 2 CsA regimens. Donor type, number of transplants, and age at transplant influence graft survival in all adult recipients. The use of LRD is still indicated in the CsA era. Diabetic status, age at transplant, and number of transplants affect patient survival. The model fits the observed data quite well. 4. Actuarial analysis and Cox regression failed to document a beneficial effect of HLA-A, B, and DR matching in patients receiving either CsA protocol. Our data do not support the HLA matching point system currently used by UNOS or the Terasaki proposal to give points based on mismatching. 5. A matched control analysis of adult CAD recipients indicates that CsA+P+AZA+ALG has alleviated the problems of our CsA+P protocol without lowering the graft and patient survival rates. Thus, the sequential therapy group has equivalent graft and patient survival rates but shorter duration of ATN, lower serum creatinine levels at 1 year, and fewer patients who require modifications of protocol. Sequential therapy is our treatment of choice.

Adult↗