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Papers by Daniel Canafax

Research paper thumbnail of Clinical efficacy of antimicrobial drugs for acute otitis media: Metaanalysis of 5400 children from thirty-three randomized trials

The Journal of Emergency Medicine, 1995

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

Journal of Chromatography B Biomedical Sciences and Applications, 1988

Research paper thumbnail of An Implantable Pump for Intrarenal Infusion of Immunosuppressants in a Canine Autotransplant Model

Pharmaceutical Research, Dec 1, 1988

We developed a canine renal allograft model utilizing implantable infusion pumps and biocompatibl... more 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.

Research paper thumbnail of The Pharmacokinetic Advantage of Local 6-MERCAPTOPURINE Infusion in a Canine Renal Transplant MODEL1,2

Transplantation, 1989

In light of recent technologic advances, we developed a canine renal allograft model utilizing im... more 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.

Research paper thumbnail of Review of cyclosporine pharmacokinetic trials in healthy volunteers and kidney and liver transplant recipients: SangCyA versus neoral and sandimmune

Transplantation Reviews, 1999

Research paper thumbnail of Effect of Streptococcus pneumoniae and Influenza A Virus on Middle Ear Antimicrobial Pharmacokinetics in Experimental Otitis Media

Pharmaceutical Research, Jun 1, 1994

Antimicrobial treatment failures in children with acute otitis media and concomitant viral respir... more Antimicrobial treatment failures in children with acute otitis media and concomitant viral respiratory tract infection prompted us to study the effects of influenza A virus infection on middle ear antimicrobial drug penetration. Using a chinchilla model of Streptococcus pneumoniae we compared middle ear elimination rates in 4 groups of chinchillas: (1) control, (2) influenza A virus inoculation alone intranasally, (3) both influenza A and S. pneumoniae inoculation directly into the middle ear, and (4) S. pneumoniae inoculation alone into the middle ear. After infection was established, a solution containing amoxicillin, sulfamethoxazole, and trimethoprim was instilled into the middle ear and removed 4 hours later. The rate constant of elimination and half-life were calculated from measured drug concentrations initially and at 4 hours. S. pneumoniae infection alone significantly shortened the middle ear elimination half-life compared with the control group: amoxicillin, 2.65 +/- 0.73 vs. 6.63 +/- 2.55 hr; sulfamethoxazole, 1.75 +/- 0.28 vs. 2.74 +/- 0.6 hr; and trimethoprim, 1.06 +/- 0.14 vs. 1.56 +/- 0.34 hr (n = 16 ears, p values all < 0.01). The combined influenza virus and S. pneumoniae infection significantly lengthened the half-life compared with the S. pneumoniae infection alone: amoxicillin, 5.65 +/- 6.44 vs. 2.65 +/- 0.73 hr; sulfamethoxazole, 2.5 +/- 0.85 vs. 1.75 +/- 0.28 hr; and trimethoprim, 1.26 +/- 0.42 vs. 1.06 +/- 0.14 hr (n = 16 ears, p values all < 0.01). Influenza virus produced the longest half-lives for all 3 antimicrobials: amoxicillin 25.52 +/- 14.96 hr; sulfamethoxazole, 5.46 +/- 0.87 hr; and trimethoprim, 2.57 +/- 0.75 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Research paper thumbnail of Mizoribine Pharmacokinetics and Pharmacodynamics in a Canine Renal Allograft Model of Local IMMUNOSUPPRESSION1,2

Transplantation, 1992

We utilized a canine renal transplant model to estimate the first-pass extraction of mizoribine (... more We utilized a canine renal transplant model to estimate the first-pass extraction of mizoribine (MZB) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (i.a.) versus intravenous (i.v.) MZB delivery, with and without a background of oral cyclosporine. Five autotransplanted mongrel dogs with programmable, implantable pump/catheter systems were given MZB by both i.v. bolus (5 mg/kg) and i.a. infusion (5.0 mg/kg/day). Mean +/- SD elimination half-life was 3.02 +/- 0.81 hr, and the transplanted kidney removed as much as 47-59% (mean 56%) of locally infused MZB. With increasing local and systemic MZB delivery in a single autografted dog undergoing both i.a. and i.v. pump/catheter placement, renal extraction decreased from at least 47% (5.0 mg/kg/day) to 33% (7.5 mg/kg/day), finally to 18% (10.0 mg/kg/day). A dose of 3.0 mg/kg/day MZB did not significantly prolong survival of renal allograft recipients over that of untreated controls (median survival time [MST] = 8 days) when administered either locally (MST = 9 days) or systemically (MST = 12 days). All dogs receiving 4.0 mg/kg/day MZB i.a. died from rejection, and a survival advantage was still not realized (MST = 7 days). In contrast, 4.0 mg/kg/day i.v. prolonged survival over controls (MST = 14 days; P = 0.03) but not when directly compared with the i.a. group (P = 0.30), and produced death from severe debility in five of seven animals with significantly higher mean systemic MZB levels (P = 0.02). Four of six dogs receiving 5.0 mg/kg/day MZB i.a. (MST = 14 days) and two of four dogs receiving 5.0 mg/kg/day i.v. (MST = 14 days) died from severe debility, though survival in both groups was prolonged over control values (P = 0.01 and P = 0.05, respectively). Coadministration of a subtherapeutic dose of oral CsA (5 mg/kg/day) significantly prolonged the overall survival of dogs receiving MZB 4.0 mg/kg/day i.a. (MST = 23; P = 0.01) but not i.v. (MST = 11; P = 1.00), so that a significant difference in overall survival between the combined MZB i.a. + CSA and MZB i.v. + CSA groups was now realized in favor of the former (P = 0.04). We conclude that at local doses required to achieve immunosuppression, the transplanted kidney was not able to extract enough MZB to prevent death from systemic toxicity, presumably as a result of saturation of renal elimination mechanisms, so that an overall survival benefit was not realized.(ABSTRACT TRUNCATED AT 400 WORDS)

Research paper thumbnail of HPLC Determination of 6-Thiouric Acid and 6-Mercaptopurine in Organ Transplant Patient Serum

Http Dx Doi Org 10 1080 01483918808068358, Dec 5, 2006

Page 1. JOURNAL OF LIQUID CHROMATOGRAPHY, 11(4), 971-981 (1988) HPLC DETERMINATION OF 6-THIOURIC ... more Page 1. JOURNAL OF LIQUID CHROMATOGRAPHY, 11(4), 971-981 (1988) HPLC DETERMINATION OF 6-THIOURIC AND 6-MERCAPTOU R INE IN ORGAN TRANSPLANT PATIENT SERUM Gary R. Erdmann, Gary LC Chan, and Daniel M. Canafax ...

Research paper thumbnail of Comparative Pharmacokinetics of SANG-35 Cyclosporine Versus Neoral??? In Stable Adult Liver Transplant Recipients

Research paper thumbnail of A SERIES OF COMPARATIVE TRIALS BETWEEN SANG-35 AND OTHER CYCLOSPORINE(CsA) FORMULATIONS IN STABLE RENAL TRANSPLANT PATIENTS (Pts)

Transplantation, 1998

... Schroeder, TJ; First, MR; Alloway, RR; Canafax, DM; Gaber, AO; Gaston, R. Collapse Box ... Me... more ... Schroeder, TJ; First, MR; Alloway, RR; Canafax, DM; Gaber, AO; Gaston, R. Collapse Box ... Methods: Adult stable renal transplant pts were studied. In study A, Sang-35 was evaluated against Neoral in a 3-way crossover design with pharmacokinetic(PK) analysis at each 8th day. ...

Research paper thumbnail of Liposomal Formulation Eliminates Acute Toxicity and Pump Incompatibility of Parenteral Cyclosporine

Pharmaceutical Research, 1989

Research paper thumbnail of Studies of cyclosporine blood levels: Analysis, clinical utility, pharmacokinetics, metabolites, and chronopharmacology

Transplantation Proceedings

ABSTRACT

Research paper thumbnail of Highperformance liquid chromatographic analysis of trimethoprim and sulfamethoxazole in microliter volumes of chinchilla ear effusion and serum

Journal of Chromatography A

Simple, sensitive and reliable high-performance liquid chromatographic methods are reported for t... more Simple, sensitive and reliable high-performance liquid chromatographic methods are reported for the determination of pindolol enantiomers in human serum and urine. The methods involved a solid-phase extraction of serum and a direct injection of urine samples. The separation of R(+)- and S(-)-pindolol was accomplished on a reversed-phase cellulose-based chiral column with a mobile phase of 40:60 (v/v) acetonitrile-0.3 M aqueous sodium perchlorate at a flow-rate of 0.5 ml/min. The detection was achieved by monitoring the fluorescence emission of pindolol enantiomers at 310 nm with excitation at 270 nm. The limits of detection were 1.2 ng/ml of R(+)- and 4.3 ng/ml of S(-)-pindolol in serum, and 21 ng/ml of R(+)- and 76 ng/ml of S(-)-pindolol in urine. The external standard method was used for quantitation. The methods have been applied to the analysis of human serum and urine samples in a pharmacokinetic study.

Research paper thumbnail of Local immunosuppression of the vascu-Iarized graft

Research paper thumbnail of Feasibility of vascular catheter placement for intrarenal infusion in a canine autotransplant model

Transplantation Proceedings

Research paper thumbnail of High Performance Liquid Chromatographic Analysis of Amoxicillin in Microliter Volumes of Chinchilla Middle Ear Effusion and Plasma

Journal of liquid chromatography

Simple, sensitive and reliable high-performance liquid chromatographic methods are reported for t... more Simple, sensitive and reliable high-performance liquid chromatographic methods are reported for the determination of pindolol enantiomers in human serum and urine. The methods involved a solid-phase extraction of serum and a direct injection of urine samples. The separation of R(+)- and S(-)-pindolol was accomplished on a reversed-phase cellulose-based chiral column with a mobile phase of 40:60 (v/v) acetonitrile-0.3 M aqueous sodium perchlorate at a flow-rate of 0.5 ml/min. The detection was achieved by monitoring the fluorescence emission of pindolol enantiomers at 310 nm with excitation at 270 nm. The limits of detection were 1.2 ng/ml of R(+)- and 4.3 ng/ml of S(-)-pindolol in serum, and 21 ng/ml of R(+)- and 76 ng/ml of S(-)-pindolol in urine. The external standard method was used for quantitation. The methods have been applied to the analysis of human serum and urine samples in a pharmacokinetic study.

Research paper thumbnail of Principles of immunosuppression

Critical Care Clinics

One-year graft survival rates of 80% to 90% can now be achieved routinely for primary cadaveric t... more One-year graft survival rates of 80% to 90% can now be achieved routinely for primary cadaveric transplants with a variety of CSA-containing regimens. Further improvement of these excellent results may be difficult because large numbers of patients must be evaluated to provide meaningful conclusions. On the other hand, long-term follow-up of CSA-treated patients has revealed a trend of undaunted allograft attrition with time. Future efforts therefore should be directed at improving long-term allograft results at 5 to 10 years. Further improvement of transplant outcome may be sought through better use of the currently available immunosuppressants or from newer agents. The long-term impact of CSA administration requires further evaluation. Although potent combination protocols provide effective protection against rejection, the potential development of neoplasms must be studied in long-term follow-up. On the other hand, unwarranted fear of progressive nephrotoxicity may result in underdosing of CSA and a high incidence of late rejections. The advent of mAbs has spawned an exciting era of specific immunosuppression. These newer agents may eventually help curtail the complications associated with the current regimens.

Research paper thumbnail of Immunosuppression in renal transplantation. I. Cyclosporine and azathioprine

Clinical Transplantation

ABSTRACT

Research paper thumbnail of Immunosuppression in renal transplantation II. Corticosteroids, antilymphocyte globulin, and OKT3

Clinical Transplantation

ABSTRACT

Research paper thumbnail of Reversed-phase high-performance liquid chromatographic approach to determine total lymphocyte concentrations of 6-thioguanine, methylmercaptopurine and methylthioguanine in humans

Journal of Chromatography A

A reversed-phase high-performance liquid chromatographic (HPLC) procedure was developed to quanti... more A reversed-phase high-performance liquid chromatographic (HPLC) procedure was developed to quantify intracellular lymphocyte 6-thioguanine, methylmercaptopurine and methylthioguanine. The free base of each metabolite was obtained by acid hydrolysis, which allowed for a total determination of thiopurine metabolites. 6-Thioguanine was analyzed on an octadecylsilane column using acetonitrile-10 mM sodium phosphate (11:89), pH 7, containing 0.06% tetrabutylammonium chloride. 6-Thioguanine was oxidized with potassium permanganate, and fluorescence was measured at 330 nm excitation and 410 nm emission. Methylmercaptopurine and methylthioguanine were separated on a cyanopropylsilane column using methanol-40 mM sodium phosphate (22:78), pH 2.7, and detected by ultraviolet absorbance at 314 and 290 nm, respectively.

Research paper thumbnail of Clinical efficacy of antimicrobial drugs for acute otitis media: Metaanalysis of 5400 children from thirty-three randomized trials

The Journal of Emergency Medicine, 1995

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

Journal of Chromatography B Biomedical Sciences and Applications, 1988

Research paper thumbnail of An Implantable Pump for Intrarenal Infusion of Immunosuppressants in a Canine Autotransplant Model

Pharmaceutical Research, Dec 1, 1988

We developed a canine renal allograft model utilizing implantable infusion pumps and biocompatibl... more 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.

Research paper thumbnail of The Pharmacokinetic Advantage of Local 6-MERCAPTOPURINE Infusion in a Canine Renal Transplant MODEL1,2

Transplantation, 1989

In light of recent technologic advances, we developed a canine renal allograft model utilizing im... more 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.

Research paper thumbnail of Review of cyclosporine pharmacokinetic trials in healthy volunteers and kidney and liver transplant recipients: SangCyA versus neoral and sandimmune

Transplantation Reviews, 1999

Research paper thumbnail of Effect of Streptococcus pneumoniae and Influenza A Virus on Middle Ear Antimicrobial Pharmacokinetics in Experimental Otitis Media

Pharmaceutical Research, Jun 1, 1994

Antimicrobial treatment failures in children with acute otitis media and concomitant viral respir... more Antimicrobial treatment failures in children with acute otitis media and concomitant viral respiratory tract infection prompted us to study the effects of influenza A virus infection on middle ear antimicrobial drug penetration. Using a chinchilla model of Streptococcus pneumoniae we compared middle ear elimination rates in 4 groups of chinchillas: (1) control, (2) influenza A virus inoculation alone intranasally, (3) both influenza A and S. pneumoniae inoculation directly into the middle ear, and (4) S. pneumoniae inoculation alone into the middle ear. After infection was established, a solution containing amoxicillin, sulfamethoxazole, and trimethoprim was instilled into the middle ear and removed 4 hours later. The rate constant of elimination and half-life were calculated from measured drug concentrations initially and at 4 hours. S. pneumoniae infection alone significantly shortened the middle ear elimination half-life compared with the control group: amoxicillin, 2.65 +/- 0.73 vs. 6.63 +/- 2.55 hr; sulfamethoxazole, 1.75 +/- 0.28 vs. 2.74 +/- 0.6 hr; and trimethoprim, 1.06 +/- 0.14 vs. 1.56 +/- 0.34 hr (n = 16 ears, p values all < 0.01). The combined influenza virus and S. pneumoniae infection significantly lengthened the half-life compared with the S. pneumoniae infection alone: amoxicillin, 5.65 +/- 6.44 vs. 2.65 +/- 0.73 hr; sulfamethoxazole, 2.5 +/- 0.85 vs. 1.75 +/- 0.28 hr; and trimethoprim, 1.26 +/- 0.42 vs. 1.06 +/- 0.14 hr (n = 16 ears, p values all < 0.01). Influenza virus produced the longest half-lives for all 3 antimicrobials: amoxicillin 25.52 +/- 14.96 hr; sulfamethoxazole, 5.46 +/- 0.87 hr; and trimethoprim, 2.57 +/- 0.75 hr.(ABSTRACT TRUNCATED AT 250 WORDS)

Research paper thumbnail of Mizoribine Pharmacokinetics and Pharmacodynamics in a Canine Renal Allograft Model of Local IMMUNOSUPPRESSION1,2

Transplantation, 1992

We utilized a canine renal transplant model to estimate the first-pass extraction of mizoribine (... more We utilized a canine renal transplant model to estimate the first-pass extraction of mizoribine (MZB) during renal artery infusion and to compare the efficacy and toxicity of continuous intraarterial (i.a.) versus intravenous (i.v.) MZB delivery, with and without a background of oral cyclosporine. Five autotransplanted mongrel dogs with programmable, implantable pump/catheter systems were given MZB by both i.v. bolus (5 mg/kg) and i.a. infusion (5.0 mg/kg/day). Mean +/- SD elimination half-life was 3.02 +/- 0.81 hr, and the transplanted kidney removed as much as 47-59% (mean 56%) of locally infused MZB. With increasing local and systemic MZB delivery in a single autografted dog undergoing both i.a. and i.v. pump/catheter placement, renal extraction decreased from at least 47% (5.0 mg/kg/day) to 33% (7.5 mg/kg/day), finally to 18% (10.0 mg/kg/day). A dose of 3.0 mg/kg/day MZB did not significantly prolong survival of renal allograft recipients over that of untreated controls (median survival time [MST] = 8 days) when administered either locally (MST = 9 days) or systemically (MST = 12 days). All dogs receiving 4.0 mg/kg/day MZB i.a. died from rejection, and a survival advantage was still not realized (MST = 7 days). In contrast, 4.0 mg/kg/day i.v. prolonged survival over controls (MST = 14 days; P = 0.03) but not when directly compared with the i.a. group (P = 0.30), and produced death from severe debility in five of seven animals with significantly higher mean systemic MZB levels (P = 0.02). Four of six dogs receiving 5.0 mg/kg/day MZB i.a. (MST = 14 days) and two of four dogs receiving 5.0 mg/kg/day i.v. (MST = 14 days) died from severe debility, though survival in both groups was prolonged over control values (P = 0.01 and P = 0.05, respectively). Coadministration of a subtherapeutic dose of oral CsA (5 mg/kg/day) significantly prolonged the overall survival of dogs receiving MZB 4.0 mg/kg/day i.a. (MST = 23; P = 0.01) but not i.v. (MST = 11; P = 1.00), so that a significant difference in overall survival between the combined MZB i.a. + CSA and MZB i.v. + CSA groups was now realized in favor of the former (P = 0.04). We conclude that at local doses required to achieve immunosuppression, the transplanted kidney was not able to extract enough MZB to prevent death from systemic toxicity, presumably as a result of saturation of renal elimination mechanisms, so that an overall survival benefit was not realized.(ABSTRACT TRUNCATED AT 400 WORDS)

Research paper thumbnail of HPLC Determination of 6-Thiouric Acid and 6-Mercaptopurine in Organ Transplant Patient Serum

Http Dx Doi Org 10 1080 01483918808068358, Dec 5, 2006

Page 1. JOURNAL OF LIQUID CHROMATOGRAPHY, 11(4), 971-981 (1988) HPLC DETERMINATION OF 6-THIOURIC ... more Page 1. JOURNAL OF LIQUID CHROMATOGRAPHY, 11(4), 971-981 (1988) HPLC DETERMINATION OF 6-THIOURIC AND 6-MERCAPTOU R INE IN ORGAN TRANSPLANT PATIENT SERUM Gary R. Erdmann, Gary LC Chan, and Daniel M. Canafax ...

Research paper thumbnail of Comparative Pharmacokinetics of SANG-35 Cyclosporine Versus Neoral??? In Stable Adult Liver Transplant Recipients

Research paper thumbnail of A SERIES OF COMPARATIVE TRIALS BETWEEN SANG-35 AND OTHER CYCLOSPORINE(CsA) FORMULATIONS IN STABLE RENAL TRANSPLANT PATIENTS (Pts)

Transplantation, 1998

... Schroeder, TJ; First, MR; Alloway, RR; Canafax, DM; Gaber, AO; Gaston, R. Collapse Box ... Me... more ... Schroeder, TJ; First, MR; Alloway, RR; Canafax, DM; Gaber, AO; Gaston, R. Collapse Box ... Methods: Adult stable renal transplant pts were studied. In study A, Sang-35 was evaluated against Neoral in a 3-way crossover design with pharmacokinetic(PK) analysis at each 8th day. ...

Research paper thumbnail of Liposomal Formulation Eliminates Acute Toxicity and Pump Incompatibility of Parenteral Cyclosporine

Pharmaceutical Research, 1989

Research paper thumbnail of Studies of cyclosporine blood levels: Analysis, clinical utility, pharmacokinetics, metabolites, and chronopharmacology

Transplantation Proceedings

ABSTRACT

Research paper thumbnail of Highperformance liquid chromatographic analysis of trimethoprim and sulfamethoxazole in microliter volumes of chinchilla ear effusion and serum

Journal of Chromatography A

Simple, sensitive and reliable high-performance liquid chromatographic methods are reported for t... more Simple, sensitive and reliable high-performance liquid chromatographic methods are reported for the determination of pindolol enantiomers in human serum and urine. The methods involved a solid-phase extraction of serum and a direct injection of urine samples. The separation of R(+)- and S(-)-pindolol was accomplished on a reversed-phase cellulose-based chiral column with a mobile phase of 40:60 (v/v) acetonitrile-0.3 M aqueous sodium perchlorate at a flow-rate of 0.5 ml/min. The detection was achieved by monitoring the fluorescence emission of pindolol enantiomers at 310 nm with excitation at 270 nm. The limits of detection were 1.2 ng/ml of R(+)- and 4.3 ng/ml of S(-)-pindolol in serum, and 21 ng/ml of R(+)- and 76 ng/ml of S(-)-pindolol in urine. The external standard method was used for quantitation. The methods have been applied to the analysis of human serum and urine samples in a pharmacokinetic study.

Research paper thumbnail of Local immunosuppression of the vascu-Iarized graft

Research paper thumbnail of Feasibility of vascular catheter placement for intrarenal infusion in a canine autotransplant model

Transplantation Proceedings

Research paper thumbnail of High Performance Liquid Chromatographic Analysis of Amoxicillin in Microliter Volumes of Chinchilla Middle Ear Effusion and Plasma

Journal of liquid chromatography

Simple, sensitive and reliable high-performance liquid chromatographic methods are reported for t... more Simple, sensitive and reliable high-performance liquid chromatographic methods are reported for the determination of pindolol enantiomers in human serum and urine. The methods involved a solid-phase extraction of serum and a direct injection of urine samples. The separation of R(+)- and S(-)-pindolol was accomplished on a reversed-phase cellulose-based chiral column with a mobile phase of 40:60 (v/v) acetonitrile-0.3 M aqueous sodium perchlorate at a flow-rate of 0.5 ml/min. The detection was achieved by monitoring the fluorescence emission of pindolol enantiomers at 310 nm with excitation at 270 nm. The limits of detection were 1.2 ng/ml of R(+)- and 4.3 ng/ml of S(-)-pindolol in serum, and 21 ng/ml of R(+)- and 76 ng/ml of S(-)-pindolol in urine. The external standard method was used for quantitation. The methods have been applied to the analysis of human serum and urine samples in a pharmacokinetic study.

Research paper thumbnail of Principles of immunosuppression

Critical Care Clinics

One-year graft survival rates of 80% to 90% can now be achieved routinely for primary cadaveric t... more One-year graft survival rates of 80% to 90% can now be achieved routinely for primary cadaveric transplants with a variety of CSA-containing regimens. Further improvement of these excellent results may be difficult because large numbers of patients must be evaluated to provide meaningful conclusions. On the other hand, long-term follow-up of CSA-treated patients has revealed a trend of undaunted allograft attrition with time. Future efforts therefore should be directed at improving long-term allograft results at 5 to 10 years. Further improvement of transplant outcome may be sought through better use of the currently available immunosuppressants or from newer agents. The long-term impact of CSA administration requires further evaluation. Although potent combination protocols provide effective protection against rejection, the potential development of neoplasms must be studied in long-term follow-up. On the other hand, unwarranted fear of progressive nephrotoxicity may result in underdosing of CSA and a high incidence of late rejections. The advent of mAbs has spawned an exciting era of specific immunosuppression. These newer agents may eventually help curtail the complications associated with the current regimens.

Research paper thumbnail of Immunosuppression in renal transplantation. I. Cyclosporine and azathioprine

Clinical Transplantation

ABSTRACT

Research paper thumbnail of Immunosuppression in renal transplantation II. Corticosteroids, antilymphocyte globulin, and OKT3

Clinical Transplantation

ABSTRACT

Research paper thumbnail of Reversed-phase high-performance liquid chromatographic approach to determine total lymphocyte concentrations of 6-thioguanine, methylmercaptopurine and methylthioguanine in humans

Journal of Chromatography A

A reversed-phase high-performance liquid chromatographic (HPLC) procedure was developed to quanti... more A reversed-phase high-performance liquid chromatographic (HPLC) procedure was developed to quantify intracellular lymphocyte 6-thioguanine, methylmercaptopurine and methylthioguanine. The free base of each metabolite was obtained by acid hydrolysis, which allowed for a total determination of thiopurine metabolites. 6-Thioguanine was analyzed on an octadecylsilane column using acetonitrile-10 mM sodium phosphate (11:89), pH 7, containing 0.06% tetrabutylammonium chloride. 6-Thioguanine was oxidized with potassium permanganate, and fluorescence was measured at 330 nm excitation and 410 nm emission. Methylmercaptopurine and methylthioguanine were separated on a cyanopropylsilane column using methanol-40 mM sodium phosphate (22:78), pH 2.7, and detected by ultraviolet absorbance at 314 and 290 nm, respectively.