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Biomedical subjects

D M Canafax

Publications and source records attributed to D M Canafax.

At least 55 records · Page 3Linked to original sources
PubMed1991

Antimicrobial treatment of otitis media.

The major pathogens causing acute otitis media (AOM) are Streptococcus pneumoniae and Haemophilus influenzae, with Moraxella catarrhalis, Streptococcus pyogenes, and Staphylococcus aureus less frequently isolated. The same organisms and Staphylococcus epidermidis are found in chronic otitis media with effusion. In chronic suppurative otitis media, Pseudomonas aeruginosa and S aureus are most frequently found. Antimicrobial agents found to be most effective in treating AOM are amoxicillin, trimethoprimsulfamethoxazole, erythromycin-sulfisoxazole, amoxicillin-clavulanate, and cefaclor. Cefuroxime axetil and cefixime are alternatives for which there are less data. Currently, about 20% of AOM cases are caused by beta-lactamase-producing strains (usually H influenzae or M catarrhalis) that are resistant to amoxicillin, thus favoring the use of the other agents listed. Concentrations of antibiotics in middle ear infections range from 10% to 76% of peak serum levels for the listed agents and are higher in AOM than in chronic otitis media with effusion, emphasizing the importance of adequate dosing for successful treatment.

Acute Disease↗
PubMed1991

Clinical and pharmacokinetic basis for the antimicrobial treatment of acute otitis media.

Given the astonishing frequency in childhood of acute otitis media and its significant morbidity, such as hearing loss and possibly speech delay, improving treatment of response is essential. Since bacteria are an important cause of otitis media, antimicrobial treatment remains the cornerstone of such treatment. Over the last four decades, many clinical studies have shown that antibiotics can relieve symptoms and prevalent complications, although a universal cure is still elusive. This article summarizes the most pertinent clinical and experimental research on treating and preventing acute otitis media, with a focus on intervention trials and the pharmacokinetic behavior of antimicrobial drugs.

Acute Disease↗
PubMed1990

A reversed phase high performance liquid chromatography approach in determining total red blood cell concentrations of 6-thioguanine, 6-mercaptopurine, methylthioguanine, and methylmercaptopurine in a patient receiving thiopurine therapy.

A reversed phase high performance liquid chromatographic procedure was developed to quantify 6-thioguanine, 6-mercaptopurine, methylthioguanine, and methylmercaptopurine in red blood cells. The free base of each thiopurine was liberated from the respective nucleoside and nucleotide moiety by acid hydrolysis, which allowed for a determination of the total thiopurine present. 6-Thioguanine and 6-mercaptopurine were analyzed on an octadecylsilane column using methanol + 20 mM sodium phosphate (15:85), pH 7.5, containing 0.07% tetrabutylammonium chloride. Detection was by potassium permanganate oxidation and fluorescence detection at 290 nm excitation and 400 nm emission. Methylmercaptopurine and methylthioguanine were analyzed on a cyanopropylsilane column using methanol + 40 mM sodium phosphate (18:82), pH 2.7, and then ultraviolet absorption at 314 nm and 290 nm, respectively. The method was used to quantify the four primary thiopurines present in red blood cells of an acute lymphoblastic leukemia patient. The procedure may be a therapeutic monitoring technique that quantifies the cytotoxic drug burden in patients receiving azathioprine or 6-mercaptopurine therapy.

Child↗
PubMed1990

Azathioprine metabolism: pharmacokinetics of 6-mercaptopurine, 6-thiouric acid and 6-thioguanine nucleotides in renal transplant patients.

Despite extensive clinical experience with azathioprine (AZA), the disposition of various AZA metabolites remains obscure. We therefore evaluated the pharmacokinetics of three AZA metabolites: 6-mercaptopurine (6-MP), the immediate metabolite; 6-thiouric acid (6-TU), the final end product; and 6-thioguanine nucleotides (TGN), the active moiety; in eight renal transplant patients after oral administration of AZA. The low peak plasma 6-MP level of 73.7 +/- 23.7 ng/mL (mean +/- SD) and the short half-life (t1/2) of 1.9 +/- 0.6 hours suggest rapid conversion of 6-MP to other metabolites. A peak plasma 6-TU concentration of 1210 +/- 785 ng/mL was observed at 3.5 +/- 0.6 hours after the AZA dose. The strong correlation between 6-TU t1/2 and serum creatinine (r = 0.98, P = .0008) supported our previous work showing that 6-TU is primarily excreted by the kidneys. The total TGN levels in red blood cells (RBCs) in each patient remained largely unchanged over 24 hours with the intraindividual coefficient of variation ranging from 4.4% to 29.8%. In comparison, the mean TGN level varied considerably between patients, and ranged from undetectable to 413 pmol per 8 X 10(8) RBCs. However, there was no apparent correlation between white cell counts on day 0 (P greater than .5), day 7 (P greater than .5), or day 14 (P greater than .5) and RBC TGN level. The persistence of TGN in body tissues thus provides a pharmacokinetic rationale for the conventional once or twice daily AZA regimen.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1990

An experimental model for measuring middle ear antimicrobial drug penetration in otitis media.

Bacteria are an important cause of acute otitis media and successful treatment depends on achieving inhibitory or bacteriacidal antimicrobial drug concentrations in the middle ear. To evaluate further otitis media treatment success and failure, we developed a chinchilla model to study antimicrobial drug penetration through the middle ear mucosa. Using quantitative histomorphometry, we measured the middle ear space in 10 chinchillas and found a mean +/- SD volume of 2.09 +/- 0.08 ml and a mean +/- SD surface area of 14.41 +/- 1.48 cm2. To measure the apparent rate constant (Kc) of antibiotic elimination from the middle ear, through the middle ear mucosa, an antibiotic solution was inoculated into the middle ear cavity, and samples were aspirated between 1 and 8 hr later. In normal ears, the mean Kc +/- SD for amoxicillin was 0.118 +/- 0.013 hr-1, that for a trimethoprim 0.461 +/- 0.090 hr-1, and that for sulfamethoxazole 0.265 +/- 0.062 hr-1. In ears inoculated with type 7F Streptococcus pneumoniae to induce acute otitis media, the Kc +/- SD increased for all three drugs (P less than 0.05): amoxicilin to 0.286 +/- 0.089 hr-1, trimethoprim to 0.662 +/- 0.118 hr-1, and sulfamethoxazole to 0.411 +/- 0.056 hr-1. These values demonstrate that amoxicillin had the lowest apparent penetration rate constant of the three antibiotics but the greatest increase from normal to infected mucosa (142%). Trimethoprim had the highest apparent penetration rate constant of the three antibiotics but the smallest increase from normal to infected mucosa (44%), while the sulfamethoxazone apparent penetration rate constant increased from normal to infected mucosa by 55%.(ABSTRACT TRUNCATED AT 250 WORDS)

Amoxicillin↗
PubMed1990

An increased incidence of late acute rejection episodes in cadaver renal allograft recipients given azathioprine, cyclosporine, and prednisone.

We studied the incidence of biopsy-proven, acute rejection episodes occurring after 1 year posttransplant in cadaver renal allograft recipients. The 328 patients evaluated were given three immunosuppressive drug protocols. Group I (transplanted 9/80-6/84) (n = 75) received azathioprine, prednisone (P), and antilymphoblast globulin; group II (transplanted 9/80-6/84) (n = 83) received cyclosporine and P; group III (transplanted 7/84-12/86) (n = 170) received ALG, AZA, CsA, and P (sequential therapy). The incidence of first acute rejection episodes occurring up to 1 year posttransplant was 55% in group I and 35% in groups II and III. The incidence of late (greater than 1 year) acute rejection episodes was 6.5% in group I, 2.5% in group II, and 9.5% in group III (group II vs. III, P = 0.02). In group III, 50% of the late rejections were first, 44% second, and 6% third. The primary etiologies of this increased incidence of late acute rejection may have included subtherapeutic CsA levels and lower P doses. Sequential immunosuppressive therapy has been shown to be advantageous in the first posttransplant year. However, unless adequate immunosuppression is maintained, this approach can be associated with a significantly increased incidence of late acute rejection.

Adult↗
PubMed1990

Lessons learned and future hopes: three thousand renal transplants at the University of Minnesota.

1. The experience of 3,183 transplants between June 7, 1963 and September 30, 1990 at the University of Minnesota was reviewed. 2. Patients were divided into 4 historical periods-each era was associated with improved outcome. 3. As results have improved, the proportion of patients less than 5 years old and the proportion greater than 50 years old have increased. Type I diabetes has become the most common cause of renal failure in patients transplanted here. 4. The most important variable leading to improved outcome was donor source. Both HLA-identical and HLA-nonidentical LRD transplants have better outcome than CAD transplants (p less than 0.0001). 5. Multivariate analyses were done to determine risk factors for survival: a) in the first year, and b) in subsequent years. In the first year, age greater than 50, diabetes, and retransplantation had an adverse affect whereas LRDs and CsA immunosuppression were beneficial. Similar factors affected survival after the first year. HLA mismatch had no impact. 6. When death with graft function was excluded, diabetes and age greater than 50 were no longer risk factors, suggesting that the excess graft loss in these groups was due to patient death. 7. Chronic rejection and death with function remain the predominant causes of graft loss. 8. As protocols have evolved, results have improved, and previously "high-risk" patients are being successfully transplanted. Future efforts should be directed at decreasing graft loss from rejection and death with function.

Adult↗
PubMed1990

Principles of immunosuppression.

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.

Drug Interactions↗
PubMed1990

Evaluation of a rapid monitoring system to study heparin pharmacokinetics and pharmacodynamics.

The pharmacokinetic and pharmacodynamic characteristics of heparin were studied in 10 healthy volunteers using the Hepcon/System B-10. This coagulation-monitoring system uses each patient's body weight, height, baseline activated clotting time (ACT), and heparin dose response values to determine initial heparin doses. We administered a calculated mean +/- SD heparin doses of 85 +/- 14 U/kg to 10 subjects to achieve a mean +/- SD target ACT of 364 +/- 29 seconds. This dose produced a mean +/- SD measured peak ACT of 337 +/- 53 seconds from a mean +/- SD baseline of 121 +/- 10 seconds. The measured peak ACT values resulting from the individualized heparin doses were within 20% of the desired peak in 9 (90%) of the subjects. Using the ACT values, the average mean residence time for heparin effect was 1.2 hours and half-life was 0.8 +/- 0.2 hours, with all the subjects' values returning to within 10% of baseline by 4 hours after the dose. Using the protamine-derived heparin concentrations, heparin total-body clearance ranged from 43 to 99 ml/hr/kg (mean +/- SD 73.3 +/- 14.5 ml/hr/kg). A linear relationship was found between heparin concentration and change in ACT that was described by delta ACT = 16.85 + 136.7.(heparin concentration). We conclude that this method is easy to perform and accurate for determining initial heparin dosage requirements, and could be an important improvement over existing approaches. In addition, it is a valuable research tool for studying heparin pharmacodynamics and pharmacokinetics.

Adult↗
PubMed1990

Pharmacodynamics of local heparin infusion in a canine renal allograft model.

Inasmuch as heparin has demonstrated immunosuppressive activity in vivo and in vitro, we utilized a canine renal transplant model to estimate the first-pass extraction of heparin during renal artery infusion and to examine the effect of regional heparin delivery on the histologic features of rejection and allograft survival. Four autotransplanted mongrel dogs with programmable, implantable pump/catheter systems received a continuous intrarenal heparin infusion which was increased daily in stepwise fashion. Activated coagulation time (ACT) rose linearly with local heparin dose, indicating that heparin clearance remained constant over the dosage range studied. Comparison of these ACT values with those measured during same-dose i.v. infusion and those predicted from i.v. bolus studies revealed that there was little or no first-pass renal extraction of heparin by the transplanted kidney. In nine allografted dogs, the heparin infusion rate was adjusted according to daily ACT to maximize local heparin delivery but still maintain the ACT close to 125% of base line. There was no difference in overall survival between the heparin-treated dogs and a group of 14 untreated controls, and vascular rejection was significantly more intense in the heparin-treated animals. We conclude that intrarenal dosing of heparin to the point of producing systemic anticoagulation is limited by failure of the transplanted kidney to eliminate drug and does not prolong canine renal allograft survival.

Animals↗
PubMed1990

The pharmacoeconomics of renal transplantation: increased drug costs with decreased hospitalization costs.

We evaluated the economic and clinical effects of two immunosuppressive drug regimens used to treat recipients of human leukocyte antigen (HLA)-identical sibling donor renal transplants during the first posttransplant year. We compared consecutive patients in two groups of 30 who were given either antilymphoblast globulin (ALG), azathioprine, plus prednisone or cyclosporine, azathioprine, and prednisone for immunosuppression. We standardized all dollar values, costs and charges, to the 1986 level using our hospital's health care charge inflation rate. There were no significant differences between the two treatment groups for actual patient (100% vs 93%; p = 0.51) and graft survival rates (100% vs 93%; p = 0.51), average serum creatinine level (1.0 +/- 0.3 vs 1.0 +/- 0.2 mg%; p = 0.46), and most recent creatinine level (1.4 +/- 0.3 vs 1.4 +/- 0.7 mg%; p = 0.45). The average cyclosporine-azathioprine-prednisone costs were $3987/patient more for the first year of therapy than for ALG-azathioprine-prednisone. However, the former regimen produced an average of $9543/patient less in total hospitalization charges. This was due to both a shorter initial hospital stay and a decreased rate of rehospitalization, with a lower frequency of acute rejection episodes (p = 0.001) and infectious complications (p = 0.05). We conclude that, although this cyclosporine-containing protocol was associated with increased drug costs, it is justified by decreased hospitalization charges that resulted from improved efficacy and safety.

Azathioprine↗
PubMed1989

Bronchodilation from intravenous theophylline in patients with cystic fibrosis: results of a blinded placebo-controlled crossover clinical trial.

Most patients with cystic fibrosis (CF) eventually develop chronic obstructive pulmonary disease and theoretically could benefit from theophylline therapy. The purpose of this study was to investigate the pharmacologic response to intravenous theophylline by pulmonary function tests (PFT) and the theophylline pharmacokinetics in patients with CF. A randomized, double-blind, placebo-controlled, crossover trial was conducted in 10 ambulant patients with CF (5 females, 5 males), aged 11 to 21 years. Each patient received an intravenous dose of theophylline and normal saline over 1/2 hour on consecutive days. Spirometry and whole-body plethysmography were performed at baseline, 1, 3, 5, and 7 h after the theophylline dose, and 10 blood samples were collected over 9 h on both study days. The percent change of PFT from the baseline was recorded. Analysis of variance for balanced two-period crossover design was used to evaluate the effectiveness of theophylline therapy. The serum concentration (Conc.) vs. time data were fitted using nonlinear least-squares regression analysis. The theophylline dose administered was 7.9 +/- 0.4 (mean +/- SD) mg/kg, which produced a maximal Conc. (Cmax) of 14.6 +/- 2.7 microgram/ml. The half-life (T1/2), volume of distribution (Vd), and total body clearance (TBC) were 4.9 +/- 1.9 h, 537 +/- 124 mL/kg, and 80 +/- 16 ml/h/kg, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1989

Pharmacokinetics of 6-thiouric acid and 6-mercaptopurine in renal allograft recipients after oral administration of azathioprine.

The immunosuppressive activity of azathioprine (AZA) is unpredictable and depends on the formation of intracellular thiopurine ribonucleotides. However, the quantification of these active thiopurines presents difficult analytical problems. It has recently been postulated that plasma concentrations of 6-thiouric acid (6-TU) and 6-mercapto-purine (6-MP), metabolites of AZA, may provide more readily measurable indices of the pharmacologic activity of AZA. In order to evaluate the utility of 6-TU and 6-MP plasma concentrations in monitoring AZA therapy, we studied their pharmacokinetics in 6 renal transplant patients, and their in vitro immunosuppressive potency in a mixed lymphocyte proliferation assay. A peak plasma 6-TU concentration of 710.7 ng/ml was observed at 3.8 h after oral dosing. Good correlation was observed between the elimination t1/2 of 6-TU and serum creatinine, and between AUC over 24 h and serum creatinine. However, we did not observe a second peak in plasma 6-TU concentration that could be attributed to the degradation of active AZA metabolites. 6-MP plasma concentrations in the patients were low (mean peak concentration 36.0 ng/ml) and rapidly disappeared within 8 h. In vitro immunosuppressive activity could not be demonstrated for 6-TU over a concentration range of 1.25 ng/ml to 0.25 mg/ml. We conclude that 6-TU is pharmacologically inert and is primarily eliminated by the kidneys. Our findings currently do not support the use of plasma concentrations of 6-TU or 6-MP to monitor AZA therapy. In order to optimize AZA therapy, analytical techniques that are technically feasible and that can directly quantify the active intracellular thiopurines are being explored.

Adult↗