Search PubMed⌕ Search

Biomedical subjects

C V Fletcher

Publications and source records attributed to C V Fletcher.

At least 55 records · Page 3Linked to original sources
PubMed1994

Gender differences in human pharmacokinetics and pharmacodynamics.

Gender differences in pharmacokinetics and pharmacodynamics have long been recognized in animals. In humans, however, little attention has been paid to this field despite at least theoretical reasons to believe that gender may be an important variable in the processes of absorption, distribution, metabolism, and excretion. Gastric acid secretion, gastrointestinal blood flow, proportions of muscular and adipose tissue, amount of drug binding proteins, gender-specific cytochrome P450 isozymes, physiologic and hormonal changes during the menstrual cycle, and renal blood flow are several factors that may contribute to sex-related differences in pharmacokinetics. Clinical investigations have documented greater absorption and subsequent incorporation of iron into erythrocytes, and higher bioavailability of ethanol in females. Women have been shown to have a slower metabolism of mephobarbital and propranolol but an increased biotransformation of methylprednisolone, all three of which are metabolized by enzymes of the cytochrome P450 system. Lastly, the renal excretion of amantadine was inhibited significantly by quinidine and quinine in men but not in women. While gender-specific pharmacodynamic data are meager, evidence also supports the existence of sex-related differences. Women appear to be more prone to develop torsades de points from drugs such as quinidine and procainamide than men. A dimorphism in insulin sensitivity has been demonstrated with males having an enhanced response compared to females. Pharmacokinetic and pharmacodynamic sex-related differences exist and are complex. Future research efforts should be designed to provide more gender-specific information on drug disposition and clinical effect.

Adolescent↗
PubMed1994

Foscarnet for suppression of human immunodeficiency virus replication.

The effect of foscarnet against human immunodeficiency virus (HIV) was evaluated in nine HIV-infected individuals; six completed 28 days of induction therapy. The overall mean increase in CD4+ lymphocytes was 64 cells per mm3. The mean decline in the HIV antigen concentration was 108 pg/ml (P = 0.03), and suppression was related to systemic foscarnet exposure by a maximum-effect pharmacodynamic model.

Adult↗
PubMed1992

Comparative pharmacokinetics of zidovudine in healthy volunteers and in patients with AIDS with and without hepatic disease.

To understand whether disease caused by the human immunodeficiency virus (HIV) affects zidovudine disposition, we compared the drug's pharmacokinetics in six healthy volunteers; six persons with the acquired immunodeficiency syndrome (AIDS) and no evidence of gastrointestinal (nausea, vomiting, diarrhea), renal (elevated blood urea nitrogen, serum creatinine), or hepatic (elevated liver function tests) disease; and three patients with AIDS and hepatic disease. After a single oral dose of zidovudine, serial blood samples were analyzed for drug concentration by radioimmunoassay. A one-compartment oral absorption model was fit to the concentration-time data. The absorption rate constant (4.05 vs 2.11 hr-1) and time to maximum concentration (0.61 vs 1.03 hr) were significantly different in healthy volunteers versus patients with AIDS without hepatic disease. Differences in half-life, oral clearance, and area under the curve were not statistically significant. In the three patients with AIDS plus hepatic disease, clearance was reduced an average of 63%, and area under the curve was increased by a factor of 2.3. These comparative pharmacokinetic data do not support profound differences between zidovudine's disposition in healthy volunteers and individuals with AIDS; however, the differences and trends that were observed may represent an effect of HIV disease. Although the presence of hepatic disease clearly indicates a need to modify individual dosages, these pharmacokinetic data may have more generalized implications for zidovudine dosing as the relationships between drug concentration and therapeutic or toxic effects are clarified.

Absorption↗
PubMed1991

Acyclovir therapy in neonates.

STUDY OBJECTIVE: To determine the pharmacokinetic parameters of acyclovir disposition in neonates with renal dysfunction. DESIGN: Prospective sequential open enrollment of neonates with presumed herpes group virus infections. SETTING: Neonatal intensive care units in the greater Minneapolis-St. Paul metropolitan area. PATIENTS: Sixteen neonates with gestational ages between 27 and 40 weeks (median 38 weeks) were given acyclovir between days 1 and 56 of life to treat presumed herpes virus infections. Six infants were critically ill with multisystem disease, five infants had hepatic failure and underwent blood exchange transfusion, and five infants had renal failure. A mean of four (range 1 to 19) serum acyclovir concentrations per patient were measured by radioimmunoassay. Pharmacokinetic parameters were calculated from acyclovir concentrations in 46 samples from 16 patients. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetic disposition of acyclovir was described as a two-compartment model. Although the ranges for acyclovir clearance and terminal elimination (t 1/2 beta) were wide, a statistically significant relationship was demonstrated between clearance and beta versus serum creatinine concentration. The average t 1/2 beta for infants with serum creatinine level less than 1 mg/dl (88 mumol/L) was 5.0 hours, and 15.6 hours for those with serum creatinine level greater than 1 mg/dl. CONCLUSIONS: Neonates with hepatic or renal dysfunction or young premature infants accumulate acyclovir when dosed without adjustment for organ dysfunction. Measurement of serum creatinine or creatinine clearance can be useful in the dosing of acyclovir in neonates.

Acyclovir↗
PubMed1991

Treatment of invasive cytomegalovirus disease in solid organ transplant patients with ganciclovir.

The occurrence of cytomegalovirus infection after solid organ transplantation has been correlated with decrease patient and allograft survival. The disease has not been conquered for two majors reasons: the length of time to establish the diagnosis of CMV has been excessive, and suitable, nontoxic antiviral agents have not been available for use. The purpose of this study was to examine the current incidence and impact of tissue-invasive cytomegalovirus (TI-CMV) disease that developed in 93 patients who underwent solid organ transplantation at University of Minnesota Hospitals (3/1/87 and 6/30/89) and who were treated with antiviral agent ganciclovir ( [9-(1,3-dihydroxy-2-2-propoxymethyl)-guanine [DHPG]). During this same period of time 323 patients received kidney transplants and 71 received kidney-pancreas transplants. Three patient groups were defined: (1) no CMV; (2) CMV infection (cultural or serologic evidence of noninvasive CMV infection); and (3) evidence of TI-CMV disease based upon initial complaints of fever, malaise, dyspnea, or abdominal pain, leukopenia (WBC less than 3000/ml), and evidence of a positive CMV rapid antigen test, CMV culture, or the presence of characteristic CMV inclusion bodies upon examination of material obtained by means of bronchoscopy, upper-gastrointestinal endoscopy, colonoscopy, or liver or renal biopsy. Patients with solely fever, leukopenia, but without a rising CMV serum titer, or positive CMV urine or blood cultures were excluded from the study. A multivariate analysis revealed that rejection therapy, age greater than 50 years, and receiving an organ from a seropositive donor were all significant variables that predisposed to TI-CMV. Analysis of patient and kidney allograft survival indicated that asymptomatic CMV infection had little current impact upon patient or allograft survival, while patients who developed TI-CMV exhibited higher rates of allograft loss and mortality, despite DHPG therapy. Comparison with historical group of patients indicated that TI-CMV DHPG-treated patients exhibited a trend toward improved allograft survival that may be relevant because the historical group of patients included patients with mild CMV infection. DHPG therapy was well tolerated and produced minimal toxicity, and excellent 30-day cure rates (89.2%), although 21.2% of patients required retreatment subsequently. We are currently conducting a trial to compare the ability of DHPG administered plus an anti-CMV immune globulin preparation with acyclovir to prevent posttransplant TI-CMV disease.

Acyclovir↗
PubMed1991

Pharmacologic basis for high-dose oral acyclovir prophylaxis of cytomegalovirus disease in renal allograft recipients.

The incidence of cytomegalovirus disease, the most important infectious complication of renal transplantation, was reduced in renal allograft recipients by a regimen of prophylactic high-dose oral acyclovir. To analyze the pharmacologic aspects of our prophylactic approach, we evaluated safety, pharmacodynamics, and in vitro susceptibility data. One hundred four recipients of cadaveric renal allografts received either oral acyclovir (n = 53) in doses of up to 3,200 mg/day or a placebo (n = 51) for 12 weeks posttransplant. Leukocyte count and serum creatinine were selected as markers of laboratory safety and were evaluated pretransplant, at study midpoint (creatinine only), and at study completion. Concentrations of acyclovir in plasma were determined to verify the ability of the dosing strategy to achieve predicted values. Viral resistance was assessed by calculation of in vitro 50% inhibitory concentrations (IC50s) of acyclovir for the cytomegalovirus strains collected from the subjects. Our results showed no difference in leukocyte count or serum creatinine between the acyclovir and placebo recipients. Plasma acyclovir concentrations were maintained within the expected limits and did not differ between patients who developed cytomegalovirus disease and those who did not. The mean acyclovir IC50s for cytomegalovirus isolates were 42.6 mumol/liter in the acyclovir recipients and 48 mumol/liter in the placebo recipients. We conclude that the clinical benefit of high-dose oral acyclovir therapy occurred despite plasma drug concentrations below the mean IC50 for the patient viral isolates. Furthermore, the use of the regimen did not produce leukopenia, adversely affect renal function, or alter the susceptibility of cytomegalovirus strains to acyclovir. This approach and dose adjustment scheme may be appropriate for other immunocompromised patients at risk for cytomegalovirus infection and disease.

Acyclovir↗
PubMed1990

Patterns of antibiotic use and expenditures during 7 years at a university hospital.

Before 1982, annual retrospective drug-use audits clearly established the pattern of increased antibiotic use and expenditures at the University of Minnesota Hospital. At that point, a concurrent trend analysis system was developed to track this use by individual drug and therapeutic class, to identify trends in use for qualitative evaluation, and to provide an assessment of any intervention intended to alter use. Monthly use of all injectable antibiotics and antifungal agents, and selected oral antifungals has been tracked since 1982 as both defined daily doses and dollars. Use patterns in 1981 served as baseline. The defined daily dose index, which captures changes associated with intensity of antibiotic use per patient, increased 62% from baseline through 1988. This increase, however, resulted in a disproportionate 228% rise from baseline in antibiotic expenditures to nearly $3 million/year for 1988. The defined daily dose index peaked in 1985, declined in 1986, and remained stable for 1987 and 1988. Qualitative drug-use review programs were associated with this positive change. These results demonstrate the utility of concurrent trend analysis as a resource-management tool and as a measure of effectiveness for collaborative physician-pharmacist programs to foster safe, appropriate, and economical use of antiinfective agents.

Anti-Bacterial Agents↗
PubMed1989

Continuous infusion of high-dose acyclovir for serious herpesvirus infections.

Thirteen patients with herpesvirus infections who were unresponsive to at least 72 h of intermittent acyclovir administration received high-dose continuous infusion. Steady-state concentrations were maintained at between 20 and 98 mumol/liter. Of 12 patients who had continuous infusion for greater than 5 days, 7 (58%) resolved their infections, as determined by clinical and virologic parameters, suggesting that continuous infusion may succeed in some patients who do not respond to conventional therapy.

Acyclovir↗
PubMed1989

Evaluation of ganciclovir for cytomegalovirus disease.

Cytomegalovirus (CMV) infections are a common cause of morbidity and mortality in immunosuppressed patients. Ganciclovir is an acyclic deoxyguanosine analog structurally similar to acyclovir but with superior activity against CMV. The median ganciclovir concentration required to inhibit viral replication by 50 percent is 2.15 mumol versus 72 mumol for acyclovir. Pharmacokinetic properties of ganciclovir include biexponential decay with a terminal half-life of 2.5 hours, tissue uptake, cerebrospinal fluid penetration, and renal dependence for elimination. CMV treatment approaches have commonly used dosages of 3-15 mg/kg/d. In uncontrolled trials, the response rate of CMV retinitis is approximately 80 percent. The overall response rate for CMV pneumonitis has been approximately 50 percent. However, AIDS (acquired immunodeficiency syndrome) and other immunosuppressed patients appear to respond more favorably (approximately 70 percent) than do marrow transplant recipients. Relapse is common once ganciclovir is stopped and maintenance therapy may be required for sustained benefit. Neutropenia appears to be the drug-limiting adverse reaction. Although the development of ganciclovir-resistant CMV, risk factors for neutropenia, and alternative administration strategies all need further study, ganciclovir appears to have a role in the treatment of cytomegalovirus disease.

Acyclovir↗
PubMed1988

Concurrent zidovudine levels in semen and serum determined by radioimmunoassay in patients with AIDS or AIDS-related complex.

Zidovudine was present in the semen and serum of six patients with acquired immunodeficiency syndrome or the related complex who were receiving 200 mg of the drug orally every four to six hours. Mean semen zidovudine levels (as measured by a new radioimmunoassay) in samples collected 0.75 to 1.25 hours after oral dosing were 3.63 to 7.19 mumol/L. Levels in semen samples collected 3.0 to 4.5 hours after oral dosing were 1.68 to 6.43 mumol/L. These values are above the in vitro minimum inhibitory concentration for the human immunodeficiency virus type 1 (HIV-1). Mean serum concentrations at the early and late times after oral dosing were 0.22 to 3.07 mumol/L and 0.10 to 1.42 mumol/L, respectively. Ratios of semen/serum zidovudine levels ranged from 1.3 to 20.4. It is possible that a pH-dependent trapping mechanism, which has been described in the prostate for other antibiotics, was responsible for the relatively high semen levels observed.

AIDS-Related Complex↗
PubMed1988

Pharmacokinetics and safety of high-dose oral acyclovir for suppression of cytomegalovirus disease after renal transplantation.

The pharmacokinetics and safety of high-dose oral acyclovir for suppression of cytomegalovirus disease were evaluated in 12 patients undergoing renal transplantation. A 12-week course beginning 24 hours before transplantation was administered in doses of 800 to 3200 mg/day based on renal function. Acyclovir plasma concentrations were measured by RIA on posttransplant days 1 or 2 and 5, 6, or 7. Mean peak and trough concentrations on days 5, 6 or 7 were 25 and 18 mumol/L, respectively. The pharmacokinetic model predicted acyclovir concentrations with a precision of 4.1 mumol/L and bias of -1.19 mumol/L. Estimates of individual pharmacokinetic parameters were consistent with literature and a priori values. Two of six adverse events were attributable to acyclovir; both resolved with dose modification. The dosage adjustment scheme and pharmacokinetic model performed well, allowing us to safely administer high-dose oral acyclovir immediately after renal transplantation. We are proceeding with a placebo-controlled study to assess efficacy for suppression of posttransplant cytomegalovirus disease.

Acyclovir↗
PubMed1988

Ganciclovir pharmacokinetics during renal impairment.

Limited information is available concerning the use of ganciclovir (GCV) in patients with severe renal impairment. The pharmacokinetics of GCV were studied in a heart transplant recipient requiring hemodialysis. The total body clearance was calculated to be approximately 5% of that previously reported for patients with normal renal function. GCV was removed by hemodialysis; a single 4-h procedure decreased the concentration in plasma by approximately 50%. GCV can be safely administered to patients with renal insufficiency if concentrations in plasma are monitored.

Acyclovir↗
PubMed1988

Effect of infusion rate on amphotericin B-associated febrile reactions.

Our objective was to prospectively study febrile and chill reactions associated with two amphotericin B (AB) infusion rates, slow (2-hour) versus rapid (45 minute). Seventeen consenting bone marrow transplant recipients in whom AB was to be initiated for documented or suspected fungal infections were recruited. After standardized premedication, patients received eight daily AB infusions (0.5 mg/kg/d, concentration 0.25 mg/ml). Rate was assigned using a randomized, crossover pair design. Axillary temperature, chills, and meperidine dose required to resolve chills were monitored for each infusion. For the first pair of infusions, fever (defined as a rise of 1 degree C) occurred frequently, in 12 of 17 (70.5 percent) and 13 of 17 patients (76.4 percent), with a mean rise of 1.7 degrees C (range 1.1-3.7) and 1.7 degrees C (1.1-3.5) degrees for the 45-minute and 2-hour infusions, respectively (p greater than 0.10). Chills were observed in 15 of 17 (88.2 percent) and 14 of 17 (82.3 percent) recipients of the 45-minute and 2-hour infusions, respectively. The time of onset (p greater than 0.10) and the duration of chills (p = 0.08) were similar for both infusion rates. Meperidine requirements for rapid and slow infusions were similar as well (p = 0.12). These data suggest that for patients free of preexisting renal and cardiac disease, rapid AB infusions are well tolerated and produce adverse reactions (fever and chills) similar in nature and severity to slower infusions.

Adolescent↗
PubMed1986

Pharmacist interventions to improve prescribing of vancomycin and tobramycin.

The effect of clinical pharmacist interventions that promoted the use of nafcillin rather than vancomycin and of gentamicin rather than tobramycin, when appropriate, was evaluated. Physician information sheets and criteria describing appropriate use of the target drugs vancomycin and tobramycin were developed by a clinical pharmacist and infectious disease physicians. When drugs were prescribed for indications that did not meet the established criteria, the clinical pharmacist either contacted the prescribing physician or left the sheet in the patient's chart if the physician was not available. The average use of the target drugs and their alternatives was evaluated monthly during two six-month study periods and compared with the average use of these drugs during a three-month period before the target-drug programs were initiated. Throughout the 12-month study, on a per-patient basis, nafcillin use increased 31% while vancomycin use decreased 27% compared with the reference period; gentamicin use increased 21% while tobramycin use decreased 12% during the same period. These changes in use resulted in a net decrease in drug expenditures of $161,396. Approximately 0.5 full-time equivalent was spent on the program, and the return on investment for the service was greater than 10 to 1. Clinical pharmacist interventions through target-drug programs were effective in improving the appropriateness of vancomycin and tobramycin prescribing based on literature-derived criteria. The effects achieved by these interventions may decrease with time, and ongoing drug-use monitoring and physician education are necessary.

Anti-Bacterial Agents↗