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Biomedical subjects

T L Schwinghammer

Publications and source records attributed to T L Schwinghammer.

At least 19 recordsLinked to original sources
PubMed1995

Efficacy of mesna for prevention of hemorrhagic cystitis after high-dose cyclophosphamide therapy.

For these reasons, a definitive statement about the relative efficacy of mesna for prophylaxis of cyclophosphamide-associated HC in BMT patients cannot be made. Because HC is a frequent and potentially serious complication of high-dose cyclophosphamide therapy, the implementation of some preventive measure is mandatory in all patients. Unless medically contraindicated, provision of sufficient hydration and diuresis to maintain adequate high urine flow should be a component of all prophylactic regimens. It is unclear whether the addition of mesna therapy or bladder irrigation to intravenous hydration provides greater protection. Studies indicate that mesna probably has no adverse effect on engraftment. This is consistent with its chemistry and pharmacology, as the drug is hydrophilic and activated only in the kidneys. Thus, it is inactive in the bloodstream and unable to penetrate cell membranes and interfere with the action of cyclophosphamide. Although safety issues surrounding the use of mesna for prevention of cyclophosphamide-associated HC appear to have been resolved, efficacy issues must await the completion of further well-controlled comparative trials.

Bone Marrow Transplantation↗
PubMed1995

High-dose cyclosporine and corticosteroids for prophylaxis of acute and chronic graft-versus-host disease.

Twenty-eight consecutive recipients of HLA-identical sibling marrow grafts received prophylaxis for GVHD with high-dose cyclosporine (CsA) and corticosteroids. CsA 5 mg/kg/day (2.5 mg/kg infused over 4 h twice daily) was started on day -1 and continued until patients could take oral CsA (15 mg/kg/day). CsA doses were adjusted to maintain concentrations between 200-800 ng/ml (whole-blood HPLC) until the tapering period (days 268-361). Methylprednisolone 0.5 mg/kg/day was started on day 7, increased to 1 mg/kg/day during days 15-28, and tapered thereafter until discontinuance on day 194. Low CsA trough levels occurred in 15 patients (54%) during the i.v. administration period. Ten patients (36%) developed grade I and 3 patients (11%) developed grade II acute GVHD; there were no cases of grade III or IV disease. The actuarial incidence of chronic GVHD was 29% at 1 year but 57% at 2 years due to development of chronic GVHD after discontinuation of immunosuppressive agents. High blood CsA concentrations in stable outpatients led to dose-limiting nephrotoxicity. Infections occurred throughout the period of extended immunosuppression (from 6 to 12 months) but were not life-threatening. The actuarial incidence of leukemic relapse was 18% at 1 year and 25% at 2 years. Actuarial survival at 1 and 2 years was 68 and 51%, respectively. Despite the frequent occurrence of low CsA trough levels, this regimen appeared to be effective in preventing acute GVHD. Immunosuppressive prophylaxis beyond 1 year may be required to reduce late-onset chronic GVHD.

Adolescent↗
PubMed1993

Disposition of total and unbound etoposide following high-dose therapy.

Total and unbound etoposide pharmacokinetics were studied in 16 adult patients (median age, 34 years; range, 18-61 years) undergoing autologous bone marrow transplantation for advanced lymphoma after receiving high-dose etoposide (35-60 mg/kg) as a single intravenous infusion. Pretreatment values for mean serum albumin and total bilirubin were 3.0 +/- 0.4 g/dl and 0.5 +/- 0.4 mg/dl, respectively. Etoposide plasma concentrations and protein binding (%unbound) were determined by high-performance liquid chromatography (HPLC) and equilibrium dialysis, respectively. Pharmacokinetic parameters for unbound and total etoposide were calculated by nonlinear regression analysis using a two-compartment model. The mean (+/- SD) parameters for total etoposide included: clearance (CL), 31.8 +/- 17.7 ml min-1 m-2; volume of distribution (Vss), 11.5 +/- 5.9 l/m2, and terminal half-life (t1/2 beta), 7.2 +/- 3.7 h. Mean unbound CL was 209.6 +/- 62.7 ml min-1 m-2 and %unbound was 16% +/- 5%. The mean etoposide %unbound was inversely related to serum albumin (r2 = 0.45, P = 0.0043). The mean %unbound at the end of the etoposide infusion was higher than that at the lowest measured concentration (21% vs 13%, respectively; P = 0.017), suggesting that concentration-dependent binding may occur after high etoposide doses. The median total CL was higher in patients with serum albumin concentrations of < or = 3.0 g/dl than in those with levels of > 3.0 g/dl (34.6 vs 23.5 ml min-1 m-2, P = 0.05). Total CL was directly related to %unbound (r2 = 0.61, P = 0.0004). Unbound CL was unrelated to either serum albumin or %unbound. These results demonstrate that hypoalbuminemia is independently associated with an increased etoposide %unbound and rapid total CL after the administration of high-dose etoposide. Unbound CL in hypoalbuminemic patients is unchanged in the presence of normal total bilirubin values.

Adolescent↗
PubMed1993

Pharmacologic prophylaxis of acute graft-versus-host disease after allogeneic marrow transplantation.

The immunology, pathophysiology, incidence, clinical manifestations, grading, and prevention of acute graft-versus-host disease (GVHD) are reviewed. GVHD occurs after allogeneic marrow transplantation when immunologically competent T lymphocytes in the donor marrow identify the host's antigens as foreign and attempt to reject host tissues. Acute GVHD occurs within three months after marrow transplantation and may affect the skin, gastrointestinal tract, liver, and immune system. Even with prophylactic immunosuppression, acute GVHD occurs in 20% to 80% of patients. Moderate to severe GVHD (grades II-IV) is a major cause of morbidity and mortality after allogeneic bone marrow transplantation. Conventional GVHD prophylaxis consists of immunosuppressives such as corticosteroids, methotrexate, and cyclosporine. Methotrexate and cyclosporine are equally effective in preventing GVHD. A combination of both drugs is better than either drug alone and results in an improved survival rate. The addition of corticosteroids to methotrexate, cyclosporine, or antithymocyte globulin is also more effective than single-drug therapy. Serial administration of intravenous immune globulin may contribute additional protection against acute GVHD. There is conflicting evidence concerning the prophylactic efficacy of pentoxifylline. Elimination of T lymphocytes from the donor marrow before transplantation has been associated with less GVHD but a higher incidence of graft failure. Total elimination of GVHD in patients with leukemia may cause loss of a graft-versus-leukemia effect, resulting in increased relapse rates and decreased long-term survival. Promising experimental prophylactic agents include thalidomide, zolimomab aritox, tacrolimus, antibodies to cytokines involved in the pathogenesis of GVHD, and monoclonal antibodies against cytokine receptors on T lymphocytes. Current research efforts are also directed toward eliminating GVHD without compromising the graft-versus-leukemia effect.

Acute Disease↗
PubMed1992

Triazolam use in a university medical center.

The results of a drug-use evaluation (DUE) of triazolam at a university medical center are reported. The DUE was conducted at three institutions in a medical center complex with over 1100 beds. Indicators and thresholds were developed by the DUE subcommittee and approved by each institution's pharmacy and therapeutics committee. The medical charts of patients for whom triazolam was prescribed during January through March 1991 were reviewed. The relationship between the occurrence of adverse drug reactions (ADRs) and triazolam use was evaluated with the Naranjo ADR probability scale. Of 192 patients whose medical charts were reviewed, 123 (64%) were prescribed 0.125-mg doses. Patients who were > 70 years of age were more likely than younger patients to be prescribed this low dose (84% versus 60%). Fifty-four patients (28%) received no doses; a median of two doses (range, 1-46) were received by the remaining 138 patients. Twelve (9%) of those 138 patients experienced ADRs considered to be possibly (n = 10) or probably (n = 2) related to triazolam. Possible triazolam-associated reactions consisted of confusion (four cases), weakness and lethargy (four), and dizziness (two); probable triazolam-associated ADRs were confusion (one case) and next-day somnolence (one). Factors potentially contributing to ADRs included the presence of concomitant diseases or medications, the total number of doses received, and patient age. Of 138 hospitalized patients who had been given one or more doses of triazolam, 12 had had possible or probable triazolam-associated ADRs. The use of low doses and short-term therapy, particularly in elderly patients, may reduce the likelihood of ADRs.

Academic Medical Centers↗
PubMed1992

Program for reviewing returned medications.

A program for reviewing medication doses returned to the pharmacy department is described. Discrepancies concerning returned doses at a teaching hospital led to the creation of a returned-dose log sheet. A pharmacist enters the patient's name, medication, and administration schedule and forwards a copy to the charge nurse on the patient's unit, who records the reasons for the return. A pharmacist then uses the form to resolve any discrepancies in the pharmacy records and follows up if necessary. Monthly summaries of the forms are prepared. After a pilot phase and educational feedback, the rate of return of log sheets by nurses increased to 95%. It took nurses about 10 minutes per unit to complete a form, and pharmacists required 15 to 20 minutes for completion and follow-up. The percentage of dispensed doses that were returned decreased from 1.1% during the first month of the full program to 0.4% during the eighth month. The most common reason given by nurses for returned doses was that the dose had already been charted as having been given. The therapeutic classifications most frequently represented by the returns were gastrointestinal drugs, cardiovascular drugs, anti-infective agents, and electrolytic, caloric, and water balance drugs. The use of a log sheet to document and explain the return of scheduled doses to the pharmacy department improved communication, resolved discrepancies in the records, and reduced the rate of returns.

Medical Records↗
PubMed1991

The kinetics of cyclosporine and its metabolites in bone marrow transplant patients.

1. The pharmacokinetics of cyclosporine (CsA) and the time course of CsA metabolites were studied in five bone marrow transplant patients after intravenous (i.v.) administration on two separate occasions and once after oral CsA administration. 2. Cyclosporine and cyclosporine metabolites were measured in whole blood by h.p.l.c. 3. Cyclosporine clearance after i.v. administration decreased from 3.9 +/- 1.7 ml min-1 kg-1 to 2.0 +/- 0.6 ml min-1 kg-1 after 14 days of treatment. The mean +/- s.d. absolute oral bioavailability of cyclosporine was 17 +/- 11%. 4. Hydroxylated CsA (M-17) was the major metabolite in blood. There were no significant differences in the mean metabolite/CsA AUC ratios between the first and second i.v. studies. 5. After oral administration, the metabolite to CsA AUC ratios were higher for most metabolites compared to those observed in the second i.v. study, suggesting a contribution of intestinal metabolism to the clearance of CsA.

Adolescent↗
PubMed1991

Cyclosporine and methylprednisolone after allogeneic marrow transplantation: association between low cyclosporine concentration and risk of acute graft-versus-host disease.

A combination of cyclosporine (CSA) and methylprednisolone (MP) was used as graft-versus-host disease (GVHD) prophylaxis in 25 patients age 11-47 years (median 27 years) who received HLA-compatible sibling marrow transplants after myeloablative therapy for leukemia, myelodysplasia or lymphoma. CSA was initiated at 3 mg/kg/day in two divided doses, and the dose was adjusted to maintain a trough whole blood h.p.l.c. concentration between 200 and 800 ng/ml. While on i.v. CSA, the dose of CSA was increased for 10 of the 25 patients. The actuarial rate of grades II-IV acute GVHD was 37%. Those patients who developed moderate to severe GVHD had a significantly higher early mortality than those who did not (56% vs 12%, p = 0.02). There was a significant association between the development of acute GVHD and a mean week 2 CSA trough concentration less than 250 ng/ml. Life threatening regimen-related toxicities in the first 100 days included capillary leak syndrome, acute pancreatitis and small bowel perforation. Although the combination of CSA and MP in this dosing schedule was active in preventing acute GVHD, nephrotoxicity remained a problem, and outcome was limited by the inability to achieve the target CSA trough concentration in a substantial proportion of patients.

Acute Disease↗
PubMed1991

Pharmacokinetics and pharmacodynamics of glyburide in young and elderly nondiabetic adults.

The pharmacokinetics and pharmacodynamics of glyburide were studied in elderly and young nondiabetic adults. Healthy nondiabetic men and women 18-40 years of age (young subjects) and 60-85 years of age (elderly subjects) were recruited. After an overnight fast, the subjects were given a baseline glucose tolerance test (GTT). The next day, again after a fast, each subject was given a 5-mg oral tablet of glyburide, and the GTT was performed one hour later. Serum glucose, serum insulin, and plasma glyburide concentrations were determined. Twenty elderly (mean +/- S.D. age, 65.7 +/- 5.3 years) male (n = 10) and female (n = 10) volunteers and 15 young (22.3 +/- 4.5 years) male volunteers were enrolled. Compared with the young subjects, the elderly subjects had slower glyburide absorption, as determined from a lower peak plasma concentration and smaller area under the plasma concentration-time curve from zero to four hours (AUC0-4). The elderly subjects also had a lower glyburide elimination rate constant and higher volume of distribution and a 52% higher free fraction. There was no difference in the glyburide AUC0-24 or AUC0-infinity or in oral clearance between the groups. The elderly group had greater increases in serum glucose and insulin concentrations after the baseline GTT. After glyburide administration, the elderly group had a smaller fractional decrease in the glucose AUC0-3 from the baseline GTT result than the young subjects. Linear regression analysis of the relationship between the fractional change in glucose concentration and the glyburide AUC0-4 showed significantly different slopes between the two groups. The aging process appears to affect the pharmacokinetics and pharmacodynamics of glyburide.

Adolescent↗
PubMed1991

Autologous bone marrow transplantation following high-dose busulfan and VP-16 for advanced non-Hodgkin's lymphoma and Hodgkin's disease.

Ten patients with non-Hodgkin's lymphoma (NHL) and nine with Hodgkin's Disease (HD) received high-dose busulfan and etoposide (VP-16) prior to autologous bone marrow transplantation (ABMT). All patients with NHL and eight with HD had poor prognostic factors. Marrows from patients with NHL were purged with 4-hydroperoxy-cyclophosphamide. Busulfan (16 mg/kg body weight) was given orally over 4 days; VP-16 was administered as a single 4-h infusion. VP-16 was initiated at a dose of 60 mg/kg but reduced to 50 mg/kg after three of the first seven patients developed fatal toxicity. The 100-day regimen-related mortality was 21% (95% confidence interval 14%-46%). An absolute neutrophil count of 500/microliters was achieved at a median of 18 days in NHL and 23 days in HD. The median time to achieve a platelet count of 50,000/microliters was slower in HD (100 days) than in NHL (31 days) (p less than 0.05). Complete remissions were documented in four of nine evaluable patients with NHL and two of eight evaluable patients with HD. Actuarial survival at 18 months was 21% (95% confidence interval 3%-39%). The combination of high-dose VP-16 and busulfan as used in this study, although comparable to other regimens in efficacy, is associated with several toxicities.

Administration, Oral↗
PubMed1990

Pharmacokinetics of cephradine administered intravenously and orally to young and elderly subjects.

The pharmacokinetics of IV and oral cephradine in healthy young male and female volunteers (ages 19 to 25, n = 10) were compared to those of older individuals (ages 65 to 81, n = 9). Subjects received 1 gram of cephradine by a 5-minute intravenous (IV) infusion followed the next day by a 1-gram oral dose. Serial serum and urine samples collected over a period of 12 hours after the dose were analyzed for cephradine concentration by a microbiologic assay. After IV administration, mean serum cephradine concentrations in the elderly group were significantly higher at both 6 hours (1.52 +/- 0.41 mcg/mL) and 8 hours (0.73 +/- 0.22 mcg/mL) than in the young group at 6 hours (0.43 +/- 0.11 mcg/mL). Total systemic clearance was significantly lower (2.64 +/- 0.34 vs. 4.81 +/- 0.59 ml/min/kg) and the elimination half-life was significantly longer (1.71 +/- 0.20 vs 1.12 +/- 0.13 hours) in the elderly group (P = .0001). Systemic cephradine clearance correlated positively with creatinine clearance (r2 = 0.34, P = .0110) and negatively with age (r2 = 0.79, P = .0052). The mean volume of distribution was not significantly different between the two groups. Mean renal clearance was significantly lower in the elderly group (P = .0001), but more than 80% of the dose was excreted in the urine within 6 hours in both groups. After oral administration, the mean peak concentration and time to peak concentration did not differ between groups. The relative oral bioavailability was approximately 94% in both groups. The mean serum concentrations in the elderly were higher at both 6 and 8 hours than in the young group at 6 hours. There were no differences in pharmacokinetic parameters between male and female subjects. Because of reduced cephradine clearance secondary to an age-related decline in renal function, administration of cephradine every 8 hours, rather than every 6 hours, may be sufficient in elderly patients.

Administration, Oral↗
PubMed1988

Agranulocytosis associated with sulfasalazine.

Agranulocytosis is a rare but potentially lethal adverse effect of sulfasalazine. We report a case of sulfasalazine-associated agranulocytosis that occurred in a 79-year-old woman who had been taking the drug for approximately seven weeks. The patient had discontinued the drug on her own initiative nine days prior to admission. The patient was admitted with complaints of hoarseness, fever, odynophagia, and malaise. The total white blood cell count was 600/mm3 with a differential of 0% neutrophils, 8% bands, 67% lymphocytes, and 25% monocytes; a bone marrow aspirate and biopsy revealed maturation arrest. The patient's peripheral white blood cell count and differential progressively increased over the nine-day hospital course. Upon discharge the white blood cell count was 12,000 cells/mm3 with 66% neutrophils, 8% bands, 16% lymphocytes, and 10% monocytes. Complete blood counts should be performed periodically in patients receiving sulfasalazine, especially during the first two months of therapy. Pharmacists should counsel patients to discontinue the drug and consult their physician immediately if they develop unexplained fever, chills, sore throat, malaise, or other nonspecific illness during the initial two months of treatment.

Aged↗