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Biomedical subjects

W C Buhles

Publications and source records attributed to W C Buhles.

At least 19 recordsLinked to original sources
PubMed1998

Application of immunologic methods in clinical trials.

Immunologic effects of a new pharmaceutical molecule are often studied by in vitro immune assays and in laboratory animal models. However, immunologic activity can also be evaluated in man during the early clinical stage of drug development. Measures of immunologic response have recently served as surrogate clinical endpoints for drug approval. A variety of non-invasive measures can determine if a test molecule enhances or suppresses immunity. Both antibody and cellular immune responses to a new molecule itself can be detected and quantified in man. Assuring the successful outcome of a clinical trial incorporating immunologic parameters however, requires a realistic approach to protocol development, care in site selection, and a critical evaluation of participating laboratories.

Clinical Trials as Topic↗
PubMed1996

Effect of food on the relative bioavailability of oral ganciclovir.

The steady-state pharmacokinetics of oral ganciclovir in the fasting versus fed state were studied in 20 patients infected with human immunodeficiency virus and with a seropositive test result for cytomegalovirus in a two-way crossover study. Patients received oral ganciclovir at a dose of 1000 mg every 8 hours for 8 days. On days 4 and 8, subjects were randomly assigned to receive the morning dose either after an overnight fast or after a standardized 602-calorie, high-fat (46.5%) breakfast. Serial blood samples were obtained over the 8-hour morning dose interval. The mean time to maximum concentration (tmax) was increased from 1.8 hours in the fasting state to 3.0 hours in the fed state. Mean maximum serum concentration (Cmax) and area under the concentration-time curve from time 0 to 8 hours (AUC0-8) of ganciclovir were significantly higher in the fed state than after an overnight fast. Because food could potentially increase the bioavailability of oral ganciclovir, patients should be instructed to take each dose of oral ganciclovir with food.

Administration, Oral↗
PubMed1994

Phase I study of recombinant interleukin-1 beta in patients undergoing autologous bone marrow transplant for acute myelogenous leukemia.

A phase I trial was conducted with recombinant human interleukin-1 beta (rhIL-1 beta) in patients undergoing autologous bone marrow (BM) transplantation for acute myelogenous leukemia. rhIL-1 beta was administered at 3 dose levels (0.01, 0.02, 0.05 microgram/kg) by 30 minute intravenous infusion once a day beginning on the day of BM infusion and continuing for a total of 5 doses. A total of 17 patients were entered on the trial, and their results were compared with those of 74 consecutive historical control patients that did not receive colony stimulating factors. Moderate toxicity was observed in all patients. All 17 patients developed fever and chills within 30 minutes after initiation of rhIL-1 beta, and hypotension was observed in 14 of 17 patients 5 to 8 hours after the infusion. A total of 30% of patients required therapy (normal saline or dopamine) for treatment of hypotension. Therefore, dose escalation was discontinued at the 0.05 microgram/kg dose level. The number of days required to achieve an absolute neutrophil count greater than 500 mL in patients who received rhIL-1 beta was less than in historical patients (25 v 34; P = .02). This appeared to correlate with a reduced incidence of infection between days 0 and 28 after BM infusion (12% v 23%; P = .049). Median bilirubin, median creatinine, platelet recovery, and days in the hospital were not different between study patients and historical controls. Survival of patients who received rhIL-1 beta compared with that of historical patients was improved (30% v 20%; P = .04). These possible benefits were achieved at the cost of moderate toxicity during rhIL-1 beta administration.

Adolescent↗
PubMed1993

Ganciclovir prophylaxis of cytomegalovirus infection and disease in allogeneic bone marrow transplant recipients. Results of a placebo-controlled, double-blind trial.

OBJECTIVE: To evaluate the efficacy and safety of ganciclovir for prevention of cytomegalovirus (CMV) infection and disease. DESIGN: A randomized, placebo-controlled, double-blind trial. SETTING: University-affiliated bone marrow transplant center. PATIENTS: Cytomegalovirus-seropositive allogeneic bone marrow transplant recipients. INTERVENTIONS: Random assignment to receive either a placebo or ganciclovir at a dose of 2.5 mg/kg body weight every 8 hours for 1 week before transplant and then at a dose of 6 mg/kg once per day, Monday through Friday, after transplant when the post-transplant neutrophil count reached 1.0 x 10(9)/L. MEASUREMENTS: Cytomegalovirus infection (positive culture, seroconversion, positive histologic findings), CMV disease (pneumonia, gastroenteritis, the wasting syndrome), and study-drug toxicity. RESULTS: Cytomegalovirus infection developed in 25 of 45 placebo patients (56%) but in only 8 of 40 ganciclovir patients (20%) (P < 0.001). Cytomegalovirus disease may also have occurred less often in the ganciclovir patients (4 of 40 patients [10%] versus 11 of 45 patients [24%]; P = 0.09). The probability of CMV disease occurring within the first 120 days after transplantation was 0.29 among the placebo patients but only 0.12 among ganciclovir patients (P = 0.06). Reversible neutropenia was the only appreciable toxicity related to ganciclovir and required interruption of the study drug after transplant in 25 of 43 ganciclovir patients (58%) and in 13 of 47 placebo patients (28%) (P = 0.005). Overall survival was similar in both the placebo patients (29 of 45 [64%]) and ganciclovir patients (28 of 40 [70%]; P > 0.2). CONCLUSIONS: Prophylactic ganciclovir, started before transplant and continued after recovery of the post-transplant neutrophil count, reduces the incidence and severity of CMV infection in CMV-sero-positive bone marrow transplant recipients but is frequently associated with neutropenia.

Adolescent↗
PubMed1991

Early treatment with ganciclovir to prevent cytomegalovirus disease after allogeneic bone marrow transplantation.

BACKGROUND: Cytomegalovirus (CMV) infection is a major cause of morbidity and mortality after allogeneic bone marrow transplantation. We conducted a controlled trial of ganciclovir for the early treatment of CMV infection in asymptomatic recipients of bone marrow transplants whose surveillance cultures for CMV became positive. METHODS: Bone marrow--allograft recipients who were seropositive for CMV antibodies or who received seropositive marrow were screened for CMV excretion by culture of throat swabs, blood, urine, or bronchoalveolar-lavage fluid. In this double-blind trial, 72 patients who had marrow engraftment and were excreting virus were randomly assigned to receive either placebo or ganciclovir (5 mg per kilogram of body weight twice a day for one week, followed by 5 mg per kilogram per day) for the first 100 days after transplantation. Patients were followed for the development of biopsy-confirmed CMV disease, ganciclovir-related toxicity, and survival. RESULTS: Between assignment to the study drug and day 100 after transplantation, CMV disease developed in only 1 of the 37 patients assigned to receive ganciclovir (3 percent), but in 15 of the 35 patients assigned to receive placebo (43 percent, P less than 0.00001). The ganciclovir recipients had rapid suppression of virus excretion; 85 percent had negative cultures after one week of treatment, as compared with 44 percent of the placebo group (P = 0.001). The principal toxic reaction was neutropenia; 11 ganciclovir recipients had an absolute neutrophil count below 0.75 x 10(9) per liter, as compared with 3 placebo recipients (P = 0.052). Treatment was discontinued in 11 ganciclovir recipients and 1 placebo recipient because of neutropenia (P = 0.003). After treatment was stopped, the neutrophil count recovered in all patients. Overall survival was significantly greater in the ganciclovir group than in the placebo group both 100 days and 180 days after transplantation (P = 0.041 and 0.027, respectively). CONCLUSIONS: Early treatment with ganciclovir in patients with positive surveillance cultures reduces the incidence of CMV disease and improves survival after allogeneic bone marrow transplantation.

Adolescent↗
PubMed1991

Prevalence of resistance in patients receiving ganciclovir for serious cytomegalovirus infection.

Seventy-two AIDS patients treated with ganciclovir for cytomegalovirus (CMV) disease were prospectively monitored for the development of drug-resistant virus. No resistant strains were found in 31 patients before therapy or among seven culture-positive patients treated for less than or equal to 3 months. Of 13 culture-positive patients treated for greater than or equal to 3 months, 5 excreted virus resistant (ED50, greater than 12 microM, or ED90, greater than 30 microM) to ganciclovir. Thus, 38% of patients and receiving ganciclovir for greater than 3 months and excreting virus or, overall, 7.6% of the patients were excreting CMV resistant to the drug.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Preliminary report: effects of interleukin-1 on platelet counts.

Recombinant human interleukin-1 beta was given in 5 daily intravenous infusions to ten patients with metastatic malignant disorders as part of an antineoplastic trial. All ten patients experienced transient increases in heart rate, low-grade fevers, and rigors. A neutrophil-dominated 100% rise in leucocyte counts occurred 4-8 h after treatment. Leucocyte counts returned to baseline levels within 24 h of interleukin-1 beta infusion. A 50% rise in platelets occurred in response to interleukin-1 beta; the increase in platelet counts was first noted 6 days after treatment began and was sustained for 24 days after treatment. Interleukin-1 beta may therefore be beneficial in the treatment of conditions of thrombocytopenia associated with haematological disorders and chemotherapy for malignant disorders.

Adult↗
PubMed1989

A controlled retrospective study of ganciclovir treatment for cytomegalovirus retinopathy. Use of a standardized system for the assessment of disease outcome. UCLA CMV Retinopathy. Study Group.

To evaluate more accurately the clinical response of cytomegalovirus retinopathy to ganciclovir, a system for the assessment of disease outcome was developed that uses retinal photographs and three factors: development of new lesions, enlargement of preexisting lesions, and change in retinal opacification of lesion borders. With this system a retrospective comparison was performed of 24 ganciclovir-treated patients and 17 untreated patients with cytomegalovirus retinopathy. A masked assessment showed disease progression in 10 treated patients (43%) during a median period of 22 days. In contrast, 16 untreated patients (94%) had progression of disease during a median period of 25 days. Comparison of treated and untreated eyes also suggests that treatment may prevent deterioration of visual acuity during the same period. This study supports the conclusions of previous uncontrolled studies that ganciclovir is beneficial in the treatment of patients with acquired immunodeficiency syndrome and cytomegalovirus retinopathy. It also demonstrates the utility of the proposed system for assessment of disease outcome that can be used in future studies of therapy for necrotizing viral retinopathies.

Acquired Immunodeficiency Syndrome↗
PubMed1981

Yersinia pseudotuberculosis infection: study of an epizootic in squirrel monkeys.

An epizootic of an acutely fatal enteric disease in a colony of squirrel monkeys (Saimiri sciureus) was attributed to infection by Yersinia pseudotuberculosis serotype III. Of a total adult population of 96 animals at risk, there were six fatal cases of yersiniosis. Serological evaluation of the colony just after the outbreak ended revealed that 22 of 60 monkeys tested (37%) had significant antibody to Y. pseudotuberculosis (microagglutination titer of greater than or equal to 1:80) but did not have clinical disease. The outstanding pathological lesions noted in dying monkeys were acute, purulent, necrotic and focal enteritis primarily affecting the jejunum and ileum and focal hepatic necrosis and abscessation. Y. pseudotuberculosis was isolated from the organs of two of the dying monkeys. Using cold enrichment techniques, Yersinia was also isolated from the feces of two apparently healthy monkeys (both seropositive), from the spleen of a monkey dying of other causes, and from the colon contents of a stillborn squirrel monkey baby. All isolates had the same biotype and serotype. An episode of abortions was associated both temporally and spatially with the fatal cases of yersiniosis, and Y. pseudotuberculosis was cultured from the uterus of two of the dying monkeys, suggesting that yersinia infection may be associated with abortion, as well as with enteric infection, in these animals.

Abortion, Veterinary↗
PubMed1978

Increased bone marrow production of granulocytes and mononuclear phagocytes induced by mycobacterial adjuvants: improved recovery of leukopoiesis in mice after cyclophosphamide treatment.

The effects of complete Freund adjuvant (CFA) or Mycobacterium bovis BCG on leukopoiesis and on leukopoietic recovery from cyclophosphamide treatment in mice was studied. CFA injected subcutaneously or intraperitoneally resulted in increased blood granulocyte and monocyte counts, increased numbers of bone marrow granulocyte and mononuclear phagocyte progenitors, and increased hematopoietic colony-stimulating factor in the serum. Furthermore, the quantitative cellular response within 24 h to an induced sterile intraperitoneal inflammation (thioglycolate) was augmented by subcutaneous CFA. In mice given CFA subcutaneously, blood granulocyte counts, as well as the peritoneal granulocyte and macrophage response to intraperitoneal thioglycolate, recovered more quickly than did those of the controls after a 250-mg/kg dose of cyclophosphamide. CFA-treated mice consistently maintained blood granulocyte and monocyte counts 1.3-to 4-fold higher than those of the controls for 2 weeks while receiving 75 mg of cyclophosphamide per kg every other day. Mice pretreated with CFA intraperitoneally had higher numbers of bone marrow colony-forming units in culture and higher levels of serum colony-stimulating factor after 250-mg/kg injections of cyclophosphamide. Similarly, BCG resulted in increased bone marrow colony-forming units in culture, increased serum colony-stimulating factor, and a faster return of the peritoneal inflammatory response after cyclophosphamide injection. These results show that mycobacterial adjuvants accelerate recovery of leukopoietic functions after cyclophosphamide treatment and suggest a mechanism whereby such adjuvants afford nonspecific protection against infection in immunosuppressed mice.

Animals↗
PubMed1977

Chemoimmunotherapy for canine lymphosarcoma.

Thirty-two dogs with naturally occurring multicentric lymphosarcoma were randomly assigned to one of two treatment groups. One half of the animals received combination chemotherapy plus vitamin injections (controls) while the other half received indentical chemotherapy plus injections of chemically-modified tumor cell extract in Freund's complete adjuvant (vaccinates). Clinical staging revealed no bias between groups but showed that prognosis could be closely correlated with the severity of disease at initial presentation. Twenty dogs (62%), including 11 vaccinates and 9 controls, responded favorably to chemotherapy and were evaluated for length of first remission and total survival time. Both parameters were significantly longer in vaccinated dogs than in controls. These data suggest that immunological stimulation may be a helpful adjunct to conventional therapy in selected types of cancer when immunological principles are observed.

Animals↗
PubMed1977

Pathogenesis of infection with Rickettsia rickettsii in the dog: a disease model for Rocky Mountain spotted fever.

Dogs inoculated with Rickettsia rickettsii developed a clinical syndrome ranging in severity from a mild febrile exanthema to death within six days after inoculation. The severity of the disease appeared to be dose-related, and the signs were comparable to R. rickettsii infection in humans on a clinical and hematological basis. Dogs were rickettsemic for 10 to 14 days after infection. In most animals the level of rickettsemia was greater than or equal to 10(2.5) guinea pig intraperitoneal 50% infectious doses (GPID50). Infected dogs responded serologically as determined by indirect fluorescent antibody methods and were protected when challenged six to 12 months later with 10(7.0) GPID50 of the homologous strain of R. rickettsii. The monocyte culture technique was successfully used for the detection of rickettsemia, and the results compared favorably with those obtained by the guinea pig inoculation method of isolation.

Animals↗
PubMed1977

Adjuvant protection against bacterial infection in granulocytopenic mice.

The hypothesis that the induction of nonspecific resistance to infection by immunostimulation prior to drug-induced granulocytopenia would afford increased protection to subsequent bacterial challenge was tested in a murine model of infection with Pseudomonas aeruginosa or Staphylococcus aureus in mice rendered granulocytopenic with cyclophosphamide. Prior intraperitoneal immunostimulation of mice with complete Freund's adjuvant (CFA) or Mycobacterium bovis (Bacille Calmette-Guèrin; BCG) increased the 50% lethal dose in mice challenged subcutaneously with P. aeruginosa, but only CFA protected against challenge with S. aureus. The degree of protection was 1-2 log 10. Corynebacterium parvum provided no protection against infection with P. aeruginosa. The protective effect observed with CFA and BCG substantiates our hypothesis and indicates that nonspecific immunostimulation may be of value in protection of granulocytopenic patients from opportunistic infections.

Adjuvants, Immunologic↗
PubMed1977

Studies on the pathogenesis of Rickettsia rickettsii in the dog: clinical and clinicopathologic changes of experimental infection.

Beagle dogs inoculated with the agent of Rocky Mountain spotted fever, Rickettsia rickettsii, developed a clinical syndrome that extended from febrile exanthema to death and appeared to be dose related. Infected dogs were anorectic and lethargic and developed cutaneous lesions characteristic of Rocky Mountain spotted fever, including petechia, ecchymosis, edema, and necrosis. Hematologic changes after inoculation included anemia, leukopenia proceeding to leukocytosis, and thrombocytopenia. Changes in blood chemistry values included increases in serum alkaline phosphatase and cholesterol, and hyponatremia and hypochloremia. The prominent histopathologic change was necrotizing vasculitis. The canine disease is comparable with human Rocky Mountain spotted fever on a clinical, hematologic, biochemical, and pathologic basis, and may provide a model system for this disease in man. The results suggest the dog may be involved in the epidemiology of R rickettsii infections.

Anemia↗