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Biomedical subjects

K M Butler

Publications and source records attributed to K M Butler.

At least 37 records · Page 2Linked to original sources
PubMed1992

Phase I study of continuous-infusion soluble CD4 as a single agent and in combination with oral dideoxyinosine therapy in children with symptomatic human immunodeficiency virus infection.

To determine the safety and pharmacokinetics of recombinant soluble CD4 (sCD4) administered by continuous intravenous infusion to children with symptomatic human immunodeficiency virus type 1 infection, we conducted a phase I study at the National Cancer Institute. Three dose levels of sCD4 were evaluated: 100, 300, and 1000 micrograms/kg per day. After an initial 12 weeks of treatment with sCD4 alone, dideoxyinosine at a dose of 90 mg/m2 every 8 hours was added and subjects were observed for an additional 12 weeks. Combination therapy was continued in patients in whom it was well tolerated. In addition to toxicity and pharmacokinetic monitoring, surrogate markers of antiviral activity were evaluated. Eleven children were enrolled in the study. During the 12 weeks of treatment with sCD4 alone, and during subsequent sCD4 plus dideoxyinosine combination therapy, no significant toxic reaction attributable to sCD4 or dideoxyinosine was encountered. Low-level anti-CD4 antibodies developed in two patients. Steady-state sCD4 levels increased proportionately at higher doses. The CD4 cell counts and serum p24 antigen levels did not provide evidence of antiviral activity. We conclude that sCD4 was well tolerated at doses up to 1000 micrograms/kg per day when administered by continuous intravenous infusion; however, evidence of in vivo antiviral activity was not observed in this study.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Defining the population of human immunodeficiency virus-infected children at risk for Mycobacterium avium-intracellulare infection.

We reviewed the 22 cases of Mycobacterium avium-intracellulare (MAI) infection that occurred among 196 human immunodeficiency virus-infected children seen at the National Cancer Institute Pediatric Branch from December 1986 through April 1991, and an additional 65 charts from children with cultures negative for MAI. All patients with proven MAI were receiving antiretroviral therapy with zidovudine, dideoxyinosine, or a combination of zidovudine and dideoxycytidine. All patients had disseminated MAI infection, except one adolescent who had only evidence of localized lymphadenitis. All cases of MAI but one were diagnosed before death. The overall incidence of MAI was 11% in our patients but increased to 24% in patients whose absolute CD4 cell counts were < 100 cells/mm3. Symptoms most commonly associated with MAI infection included recurrent fever (86% of patients), weight loss or failure to thrive (64%), neutropenia (55%), night sweats (32%), and abdominal pain (27%). Children infected with MAI had a mean CD4 percentage of 2% (range, 0% to 7%) and a mean absolute CD4 count of 12 cells/mm3 (range, 0 to 48 cells/mm3), significantly lower than in the remainder of the clinic population or the group of children with cultures negative for MAI. Of 20 patients with MAI infection who were tested, 10 had measurable p24 antigen with a mean value 939 pg/ml (range, 77 to 3270 pg/ml) compared with 19 of 59 patients without MAI infection in whom the mean positive value was 413 pg/ml. There was no difference in survival time between those children with documented MAI infection (median survival time, 45.5 weeks) and those with similarly low CD4 counts and cultures negative for MAI (median survival time, 50.4 weeks). Future improvements in therapeutic options may make screening of pediatric human immunodeficiency virus-infected patients with low CD4 counts a reasonable plan.

AIDS-Related Opportunistic Infections↗
PubMed1992

Combination treatment with azidothymidine and granulocyte colony-stimulating factor in children with human immunodeficiency virus infection.

Bone marrow suppression is the major dose-limiting toxic effect of zidovudine (azidothymidine; AZT) in children with human immunodeficiency virus infection. We evaluated the effect of subcutaneously administered granulocyte colony-stimulating factor (G-CSF) in pediatric patients whose absolute neutrophil count was less than 0.8 x 10(9)/L during AZT therapy despite dosage reductions to 120 mg/m2 every 6 hours. Nineteen patients between 6 months and 20 years of age were treated with AZT and G-CSF and monitored for 2 to 12 months. All had previously shown improvement while receiving AZT but had required dosage reduction or discontinuation. By using a sliding dosing schedule of G-CSF, we attempted to maintain the absolute neutrophil count between 1.5 and 5.0 x 10(9)/L. Administration of G-CSF resulted in a significant increase in the median leukocyte count (2.0 x 10(9)/L to 4.14 x 10(9)/L; p = 0.004), and the median absolute neutrophil count (1.02 x 10(9)/L to 2.96 x 10(9)/L; p = 0.0006). G-CSF was well tolerated, but mild thrombocytopenia developed in nine children. Administration of G-CSF and AZT was discontinued in two patients because of continuing neutropenia. With doses of G-CSF ranging from 1 to 20 micrograms/kg per day, 17 of 19 patients were able to tolerate AZT at a dose of 120 to 180 mg/m2 every 6 hours. We conclude that G-CSF therapy enables patients who have had AZT-related neutropenia to receive therapeutic doses of AZT.

Adolescent↗
PubMed1992

Clinical pharmacology of 2',3'-dideoxyinosine in human immunodeficiency virus-infected children.

The pharmacokinetics of intravenous and oral 2',3'-dideoxyinosine (ddI) and the relationships between pharmacokinetic parameters and measures of response were studied in 48 human immunodeficiency virus-infected children. Disappearance of ddI from plasma after the intravenous dose was rapid and biexponential, with half-lives of 12 min and 1.0 h and a total clearance of 510 +/- 180 ml/min/m2. After oral administration, ddI absorption was limited and variable (mean bioavailability, 19% +/- 17%). A plasma ddI concentration-response relationship was observed for both decline in viral p24 antigen levels and improvement in intelligence quotient score. A limited sampling model was developed that accurately predicts the area under the ddI plasma concentration-time curve from one to three plasma samples. Although this pharmacokinetic study was done in children, the results also have relevance to adults and suggest that individualization of dose and schedule through therapeutic drug monitoring may be necessary to achieve optimal response.

Absorption↗
PubMed1992

Pseudomonas infections in children with human immunodeficiency virus infection.

Thirteen bacteremias and 25 nonbacteremic infections caused by Pseudomonas spp. occurred in 22 of 236 children with human immunodeficiency virus infection with a rate of infection of 0.098 (bacteremia, 0.030) per patient year. Four patients were neutropenic (less than 500/microliters). Central venous catheter (CVC)-related infections were most frequent (n = 20) followed by otitis externa (n = 6) and pneumonia (n = 5). Pseudomonas aeruginosa was the most common isolate and caused both CVC-related and CVC-unrelated infections, whereas other Pseudomonas spp. and Xanthomonas maltophilia were almost exclusively associated with CVC-related infections. The children who received appropriate therapy had a favorable outcome. In 7 CVC-related infections (35%) the catheter was removed. Pseudomonas spp. are of increasing importance in human immunodeficiency virus-infected children causing significant morbidity and increased hospitalization. These infections may be life-threatening if appropriate therapy is not vigorously initiated.

Adolescent↗
PubMed1991

Dideoxyinosine in children with symptomatic human immunodeficiency virus infection.

BACKGROUND: 2',3'-Dideoxyinosine (ddl) is a dideoxynucleoside with potent activity in vitro against the human immunodeficiency virus (HIV). In initial clinical trials in adults, ddl showed evidence of antiretroviral activity with little hematologic toxicity. METHODS: We conducted a phase I-II study in 43 children with symptomatic (CDC class P-2) HIV infection. Of these children, 16 (median age, 10 years) had previously received zidovudine, and 27 (median age, 2.6 years) had not. ddl was administered orally in three divided doses totalling 60, 120, 180, 360, or 540 mg per square meter of body-surface area per day for 24 weeks. Eight of the 43 patients did not complete 24 weeks of ddl: 6 died, 1 was withdrawn because of progressive disease, and the other because of toxicity. RESULTS: After oral administration, ddl was rapidly absorbed, although its bioavailability varied greatly among patients. Pancreatitis developed in two children, one receiving ddl at each of the two highest doses. The median CD4 cell count in 38 patients with paired counts increased from 0.218 x 10(9) per liter (218 per cubic millimeter) at base line to 0.327 x 10(9) per liter (327 per cubic millimeter) after 20 to 24 weeks (P = 0.001). Those with CD4 cell counts above 0.1 x 10(9) per liter (100 per cubic millimeter) at base line were significantly more likely to improve in this respect. The median levels of p24 antigen (in 27 patients with detectable levels at entry) declined from 272 pg per milliliter at base line to 77 pg per milliliter at 20 to 24 weeks (P = 0.005). The plasma concentration of ddl correlated significantly with both the degree of decline in the p24 antigen and the degree of improvement in IQ score. Improvement in clinical and immunologic measures occurred in both the previously untreated patients and in those who had been treated with zidovudine. CONCLUSIONS: Dideoxyinosine was well tolerated and showed promising antiretroviral activity in HIV-infected children. The correlation between the clinical response and the plasma concentration of ddl indicates that bioavailability is an important consideration in the use of ddl to treat HIV infection and that individualized pharmacokinetic monitoring and dose adjustment may be important for optimal activity.

Administration, Oral↗
PubMed1989

Penetration of cefuroxime into ventricular fluid in cerebrospinal fluid shunt infections.

The penetration of intravenously administered cefuroxime into ventricular fluid was assessed in five pediatric patients with ventriculoperitoneal shunt infections and in one with a ventriculostomy infection. Patients received a total dose of 200 to 230 mg of cefuroxime per kg of body weight per day administered at 8-h intervals. Levels of cefuroxime in ventricular fluid ranged from 1.6 to 22.5 micrograms/ml and were associated with cerebrospinal fluid bactericidal titers ranging from less than 1:2 to 1:16 against infecting staphylococcal isolates. Five infections were cured with cefuroxime monotherapy. On the basis of MIC data, one patient had vancomycin substituted for cefuroxime and the infection was cured.

Adolescent↗
PubMed1988

Candida: an increasingly important pathogen in the nursery.

Advances in neonatal care now permit the survival of very immature infants. Although candidiasis is not a new disease, the spectrum of clinical disease has greatly widened and the rate of invasive disease has increased significantly. This article reviews the history, microbiology, and epidemiology of candidal infections, both superficial and invasive. Particular attention is paid to the pathogenesis of and risk factors associated with the development of invasive disease, as well as its clinical manifestations, diagnosis, and treatment.

Candidiasis↗
PubMed1988

Group F Streptococcus. An unusual cause of arthritis.

Bacterial arthritis is a serious infection in children occurring either as the result of direct inoculation of organisms into the joint space, of spreading from a contiguous focus of infection, or of hematogenous seeding of the synovium. Although the etiologic agent can be identified in 60% to 70% of cases, joint fluid cultures may remain negative in a substantial number of patients. The most likely etiologic agent depends both on the route of infection and the age of the child. Overall Staphylococcus aureus, Hemophilus influenzae type b and streptococci are the leading causes of bacterial arthritis. Lancefield groups A, B, C, D, and G have all been implicated. However, septic arthritis due to hematogenous seeding with Group F Streptococcus has not been previously reported. A normal 10-month-old boy presented with acute monoarticular arthritis of the knee and had Group F Streptococcus isolated from the blood. Antimicrobial therapy resulted in complete resolution of the arthritis.

Arthritis, Infectious↗
PubMed1987

Interaction of soluble fibronectin with group B streptococci.

Fibronectin binds to a variety of bacterial species, and we hypothesized that differential fibronectin binding might influence the invasive potential of group B streptococci (GBS). Human plasma fibronectin purified by a standard two-step chromatographic procedure was radiolabeled with 3H. Fifty GBS strains (invasive, colonizing, or bovine) representing serotypes Ia (10 strains), Ib (6 strains), Ia/c (6 strains), II (10 strains), III (11 strains), IV (1 strain), and nontypable (6 strains) were tested. No source or serotype variability was detected among GBS strains, and binding was uniformly less than 1.5% of available fibronectin. Lack of detectable binding occurred at both the log and stationary growth phases and persisted despite treatment with trypsin or neuraminidase or opsonization with immunoglobulin G containing high levels (greater than 40 micrograms/ml) of antibody specific for the Ia, II, or III GBS capsular polysaccharides. Incubation with GBS did not inhibit fibronectin binding to the Cowan 1 strain of Staphylococcus aureus. Strain COH 31-15, an isogenic, type III, capsule-deficient mutant of COH 31r/s, also failed to bind fibronectin. In contrast to other streptococci, GBS do not have readily detectable receptors for soluble fibronectin as part of their surface structures. If present, binding sites for soluble fibronectin are deep to surface structures, obscured from host defense systems, or require the presence of other factors to facilitate their recognition of fibronectin. The uniform ability of GBS to resist binding to soluble fibronectin could be a significant virulence factor in the pathogenesis of invasive infections of infants.

Chromatography, Affinity↗
PubMed1986

A trial of prophylactic thiotepa or mitomycin C intravesical therapy in patients with recurrent or multiple superficial bladder cancers.

There were 40 consecutive patients with recurrent or multiple superficial stage Ta or T1 transitional cell cancer assigned randomly to receive prophylactic thiotepa or mitomycin C intravesical chemotherapy. Patients received 8 weekly instillations followed by 22 monthly treatments of either 60 mg. thiotepa or 40 mg. mitomycin C. Of 25 patients randomized to receive mitomycin C 4 had recurrence in a total of 337 patient-months (1.19 per 100 patient-months), while disease recurred in 1 of 15 patients randomized to receive thiotepa who were followed for a total of 220 patient-months (0.45 per 100 patient-months). No significant difference in recurrence rate was noted for either drug group (p equals 0.18). Toxicity requiring cessation of therapy was observed in 7 patients (28 per cent) on mitomycin C and none on thiotepa.

Carcinoma, Transitional Cell↗
PubMed1985

Comparison of epsilon aminocaproic acid and normal saline for postoperative bladder irrigation following transurethral resection of prostate.

A prospective, randomized, double-blind trial of bladder irrigation with a 0.5% solution of epsilon aminocaproic acid (EACA) versus normal saline plus placebo was undertaken in 75 patients undergoing transurethral resection of the prostate for benign or malignant disease. Systemic absorption after irrigation with EACA was not detectable. No significant advantage, however, was demonstrated for the EACA solution over normal saline irrigation in measured postoperative blood loss, irrigant volume, hours of catheterization, or length of hospital stay.

Aminocaproates↗