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Biomedical subjects

W T Hughes

Publications and source records attributed to W T Hughes.

At least 19 recordsLinked to original sources
PubMed1998

Use of dapsone in the prevention and treatment of Pneumocystis carinii pneumonia: a review.

Dapsone, with or without trimethoprim or pyrimethamine, has strong anti-Pneumocystis carinii activity, as demonstrated by in vitro methods, animal studies, and clinical trials. The drug blocks folic acid synthesis of P. carinii by inhibition of dihydropteroate synthetase activity. Dapsone is efficiently absorbed (70%-80%) from the gastrointestinal tract, reaches peak serum concentration in 2-6 hours, and is adequately distributed to the fluid of the alveolar spaces. Synergistic effects against P. carinii are noted when trimethoprim is combined with dapsone. This combination is recommended for therapeutic use for P. carinii pneumonia (PCP) as an alternative for patients who cannot take trimethoprim-sulfamethoxazole (TMP-SMZ). Evidence from more than 40 studies of dapsone as prophylaxis for PCP in AIDS patients shows that dapsone, either alone or in combination with pyrimethamine, is as effective as aerosolized pentamidine or atovaquone but slightly less effective than TMP-SMZ. Adverse effects include rash, anemia, methemoglobinemia, agranulocytosis, and hepatic dysfunction. Desensitization can be accomplished with many cases. Dapsone is the most cost-effective prophylaxis currently available for PCP.

Animals↗
PubMed1998

Effects of aerosolized synthetic surfactant, atovaquone, and the combination of these on murine Pneumocystis carinii pneumonia.

An immunosuppressed rat model was used to determine the pharmacokinetics of aerosolized atovaquone (administered with and without a synthetic surfactant) and to evaluate the efficacy of inhaled atovaquone in the prevention and treatment of Pneumocystis carinii pneumonia (PCP). After a single dose by aerosol, mean peak concentrations of atovaquone averaged 52 microg/mL in plasma and 31 microg/g in lungs of rats infected with P. carinii. When atovaquone was combined with surfactant, mean peak concentrations of 94 microg/mL in plasma and 51 microg/g in lung were achieved. Aerosolized synthetic surfactant alone significantly increased survival of rats with PCP and, when combined with atovaquone, increased plasma and lung concentrations of the drug and eradication of the organism.

Administration, Inhalation↗
PubMed1998

Current issues in the epidemiology, transmission, and reactivation of Pneumocystis carinii.

Issues related to the epidemiology, transmission, and reactivation of Pneumocystis carinii remain controversial. In this article, current studies related to geographic variations in the prevalence of P. carinii pneumonia are reviewed. In addition, extensive investigations show that exposure to P. carinii occurs early in life, followed by seemingly complete clearance of the organisms. Recent molecular techniques show that P. carinii pneumonia during periods of immune suppression can occur either by reactivation or by acquisition of new organisms. These studies are analyzed and a composite model of P. carinii infection is proposed.

Disease Transmission, Infectious↗
PubMed1997

Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia.

BACKGROUND: Recombinant human granulocyte colony-stimulating factor PO1 CA-20180ilgrastim) hastens the recovery from neutropenia after P30 CA-21765emotherapy, but its role in the management of childhood leukemia is unclear. METHODS: We randomly assigned 164 patients with acute lymphoblastic leukemia (age range, 2 months to 17 years) to receive placebo or G-CSF (10 microg per kilogram of body weight per day subcutaneously), beginning one day after the completion of remission-induction therapy and continuing until the neutrophil count was greater than or equal to 1000 per cubic millimeter for two days. The clinical and laboratory effects of this therapy were documented for 21 days. The area under the plasma G-CSF concentration-time curve was measured on days 1 and 7 in both groups. RESULTS: Responses to the growth factor could be assessed in 148 patients (73 in the G-CSF group and 75 in the placebo group). G-CSF treatment did not significantly lower the rate of hospitalization for febrile neutropenia (58 percent in the G-CSF group vs. 68 percent in the placebo group; relative risk, 0.85; 95 percent confidence interval, 0.59 to 1.16), increase the likelihood of event-free survival at three years (83 percent in both groups), or decrease the number of severe infections (five in the G-CSF group vs. six in the placebo group). Patients treated with G-CSF had shorter median hospital stays (6 days vs. 10 days, P=0.011) and fewer documented infections (12 vs. 27, P=0.009). The median total costs of supportive care were similar in the G-CSF and placebo groups ($8,768 and $8,616, respectively). Among patients who did not have febrile neutropenia during the first week of G-CSF or placebo injections, higher systemic exposure to the growth factor on day 7 was significantly related to a lower probability of subsequent hospitalization (P=0.049). CONCLUSIONS: G-CSF treatment had some clinical benefit in children who received induction chemotherapy for acute lymphoblastic leukemia, but it did not reduce the rate of hospitalization for febrile neutropenia, prolong survival, or reduce the cost of supportive care.

Adolescent↗
PubMed1997

1997 guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Infectious Diseases Society of America.

This is the first in a series of practice guidelines commissioned by the Infectious Diseases Society of America through its Practice Guidelines Committee. The purpose of these guidelines is to provide assistance to clinicians when making decisions on treating the conditions specified in each guideline. The targeted providers are internists, pediatricians, and family practitioners. The targeted patients and setting for the fever and neutropenia guideline are hospitalized individuals with neutropenia secondary to cancer chemotherapy. Panel members represented experts in adult and pediatric infectious diseases and oncology. The guidelines are evidence-based. A standard ranking system was used for the strength of the recommendations and the quality of the evidence cited in the literature reviewed. The document has been subjected to external review by peer reviewers as well as by the Practice Guidelines Committee and was approved by the IDSA Council. An executive summary, algorithms, and tables highlight the major recommendations. The guideline will be listed on the IDSA home page at http://www.idsociety.org.

Adult↗
PubMed1997

Novel anti-Pneumocystis carinii effects of the immunosuppressant mycophenolate mofetil in contrast to provocative effects of tacrolimus, sirolimus, and dexamethasone.

The effects of three new immunosuppressive drugs used for organ transplantation, mycophenolate mofetil, tacrolimus, and sirolimus, were compared with those of dexamethasone in provocation of Pneumocystis carinii pneumonitis in virus-free Sprague-Dawley rats. Rats injected daily with tacrolimus showed a dose-related response to the point of severe P. carinii pneumonitis 4 weeks after initiation of drug administration identical to those animals treated with high-dose dexamethasone. Thirty percent of rats treated with sirolimus had mild P. carinii infection. Surprisingly, mycophenolate mofetil had an anti-P. carinii effect. None of the animals had discernible P. carinii infection when treated with mycophenolate mofetil alone or combined with dexamethasone. Mycophenolate mofetil is unique because of its dual activity as a potent immunosuppressant as well as an antimicrobial with action against P. carinii.

Animals↗
PubMed1997

Efficacy of lasalocid against murine Pneumocystis carinii pneumonitis.

The efficacy of the ionophore lasalocid against Pneumocystis carinii pneumonitis in corticosteroid-immunosuppressed Sprague-Dawley rats was investigated. Lasalocid was effective in the prevention of the pneumonitis in a dose-dependent manner. At dosages of 0, 5, 10, and 20 mg/kg/day, P. carinii infection rates were 92, 60, 20, and 0%, respectively, during dexamethasone immunosuppression. Also, lasalocid compared favorably with other drugs known to have anti-P. carinii activity, including trimethoprim-sulfamethoxazole, atovaquone, and dapsone-trimethoprim.

Animals↗
PubMed1997

Pneumocystis carinii infection alters GTP-binding proteins in the lung.

The GTP-binding regulatory proteins (G proteins) in the membranes of the lung parenchyma from normal, uninfected ferrets were compared to those from immunosuppressed animals with and without Pneumocystis carinii pneumonitis. In lung membranes, pertussis toxin (PT) catalyzed ADP ribosylation of a 41-kDa protein; treatment with cholera toxin (CT) led to ribosylation of a 44-kDa polypeptide. Compared to that in the normal ferrets, the level of the 44-kDa protein was dramatically suppressed in the P. carinii-infected animals. Western blot analysis with specific antibodies to alpha s (which recognized CT substrates), alpha common (which reacted to PT substrates), the alpha q/11 epitope, and the beta subunit demonstrated that these proteins were decreased in animals with P. carinii pneumonitis (PCP). Western blotting of PCP-free membranes with a pan-Ras antibody revealed a 21-kDa polypeptide (corresponding to small G proteins). The level of the 21-kDa protein in membranes from PCP-affected animals was only 30% of that in membranes from PCP-free animals. Finally, analogous studies performed with rat lung membranes revealed similar findings. These data suggest that, independent of its exacerbation of immunosuppression, PCP leads to extensive changes in the GTP-binding proteins in the lung.

Adenosine Diphosphate↗
PubMed1996

Acute fulminating babesiosis in hamsters infected with Babesia microti.

In this study, Babesia microti (ATCC30222) from mice was adapted to golden hamsters. The parasite was passaged to immunosuppressed and then adapted to normal hamsters. When 30 normal hamsters were inoculated with this strain, parasitaemia increased to 74% of erythrocytes by day 7 and 70% of the hamsters died. By day 12, parasitaemia extended to 90%, with 97% mortality. Hearts and kidneys from infected animals were enlarged. Histopathology revealed acute myocarditis, hepatitis, pneumonitis, glomerulonephritis and splenomegaly. Giemsa, Acridine Orange and Rhodamine staining of the parasite were compared. Scanning electron microscopy of blood from infected hamsters revealed from 1 to 5 intra-erythrocytic parasites.

Acute Disease↗
PubMed1996

Monodrug efficacies of sulfonamides in prophylaxis for Pneumocystis carinii pneumonia.

A remarkably high rate of adverse events is associated with the use of trimethoprim-sulfamethoxazole in patients with human immunodeficiency virus type 1 infection. We examined the efficacies of sulfonamides alone in the prevention of Pneumocystis carinii pneumonitis, with the assumption that at least some of the adverse events with the drug combination might be due to trimethoprim. With the immunosuppressed rat model, eight sulfonamides were studied at 100, 10, and 1.0 mg/kg/day (10 rats per dosage and drug). P. carinii infection was prevented in all animals (100%) receiving dosages of as little as 1.0 mg of sulfamethoxazole, sulfamethoxypyridazine, and sulfadimethoxine per kg per day, as little as 10 mg of sulfameter, sulfachlorpyridazine, and sulfaquinoxaline per kg per day; and 100 mg of sulfaguanidine and sulfanilamide per kg per day. These studies suggest that a sulfonamide, such as sulfamethoxazole, might provide effective prophylaxis for P. carinii pneumonitis without trimethoprim.

Animals↗
PubMed1996

Search for extrapulmonary Pneumocystis carinii in an animal model.

Pneumocystis carinii-infected immunosuppressed ferrets and rats were searched for P. carinii cysts and trophozoites in extrapulmonary organs, including the heart, liver, stomach, kidney, and spleen. Foci of P. carinii were found in the liver or kidney of 4 (10%) of 40 ferrets but in no extrapulmonary sites of 30 rats with P. carinii pneumonitis. Attempts to identify P. carinii from immunosuppressed rat or ferret blood or propagate the organism intraorbitally in immunosuppressed rats were unsuccessful. Pneumocystis carinii was identified from aspirated stomach contents of ferrets but in none of the rats infected with P. carinii pneumonitis.

Animals↗