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Biomedical subjects

R Saral

Publications and source records attributed to R Saral.

At least 91 records · Page 5Linked to original sources
PubMed1986

Infection management during antileukemia treatment-induced granulocytopenia: the role for oral norfloxacin prophylaxis against infections arising from the gastrointestinal tract.

Aerobic gram negative bacterial infections occur commonly in patients with acute leukemia undergoing intensive chemotherapy-induced bone marrow aplasia, and often arise from the gastrointestinal (GI) tract. The value of oral prophylactic norfloxacin (400 mg every 12 hours) in preventing bacterial infections was determined for 68 adults with acute leukemia by a prospective, randomized, double-blind, placebo-controlled trial. The efficacy of norfloxacin administered prophylactically throughout the course of intensive therapy and deep (less than 100 mm/3), prolonged (median 32 day) granulocytopenia against infections arising from the GI tract was demonstrated by its impact on the clinical manifestations of infection, microbiologically documented gram negative bacterial infections, overall antibiotic management, and GI colonization. Although there was no difference with respect to survival, norfloxacin decreased overall morbidity associated with gram-negative infections, was well tolerated, did not impinge on systemic antibacterial or antitumor therapy, and did not predispose to the development of bacteria resistant either to itself or to multiple other antibiotics. The advantages of norfloxacin relative to other oral agents used for GI prophylaxis and the potential beneficial effects of norfloxacin or overall medical cost are discussed. Oral norfloxacin achieves the goals of GI prophylaxis by effectively suppressing early infection arising from the GI tract and inhibiting GI colonization by multiply resistant pathogens that could give rise to late-onset infections during profound chemotherapy-induced bone marrow aplasia.

Acute Disease↗
PubMed1985

Suppression of thyrotropin in the low-thyroxine state of severe nonthyroidal illness.

In a prospective study, we assessed the role of thyrotropin in the development of the low-thyroxine state that is associated with severe illness. We measured the serum thyrotropin and thyroid hormone concentrations longitudinally in 35 patients with hematopoietic cancer or aplastic anemia who were treated by bone-marrow transplantation. In 19 patients thyroxine declined sharply after bone-marrow transplantation and was associated with a reduction of the serum thyrotropin in the 17 patients tested, often to levels below the normal range. The serum triiodothyronine level, free thyroxine index, and free thyroxine level also declined in these patients. In the patients who recovered, clinical improvement was accompanied by the return of thyrotropin and thyroid hormone concentrations to their pretreatment ranges. These and related findings suggest that the low-thyroxine state of severe illness is the result of several events, one of which is failure of the normal negative-feedback control of the pituitary-thyroid axis due to illness-associated, decreased secretion of thyrotropin. The notion that such patients are "euthyroid" must be questioned, but the possible value of thyroid hormone-replacement therapy in these circumstances remains to be determined.

Adolescent↗
PubMed1985

Direct detection of the human papovavirus BK in urine of bone marrow transplant recipients: comparison of DNA hybridization with ELISA.

Urine specimens from bone marrow transplant (BMT) recipients and from controls were directly tested for BK virus (BKV) DNA sequences by dot hybridization and for BKV antigen by a double-antibody indirect ELISA. A total of 158 specimens from 55 BMT patients (57 collected prior to or at the time of transplantation and 101 in the posttransplant period) and single urines from 125 control subjects were examined by both methods. A molecularly cloned, 32P-labelled BKV probe was hybridized with urine sediments that were spotted directly on nitrocellulose filters and denatured in situ. BKV DNA sequences were detected in 1 (1.8%) pretransplant and 22 (21.8%) posttransplant urines of BMT patients, and in none of control urines. In ELISA of urine supernatants, BKV antigen was detected in 1 (1.8%) pretransplant and 21 (20.8%) posttransplant urines of BMT patients and in 1 (0.8%) of the control urines. The results of the two tests correlated as follows: 16 urines were positive and 253 urines negative by both methods; seven specimens were positive by DNA hybridization only and seven were positive by ELISA alone. Virus excretion in urine was demonstrated in 20 (36.4%) patients by DNA hybridization, in 19 (34.5%) patients by ELISA, in 15 (27.3%) patients by both methods, and in 24 (44%) patients by at least one of the two tests.

Adolescent↗
PubMed1985

Drug resistance patterns of herpes simplex virus isolates from patients treated with acyclovir.

A decrease in the in vitro sensitivity to acyclovir (ACV) was observed in successive isolates of herpes simplex virus type 1 from three immunocompromised patients during intravenous therapy with this drug. The ACV-resistant isolate from patient 1 was cross-resistant to dihydroxypropoxymethylguanine and bromovinyldeoxyuridine, but still susceptible to three fluoro-substituted pyrimidines, 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine (FIAC), 2'-fluoro-5-iodo-1-beta-D-arabinofuranosyluracil (FIAU), and 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylthymine (FMAU). The thymidine kinase (TK) from the resistant isolate showed a 50-fold or greater reduction in affinity for thymidine, FIAU, FMAU, and ACV, but the total enzyme activity was similar to that of the sensitive isolate. The ACV-resistant isolate from patient 2 was also resistant to dihydroxypropoxymethylguanine, bromovinyldeoxyuridine, and the fluoro-substituted compounds; TK activity for this isolate was less than 1% of the patient's pretherapy isolate. An isolate obtained during a subsequent recurrence in patient 2 was susceptible to ACV and the other TK-dependent agents. The ACV-resistant isolate from patient 3 was partially resistant to FIAC and FIAU but still susceptible to FMAU; the viral TK had a 10-fold-lower affinity for ACV, FIAU, and FMAU than did the sensitive pretherapy isolate, while the level of TK activity detected was reduced to 6%. In none of the isolates studied was a change in sensitivity to phosphonoformic acid observed. Compared with the corresponding pretherapy ACV-sensitive isolates, there was a 30-fold decrease in neurovirulence for mice of the two drug-resistant isolates with diminished levels of thymidine-phosphorylating activity and no change in virulence for the third isolate. These findings indicate that mixed patterns of drug-resistance to TK-dependent antiviral compounds can occur in clinical isolates, resulting from changes in either the amount or the affinity of viral TK activity.

Acyclovir↗
PubMed1985

Detection of Epstein-Barr virus DNA in mouthwashes by hybridization.

An assay for the presence of Epstein-Barr virus (EBV) DNA was developed by using a cloned EBV DNA probe. After preliminary testing showed the assay to be sensitive and specific, it was applied to 135 mouthwashes from bone marrow transplant recipients, and 21 of these tests were positive. The concentration of EBV DNA in mouthwashes in some cases was as high as 10(8) genome equivalents per ml. When compared with the lymphocyte transformation assay on the same samples, the sensitivity was 75% and the specificity was 97%. In contrast to the lymphocyte transformation assay, the hybridization was semiquantitative and yielded results in 72 h. Potential applications include monitoring the effects of various interventions, such as immunosuppressive and antiviral chemotherapy, on EBV shedding.

Bone Marrow Transplantation↗
PubMed1985

Genetic analysis of the susceptibility of mouse cytomegalovirus to acyclovir.

Eight independently derived mouse cytomegalovirus (MCMV) mutants resistant to acyclovir (ACV) were obtained by the sequential plating of wild-type virus in increasing concentrations of ACV. Results of complementation studies among these eight mutants suggest that all had mutations within the same or closely associated genes. A ninth MCMV mutant resistant to phosphonoacetate (PAA) derived by plating wild-type virus in the presence of 100 micrograms of PAA per ml displayed coresistance to ACV and was unable to complement any of the ACV-derived mutants. Recombination experiments among all combinations of the nine MCMV mutants were performed and supported the complementation data in that no recombination could be detected. Seven of the eight ACV-resistant mutants demonstrated cross-resistance to PAA and hypersensitivity to aphidicolin. The one mutant not coresistant to PAA was more susceptible to PAA than was the parent virus. Only a few mutants demonstrated coresistance when the mutants were tested against 9-beta-D-arabinofuranosyladenine (ara-A). The ACV mutant that demonstrated increased susceptibility to PAA was 30-fold more susceptible to ara-A but remained unchanged in susceptibility to aphidicolin. Two of the parent-mutant combinations were selected for DNA synthesis analysis in the presence of ACV (5 microM). A significant decrease in DNA synthesis was demonstrated for both parent viruses, and there was little effect on mutant virus DNA synthesis at the same drug concentration. These results suggest that susceptibility of MCMV to ACV is confined to a product of a single gene and that a mutation of this gene can lead to an altered phenotype when compared with parent virus in susceptibility of DNA synthesis to PAA, ara-A, and aphidicolin, drugs that are known to inhibit DNA polymerase activity.

Acyclovir↗
PubMed1985

Late-onset interstitial pneumonia following allogeneic bone marrow transplantation.

Although most episodes of interstitial pneumonia (IP) following allogeneic bone marrow transplantation occur during the second or third month, occasional cases occur later. The records of 139 patients transplanted for leukemia over 6 years were reviewed in this study to examine cases of IP occurring beyond 100 days following marrow transplantation. Ten episodes of IP occurred among the 67 patients who survived 100 days (an actuarial probability of 18%). All cases occurred within the first year. An infectious cause was established in 80%. The case fatality rate was 60%. Although most infectious cases of IP occurring before 100 days are caused by cytomegalovirus, the late-onset cases in this study were caused by a heterogeneous group of pathogens, some of which were amenable to specific therapies. Thus, an aggressive approach to establishing a specific diagnosis should be made in cases of IP occurring more than 100 days after marrow transplantation.

Adolescent↗
PubMed1985

Autologous bone marrow transplantation in acute leukemia: a phase I study of in vitro treatment of marrow with 4-hydroperoxycyclophosphamide to purge tumor cells.

This phase I study was conducted to determine the maximal safe concentration of 4-hydroperoxycyclophosphamide (4HC) that could be used for in vitro treatment of bone marrow from patients with acute leukemia undergoing autologous bone marrow transplantation. Concentrations of 40 to 120 micrograms/mL of 4HC were used in 30 patients with relapsed or high-risk acute leukemia and in six patients with nonleukemic malignancies. All patients received marrow-lethal cytoreductive therapy followed by infusion of the 4HC-treated marrow. Complete inhibition of granulocyte and macrophage colony-forming cells was obtained at 80 micrograms/mL. Nevertheless, only one transplant-related death and otherwise full hematologic recovery was observed at concentrations of 4HC up to 100 micrograms/mL. At 120 micrograms/mL, there were three transplant-related deaths, including two of the three patients who required the infusion of reserve marrow. Among the acute leukemia patients, three remain in complete remission at 1,337, 1,017, and 967 days after transplant. Among the nonleukemic patients, two remain in complete remission at 1,081 and 1,017 days after transplant. At the maximum safe concentration of 4HC (100 micrograms/mL), satisfactory hematologic recovery can be obtained, despite elimination of detectable hematopoietic progenitors.

Acute Disease↗
PubMed1984

Herpes virus infections: clinical manifestations and therapeutic strategies in immunocompromised patients.

Herpesvirus infections are a major cause of morbidity and mortality in immunosuppressed patients. Bone marrow and organ transplant recipients are model patient populations for studying the natural history of herpesvirus infections because the infections occur predictably after transplantation. Herpes simplex virus infections occur within the first month after transplantation and may cause severe mucocutaneous disease. Cytomegalovirus infections occur one to three months after transplantation and are the major viral cause of morbidity and mortality. Varicella-zoster virus infections occur four to five months after transplantation and rarely cause life-threatening infection. Further studies of Epstein-Barr virus are necessary to determine its significance as a pathogen. The development of new antiviral agents has introduced effective therapeutic approaches for herpes simplex virus infections and varicella-zoster virus infections. Efforts to treat or prevent cytomegalovirus infections in transplant recipients have had limited success. However, new therapeutic strategies may lead to therapies which may reduce the severity of these infections and lead to increased survival in bone marrow transplant and organ transplant recipients.

Antiviral Agents↗
PubMed1984

Preliminary results of high-dose busulfan and cyclophosphamide with syngeneic or autologous bone marrow rescue.

The toxic effects of high-dose busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) with autologous or syngeneic bone marrow rescue were evaluated in 19 patients (11 with acute myelocytic leukemia, one with acute lymphocytic leukemia, one with acute myelofibrosis, two with chronic myelocytic leukemia, one with Hodgkin's disease, and three with non-Hodgkin's lymphoma). Their mean age was 26 years (range, 6-50); nine patients had syngeneic and ten had autologous bone marrow rescue (six of whom had in vitro bone marrow incubation with 4-hydroperoxycyclophosphamide). Severe myelosuppression was expected and was seen in all patients; leukocyte and platelet count recovery occurred at a median of 19 days (range, 11-59) and 30 days (range, 20-89), respectively. Nausea, vomiting, and diarrhea were frequent but readily managed with vigorous medical therapy. Stomatitis was severe in 14 patients. Skin, renal, cardiac, pulmonary, and CNS complications directly attributable to drug-related toxic effects were transient and non-life-threatening. Hepatic function abnormalities were common but tended to be transient. Most patients tolerated high-dose busulfan and cyclophosphamide with manageable side effects. Hepatic veno-occlusive disease was fatal in two patients, while diffuse interstitial pneumonitis with disseminated herpes virus infection was fatal in three patients with lymphoma. All patients treated in relapse or without previous therapy had a complete tumor response. Further studies with this regimen should be pursued.

Acute Disease↗
PubMed1983

Marrow transplantation for acute nonlymphocytic leukemia after treatment with busulfan and cyclophosphamide.

Fifty-one patients with acute nonlymphocytic leukemia (16 with end-stage disease, 17 in second or third remission or in early relapse, and 18 in first remission) were given infusions of HLA-identical sibling marrow after cytoreduction with high doses of busulfan and cyclophosphamide. Actuarial two-year survival rates were 0 per cent, 29 per cent, and 44 per cent, respectively. Twelve patients are still alive and in remission after 327 to 1488 days, with 10 surviving beyond two years. Acute graft-versus-host disease and viral pneumonia were the major causes of death. Leukemic cells failed to clear in one patient with end-stage disease, and a relapse with meningeal leukemia occurred in another. Only one other relapse was seen--in a patient given a transplant during a third remission. Survival was favorably affected by younger age and transplantation during first remission. We conclude that high-dose chemotherapy with busulfan and cyclophosphamide, followed by allogeneic-marrow transplantation, can produce long-term remission of acute leukemia. Chemotherapy with high-dose busulfan and cyclophosphamide before transplantation provides an effective alternative to cyclophosphamide and total-body irradiation before transplantation for the treatment of acute nonlymphocytic leukemia.

Acute Disease↗