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Biomedical subjects

J Kahn

Publications and source records attributed to J Kahn.

At least 181 records · Page 10Linked to original sources
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Efficacy and safety of adefovir dipivoxil with antiretroviral therapy: a randomized controlled trial.

CONTEXT: Adefovir dipivoxil is a nucleotide analog that has demonstrated effective antiretroviral activity against human immunodeficiency virus (HIV) with once-daily administration. OBJECTIVE: To determine if adefovir confers antiretroviral or immunologic benefit when added to stable antiretroviral therapy. DESIGN: Multicenter, 24-week, randomized, double-blind, placebo-controlled study. Enrollment was conducted from June 3, 1996, through May 6, 1997. SETTING: Thirty-three US HIV treatment centers. PARTICIPANTS: Of 1171 patients screened, 442 patients infected with HIV receiving stable antiretroviral therapy for at least 8 weeks with plasma HIV RNA greater than 2500 copies/mL and CD4+ cell count above 0.20 x 10(9)/L were randomized. INTERVENTION: Patients were randomized to receive either a single 120-mg/d dose of adefovir dipivoxil (n = 219) or an indistinguishable placebo (n = 223). All patients received L-carnitine, 500 mg/d. Open-label adefovir was offered after 24 weeks and was continued until the end of the study. MAIN OUTCOME MEASURES: Changes in HIV RNA from baseline, based on area under the curve and CD4+ cell levels, adverse events, and effect of baseline genotypic resistance on response to adefovir. RESULTS: Patients assigned to adefovir demonstrated a 0.4-log10 decline from baseline in HIV RNA compared with no change in the placebo group (P<.001), which continued through 48 weeks. CD4+ cell counts did not change. During the initial 24 weeks, elevated hepatic enzyme levels (P<.001), gastrointestinal tract complaints (P<.001), and weight loss (P<.001) were associated with use of adefovir. Between 24 weeks and 48 weeks elevations in serum creatinine occurred in 60% of patients, usually returning to baseline after discontinuation of adefovir. Patients with lamivudine or lamivudine and zidovudine resistance mutations demonstrated anti-HIV effects with adefovir (P< or =.01 vs placebo group). CONCLUSIONS: This study suggests that once-daily adefovir therapy reduces HIV RNA and is active against isolates resistant to lamivudine or lamivudine and zidovudine. Nephrotoxicity occurred when treatment extended beyond 24 weeks but was reversible.

Adenine↗
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Erythrocyte membrane ATP binding cassette (ABC) proteins: MRP1 and CFTR as well as CD39 (ecto-apyrase) involved in RBC ATP transport and elevated blood plasma ATP of cystic fibrosis.

In addition to the better-known roles of the erythrocyte in the transport of oxygen and carbon dioxide, the concept that the red blood cell is involved in the transport and release of ATP has been evolving (J. Luthje, Blut 59, 367, 1989; G. R. Bergfeld and T. Forrester, Cardiovasc. Res. 26, 40, 1992; M. L. Ellsworth et al., Am. J. Physiol. 269, H2155, 1995; R. S. Sprague et al., Am. J. Physiol. 275, H1726, 1998). Membrane proteins involved in the release of ATP from erythrocytes now appear to include members of the ATP binding cassette (ABC) family (C. F. Higgins, Annu. Rev. Cell Biol. 8, 67, 1992; C. F. Higgins, Cell 82, 693, 1995). In addition to defining physiologically the presence of ABC proteins in RBCs, accumulating gel electrophoretic evidence suggests that the cystic fibrosis transmembrane conductance regulator (CFTR) and the multidrug resistance-associated protein (MRP1), respectively, constitute significant proteins in the red blood cell membrane. As such, this finding makes the mature erythrocyte compartment a major mammalian repository of these important ABC proteins. Because of its relative structural simplicity and ready accessibility, the erythrocyte offers an ideal system to explore details of the physiological functions of ABC proteins. Moreover, the presence of different ABC proteins in a single membrane implies that interaction among these proteins and with other membrane proteins may be the norm and not the exception in terms of modulation of their functions.

ATP-Binding Cassette Transporters↗
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The impact of overweight on the development of diabetes after heart transplantation.

BACKGROUND: Overweight is defined with a body mass index (BMI) >25. A BMI >25 is known as an independent risk factor for increased morbidity and mortality. The influence of an increased BMI on the development of diabetes and on survival after heart transplantation (HTX) was investigated. METHODS: A total of 137 patients (116 men, 21 women), who underwent HTX at our Department from 1986 to 2002, were included in the study. For group stratification, the pre-operative BMI values were taken (group I: BMI 25). Groups were compared for primary disease, age and sex, development of renal failure, development of diabetes, and survival. The probability of survival and the freedom-from-diabetes interval were calculated by the use of Kaplan-Meier method. RESULTS: No significant differences between groups I and II were found concerning primary disease, age and sex, and occurrence of renal failure. There was a tendency towards increased survival (p = 0.18) in group I. Patients of group II developed diabetes after HTX more frequently than those of group I (p < 0.001). Cox regression revealed that pre-operative BMI >25 is a highly significant independent risk factor for post-operative development of diabetes mellitus (DM) (p < 0.001). CONCLUSION: Overweight prior to HTX appears to negatively influence long-term survival after HTX, although this difference did not reach statistical significance. Pre-operative overweight is a significant and independent risk factor for the development of post-transplant diabetes.

Adult↗
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Effect of thermochemotherapy on the development of spontaneous lung metastases.

Effect of local hyperthermia given alone or in combination with cyclophosphamide and/or hyperglycaemia on the development of lung metastasis was studied using a non-immunogenic mouse fibrosarcoma, FSa-II. Incidence of lung metastasis was dependent upon the tumour size, and was increased when tumour-bearing mice were restrained in animal holders which were used for heat-treatment of animal tumours. The frequency of the metastatic spread was decreased following local hyperthermia at 41.5 degrees and 45.5 degrees C when compared to that following sham treatment. This decrease was independent of the heat dose. Similar reduction in the incidence of metastasis was observed after hyperthermia given following glucose administration. The administration of cyclophosphamide effectively inhibited the development of lung metastasis. However, the magnitude of the inhibition was identical to that following hyperthermia alone. In conclusion, hyperthermia given alone, or in combination with hyperglycaemia or cyclophosphamide, inhibited the development of lung metastasis.

Animals↗
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The effect of bleomycin administered in combination with hyperthermia on a C3H mouse fibrosarcoma.

The effect of bleomycin (BLM) on a murine fibrosarcoma, FSa-II, was investigated at elevated temperatures. Animals were C3Hf/Sed mice derived from our defined flora mouse colony. Single-cell suspensions of the tumour were transplanted into the murine foot. Tumours with an average diameter of 4 mm were treated in a water bath where a desired temperature was maintained. Some animal groups received an intraperitoneal injection of glucose 60 min before hyperthermia to reduce tumour tissue pH. Hyperthermia was given for 60 min at 41.5 degrees C, 30 min at 43.5 degrees C, or 60 min at 43.5 degrees C, and tumour growth (TG) time to reach 1000 mm3 was studied. BLM treatment at 41.5 degrees C for 60 min prolonged the TG time compared to BLM treatment at a room temperature. The identical prolongation was observed following BLM treatment given at 43.5 degrees C for 30 min, although the growth prolongation was greater following BLM treatment given at 43.5 degrees C for 60 min than the other two treatments. This greater prolongation is probably attributable to an additive effect; namely hyperthermia of 43.5 degrees C for 60 min induces substantial lethal damage by itself while the other two heat treatments do not induce significant damage. It is interesting to note that this kind of enhancement was observed at a low temperature of 41.5 degrees C. A glucose injection before BLM and hyperthermia treatments further enhanced tumour response. These observations agree with our previous observations following in vitro treatments of the same tumour cells, and indicate that BLM is a good drug to be combined with hyperthermia.

Animals↗
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The effect of cis-diamminedichloroplatinum(II) treatment at elevated temperatures on murine fibrosarcoma, FSa-II.

The effect of cis-diamminedichloroplatinum(II) (cis-DDP) on the murine fibrosarcoma cells was investigated in vitro and in vivo. For in vitro experiments tumour cell suspensions containing a given amount of cis-DDP were treated in water bath maintained at a desired temperature, and cell survival was determined by the lung colony assay. The D0 or the time to reduce survival from 1.0 to 0.37 on the exponential portion of the survival curve was determined and 1/D0 was plotted as a function of 1/T, where T stands for the absolute temperature. The slope of this Arrhenius plot indicated that the activation energy for chemical reaction of cis-DDP was 44 kcal/M between the temperature range from 37 to 41 degrees C. For in vivo experiments tumours were transplanted into the foot and treated by immersing the animal foot into a water bath when each tumour reached an average diameter of 4 mm (35 mm3). The drug was injected i.p. immediately before hyperthermia. The tumour growth (TG) time or the time required for a tumour to reach 1000 mm3 from the treatment day was determined, and the median TG time was obtained by logit analysis. Dose-response curves between the TG time and drug dose indicated that the cytotoxic effect of cis-DDP was enhanced at elevated temperatures. This enhancement increased with increasing temperature from room temperature to 43.5 degrees C. Because of short plasma half-time of cis-DDP, continuous infusion and pulse injections were attempted.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
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The cytotoxic effect of cis-diamminedichloroplatinum(II) on cultured Chinese hamster ovary cells at elevated temperatures: Arrhenius plot analysis.

The effect of cis-diamminedichroloplatinum (II) (cis-DDP) and hyperthermia on cultured Chinese hamster ovary (CHO) cells were investigated. Cells were treated with 6 microM cis-DDP for various durations of time at temperatures ranging from 37 to 43 degrees C, and cell survival curves were determined as a function of treatment time. The cytotoxic effect of cis-DDP increased with increasing temperatures, indicating that hyperthermia enhanced cytotoxicity of cis-DDP. Arrhenius analysis of surviving fraction data (6 microM cis-DDP) yielded activation energies of 61 kcal/M between 37 and 41 degrees C and 213 kcal/M between 41 and 43 degrees C. Further experiments using two different drug concentrations (3 and 12 microM) confirmed these activation energies in these two different temperature ranges. However, the activation energy for 12 microM cis-DDP given in the temperature range 33-37 degrees C was 22 kcal/M, which is smaller than those found above 37 degrees C. This activation energy appeared to be identical to that reported for the degradation or depurination of DNA. The activation energy between 37 and 41 degrees C, i.e. approximately 61 kcal/M, was twice as great as that found for alkylation of thio-TEPA, an alkylating agent. This may indicate that the mechanism of action of cis-DDP differs from that of thio-TEPA. A greater activation energy observed in the range of 41-43 degrees C is most likely attributable to the additive effect of hyperthermia and thermal enhancement for cis-DDP. Although only one data point is available at the temperature above 43 degrees C, it suggests that the activation energy is identical to that for hyperthermia alone.

Animals↗
PubMedDate not supplied

Cytotoxic effect of 1,3 bis (2-chloroethyl)-N-nitrosourea at elevated temperatures: Arrhenius plot analysis and tumour response.

The effect of hyperthermia on the cytotoxicity of 1,3-bis-(2-chloroethyl)-N-nitrosourea (BCNU) was investigated in vitro and in vivo. Tumour cells were early-generation isotransplants of a spontaneous C3Hf/Sed mouse fibrosarcoma, FSa-II. For in vitro studies, single cell suspensions containing 1.0 x 10(6) cells/ml were treated in a water bath where a desired temperature was maintained by a constant-temperature circulator. Cell survival was determined by lung colony assay immediately thereafter. For in vivo studies the tumour cell suspensions were transplanted into the dorsal site of the C3Hf/Sed mouse foot. Tumours were treated by immersing animal feet into a constant-temperature water bath when tumours reached an average diameter of 4 mm (35 mm3). The tumour growth (TG) time or the time for one-half of the treated tumours to reach 1000 mm3 from initial treatment day was used as an endpoint. BCNU dose-cell survival curve at 37 degrees C was exponential with a D0 of 1.1 microgram/ml. Dose-cell survival curves at 37-43 degrees C were determined as a function of treatment time at pH 6.7 and 7.4. BCNU of 1 microgram/ml was added immediately before treatment. The slope of the survival curve became steeper with increasing temperature, indicating that the cytotoxic effect of BCNU was enhanced by hyperthermia. The Arrhenius plot analysis showed that activation energies at pH 6.7 and 7.4 were 53 and 51 kcal/M, respectively (no significant difference). Of interest in this analysis was that the Arrhenius plot did not show a breaking point which has been observed for other agents. Further investigation demonstrated that the decomposition of BCNU, which has been reported to be essential for production of reactive intermediates, occurred in aqueous medium at elevated temperatures. The magnitude of this decomposition depended on treatment temperature. As a result, preheated BCNU became less cytotoxic with an increase in preheating temperatures. The activation energy for this decomposition was about one-half of the activation energy for BCNU cytotoxicity. Studies in vivo indicated that the effect of BCNU was enhanced with increasing temperatures, and the enhancement was greatest when BCNU was administered i.p. immediately before hyperthermia. A glucose dose of 5 g/kg administered i.p. 60 min before hyperthermia further enhanced the antitumour effect of BCNU.

Animals↗
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Who owns our genes?

Explore the source record for details and available documents.

Genes↗
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Swinging on the pendulum. Shifting views of justice in human subjects research.

Federal policies on human subjects research have performed a near-about face. In the 1970s, policies were motivated chiefly by a belief that subjects needed protection from the harms and risks of research. Now the driving concern is that patients, and the populations they represent, need access to the benefits of research.

Attitude to Health↗
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A phase I/II study of recombinant tumor necrosis factor and recombinant interferon gamma in patients with AIDS-related complex.

A clinical trial was conducted to determine the tolerance and toxicity of recombinant tumor necrosis factor (rTNF) and recombinant interferon gamma (rIFN-gamma) when administered concurrently by continuous intravenous infusion to 11 patients with the AIDS-related complex (ARC). In addition, HIV culture, p24 antigen levels, and CD4 positive lymphocytes were monitored to obtain preliminary evidence of antiviral and immunologic effects. Two 5-day treatment cycles were separated by a 9-day washout period. Two patients were entered at each dosage level and each patient received the two 5-day treatment cycles at two sequential dose levels ranging from 1 to 25 micrograms/m2. Two patients did not complete their second treatment cycle--one due to the development of a rash, the second due to central venous catheter discomfort. The occurrence of phlebitis with peripheral vein administration of these agents necessitated administration via central venous catheter. With the exception of a single patient who developed severe headache at the 25 micrograms/m2 dose, severe clinical toxicities were not observed. Fever, chills, headache, and myalgias were the most significant clinical toxicities observed and all were dose dependent. The percentage fall in total granulocytes was dose dependent and ranged from 17% at the 1 microgram/mm2 dose to 48% at both the 15 and 25 micrograms/mm2 dose levels. The mean nadir granulocyte count was 1694/mm3. No significant renal or hepatic toxicity was observed. Of 22 treatment cycles the CD4 cell number was increased in 11, unchanged in 7, and decreased in 4. The mean CD4 cell number did not change significantly (176 +/- 143/mm3 pretherapy versus 279 +/- 305/mm3 posttherapy).(ABSTRACT TRUNCATED AT 250 WORDS)

AIDS-Related Complex↗