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Biomedical subjects

M Israel

Publications and source records attributed to M Israel.

At least 73 records · Page 4Linked to original sources
PubMed1989

[Changes in the immunological reactivity of young children attending nursery schools with polymer floor covering].

The purpose of this study is to make investigations for establishing the unfavourable effect rate of some of the properties of the synthetic floorings on the immunological reactivity of the organism of children. The health status of 429 children, age 3-5 years from 3 kindergartens in Sofia is traced in dynamic: the control group of 226, attending kindergartens with wood floorings and 203--the test group--attending kindergartens with polymeric floorings. The serum levels of immunoglobulins IgG, IgA, IgM are determined after the radial immunodiffusion method of Maucini. Measures are performed on the microclimatic parameters and electrostatic field as well. The results points out that the morbidity if the test group children is about twice higher in comparison with that of the control group, which correlates with the raised concentrations of the immunoglobulin serum levels. The highest morbidity is from acute respiratory infections and tonsillitis, as a consequence from the deteriorated thermoprotective properties of the synthetic floorings, potentiated under the electrostatic field effect. The results will serve the carrying out of preventive measures for health state promotion of the rising generation.

Bulgaria↗
PubMed1988

Anthracycline-induced DNA breaks and resealing in doxorubicin-resistant murine leukemic P388 cells.

Energy-dependent drug efflux is believed to be a major factor in cellular resistance to doxorubicin (DOX). However, recent studies have shown that decreased retention alone cannot account for anthracycline resistance, and possibly other factors, such as drug metabolism, free radical scavengers, and altered DNA damage/repair, may be involved. We have measured DOX-induced DNA damage and its repair in P388 cells sensitive (P388/S) and resistant (P388/R) to DOX. Our studies show 2- to 5-fold less DNA damage, measured as protein-associated single-strand DNA breaks, in P388/R cells when compared to similarly treated P388/S cells. The repair of DNA in whole cells, expressed as percent DNA rejoined, was complete in 4 hr in P388/R, whereas no repair was seen in P388/S cells until 20 hr. No difference in repair of DNA lesions was observed when nuclei were used in repair experiments. The absence of repair in sensitive whole cells may be due to high retention or slow drug efflux. Increase of cellular DOX retention by exposure of cells to trifluoperazine (TFP) or verapamil (VPL) did not result in the increase of DNA damage in P388/R cells. DOX analogs, N-trifluoroacetyladriamycin-14-valerate (AD 32), 4'-O-tetrahydropyranyladriamycin (THP-adriamycin), and N-benzyladriamycin-14-valerate (AD 198), induced 2- to 4-fold more DNA damage than DOX in resistant cells. There was no difference in the poly(ADP-ribose) synthesis of P388/S and P388/R cells exposed to DOX or AD 32. Since ADP-ribose polymer synthesis is associated with free radical-induced DNA damage and is indicative of DNA repair by an excision-repair mechanism, data from these studies suggest that DNA breaks in anthracycline-exposed cells may not be due to free radical production but rather to other mechanisms, such as inhibition of DNA topoisomerase II activity. The present studies, in addition to emphasizing the role of DNA damage in resistance, also underscore the relative importance of DNA topoisomerase II function in anthracycline cytotoxicity.

Animals↗
PubMed1988

Fast atom bombardment mass spectrometric analysis of anthracyclines and anthracyclinones.

A mass spectral characterization of a set of anthracyclines and anthracyclinones comprised of daunorubicin, adriamycin and their modified analogs was carried out by using negative and positive fast atom bombardment (FAB) ionization techniques. Addition of more than one hydrogen to the molecular ions of the anthracyclines was observed. The choice of the FAB matrix played an important role in the characterization of these compounds. The dominant ions in the molecular ion region were M-. (or M+.) and MH- (or MH+.2) when sulfolane and glycerol, respectively, were employed as the FAB solvents. The major fragmentation was cleavage of the glycosidic bond with the charge retention mainly on the aglycone moiety. Aromatization of the tetracyclic ring promoted further fragmentation of the aglycone moiety. The anthracyclinones could be characterized only by negative FAB ionization using sulfolane as the FAB matrix. The assigned fragmentation pathways were confirmed by acquiring metastable ion spectra using B/E linked-field scans.

Antibiotics, Antineoplastic↗
PubMed1988

Effectiveness of neonatal transport in New York City in neonates less than 2500 grams--a population study.

In the past two decades, there has been a gradual trend to regionalization of perinatal care, categorization of hospitals and transport services for neonatal health care. The literature alludes to both beneficial and deleterious effects of neonatal transport (T) but no controls such as a matched nontransport (NT) population have been utilized to date. The major goal of this study was to evaluate the effect of neonatal transport from Level I and II high risk less than or equal to 2500 gm. neonates (born in NYC in one calendar year, 1979) compared to a cohort nontransported population matched for hospital of birth, weight, race, sex and risk. All transported less than or equal to 2500 gm. from Level I and II (n = 328) were studied and a stratified random sample of the nontransported (NT) infants less than or equal to 2500 gm. from these same hospitals (n = 2042) was used for comparison. The principle outcome variable was survival. The major conclusion of this study is that in Level I and II hospitals the transport group had a significantly increased survival in infants who were sick (Apgar less than 6) compared to cohorted nontransported controls. Interhospital differences in survival were noted among Level I and II but not seen in the subdivisions of (A) and (B) hospitals.

Demography↗
PubMed1988

Carbamazepine in psychiatry: a review.

Carbamazepine is a tricyclic compound structurally related to imipramine that has been used since the 1960's for the treatment of trigeminal neuralgias and then approved as an anticonvulsant in the U.S. in 1974. In the last decade the use of carbamazepine has been expanded to include the treatment of certain disorders of mood and behaviour. In this paper possible clinical applications of carbamazepine in psychiatry are reviewed along with its pharmacokinetic and pharmacodynamic profile. Also discussed are adverse reactions and drug interactions which are relevant to its use.

Aggression↗
PubMed1987

Comparative metabolism and elimination of adriamycin and 4'-epiadriamycin in the rat.

Adriamycin (ADR) and 4'-epiadriamycin (epi-ADR) show comparable biological properties in most in vitro and in vivo test systems. However, in animal studies epi-ADR demonstrates diminished toxicity, especially toward cardiac tissue, compared with ADR. A similar reduction in anthracycline-induced cardiotoxicity with epi-ADR, relative to ADR, is claimed in connection with the clinical evaluation of this agent. The present study was undertaken in an attempt to find a possible pharmacological basis for this observed differential toxicity. Following identical bolus doses (10 mg/kg) of drug administered to rats, no differences were seen in plasma drug levels of the two agents at 4, 7, and 24 h. However, differences in the rate and extent of drug elimination were clearly noted. Thus, following either 24-h infusion or bolus drug administration, parent drugs were eliminated largely in the bile, with the recovery of epi-ADR [50% (infusion) and 40% (bolus) in 54 h and 55 h respectively] exceeding that of ADR [31% (infusion) and 23% (bolus) at the corresponding times]. Recovery of a bolus drug dose in the urine was only 4.8% for epi-ADR vs 3.3% for ADR in 60 h. For each drug the only significant metabolite seen was the corresponding 13-carbinol derivative, adriamycinol (AMNOL) or 4'-epiadriamycinol (epi-AMNOL). The 13-carbinol metabolite represented a larger part of the recovered dose for ADR [15% (infusion) and 18% (bolus) in bile, 0.3% in urine] than for epi-ADR [7% (infusion) and 11% (bolus) in bile, 0.04% in urine]. Epi-ADR was found to be a four fold poorer substrate than ADR for conversion to its 13-carbinol metabolite by aldo-keto reductase enzymes in crude rat liver homogenate preparations. This latter finding provides an explanation for the metabolic and toxicologic differences observed with these agents in whole animals. Previous studies with ADR have reported that degenerative changes in rat cardiac tissue were accompanied by an accumulation of AMNOL during chronic drug administration. Thus, the present study suggests that the reported lower toxicity of epi-ADR compared to ADR for the heart may result from a more extensive elimination of parent drug in bile and urine, as well as diminished metabolic conversion to its 13-carbinol metabolite by ubiquitous aldo-keto reductase enzymes.

Animals↗
PubMed1987

Comparative effects of adriamycin and DNA-non-binding analogues on DNA, RNA, and protein synthesis in vitro.

Drug-DNA binding is claimed to be the basis by which the antitumor antibiotic adriamycin (doxorubicin) inhibits DNA and RNA synthesis in vitro. However, in preliminary studies the DNA-non-binding adriamycin analogue N-trifluoroacetyladriamycin-14-valerate (AD 32) showed somewhat greater inhibition of DNA and RNA synthesis than adriamycin under identical conditions. The kinetics of macromolecule synthesis inhibition induced by adriamycin and AD 32, and the two principal DNA-non-binding metabolites of AD 32, N-trifluoroacetyladriamycin (AD 41) and N-trifluoroacetyladriamycinol (AD 92), have now been subjected to comparative study in cultured CEM (human leukemic lymphoblastic) cells. At equimolar concentrations (10 microM), or at concentrations related to their 50% growth-inhibitory values vs CEM cells, AD 32 was consistently found to be more inhibitory than adriamycin of DNA and RNA synthesis, as measured by the incorporation of tritiated thymidine and uridine, respectively, into acid-precipitable fractions relative to untreated controls. Marked inhibitory activity was apparent with 10 microM AD 32 even at the earliest sampling time (15 min); with adriamycin at the same concentration the maximal effect was not achieved until 3 h. AD 32 at 4.8 microM concentration continued to show strong inhibition of nucleic acid synthesis, whereas adriamycin at 1.0 microM was essentially inactive. Like AD 32, AD 41 and AD 92 showed greater inhibition than adriamycin of DNA and RNA synthesis at the early sampling times, although in all instances the effects of AD 32 were more profound. AD 32 at 10 microM concentration produced a moderate but significant inhibition of the incorporation of tritiated methionine into protein compared with adriamycin, which at this concentration was not active. Parallel HPLC analytical studies with similar drug-treated cultures indicated that, while small amounts of adriamycin were found in cells treated with 10 microM AD 32, the amount of adriamycin present at 15 min was only a small fraction (less than 5%) of the amount of adriamycin achieved at 3 h in cultures treated with 1.0 microM adriamycin, a concentration already shown to be only slightly inhibitory of nucleic acid synthesis under the culture conditions. The present study thus confirms the marked DNA and RNA synthesis-inhibitory effects of AD 32, and establishes that this inhibitory activity is not due to conversion of AD 32 into adriamycin. These findings accordingly call into question the validity of the drug-DNA binding mechanism as the explanation for the nucleic acid synthesis inhibitory effects seen with ADR.

Cell Survival↗
PubMed1987

Effects of N-trifluoroacetyladriamycin-14-valerate (AD-32) on human bladder tumor cell lines.

We have compared the in vitro activity of N-trifluoroacetyladriamycin-14-valerate (AD-32) and doxorubicin hydrochloride (ADR) on the clonal growth of human bladder tumor cell lines (HBTCL). In order to determine the relatively toxicity of ADR and AD-32 on hematopoietic stem cells, CFU-GM assays were set up using 10 normal human bone marrow samples. The mean lethal dose for 50% of the colonies (LD-50) for ADR was 1.6 +/- 1.4 microM and that for AD-32, 3.9 +/- 4.9 microM (P less than 0.55), suggesting that these agents have similar bone marrow toxicity. Both drugs produced enhanced inhibition of clonal growth of HBTCL with increasing C X Ts. The spectrum of activity of the two drugs was similar against a panel of seven HBTCL. The activity of ADR was inhibited at 4 degrees C while the activity of AD-32 was unaffected by temperature. ADR was more effective against HBTCL in the log growth phase than the plateau phase while the reverse was found using AD-32. Verapamil was found to enhance the activity of both ADR and AD-32 against a HBTCL (T24), found to be resistant to both agents. The lipophilic properties of AD-32, along with its enhanced activity when used over prolonged periods of time and its activity against tumor cells in the plateau phase, suggest that AD-32 could be useful in the management of patients with superficial bladder cancer.

Biological Transport↗
PubMed1987

Effect of cetiedil on acetylcholine release and intramembrane particles in cholinergic synaptosomes.

The release of acetylcholine (ACh) from instantly frozen Torpedo electric organ synaptosomes in the course of stimulation is systematically associated with an increase in the number of large intramembrane particles counted on freeze-fracture replicas. The drug cetiedil, which is a potent inhibitor of ACh release, also blocks the increase in the number of large particles. The blockage was studied either after ionophore A 23187 or Glycera neurotoxin action in the presence of calcium.

Acetylcholine↗
PubMed1987

Effect of morpholinyladriamycin analogs and adriamycin on the activities of DNA polymerase alpha and RNA polymerase II of chicken leukemia cells.

The new adriamycin (ADR) derivatives, 3'-deamino-3'-(4"-morpholinyl)adriamycin (MRA) and 3'-deamino-3'-(3"-cyano-4"-morpholinyl)-adriamycin (MRA-CN), were studied, in comparison with ADR, for their inhibitory effects on DNA and RNA syntheses in vitro using isolated DNA and RNA polymerases from both Escherichia coli and chicken (myeloblastosis) leukemia cells. Under standard assay conditions, MRA and ADR demonstrated a similar inhibitory effect on the enzymes, whereas MRA-CN showed a slightly greater inhibitory activity than ADR or MRA at low drug concentrations, but with the inhibitory effect plateauing when drug concentration reached 10 microM. Both the A and B forms of the MRA-CN diastereoisomers were effective as inhibitors. Kinetic studies of the inhibition showed that unlike ADR, MRA-CN inhibition of DNA or RNA synthesis could not be reversed by increasing DNA-template concentration in the reaction mixture. Whereas ADR or MRA relaxed completely 1 microgram of pBR322 supercoiled DNA at a drug concentration of 15 microM, MRA-CN, at 60 microM, produced a mixture of intermediate relaxation forms of the DNA. A complete relaxation was achieved at 300 microM MRA-CN. Both DNA relaxation and fluorescence spectroscopic studies indicated that DNA-drug interactions occurred in the following order: ADR (or MRA) greater than MRA-CN greater than N-trifluoroacetyl-ADR-14-O-hemiadipate (a DNA-nonbinding anthracycline).

Animals↗
PubMed1987

Metabolic activation of N-acylanthracyclines precedes their interaction with DNA topoisomerase II.

The N-acylanthracyclines AD32 (N-trifluoroacetyladriamycin-14-valerate) and AD143 (N-trifluoroacetyladriamycin-14-O-hemiadipate) are analogs of Adriamycin (ADR) undergoing clinical or advanced pre-clinical screening. Their principal metabolites, following the cleavage of the 14-acyl side-chain, are N-trifluoroacetyladriamycin (AD41) and its reduced form N-trifluoroacetyladriamycinol (AD92). Both these compounds are biologically active and detectable in treated patients, laboratory animals, and in tissue culture cells. Unlike ADR, AD32, as well as AD143 and metabolites, show no detectable binding to double-strand DNA. Their effects on DNA have been previously investigated in vivo and in vitro using the alkaline filter-elution assay. It has been shown that all of the compounds cause approximately equivalent amounts of protein-associated DNA breaks (PAB) and DNA-protein crosslinks in a mouse lymphoma and in tissue-culture leukemia cells. In order to establish whether the induction of PAB by the drugs requires DNA topoisomerase II mediation, cleavage mapping analysis was done with tested compounds using purified human topoisomerase II. DNA fragmentation was significantly enhanced in the presence of the enzyme and either AD41 or AD92. In contrast, no fragmentation enhancement was observed in the presence of the parental drugs AD32 or AD143. The results strongly suggest that metabolic activation of N-acylanthracyclines by nonspecific esterases is a prerequisite for their interaction with DNA topoisomerase II and for stabilization of the cleavable complex.

Animals↗
PubMed1986

Interaction of N-trifluoroacetyladriamycin-14-O-hemiadipate with chicken leukemia RNA polymerase. Formation of drug-enzyme complex.

The biochemical mechanism of the N-trifluoroacetyladriamycin-14-O-hemiadipate-induced inhibition of RNA synthesis in vitro by chicken (myeloblastosis) leukemia RNA polymerase II was studied. The inhibition was found to be dependent upon preincubation of the drug with the enzyme prior to enzyme assays, suggesting that drug-enzyme interactions occur. A drug-enzyme association complex was subsequently isolated through glycerol gradient sedimentation and further characterized by fluorescent microscopic studies. The drug was dissociated from the complex upon sodium dodecyl sulfate (SDS)-gel electrophoresis, revealing the non-covalent nature of the binding between the drug and the RNA polymerase.

Animals↗
PubMed1986

Adriamycin analogues. Preparation and biological evaluation of some thio ester analogues of adriamycin and N-(trifluoroacetyl)adriamycin 14-valerate.

On the consideration that the highly active DNA-nonbinding adriamycin analogues N-(trifluoroacetyl)adriamycin 14-valerate and N-(trifluoroacetyl)adriamycin 14-O-hemiadipate undergo initial metabolic conversion to N-(trifluoroacetyl)adriamycin by the action of nonspecific serum and tissue esterases, a number of N-(trifluoroacetyl)adriamycin 14-thio esters have been prepared and studied for in vitro growth inhibition, vs. human-derived CCRF-CEM leukemic lymphocytes, and in vivo antitumor activity, vs. murine P388 leukemia, relative to the rate of thio ester deacylation induced by esterases present in mouse serum. Products were obtained by reaction of N-(trifluoroacetyl)-14-bromodaunorubicin with thioacetic, thiopropionic, thiobutyric, thiovaleric, and thiobenzoic acids in ethanol, in the presence of potassium carbonate. Because little is known about similar thio ester derivatives of adriamycin itself, the corresponding adriamycin 14-thio esters were also prepared and evaluated for antitumor activity; with these products, determination of their extent of interaction with calf thymus DNA was also performed. For the adriamycin thio ester products, significant in vivo anti-P388 activity was seen with the thioacetate, thiovalerate, and thiobenzoate derivatives, although no compound matched the curative effects of N-(trifluoroacetyl)adriamycin 14-valerate in this system. With respect to the N-(trifluoroacetyl)adriamycin 14-thio ester products, although the corresponding oxo ester analogues are all significantly biologically active, none of the thio ester derivatives showed activity in vitro or in vivo.

Animals↗
PubMed1986

Adriamycin analogues. Preparation and biological evaluation of some N-(trifluoroacetyl)-14-O-[(N-acetylamino)acyl]adriamycin derivatives.

In connection with structure-activity studies related to the novel DNA-nonbinding adriamycin analogues N-(trifluoroacetyl)adriamycin 14-valerate (AD 32) and N-(trifluoroacetyl)adriamycin 14-O-hemiadipate (AD 143), we have now prepared a series of N-(trifluoroacetyl)adriamycin derivatives with N-acylamino acid esters at the 14-carbinol position. Target compounds were made by reaction of N-(trifluoroacetyl)-14-iododaunorubicin with the sodium salts of N-acylamino acids generally in dimethylformamide-ethylene glycol solvent. Products were evaluated for in vitro growth-inhibitory activity and, to a limited extent, in vivo antitumor activity in the murine P388 leukemia system. ID50 values for the target compounds vs. cultured CCRF-CEM cells were generally in the same range as those for the above-mentioned DNA nonbinding adriamycin analogues. Of the four compounds tested for in vivo activity, although none was as effective as N-(trifluoroacetyl)adriamycin 14-valerate, all showed significant activity in the P388 assay system, with three of the compounds, at the doses used, being essentially equiactive with an optimal dose of adriamycin. Studies on the rate of esterase-mediated deacylation of the products, in a defined system containing unfractionated mouse serum as the source of enzyme, showed no relationship between the in vitro and in vivo activities of these compounds and the relative ease at which the side-chain ester substituents were hydrolyzed.

Animals↗
PubMed1986

Depression in dialysis patients: a review of psychological factors.

A review of the literature reveals that the incidence and prevalence of depression among dialysis patients is unknown but that estimates may vary from 20 to 50 percent. Diagnostic and methodological problems related to the population are examined and the notion that depression in this population may represent a qualitatively different entity, is evaluated. Finally, several theoretical models of depression are described and their particular relevance to depression among dialysis patients is discussed.

Adaptation, Psychological↗