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Biomedical subjects

I Guest

Publications and source records attributed to I Guest.

At least 19 recordsLinked to original sources
PubMed2001

Bone marrow stem cell protection from chemotherapy by low--molecular-weight compounds.

The stem cells of the bone marrow have the capacity for both self-renewal and derivation of all the blood cell lineages. Consequently, toxicity to these cells can result in neutropenia, agranulocytosis, thrombocytopenia, pancytopenia, or aplastic anemia. Many anticancer drugs adversely affect the bone marrow, and neutropenia is a common limiting factor in dose escalation. In this review, we discuss agents that appear to have potential as bone marrow sparing agents. Computerized catalogs of the National Library of Medicine and Medline were searched for reports on low-molecular-weight compounds that detailed effects on the hematopoietic progenitor cells. The most promising agents are the endogenous peptides p-glutamic acid-glutamic acid-aspartic acid-cysteine-lysine and acetyl-serine-aspartic acid-lysine-proline, and the exogenous compounds amifostine and ammonium trichloro[dioxoethylene-O,O']tellurate, but several others are also discussed. These compounds preserve stem cell function in the presence of antineoplastic drugs of diverse pharmacological classes, and they do so by various mechanisms of action. Their present status in clinical practice is also detailed. More needs to be learned about their mechanisms of action and therapeutic potential, but the results are encouraging for some of these compounds and more clinical trials should be expected.

Amifostine↗
PubMed2000

Drugs toxic to the bone marrow that target the stromal cells.

Drugs that cause toxicity to the bone marrow are a heterogeneous group of compounds that act by various mechanisms. The etiology of this pathology is poorly understood but the highly proliferative nature of the hematopoietic cells is assumed to make the bone marrow more sensitive to toxicity. Recent evidence suggests that drugs can also affect specific aspects of stromal cells and the extracellular matrix that they establish. The data support the view that characteristics other than a high proliferation rate could confer susceptibility of the bone marrow to the toxic effects of drugs. This article discusses those drugs that have been shown to have direct effects on the bone marrow stromal cells.

Animals↗
PubMed1999

Drugs that induce neutropenia/agranulocytosis may target specific components of the stromal cell extracellular matrix.

The etiology of drug-induced agranulocytosis is poorly understood. Many drugs that induce neutropenia or agranulocytosis can be metabolized to reactive intermediates that covalently bind to macromolecules. Until now, the myeloid precursor cell or an earlier committed progenitor cell has been favoured as the target for toxicity, due to evidence in some cases of cytotoxic action or antibodies against neutrophils. In the bone marrow, where neutrophils mature, certain components of the stromal microenvironment, e.g. intracellular adhesion molecule 1, vascular cell adhesion molecule 1, CD11b/CD18, heparan sulfate proteoglycans, fibronectin and hemonectin are essential for normal myeloid maturation. This article proposes that drugs implicated in agranulocytosis, or more likely their reactive metabolites, interact with specific components of the extracellular matrix and interfere with the normal regulation of granulopoiesis.

Agranulocytosis↗
PubMed1998

Examination of possible toxic and immune mechanisms of clozapine-induced agranulocytosis.

We investigated three patients who developed agranulocytosis and seven patients who demonstrated neutropenia during therapy with clozapine as well as five patients who were asymptomatic while on clozapine. One of the three agranulocytic patients had previously developed severe neutropenia during clozapine therapy. We examined mature neutrophils to determine if these cells demonstrated increased susceptibility to clozapine or clozapine metabolites that had been generated chemically. Increased susceptibility was found in the cells of some patients, but it was not a consistent finding. We also examined the effects of clozapine or its chemically-generated metabolites on the development of haematopoietic precursor cells derived from the peripheral blood. Clozapine metabolites, but not clozapine, directly inhibited colony formation of all lineages in a dose-dependent manner; there was no evidence of a specific sensitivity of the myeloid precursors. Acute sera from one of the three patients who developed agranulocytosis was inhibitory to the growth of all precursor cells at a concentration of 10% but none of the plasma were inhibitory. In six patients with neutropenia or agranulocytosis, attempts were made to isolate antigen-specific T cells, wherein the antigen was a hapten carrier complex of clozapine metabolites covalently bound to leukocyte macromolecules. No clozapine metabolite-specific clones to these antigens were detected.

Adult↗
PubMed1998

Enzyme-linked immunosorbent assay for ondansetron captured from airborne samples.

A simple and relatively rapid enzyme-linked immunosorbant assay method for the anti-emetic drug ondansetron has been developed for its quantitation in solution. This has been optimised for use with samples that have been obtained following extraction of filters after the drug's capture from air samples in the workplace. The assay has the sample throughput (40 duplicate samples in 3 h), specificity, sensitivity (LOD of 10.5 ng drug ml-1) and precision (RSD < 11%) necessary for its use in determining airborne concentrations of ondansetron in such samples as part of an occupational health and hygiene monitoring programme.

Air Pollutants, Occupational↗
PubMed1994

Mechanism of trimethylamine-induced inhibition of macromolecular synthesis by mouse embryos in culture.

The effects of trimethylamine (TMA) on uptake mechanisms and lysosomal function were studied in mouse embryos, isolated yolk sacs and limb buds. TMA at 0.75 mM did not inhibit uptake of [14C]sucrose by yolk sacs of day 9 embryos or by day 15 isolated yolk sacs but did inhibit uptake of 125I-labelled bovine serum albumin ([125I]BSA) by day 15 isolated yolk sacs. Concentrations of TMA up to 2.5 mM did not inhibit lysosomal degradation of [125I]BSA by isolated yolk sacs, as judged by the release of trichloroacetic acid (TCA)-soluble radioactivity into the culture media. The inhibition of [125I]BSA uptake induced by TMA was reversible on removal of TMA. When day 8 embryos were cultured in serum containing [3H]leucine-labelled proteins, uptake and incorporation of radioactivity in 0.75 mM TMA-treated embryos was 47 and 44%, respectively, of that in untreated controls. TMA at 0.75 mM did not inhibit the uptake and incorporation of free [3H]leucine into embryonic protein nor the amount of free [3H]leucine taken up or incorporated into protein by day 12 isolated limb buds. It is concluded that the reduced macromolecular synthesis in embryos exposed to TMA is due to an inhibition of receptor-mediated uptake of nutrients by the yolk sac.

Animals↗
PubMed1994

Inhibition of mouse embryonic, yolk sac, and limb-bud functions by the methyl isocyanate metabolite S-(N-methylcarbamoyl)glutathione.

We previously reported that S-(N-methylcarbamoyl)glutathione (SMG), a conjugate formed by the reversible reaction between methyl isocyanate and glutathione, inhibited the development of mouse embryos in culture. The present study was done to determine whether SMG produced embryotoxicity by inhibiting yolk sac functions. For this purpose we determined the effects of an embryotoxic concentration of SMG on mouse yolk sac uptake mechanisms and lysosomal proteolysis as well as on the incorporation of [3H]leucine in mouse embryonic and limb-bud proteins. After 5 h of culture, SMG inhibited the uptake of [14C]sucrose and 125I-labelled bovine serum albumin in isolated day 15 yolk sacs to 62 and 77% of control, respectively. Lysosomal proteolysis was not inhibited, as judged by the release of trichloroacetic acid soluble radioactivity into the culture media. Uptake and incorporation of [3H]leucine from free [3H]leucine or from [3H]leucine-labelled protein in SMG-treated day 9 embryos were inhibited, respectively, to 61 and 25% of the control uptake during a 16-h labelling period. SMG also inhibited the incorporation of free [3H]leucine into limb-bud proteins. SMG-induced inhibition of 125I-labelled bovine serum albumin uptake by yolk sacs was partially prevented by the thiol donors N-acetylcysteine and glutathione but not by acivicin (gamma-glutamyl transpeptidase inhibitor) and aminooxyacetic acid (cysteine conjugate beta-lyase inhibitor). These data suggest that SMG suppresses embryonic growth primarily by an inhibition of nutrient uptake by the yolk sac. We postulate that this inhibition is due to tissue carbamoylation by methyl isocyanate released from SMG.

Aminooxyacetic Acid↗
PubMed1994

Evaluation of the rat embryo culture system as a predictive test for human teratogens.

Ingestion of the anticonvulsant drug valproic acid and of the angiotensin converting enzyme inhibitor captopril during pregnancy has been associated with abnormal fetal outcome in humans. In contrast, the use of the antiinflammatory drug ibuprofen and the antihistamine diphenhydramine has not been documented to be embryotoxic in humans. We evaluated the rat embryo culture system as a predictive model of teratogenesis, using these four drugs as test agents. Valproic acid, ibuprofen, and diphenhydramine were embryotoxic, inducing concentration-dependent decreases in growth and a significant increase in anomalies. Valproic acid caused an increase in neural tube defects, ibuprofen increased the incidence of abnormal maxillary processes, and diphenhydramine increased the number of embryos with distorted body morphology. These abnormalities were induced at concentrations of valproic acid and diphenhydramine that are used clinically, but ibuprofen only induced toxicity at concentrations greatly exceeding the therapeutic range. Captopril was not embryotoxic up to 5 mM, the highest concentration tested. These results suggest that the rat embryo culture system produces both false positive and false negative data on the teratogenic potential of drugs. Although such an in vitro assay may be suitable to determine the mechanism of teratogenesis, it is not a sensitive indicator of potential human teratogens on its own. These data support the view that in vitro systems can only supplement clinical and epidemiological observations in humans, possibly as a method to determine mechanisms of actions of teratogens.

Abnormalities, Drug-Induced↗
PubMed1993

The Bhopal accident and methyl isocyanate toxicity.

The Bhopal accident, the world's worst industrial disaster, in which nearly 40 metric tons of methyl isocyanate (MIC) was released from the Union Carbide pesticide plant, occurred nearly 10 yr ago during the night of December 2 and 3, 1984. Over 3000 people residing in areas adjacent to the plant died of pulmonary edema within 3 d of the accident. Follow-up studies revealed pulmonary, ophthalmic, reproductive, immunologic, neurological, and hematologic toxicity among the survivors. Despite high reactivity, MIC can traverse cell membranes and reach distant organs, perhaps as a reversible conjugate with glutathione, which may explain some of the systemic effects of MIC. MIC can be degraded as a result of pyrolysis and interaction with water, but none of the breakdown products can duplicate the toxicity observed in Bhopal and in animal models. MIC may be the most toxic of all isocyanates because of its very high vapor pressure relative to other isocyanates and because of its ability to exert toxic effects on numerous organ systems.

Accidents, Occupational↗
PubMed1993

Selective growth inhibition of the male progeny of mice treated with trimethylamine during pregnancy.

Injections of 1-7.5 mmol trimethylamine (TMA) per kilogram into mice daily from day 6 to day 15 (period of organogenesis) of gestation caused a dose-dependent decrease in fetal weights and in postnatal growth. The decrease in postnatal body weight gain, in brain and kidney weights, and in brain protein and DNA was more marked in the male than in the female offspring of TMA-treated animals; seminal vesicle weight and serum testosterone levels were also reduced. It is suggested that the selective growth inhibition of male progeny might be due to a decrease in testosterone synthesis. Since endogenous TMA levels are influenced by renal and liver disease and food habits, it might be one of the environmental factors influencing pregnancy outcome.

Animals↗
PubMed1992

Toxicity of the methyl isocyanate metabolite S-(N-methylcarbamoyl)GSH on mouse embryos in culture.

Methyl isocyanate, the chemical involved in the 1984 accident at Bhopal, India, forms a labile conjugate, S-(N-methylcarbamoyl)GSH (SMG), by way of a reversible reaction with GSH. We studied the toxicity of SMG on mouse embryos explanted on day 8 of gestation and cultured in rat serum for 42 hr. SMG caused concentration-dependent decreases in growth and development over the range 0.1-2 mM, without causing significant mortality. At a concentration of 2 mM, SMG completely arrested embryo development, but heartbeat was absent in only one of nine embryos at 42 hr. At a concentration of 0.25 mM, SMG reduced embryo size to 75% and protein content to 63% of the control; 18% of embryos failed to rotate. At this concentration (0.25 mM), which was selected for all other studies, spinal kinks and somite pair distortion in the region of the forelimb were evident in 38% of embryos; no other abnormalities were noted. DNA content of and thymidine incorporation by embryos and yolk sacs was reduced by SMG, although this was more pronounced in the yolk sac than in embryos. At subtoxic concentrations, the L-cysteine precursor (-)-2-oxo-4-thiazolidine-carboxylic acid did not, but GSH did, inhibit embryotoxicity of SMG. It is concluded that SMG exerts embryotoxic and dysmorphogenic effects and may contribute to systemic toxicity of methyl isocyanate.

Animals↗
PubMed1992

Teratogenic and macromolecular synthesis inhibitory effects of trimethylamine on mouse embryos in culture.

Trimethylamine (TMA) is an aliphatic amine, and its blood levels can increase after ingestion of certain foods, such as fish, and during disease states, such as chronic renal failure. We recently reported that TMA can inhibit fetal development in vivo and in vitro in mice. The present studies were done to find out if the inhibitory effects of TMA on embryonic development are caused by a decrease in macromolecular synthesis, using mouse embryo cultures as the experimental model. At a submaximally toxic concentration (0.75mM), TMA inhibited the growth of embryos to approximately 70% of control and caused neural-tube defects in 73% of embryos. By 42 h of culture, DNA, RNA, and protein content of TMA-treated embryos were approximately 50% of the control values. Embryotoxic effects of TMA were not caused by changes in pH and osmolarity of the culture media. The inhibitory effects of TMA on embryonic growth were time dependent and apparent at 2-4 h of culture. The inhibition of growth was accompanied by a decrease in the incorporation of tritium-labeled thymidine, uridine, and leucine into DNA, RNA, and proteins, respectively. Thiols (L- and D-cysteine, glutathione) and the antioxidant L-ascorbic acid did not cause significant antagonism of embryotoxic effects of TMA. It is concluded that TMA exerts teratogenic effects on mouse embryos in culture and inhibits their growth by reducing macromolecular synthesis; these effects may not involve glutathione depletion or generation of free radicals.

Abnormalities, Drug-Induced↗
PubMed1991

Developmental toxicity of methylamines in mice.

Monomethylamine (MMA), dimethylamine (DMA), and trimethylamine (TMA) are endogenous substances as well as metabolites of methyl isocyanate, the chemical involved in the 1984 accident at Bhopal, India. Although methylamines exert several toxic effects including inhibition of protein turnover and oocyte RNA synthesis, their reproductive toxicity has not been investigated. We therefore studied the possible developmental toxicity of these amines using pregnant CD-1 mice and mouse embryo culture as experimental models. Intraperitoneal injections (daily from d 1 to 17 of gestation) of TMA at 2.5 and 5 mmol/kg/d significantly (p less than .001) decreased fetal body weight but not the placental weight or maternal body weight gain; however, 5 of 11 mice treated with 5 mmol/kg TMA died. Similar treatment with DMA and MMA did not exert any obvious maternal or fetal effects. All three methylamines, when added to embryos in culture, caused dose-dependent decreases in size, DNA, RNA, and protein content as well as embryo survival; the order of toxicity was TMA greater than DMA greater than MMA. The ability of methylamines to adversely affect fetal development suggests that these amines, especially trimethylamine, may act as endogenous teratogens under certain conditions.

Animals↗
PubMed1991

Effects of cocaine on rat embryo development in vivo and in cultures.

Intraperitoneal injections of 6.25, 12.5, 25, 50, and 100 mumols/kg cocaine into pregnant Sprague-Dawley rats once a day from d 0 to 19 of gestation caused a dose-dependent increase in fetal soft tissue malformations, primarily of the genitourinary tract. At 100 mumols/kg, all implants were lost and three of the five animals died after six to seven injections. At 50 and 100 mumols/kg but not at lower doses, cocaine caused a small but significant decrease in body weight and food intake. Cocaine did not affect mean fetal and placental weights, although it increased the number of runts and edematous fetuses, and did not cause skeletal malformations. After intraperitoneal injection of 50 mumols/kg, the plasma t1/2 of cocaine was 21 +/- 5 min and peak plasma concentration (1682 +/- 260 pmol/mL, measured by HPLC) was achieved in 5-10 min; a lower peak plasma concentration (486 +/- 103 pmol/mL) was achieved in 20-60 min after s.c. injection. Concentrations of dopamine, epinephrine, and norepinephrine in brains of fetuses or newborn pups (less than 12 h old) of cocaine (50 mumols/kg)-treated rats were not significantly elevated. Cocaine injections did not affect gestational duration nor the growth pattern and the locomotor activity of offspring. However, three pups born to one cocaine-treated animal died 20 d after birth. Cocaine inhibited the growth of 10.5-d-old embryos in culture in a concentration-dependent manner and was more toxic than procaine. Approximately 80% of cocaine was metabolized during a 48-h period in embryo culture medium. It is concluded that cocaine possesses teratogenic potential that may be partly independent of maternal toxicity.

Animals↗
PubMed1991

Ontogeny of responses of rabbit aorta to atrial natriuretic factor and isoproterenol.

Ontogeny of the vasorelaxant effects of atrial natriuretic factor (ANF) and isoprenaline and of the vasoconstrictor effects of potassium and phenylephrine were studied on aortic strips from rabbits aged 1, 2, 3, 6, 10 and 32-48 (adult) weeks. ANF caused complete relaxation of phenylephrine- and potassium-contracted aortic strips from all age groups of rabbits and its potency was not altered by age and by the agent used to cause contractions. On the other hand, the vasorelaxant efficacy and potency of isoproterenol decreased with age. Also, isoprenaline was less potent and efficacious on aortic strips contracted with potassium than on strips contracted with phenylephrine. The sensitivity of aorta to phenylephrine increased after 2 weeks of age, but that to potassium remained the same at all ages. In conclusion, our data indicate that the vasorelaxant effects of ANF and the vasoconstrictor effects of potassium on rabbit aorta are not altered by age whereas the sensitivity of the vascular smooth muscle to isoproterenol decreases and that to phenylephrine increases with maturation.

Aging↗
PubMed1990

Dissociation between maternal and fetal toxicity of methyl isocyanate in mice and rats.

The contribution of maternal hormonal changes and pulmonary damage on the fetal toxicity of methyl isocyanate (MIC) was studied in mice and rats. Exposure to MIC decreased maternal plasma progesterone levels in mice that lost but not in mice that retained pregnancy. Fetal toxicity of MIC was not related to changes in maternal plasma corticosterone levels. Neither chronic administration of progesterone nor the suppression of pulmonary edema with dexamethasone decreased fetal toxicity of MIC. Embryos exposed in utero or in vitro to MIC vapor exhibited a concentration-dependent decrease in growth in culture. An acute dose (3 mmol/kg) of the MIC metabolites (methylamine, dimethylamine, trimethylamine, dimethyl urea) did not exert fetal toxicity. These data suggest that the fetal toxicity of MIC is partly independent of maternal toxicity and may result from its transfer across the placenta and interaction with fetal tissues.

Administration, Inhalation↗