Biomedical subjects

D C Baker

Publications and source records attributed to D C Baker.

At least 55 records · Page 3Linked to original sources

PubMed1990

Uptake kinetics of 2',3'-dideoxyinosine into brain and cerebrospinal fluid of rats: intravenous infusion studies.

The pharmacokinetics of 2',3'-dideoxyinosine (ddl) and its distribution to plasma, brain tissue and cerebrospinal fluid (CSF) were determined during and after 2-hr i.v. infusions of ddl (125 mg/kg/hr) in rats to define its specific pharmacokinetic parameters for subsequent studies of prodrugs designed to target this compound to the brain. Steady-state plasma concentrations of 50 micrograms/ml were obtained within 30 min after the start of infusions corresponding to a total clearance of 2.4 l/kg/hr. Postinfusion, ddl concentrations declined biphasically from plasma with alpha T1/2 = 3 min and beta T1/2 = 35 min. STeady-state concentrations of ddl in brain tissue and CSF were 2.6 micrograms/g in tissue and 0.81 microgram/ml in CSF, respectively. These values represent 4.7 and 1.5%, respectively, of the simultaneously determined plasma concentration. The estimated brain vascular space contribution to the observed brain uptake was 4.1%, obtained by least squares fitting of a compartmental pharmacokinetic model to the uptake data. Postinfusion, the elimination of ddl from the brain and CSF was significantly slower than from plasma, resulting in increased brain/plasma and CSF/plasma ratios after the infusions. The low steady-state brain/plasma or CSF/plasma ratios suggest rapid disappearance of ddl from the CNS relative to its rate of entry. These data indicate that ddl penetrates poorly into the brain. Thus, prodrugs with enhanced blood-brain barrier transport may improve the delivery of ddl to the brain.

Animals↗

PubMed1990

Platelet aggregation studies in dogs with acute Ehrlichia platys infection.

Ten adult dogs (5 Beagles and 5 mixed-breed dogs) were inoculated IV with canine platelets containing Ehrlichia platys. Inclusions and morulae of E platys developed in platelets of infected dogs at 10 to 14 days after inoculation, followed by marked thrombocytopenia at 14 to 21 days. Parasitemia and marked thrombocytopenia recurred at 24 to 28 days after inoculation. Increased numbers of megakaryocytes were observed in marrow aspirate smears from infected dogs, indicative of regenerative thrombocytopenia. Prior to infection, platelet-rich plasma from these dogs was determined to have similar aggregatory response to arachidonate. After infection with E platys, the aggregatory response of platelet-rich plasma to collagen or 3 dilutions of adenosine diphosphate was evaluated. A statistically significant (P less than 0.05) inhibition of platelet aggregatory response to the lowest dilution of adenosine diphosphate was detected for mixed-breed dogs, whereas aggregation responses were unchanged in Beagles. Results indicate that platelet activation may occur in dogs with acute ehrlichial infection.

Animals↗

PubMed1989

Thermopsis montana-induced myopathy in calves.

Six heifer calves were administered the dried and ground whole plant of Thermopsis montana by gavage once daily for 2 to 4 days at an initial dosage rate of 1 g/kg of body weight. Two of the 6 heifers died after the second dose, and the remaining 4 calves were humanely killed and their tissues were examined. Serum creatine kinase and aspartate transaminase activities were significantly (P less than 0.05) increased after initiation of plant administration. All calves had skeletal muscular degeneration or evidence of regeneration and repair of damaged myofibers in all skeletal muscle groups examined. Myoglobinuria and cardiac muscle degeneration were not detected in any of the calves.

Animals↗

PubMed1989

Hound's-tongue (Cynoglossum officinale) poisoning in a calf.

Cynoglossum officinale was believed to be responsible for the death of one calf and possibly 5 other calves in a group of 9 calves being fed chopped hay contaminated by this plant. The plant, commonly known as hound's tongue, contains pyrrolizidine alkaloids and has been determined to be toxic to horses fed contaminated hay, but was fed to cattle at the same time with no effect.

Animal Feed↗

PubMed1989

Biosynthesis of 9-beta-D-arabinofuranosyladenine: hydrogen exchange at C-2' and oxygen exchange at C-3' of adenosine.

The data presented here describe new findings related to the bioconversion of adenosine to 9-beta-D-arabinofuranosyladenine (ara-A) by Streptomyces antibioticus by in vivo investigations and with a partially purified enzyme. First, in double label in vivo experiments with [2'-18O]- and [U-14C]adenosine, the 18O:14C ratio of the ara-A isolated does not change appreciably, indicating a stereospecific inversion of the C-2' hydroxyl of adenosine to ara-A with retention of the 18O at C-2'. In experiments with [3'-18O]- and [U-14C]-adenosine, [U-14C]ara-A was isolated; however, the 18O at C-3' is below detection. The adenosine isolated from the RNA from both double label experiments has essentially the same ratio of 18O:14C. Second, an enzyme has been isolated and partially purified from extracts of S. antibioticus that catalyzes the conversion of adenosine, but not AMP, ADP, ATP, inosine, guanosine, or D-ribose, to ara-A. In a single label enzyme-catalyzed experiment with [U-14C]adenosine, there was a 9.9% conversion to [U-14C]ara-A; with [2'-3H]-adenosine, there was a 8.9% release of the C-2' tritium from [2'-3H]adenosine which was recovered as 3H2O. Third, the release of 3H as 3H2O from [2'-3H]adenosine was confirmed by incubations of the enzyme with 3H2O and adenosine. Ninety percent of the tritium incorporated into the D-arabinose of the isolated ara-A was in C-2 and 8% was in C-3. The enzyme-catalyzed conversion of adenosine to ara-A occurs without added cofactors, displays saturation kinetics, a pH optimum of 6.8, a Km of 8 X 10(-4) M, and an inhibition by heavy metal cations. The enzyme also catalyzes the stereospecific inversion of the C-2' hydroxyl of the nucleoside antibiotic, tubercidin to form 7-beta-D-arabinofuranosyl-4-aminopyrrolo[2,3-d]pyrimidine. The nucleoside antibiotic, sangivamycin, in which the C-5 hydrogen is replaced with a carboxamide group, is not a substrate. On the basis of the single and double label experiments in vivo and the in vitro enzyme-catalyzed experiments, two mechanisms involving either a 3'-ketonucleoside intermediate or a radical cation are proposed to explain the observed data.

Adenosine↗

PubMed1989

Stereospecific 2'-amination and 2'-chlorination of adenosine by Actinomadura in the biosynthesis of 2'-amino-2'-deoxyadenosine and 2'-chloro-2'-deoxycoformycin.

2'-Amino-2'-deoxyadenosine and 2'-chloro-2'-deoxycoformycin (2'-CldCF) are two nucleoside antibiotics produced by Actinomadura. The biosynthesis of these two nucleoside antibiotics has been studied by the addition of [U-14C]adenosine with or without unlabeled adenine to cultures of Actinomadura. By this experimental approach, it is possible to demonstrate that adenosine is the direct precursor for the biosynthesis of 2'-amino-2'-deoxyadenosine and 2'-CldCF. These conclusions are based on the observation that the percentage distribution of 14C in the aglyconic and pentofuranosyl moieties of 2'-amino-2'-deoxyadenosine and 2'-CldCF were similar to the distribution of 14C in the adenine and ribosyl moieties of the [U-14C]adenosine (i.e., 48:52) added to cultures of Actinomadura. Experimentally, the percentage distribution of 14C in the (i) adenine:2-amino-2-deoxy-beta-D-ribofuranose of 2'-amino-2'-deoxyadenosine is 51:49; (ii) 8-(R)-3,6,7,8-tetrahydroimidazo[4,5-d]-[1,3-diazepin-8-o1]:2 -chloro-2- beta-D-ribofuranose of 2'-CldCF is 45:55; and (iii) adenine:ribose of the adenosine isolated from the RNA of Actinomadura is 42:58. Further proof that adenosine is the direct precursor for the biosynthesis 2'-amino-2'-deoxyadenosine and 2'-CldCF was demonstrated by the addition of 75 mumol of unlabeled adenine together with [U-14C]adenosine to nucleoside-producing cultures of Actinomadura. The percentage distribution of 14C in the aglycon and the sugar moieties of 2'-amino-2'-deoxyadenosine and 2'-CldCF were 46:54 and 47:53, respectively; the percentage distribution of 14C in the adenine and ribose moieties of the adenosine isolated from the RNA of Actinomadura was 51:49. These data show that the hydroxyl on C-2' of the ribosyl moiety of adenosine undergoes a replacement by a 2'-amino or a 2'-chloro group to form 2'-amino-2'-deoxyadenosine or 2'-CldCF with retention of stereconfiguration at C-2'. Finally, Actinomadura can utilize inorganic chloride from the medium as demonstrated by the isolation of [36Cl]2'-CldCF following the addition of [36Cl]chloride to the culture medium. Mechanisms for the regioselective modification of the C-2' hydroxyl group and stereospecific insertion of the amino and chloro groups are discussed.

Actinomycetales↗

PubMed1989

Pathology in hamsters administered Solanum plant species that contain steroidal alkaloids.

Syrian hamsters were orally administered ground plant material from either Solanum sarrachoides, S. melongena, S. eleagnifolium, or S. dulcamara. Six of eight hamsters administered S. eleagnifolium and eight of 10 hamsters administered S. dulcamara died following administration of plant material and had gastric glandular mucosal necrosis and small intestinal mucosal necrosis with little inflammation. Hamsters administered S. sarrachoides or S. melongena did not die and had only lesions compatible with gastric distension. Both S. eleagnifolium and S. dulcamara contained solasodine glycoalkaloids(s), and S. dulcamara also contained an equal amount of other glycoalkaloids which were probably derived from soladulcidine (dihydrosolasodine). The lesions produced by these two plants were similar to those reported earlier to be caused by sprout material of S. tuberosum (in which solanidane alkaloids predominate) and by an alkaloid extract of S. tuberosum sprouts. Because of similarities in saponin-like activity and structure of solasodine glycoalkaloids to the solanidine glycoalkaloids of potato sprouts, the glycoalkaloids of S. dulcamara and S. eleagnifolium were probably the agents responsible for the lesions observed.

Animals↗

PubMed1989

Oral, osmotic minipump, and intramuscular administration to sheep of the Veratrum alkaloid cyclopamine.

Logistic and biologic aspects of three separate means of administration of cyclopamine for experimental induction of terata or embryonic death in sheep were examined. Oral capsule administration of crystalline cyclopamine is logistically simple and biologically effective, but costly in terms of amount of compound required. Embryos were affected in five of seven ewes dosed cyclopamine orally at higher levels (four nonpregnant and one with cyclopia). Intramuscular administration of cyclopamine dissolved in ethanol was logistically simple but without biologic effect at levels tested. Three of three treated ewes had normal offspring. Osmotic minipump administration of powdered cyclopamine suspended in propylene glycol was logistically unsatisfactory with serious delivery complications. Osmotic minipump administration of cyclopamine dissolved in ethanol was logistically very satisfactory, and one ewe among three treated animals was nonpregnant at term. There were no nonpregnant ewes nor deformed offspring in 17 controls.

Administration, Oral↗

PubMed1989

Photosensitization of cattle in Montana: is Descurainia pinnata the culprit?

Recurrent photosensitization of cattle in Montana has been blamed on Descurainia pinnata, tansy mustard. Two feeding trials were conducted to determine if tansy mustard was phototoxic. Pen-fed cattle consumed 2.4 and 4.1 kg/hd/day of tansy mustard in the 2 trials, and no photosensitization was detected. Liver clearance of BSP was within normal limits, as were blood chemistry values for AST, CK and GGT. Field cases have confirmed that tansy mustard was present and grazed in pastures where affected animals have grazed. We suspect that other factors may be necessary to predispose cattle to photosensitization by tansy mustard, and future work will attempt to determine the cause of the photosensitization.

Animals↗

PubMed1989

Toxicosis in pigs fed selenium-accumulating Astragalus plant species or sodium selenate.

Three groups of 5 pigs each were fed a high selenium (Se) diet by mixing either Astragalus praelongus (31.6 ppm Se in feed), A bisulcatus (31.7 ppm Se in feed), or sodium selenate (26.6 ppm Se in feed) with commercial hog feed. Ten control pigs were fed only commercial hog chow containing trace selenium (0.44 ppm Se). Pigs were fed for 9 weeks and necropsied when they had ataxia or paralysis. Blood was collected for hematologic and serum biochemical determinations, and samples of various tissues were collected and fixed in neutral-buffered 10% formalin for histologic evaluation or frozen for determination of selenium concentration. All forms of selenium induced clinical signs of weight and hair loss, with cracked hooves and inflamed coronary bands developing in all Na2SeO4-fed pigs and 1 A praelongus-fed pig, but not in A bisulcatus-fed pigs. Serum calcium, phosphorus, and albumin concentrations were unchanged or significantly decreased from prefeeding values in groups fed selenium. Serum aspartate transaminase (AST) activities in Astragalus species-fed groups, and amylase activities and PCV in all groups of pigs fed selenium, were increased. Serum alkaline phosphatase and creatine kinase activities were significantly increased in the A praelongus-fed pigs and significantly decreased in Na2SeO4-fed pigs. Terminal tissue and body fluid selenium concentrations were determined in all groups of pigs fed selenium and compared with values in control pigs. Urine and bile concentrations were increased by the greatest factor (40 to 100x), with tissue concentrations of selenium increased by a lesser factor (6 to 17x).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Synthesis and evaluation of a series of 1-(3-alkyl-2,3-dideoxy-alpha,beta-D-erythro-pentofuranosyl)thymines.

A series of 1-(3-alkyl-2,3-dideoxy-alpha,beta-D-erythro-pentofuranosyl)thymines (3'-alkyl-3'-deoxythymidines) has been prepared from 5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-D-glycero-pent-2- enono-1,4-lactone ((S)-5-[(tert-butyldiphenylsilyl)oxymethyl]-2(5H)- furanone) by Michael addition of the appropriate organocopper reagent, followed by reduction of the lactone, acetylation of the resulting hemiacetal, and trimethylsilyl triflate-catalyzed coupling with 2,4-di-O-(trimethylsilyl)thymine. The protected nucleosides were desilylated by using tetrabutylammonium fluoride to give anomeric mixtures of the free nucleosides. The unsubstituted 2',3'-dideoxynucleoside analog was similarly prepared from 5-O-(tert-butyldiphenylsilyl)-2,3-dideoxy-D-glycero-pentono- 1,4-lactone ((S)5-[(tert-butyldiphenylsilyl)-oxymethyl]-dihydro-2(3H)-fu r anone).

Acetylation↗

PubMed1988

8-Ketodeoxycoformycin and 8-ketocoformycin as intermediates in the biosynthesis of 2'-deoxycoformycin and coformycin.

An enzyme has been isolated from cell-free extracts of Streptomyces antibioticus that can catalyze the reduction of 8-ketodeoxycoformycin (8-KetodCF) and 8-ketocoformycin (8-ketoCoF) to the naturally occurring nucleoside analogues 2'-deoxycoformycin (dCF) and coformycin (CoF), respectively. The partially purified reductase requires NADPH as the cofactor and stereospecifically reduces the 8-keto group of both ketonucleoside substrates to a hydroxyl group with the R configuration at C-8. This is the same configuration of the hydroxyl group as that of the dCF and CoF isolated from S. antibioticus. The reduction proceeds at the nucleoside level, and ATP is not required. The reductase is stereospecific for the NADPH cofactor in that it transfers the pro-S but not the pro-R hydrogen from C-4 of NADPH to the 8-keto group. The apparent Km for 8-ketodCF and 8-ketoCoF were 250 and 150 microM, respectively. These in vitro results, which show that 8-ketodCF and 8-ketoCoF may be intermediates in the biosynthesis of dCF and CoF, support and extend our earlier results from in vivo studies which established that adenosine and C-1 of D-ribose are the carbon-nitrogen precursors of dCF. A possible mechanism for the formation of dCF is presented.

Adenosine Deaminase Inhibitors↗

PubMed1988

3H-amino acid incorporation into proteins during chronic aflatoxin induced coagulation defects in rabbits.

Eighteen New Zealand White rabbits were divided equally into three groups and administered either 0.2 ml dimethyl sulfoxide (DMSO)/day, 0.06 mg/kg/day Aflatoxin B1 (AFB1) in DMSO, or 0.09 mg/kg/day AFB1 in DMSO. Incorporation of 3H-amino acids into total serum protein, fibrinogen and platelet proteins was determined during the intoxication and developing coagulation defect. Ten of 18 rabbits administered AFB1 in DMSO died or developed prolonged coagulation times. There was no significant difference in specific incorporation of 3H-amino acids into total serum protein, fibrinogen or platelet proteins between groups, nor was there a difference in incorporation between rabbits with normal coagulation times and those with prolonged coagulation times. Correlation between plasma fibrinogen concentration and specific incorporation of 3H-amino acid into fibrinogen was not significant. In vivo inhibition of 3H-amino acid incorporation into plasma proteins or platelets could not be demonstrated.

Aflatoxin B1↗

PubMed1988

Mechanism of death in Syrian hamsters gavaged potato sprout material.

Greened or sprouted potatoes contain increased concentrations of steroidal alkaloids that have caused intoxication and death in a wide variety of animal species, however, the cause of death in these animals has not been determined. Potato alkaloids can cause death when parenterally administered, and is attributed to the acetylcholinesterase inhibitory activity of solanine and chaconine. To determine the cause of death in animals ingesting potato sprout material, 40 Syrian hamsters were divided into 4 equal groups and gavaged once on day 0 either water, 300 mg of potato sprout material, 400 mg of potato sprout material, or 500 mg of potato sprout material. Tissues were examined grossly and microscopically at 72 hr post-gavaging and brain acetylcholinesterase activity of each hamster was measured. The 300-mg dose group had increased mean acetylcholinesterase activity compared with control hamster mean activity, and the 400-mg and 500-mg dose groups had 90% and 84% of the mean acetylcholinesterase activity of the control hamster mean activity. There was severe gastric and proximal small intestinal mucosal necrosis in those hamsters which died prior to euthanasia. Additionally, several hamsters had valvular endocarditis and infarcts. Death could not be attributed to the slight acetylcholinesterase inhibition in the 2 higher dose hamster groups and was related to the severe gastrointestinal necrosis which occurred in hamsters of these groups.

Acetylcholinesterase↗

PubMed1988

Cattle grazing Wahweap milkvetch in southeastern Utah.

Cattle's grazing of the locoweed Wahweap milkvetch (Astragalus lentiginosus var. wahweapensis) was evaluated on desert and foothill winter range during the winter of 1986 to 1987. Dry, dead stalks of Wahweap milkvetch that had grown in 1985 and 1986 made up 15% of cattle diets overall, and 24% of diets when cattle grazed gravelly benches where it was abundant. Nutritional quality of Wahweap milkvetch was higher than of most associated forage, but its alkaloid concentration varied among the senescent stages. One cow aborted and two cows developed clinical signs of locoweed poisoning, including water belly (hydrops amnii). Microscopic lesions consisting of cytoplasmic foamy vacuolation were evident in both the dam and fetus. Because senescent stalks of Wahweap milkvetch are palatable and readily grazed by cattle, ranchers should not permit cattle to graze infested sites until other green forage is available in the spring.

Animal Feed↗

PubMed1988

Toxicoses in livestock from the hemlocks (Conium and Cicuta spp.).

The hemlocks, Conium maculatum (poison-hemlock) and Cicuta spp. (waterhemlock), are poisonous plants that cause sizeable losss to the livestock industry. Clinical signs of poisonhemlock toxicosis are similar in all species of livestock and include muscular weakness, incordination, trembling, initial central nervous system stimulation, depression and death from respiratory paralysis. Poison-hemlock also causes skeletal defects in the offspring of cattle, pigs and sheep and cleft palate in pigs when ingested during specific periods of gestation. The primary toxicants in poison-hemlock are coniine and gamma-coniceine. Coniine predominates in mature plants and seed, whereas gamma-coniceine predominates in early growth of the plant. Waterhemlock is the most violently toxic poisonous plant known. The toxicant is cicutoxin, which acts on the central nervous system, causing violent convulsions and death. Clinical signs of poisoning appear within 15 min after ingestion of a lethal dose and include excessive salivation, nervousness, tremors, muscular weakness and convulsive seizures interspersed by intermittent periods of relaxation and a final paralytic seizure resulting in anoxia and death. Elevated activities of lactic dehydrogenase, aspartate aminotransferase and creatine kinase in blood are observed, indicative of muscular damage. Toxicoses from poisonhemlock and waterhemlock generally occur in early spring when both plants emerge before other, more palatable plants begin to grow. All parts of the poison-hemlock plant are toxic. The root or tubers of waterhemlock are toxic; however, experimental evidence concerning the toxicity of other plant parts is inconclusive.

Alkaloids↗

PubMed1988

Substrate properties of analogs of myo-inositol.

The hydrolysis of the minor cell membrane lipid phosphatidylinositol-4,5-bisphosphate mediates the action of many growth factors and hormones. As an approach to the development of specific inhibitors of this process, we have synthesized a series of analogs of myo-inositol and have evaluated their ability to serve as substrates for phosphatidylinositol synthetase. Modification at the 2-, 3-, or 4-positions produced compounds unable to serve as substrates, but several 5-modified analogs retained activity as substrates of phosphatidylinositol synthetase. The product formed from 5-deoxy-5-fluoro-myo-[3H]inositol by phatidylinositol synthetase was hydrolyzed by phospholipase D and gave 5-deoxy-5-fluoro-myo-inositol as the radiolabeled product. Two analogs, 5-deoxy-myo-inositol and 5-deoxy-5-fluoro-myo-inositol, were shown to permeate L1210 leukemia cells and be incorporated into cellular phospholipid. Analysis of the radiolabeled lipids formed on incubation of L1210 cells with 5-deoxy-5-fluoro-myo-[3H]inositol indicated that the fradulent lipid formed was further phosphorylated to the monophosphate but not to the diphosphate form.

CDP-Diacylglycerol-Inositol 3-Phosphatidyltransfer↗

PubMed1988

Individual animal susceptibility and its relationship to induced adaptation or tolerance in sheep to Galega officinalis L.

Oral administration of Galega officinalis L to sheep demonstrated a marked variation in individual animal susceptibility to the toxic effects of the plant. As little as 5 g/kg of dried ground plant induced moderate tracheal frothing in 1 ewe while nearly 5 times that amount failed to elicit any recognizable toxic effects such as frothing, pulmonary edema or hydrothorax in others. Ten g/kg induced severe effects in 3 ewes. Ewes administered levels of plant between 5 and 24 g/kg had toxic effects whose severity was often unrelated to level administered. There was no apparent difference in average severity of clinical signs of toxicity nor pathologic lesions to challenge doses of 24 g/kg of the plant between groups of ewes with an immediate previous history of increasing doses of the plant and others with no history of ingesting the plant. Previously reported apparent induced adaptation or tolerance to G officinalis L in some animals is more likely to have been a result of the extreme variation in individual animals susceptibility.

Adaptation, Physiological↗