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Biomedical subjects

D J Reynolds

Publications and source records attributed to D J Reynolds.

At least 73 records · Page 4Linked to original sources
PubMed1991

Acute toxicity of amine-boranes and related derivatives in mice.

Three boron derivatives, i.e. trimethylamine-carbomethoxyborane, tetrakis-mu-(trimethylamine-boranecarboxylato)-bis(trimethylamine- carboxyborane)-dicopper(II), and N,N-dimethyl-n-octadecylamine borane were evaluated for acute toxicity in male mice, at 1, 2 or 5 x their therapeutic dose in rodents for pharmacological activity. Based on organ weights, clinical chemistry, hematopoietic parameters and tissue morphology, the trimethylamine-carbomethoxyborane was shown to be free of toxicity. The dicopper(II) complex and N,N-dimethyl-n-octadecylamine borane demonstrated slight toxicity with marginal disturbance in hepatic and kidney morphology. The dicopper(II) complex may cause marginal myocardial damage and the N,N-dimethyl-n-octadecylamine borane caused elevations in cholic acid. All three derivatives demonstrated reductions in hematocrit.

Animals↗
PubMed1991

Endocytic mechanisms utilized by chlamydiae and their influence on induction of productive infection.

The microfilament-disrupting drug cytochalasin D and, initially, inoculation at 20 degrees C were used to differentiate between phagocytosis (sensitive to both treatments) and pinocytosis (resistant to both treatments) to assess whether chlamydial uptake into McCoy cells occurred by one or both mechanisms and whether each could contribute to productive infection. Both treatments suppressed the infectivity of Chlamydia trachomatis L2/434/Bu and C. psittaci GPIC (the guinea pig inclusion conjunctivitis strain) following static inoculation by only 50%, indicating that there was simultaneous operation of both phagocytosis and pinocytosis during uptake that led to productive infection. Measurement of the entry of organisms by two separate assays established that both strains predominantly used a cytochalasin D-resistant (pinocytic) mechanism, implying that phagocytic uptake was coupled to a higher frequency of productive infection. Integration of the data on infectivity and entry allowed the potential for an organism to infect a host cell to be quantified. This synthesis revealed that for both strains the infectivity potential following phagocytic entry was ca. 10-fold greater than that following pinocytic entry. However, both entry mechanisms were exploited more efficiently by strain L2/434/Bu than by strain GPIC (unless the latter was inoculated with centrifugation), indicating that intrinsic strain properties are more important for infectivity potential than the endocytic mechanism utilized.

Cell Line↗
PubMed1990

Identification of a novel inositol phosphate recognition site: specific [3H]inositol hexakisphosphate binding to brain regions and cerebellar membranes.

[3H]Inositol hexakisphosphate (InsP6) binds with a heterogeneous distribution to frozen sections of unfixed rat brain and is displaced by unlabelled InsP6. The pattern of binding correlates with binding to neuronal cell bodies. [3H]InsP6 binding to cerebellar membranes has been further characterised, is reversible, and saturable, and exhibits high specificity for inositol polyphosphates. The IC50 for competition by unlabelled InsP6 is approximately 100nM, whereas inositol 1,3,4,5,6 pentakisphosphate (Ins(13456)P5), inositol 1,3,4,5 tetrakisphosphate (Ins(1345)P4), and inositol 1,4,5 trisphosphate (Ins(145)P3) bind with an affinity at least one order of magnitude lower. [3H]InsP6 binding is clearly distinct from previously characterised Ins(145)P3 (ref. 1, 2) and Ins(1345)P4 (ref. 3) binding, both in terms of pharmacology and brain distribution.

Animals↗
PubMed1990

Substituted cyclic imides as potential anti-gout agents.

N-substituted cyclic imides of phthalimide, 2,3-dihydrohalazine-1,4-dione, and diphenimide were shown to reduce the serum uric acid levels in normal and hyperuric mice at 20 mg/kg/day I.P. for 14 days. The agents were potent inhibitors of commercial xanthine dehydrogenase and xanthine oxidase enzyme activities with IC50 values from 10(-7) to 10(-8) M concentrations of drug.

Allopurinol↗
PubMed1990

Evidence for presynaptic 5-hydroxytryptamine3 recognition sites on vagal afferent terminals in the brainstem of the ferret.

Antagonists acting at the 5-hydroxytryptamine3 receptor are potent anti-emetic agents in cases of cytotoxic- and radiation-induced vomiting, and binding sites for these compounds have been described in brainstem areas known to be involved in mediation of nausea and vomiting. We have used autoradiography to examine the distribution of one of these antagonists, [3H]granisetron in the caudal brainstem of the ferret, a commonly used animal model for physiological investigations of emesis. The highest density of binding sites was found to be in the dorsomedial region of the nucleus of the solitary tract, the principal terminus for gastric vagal afferent fibres. Lower levels of binding were observed in the area postrema and the dorsal motor nucleus of the vagus. Following unilateral nodose ganglion excision, displaceable binding of [3H]granisetron in the nucleus of the solitary tract was attenuated on the ipsilateral side by 65%. Bilateral subdiaphragmatic vagotomy abolished binding of [3H]granisetron in the entire dorsal vagal complex. These results provide strong circumstantial evidence that 5-hydroxytryptamine3 receptors are located on vagal afferent terminals in the ferret brainstem.

Afferent Pathways↗
PubMed1990

Characterization of the cytochalasin D-resistant (pinocytic) mechanisms of endocytosis utilized by chlamydiae.

The cytochalasin D-resistant (pinocytic) portion of the entry of two chlamydia strains (Chlamydia trachomatis L2/434/Bu and Chlamydia psittaci GPIC [guinea pig inclusion conjunctivitis]) was examined. By ultrastructural criteria, few organisms of either strain were observed in association with coated host-cell plasma membrane during entry into McCoy cells; this argues against a coated-pit mechanism of entry. When association with a coated membrane was seen, coat material appeared to pinch off ahead of internalizing chlamydiae. However, entry of both strains was substantially reduced by cytosol acidification, a procedure shown to prevent coated-pit vesiculation (K. Sandvig, S. Olsnes, O. W. Petersen, and B. van Deurs, J. Cell Biol. 105:679-689, 1987). No conclusive evidence of displacement of the fluid-phase marker [3H]sucrose from constitutively forming endocytic vesicles was found. Indeed the entry of strain 434 (but not strain GPIC) was accompanied by the influx of a large volume of fluid, suggesting an inducible mechanism. Additionally, entry of strain 434 (but not strain GPIC) was partially inhibitable by amiloride, yet the drug had no effect on the entry of transferrin, a ligand known to enter solely via coated pits. Our findings endorse the view that chlamydial entry can occur via a pathway involving coated pits. However, the unusual morphology of entry and lack of fluid exclusion are consistent with a process whereby although chlamydiae are not fully enclosed by coat material, their entry is dependent on the vesiculation of coated pits. Furthermore, the data support the proposition that a significant proportion of the entry of strain 434 occurs via an inducible pathway independent of coated-pit uptake.

Ammonium Chloride↗
PubMed1989

Localization of 5-HT3 receptor binding sites in human dorsal vagal complex.

Binding of the 5-HT3 receptor ligand [3H]BRL 43694 was investigated in the human medulla oblongata using in vitro autoradiography. High levels of saturable, displaceable binding (Bmax 1.88 pmol/mg protein, Kd 1.21 nM) were seen in the dorsal vagal complex but in no other medullary region. The results provide evidence for the existence of 5-HT3 receptor binding sites in a brain region involved in the control of vomiting in man.

Aged↗
PubMed1988

Simultaneous quantification of zidovudine and its glucuronide in serum by high-performance liquid chromatography.

A sensitive high-performance liquid chromatography (HPLC) assay has been developed to simultaneously determine levels of the anti human immunodeficiency virus agent, zidovudine (AZT), and its major metabolite (the 5'-O-glucuronide) in serum. Samples were first mixed with an internal standard (a stereoisomer of AZT), then prepared for analysis using solid-phase extraction columns and chromatographed using a reversed-phase analytical column. Isocratic elution with a mobile phase of 15% acetonitrile, buffered to pH 2.70 with ammonium phosphate, gave good resolution of the three analytes and endogenous serum components. The HPLC analysis time required per sample was 34 min and analyte recoveries were reproducibly high (greater than 93%). Replicate analyses of prepared standards gave satisfactory precision and accuracy, with coefficients of variation less than 15% and deviations from expected concentrations less than 10%.

AIDS-Related Complex↗
PubMed1988

Pathology of calves with diarrhoea in southern Britain.

Twenty-one moribund calves with diarrhoea were purchased from 11 farms, their faeces examined for enteropathogens and samples of intestinal tissue removed under anaesthesia. Lesions and presence of enteropathogens on the mucosal surface were scored by histological examination of immunostained paraffin sections. Two or more enteropathogens were detected in 19 calves. Cryptosporidium appeared to be the principal cause of diarrhoea in six calves, rotavirus in four, Salmonella typhimurium in two, bacteria adherent to the surface of the large intestine in two, coronavirus in one and K99+ Escherichia coli in one calf. Diarrhoea in four calves was the consequence of mixed infections in which no one enteropathogen appeared to predominate. In one calf no enteropathogen was detected. Diarrhoea was associated with infections and lesions throughout the small and large intestines. The enteropathogens most frequently associated with lesions in the small intestines were rotavirus, coronavirus and cryptosporidium; in the large intestines they were coronavirus and bacteria apparently adherent to the mucosal surface.

Animals↗
PubMed1988

Effects of 2,3-dihydrophthalazine-1,4-dione on Sprague Dawley rats lipid metabolism and serum lipoproteins.

2,3-Dihydrophthalazine-1,4-dione effectively lowers serum levels of cholesterol and triglycerides in Sprague Dawley rats after two weeks, after which the cholesterol levels continued to decline. The maximum serum lipid lowering effect on cholesterol or triglyceride levels was during the seventh and eighth week of drug administration. Similar magnitudes of reduction in lipids were observed in hyperlipidemic diet induced mice after four weeks of drug administration of 20 mg/kg.day. Lipid levels in liver, small intestines and aorta wall tissue were significantly reduced after eight weeks of drug administration, but no significant increase in fecal lipids was noted. The cholesterol content in the chylomicrons and in the VLDL and LDL-fractions was significantly reduced whereas HDL cholesterol was elevated by 112%. Neutral lipids and the triglyceride content were not altered in the chylomicron, VLDL and LDL; however, reductions of both levels were observed in the HDL fraction. The phospholipid content was reduced in the LDL and elevated in the other three fractions. Incorporation studies into lipoprotein fractions showed a decrease in cholesterol incorporation in chylomicrons, VLDL and LDL with an increase in HDL cholesterol incorporation. Palmitic acid incorporation was reduced in the chylomicron, VLDL and HDL fractions. 32P-Incorporation was reduced in the HDL fraction. Leucine incorporation into the apoproteins of all four fractions was elevated. Rate limiting enzymes involved in de novo cholesterol, fatty acid and triglyceride synthesis were inhibited by 2,3-dihydrophthalazine-1,4-dione after eight weeks of administration. There was no evidence that the drug caused an increase in peroxisome formation as measured by liver catalase activity nor the release of lysosomal hydrolytic enzymes as measured by acid phosphatase and cathepsin activities. The drug afforded no deleterious effects on clinical chemistry parameters after eight weeks administration.

Animals↗
PubMed1988

Acute toxicity of helenalin in BDF1 mice.

The acute toxicity of helenalin, a sesquiterpene lactone isolated from Helenium microcephalum, was examined in male BDF1 mice. The 14-day LD50 for a single ip dose of helenalin in male mice was 43 mg/kg. A single ip injection of 25 mg helenalin/kg increased serum alanine aminotransferase (ALT), lactate dehydrogenase (LDH), urea nitrogen (BUN), and sorbitol dehydrogenase within 6 hr of treatment. Multiple helenalin exposures, ip injection of 25 mg helenalin/kg for 3 days, increased differential polymorphonuclear leukocyte counts and decreased lymphocyte counts. Serum ALT, BUN, and cholesterol levels were also increased by multiple helenalin exposures at 25 mg helenalin/kg/day. Helenalin significantly reduced liver, thymus, and spleen relative weights and histologic evaluation revealed substantial effects of multiple helenalin exposures on lymphocytes of the thymus, spleen, and mesenteric lymph nodes. No helenalin-induced histologic changes were observed in the liver or kidney. Multiple helenalin exposures (25 mg/kg/day) significantly inhibited hepatic microsomal enzyme activities (aminopyrine demethylase and aniline hydroxylase) and decreased microsomal cytochromes P-450 and b5 contents. Three concurrent days of diethyl maleate (DEM) pretreatment (3.7 mmol DEM/kg, 0.5 hr before helenalin treatment) significantly increased the toxicity of helenalin exposure. The present studies indicate that the hepatic microsomal drug metabolizing system and lymphoid organs are particularly vulnerable to the effects of helenalin. In addition, helenalin toxicity is increased by DEM pretreatments which have been shown to decrease glutathione concentrations.

Animals↗
PubMed1987

A preliminary study on the anti-emphysema drug, 2-trifluoro-acetamidobenzenesulfonyl fluoride in CF1 mice.

2-Trifluoroacetamidobenzenesulfonyl fluoride was shown to be a potent inhibitor of porcine pancreatic elastase activity with an ID50-30.3 microM. When this enzyme was infused I.V. in mice inducing higher elastase activity in the blood, the agent at 20 mg/kg for 5 days suppressed elastase activity significantly below the value observed in normal mice. The drug was absorbed better by the I.P. route than the P.O. route. A more consistent and higher blood level of the drug was achieved by the I.P. route as opposed to the I.V. or oral routes. The drug distributed rapidly to all tissues concentrating in the skin and carcass. Approximately 56% of the drug was eliminated within 48 hr. The majority of the eliminated drug and its metabolites was via the urine. Whereas the LD50 value was greater than 350 mg/kg I.P. there was elevation in serum alkaline phosphotase activity; cholesterol and triglyceride levels were reduced, and the organ weight of the reproductive organs was markedly reduced. Further evaluation of this drug is necessary to determine if the observed acute toxicity findings are restrictive for the use of this agent in the treatment of emphysema.

Animals↗
PubMed1987

Synthesis and hypolipidemic activity of 3-imino-1-oxoisoindolines in rodents.

A series of substituted 3-imino-1-oxoisoindolines derivatives demonstrated significant hypolipidemic activity, lowering both serum cholesterol and triglycerides levels after 16 days of dosing at 20 mg/kg/day ip in CF1 mice. 2-Butyl-3-butylimino-1-oxoisoindoline lowered serum cholesterol levels 52% and serum triglyceride 42%. 2-Pentyl-3-imino-1-oxoisoindoline lowered serum cholesterol levels 42% and serum triglyceride 61%. These derivatives resulted in better activity than the parent compound, 3-imino-1-oxoisoindoline. These studies showed that compounds with N-alkyl substitution of nitrogen atoms in the ring and outside the ring possessed potent hypolipidemic activity at the low dose of 20 mg/kg/day ip in normolipidemic CF1 mice. Studies with 2-butyl-3-butylimino-1-oxoisoinodine in rats showed that serum cholesterol was reduced 60% and serum triglyceride 43% after 14 days of dosing at 20 mg/kg/day, orally. Treatment with this agent lowered lipid levels in the liver and aorta tissue, with increases in lipid levels in the small intestine tissue. Higher levels of cholesterol and phospholipids were excreted in the feces of treated animals compared to the control. Cholesterol levels of the very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) fractions were reduced, whereas the HDL cholesterol levels were elevated significantly. This ratio of low-density lipoprotein (LDL) cholesterol:HDL cholesterol levels suggests that the agent may be effective in treating hyperlipidemic states in humans.

Animals↗
PubMed1987

Hypolipidemic activity of o-(N-phthalimido)acetophenone in Sprague Dawley rats.

o-(N-Phthalimido)acetophenone has proven to be an effective hypolipidemic agent in rats at 20 mg/kg/day orally. The agent suppressed the activity of the rate-limiting enzyme of the liver involved in de novo synthesis of triglycerides. The synthetic rate-limiting enzyme for cholesterol esters was also inhibited by the drug in vivo. o-(N-Phthalimido)acetophenone lowered cholesterol in the liver and the aorta wall and generally caused an increase in phospholipids in body tissues. Serum lipoproteins were modulated by the drug with a decrease in cholesterol and triglycerides in the chylomicron, very low-density lipoproteins (VLDL), and low-density lipoproteins (LDL) and an increase in high-density lipoprotein (HDL) cholesterol. The phospholipid content was increased in the chylomicron, VLDL, and LDL fractions. In hyperlipidemic rats, o-(N-phthalimido)acetophenone lowered elevated blood lipid levels at 20 mg/kg/day orally after 3 weeks of administration. The hypolipidemic rat after drug treatment had a lower LDL cholesterol and a higher HDL cholesterol content, which is therapeutically desirable to protect against cardiovascular disease.

Acetophenones↗
PubMed1986

Microbiology of calf diarrhoea in southern Britain.

Faeces samples from calves with diarrhoea in 45 outbreaks were examined for six enteropathogens. Rotavirus and coronavirus were detected by ELISA in 208 (42 per cent) and 69 (14 per cent) of 490 calves respectively; calici-like viruses were detected by electron microscopy in 14 of 132 calves (11 per cent). Cryptosporidium were detected in 106 of 465 (23 per cent), Salmonella species in 58 of 490 (12 per cent) and enterotoxigenic Escherichia coli bearing the K99 adhesin (K99+ E coli) in nine of 310 calves (3 per cent). In the faeces of 20 per cent of calves with diarrhoea more than one enteropathogen was detected; in 31 per cent no enteropathogen was found. Faces samples from 385 healthy calves in the same outbreaks were also examined. There was a significant statistical association of disease with the presence of rotavirus, coronavirus, Cryptosporidium and Salmonella species (P less than 0.001). Healthy calves were not examined for calici-like viruses and the association of K99+ E coli with disease was not analysed because there were too few positive samples. Rotavirus infections were more common in dairy herds and single suckler beef herds whereas Salmonella infections were more often found in calf rearing units. Cryptosporidium were more common in single and multiple suckler beef herds. K99+ E coli were found in one dairy herd and one multiple suckler beef herd both with unhygienic calving accommodation. Variations in coronavirus detection among different farm types were not statistically significant. In this survey rotavirus was the most commonly detected agent in calf diarrhoea and Cryptosporidium were found in approximately one quarter of affected calves. Infection with Salmonella species was widespread, but K99+ E coli infections were less common in the United Kingdom than in other countries.

Animals↗
PubMed1985

Studies on the relationship between coronaviruses from the intestinal and respiratory tracts of calves.

An immunofluorescence test on smears of nasal epithelial cells was used to detect coronavirus infection in the respiratory tract of calves. Thirteen gnotobiotic calves were infected with coronavirus isolates derived from faeces or respiratory material: virus was detected in faeces and nasal swabs from all animals. In 115 calves from a field survey, there was a significant association between coronavirus excretion from both respiratory and enteric routes in calves with diarrhoea. In a further 12 calves, at necropsy, the predilection sites for coronavirus growth were the distal small intestine, large intestine and the epithelia of the nasal cavity and trachea. Antigen was not found in lung tissue by immunofluorescence or immunoperoxidase staining. Infection with enteric coronavirus induced immunity to reinfection and to heterologous challenge with two coronavirus isolates derived from the respiratory tract. Nine coronaviruses were cultivated, cloned and antisera to three were prepared in pigs. There was complete virus neutralisation in tests with homologous sera and significant cross reactions with the eight other isolates which were of intestinal and respiratory origin. Thus, these bovine coronavirus isolates belonged to the same serotype despite the source of virus.

Animals↗