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Biomedical subjects

R A Wall

Publications and source records attributed to R A Wall.

At least 19 recordsLinked to original sources
PubMed1996

Determination of an arylacetamide antiarrhythmic in rat blood and tissues using reversed-phase high-performance liquid chromatography.

A method was developed for quantification of (+)-trans-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzo[b-] thiophene-4-acetamide (compound I), an antiarrhythmic drug, in rat whole blood, heart, brain, liver and skeletal muscle. Blood and tissue samples were homogenized and purified by chemical extraction. Chromatographic separations were achieved using reversed-phase high-performance liquid chromatography (HPLC) coupled with UV detection (215 nm). Drug recoveries from the extraction procedure ranged from 77 to 90%. Within- and between-day reproducibility of peak area (coefficient of variation) ranged from 1.1 to 15.7%. The detection limit was 80-200 ng/ml (in a 500-microliters extracted solution) depending on the type of biological sample. This method was used in a pharmacokinetic study of compound I disposition in rats after a bolus intravenous dose of 3.1 mg/kg.

Animals↗
PubMed1996

Role of hydrazine in the mechanism of isoniazid hepatotoxicity in rabbits.

Isoniazid (INH) continues to be a highly effective drug in the chemoprophylaxis and treatment of tuberculosis; however, its use is associated with hepatotoxicity (predominantly hepatic necrosis) in 1-2% of individuals. The INH metabolites, acetylhydrazine and hydrazine, have each been implicated as the causative hepatotoxin in INH-induced hepatotoxicity. Using a model of INH-induced hepatotoxicity in rabbits, in which INH-induced hepatotoxicity manifests as hepatic necrosis, hepatic steatosis (hepatic fat accumulation) and hypertriglyceridaemia (elevated plasma triglycerides), we compared the severity of these measures of toxicity with plasma levels of INH, acetylhydrazine and hydrazine. Plasma INH and acetylhydrazine were not correlated with markers of INH-induced hepatic necrosis or fatty changes. Plasma hydrazine at 32 h was correlated significantly with plasma argininosuccinic acid lyase (ASAL, a sensitive marker of hepatic necrosis) activity as area under the curve (r2 = 0.54, P < 0.002) and log plasma ASAL activity at 48 h after the first dose of INH (r2 = 0.53, p < 0.005), but not with fatty changes. These results show in this model of INH-induced hepatotoxicity in rabbits that hydrazine, and not INH or acetylhydrazine, is most likely involved in the pathogenic mechanism of hepatic necrosis.

Animals↗
PubMed1995

A model of isoniazid-induced hepatotoxicity in rabbits.

Isoniazid (INH) continues to be an effective drug used for chemoprophylaxis and treatment of tuberculosis. Unfortunately, INH is associated with significant hepatotoxicity in up to 2% of individuals exposed, and if this adverse event is not recognized early it can be fatal. Research on INH-induced hepatotoxicity has been hampered by the lack of a suitable animal model that closely resembles the toxicity in humans. The mechanism of INH-induced hepatotoxicity is still unknown. The present study describes the development of a reliable model of INH-induced hepatotoxicity in rabbits. The protocol involves repeated injections of INH over a 2-day period, resulting in significant hepatic necrosis as indicated by elevations of plasma argininosuccinic acid lyase activity. Pretreatment with phenobarbital increased the occurrence of INH-induced hepatic necrosis from approximately 60% (9 out of 15 rabbits) with INH alone to more than 90% (13 out of 14 rabbits). Morphological indices were used to demonstrate the presence of INH-induced hepatotoxicity, and biochemical indices were used to demonstrate both the presence and severity of INH-induced hepatotoxicity in this model. This model may prove useful for further investigations into the mechanism of INH-induced hepatotoxicity.

Administration, Oral↗
PubMed1995

Disposition kinetics of trimethoprim in rainbow trout (Oncorhynchus mykiss).

1. The pharmacokinetics of trimethoprim (TMP) following intra-aortic administration were investigated in rainbow trout. 2. The disposition kinetics for TMP were best described by a three-compartment open model. The disappearance of TMP from fish blood was characterized by rapid and pronounced distribution phases and a slow terminal elimination phase. 3. In contrast with pharmacokinetic data of TMP in mammals, the present study documented a long terminal elimination t1/2(36.1 h), large Vdss(5980 ml/kg) and small Clb(2.4 ml/min/kg) for TMP in rainbow trout, thus illustrating the slow biotransformation and elimination capacity, particularly the strong 'holding' capacity (storage) for the drug in trout. 4. The pharmacokinetic profiles in the present study indicated no dose dependency of TMP following three different bolus doses (5, 10 and 50 mg/kg). Hence, the first-order kinetic assumption was verified. 5. Urinary excretion of TMP was a minor elimination route in trout (14.4% dose).

Animals↗
PubMed1993

Localization of the meningococcal receptors for human transferrin.

The interaction between gold-labelled human transferrin (Au-HTF) with live meningococci after growth in vivo or in different in vitro conditions was examined by electron microscopy to localize and quantify the numbers of HTF-binding sites on the cell surface. It was clearly demonstrated that HTF binds to the surface of live meningococci (of different serogroups and serotypes) after growth in either iron-sufficient or iron-restricted cultures, although the degree of labelling was always higher (2- to 35-fold) in the latter case. The commensal Neisseria polysaccharea behaved similarly. Ultrathin sections showed that Au-HTF was localized predominantly on the outer membrane of the cells and vesicles, with hardly any internalization. Au-HTF labelling on meningococci was significantly reduced after incubation with unlabelled HTF or with rabbit antiserum containing antibodies against transferrin-binding proteins (TBPs), demonstrating the specificity of the interaction. These sera also blocked binding between HTF and outer membrane proteins on Western immunoblots. Direct evidence of the expression of the TBPs (Western blots) and localization of the HTF receptor (electron microscopy) on in vivo-grown meningococci was obtained from organisms derived without laboratory culturing from the cerebrospinal fluid of a patient. There was considerable cell-to-cell variation in the amount of labelling present on cells of the same sample (in vitro- or in vivo-grown organisms) and between different strains. The degree of binding varied with time of incubation of the cells with Au-HTF. The gold particles frequently formed discrete circles on the cell surfaces of the in vitro-grown organisms; these circles appear to be associated with outer membrane vesicle formation. The results show that the TBPs, which form part of the active components of the HTF receptor(s), are expressed in vivo and are surface exposed and immunogenic and that antibodies against them can interfere with the HTF binding of the meningococcal cells, which may affect iron utilization. This study further supports the concept of regarding the TBPs as future vaccine candidates.

Animals↗
PubMed1992

A comparison of the variable antigens expressed by clone IV-1 and subgroup III of Neisseria meningitidis serogroup A.

Serogroup A Neisseria meningitidis of subgroup III has caused two pandemics of meningococcal meningitis since 1966 and recently spread to East Africa. The last epidemics in West Africa in the early 1980s were caused by clone IV-1. Surface antigens of clone IV-1 strains from West Africa and subgroup III strains from both pandemic waves were analyzed. Lipopolysaccharide was stable within clone IV-1 but variable in subgroup III. Pili from clone IV-1 possessed class I epitopes, while those from subgroup III also possessed class IIa epitopes. Certain class 5 protein variants were expressed by both bacterial clones, possibly reflecting either inheritance of primeval genes or horizontal transmission. Exposure of Gambians to clone IV-1 bacteria stimulated production of bactericidal antibodies cross-reactive with subgroup III bacteria in some individuals but of type-specific antibodies in others. Gambians without bactericidal antibodies usually became healthy carriers rather than developing meningococcal disease on exposure to virulent meningococci.

Africa, Western↗
PubMed1992

Association of Haemophilus ducreyi with cell-culture lines.

The association of Haemophilus ducreyi with epithelial cell cultures was studied by light microscopy, electronmicroscopy and viable counts. Associated organisms were engulfed by epithelial cells and sequestered from the cell-surface environment. Large numbers of organisms within epithelial cells appeared to induce cell lysis and release of H. ducreyi. Such a mechanism occurring in vivo may assist H. ducreyi to evade the bactericidal action of polymorphonuclear leucocytes and may explain some of the tissue damage seen in genital ulcers caused by H. ducreyi.

Animals↗
PubMed1991

Variation in class 5 protein expression by serogroup A meningococci during a meningitis epidemic.

Serogroup A meningococci were isolated from patients and healthy carriers in The Gambia between 1982 and 1988. The class 5 proteins expressed by these bacteria were identified by electrophoretic migration and by serologic tests. Three protein serologic groupings (seroclasses) called A (protein 5a), B (proteins 5b, 5d, or 5e), and C (protein 5c or 5C) were found among 331 bacterial isolates. The number of class 5 proteins expressed per isolate varied from none to four, with a median of two. The class 5 protein composition differed for certain paired isolates obtained from the nasopharynx, blood, and cerebrospinal fluid of diseased patients and for certain pairs of sequential isolates from the nasopharynx of healthy carriers; the medical relevance of this variation remains unclear, although the 5C protein was preferentially isolated from the nasopharynx and the 5a protein from diseased patients. The data show that a large proportion of healthy carriers in The Gambia were exposed to bacteria expressing each of the three seroclasses and that many people were exposed to bacteria expressing each of the three seroclasses and that many people were exposed to two or all three seroclasses during the epidemic of 1982-1983.

Antibodies, Monoclonal↗
PubMed1991

Inhibition of the metabolism of paracetamol by isoniazid.

1. The effect of isoniazid given daily for 7 days on paracetamol (acetaminophen) kinetics and metabolism was studied in 10 healthy volunteers. Paracetamol, 500 mg, was given before isoniazid, on day 7 of isoniazid administration, and 2 days after the last dose of isoniazid. 2. On day 7, isoniazid markedly inhibited the formation clearance of the glutathione and catechol metabolites by 69.7% and 62.2%, respectively. Total paracetamol clearance was lowered by 15.2%. There was no effect of isoniazid on the non-oxidative pathways of paracetamol elimination. 3. Two days after isoniazid was discontinued, paracetamol metabolism had returned to pre-isoniazid values.

Acetaminophen↗
PubMed1991

Canadian multicenter azidothymidine trial: AZT pharmacokinetics.

The study objective was to describe the pharmacokinetics of azidothymidine (AZT) in a large population of early, asymptomatic human immunodeficiency virus (HIV)-infected individuals. The study design was a multicenter, prospective, descriptive single-dose pharmacokinetic study. Each of 66 fasting, male, HIV-infected homosexuals older than 18 years of age and in CDC classifications II, III, and IVC2 received a single 400-mg oral dose of AZT with subsequent pharmacokinetic measurements performed during an 8-h period for AZT and its major metabolite, glucuronylazidothymidine (GAZT). Results were obtained in 65 patients (36 smokers, 29 nonsmokers), of whom 3 were noted to have hepatic dysfunction. In those with normal hepatic function, the following parameters were described: AZT, area under the curve (AUC) +/- SD, 9.9 +/- 5.7 microM.h, maximum concentration (Cmax) +/- SD, 7.3 +/- 4.7 microM; time to maximum concentration (Tmax) +/- SD, 0.93 +/- 0.42 h, and half-life (t1/2) +/- SD, 1.0 +/- 0.8 h. Corresponding values for GAZT were: AUC +/- SD 35.7 +/- 10.3 microM.h, Cmax +/- SD 21.3 +/- 7.3 microM, Tmax +/- SD 1.2 +/- 0.50 h, t1/2 +/- SD 0.98 +/- 0.62 h, No significant differences were found in comparisons of study site, CDC classification of disease, smokers versus nonsmokers, and in patients with hepatic dysfunction, although a higher AUC and earlier Cmax for AZT was noted in the latter group. It is concluded that AZT pharmacokinetics are similar in patients with early asymptomatic HIV disease when compared with previous reports in patients with later disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Comparison of methods for the analysis of outer membrane antigens of Neisseria meningitidis by western blotting.

The method of extraction of outer membrane proteins (OMPs), the conditions of electrophoretic transfer, and the conditions of antibody binding, were compared in Western blotting studies of Neisseria meningitidis outer membrane antigens. The OMP profiles obtained by SDS-PAGE of outer membrane vesicles extracted with lithium chloride/sodium acetate were compared with profiles obtained by Sarkosyl extraction; these profiles were further compared with the patterns obtained by 125I-labelling of surface-exposed proteins. Sarkosyl extracts gave profiles most closely resembling those of 125I-labelled whole-cells and gave the best resolution of the major proteins. After transfer in Tris-glycine-methanol buffer some proteins, including the major proteins, were not completely transferred and remained in the gel, with the class 2/3 and 5 proteins not effectively detected on nitrocellulose by amido black staining. There was weak antibody recognition of the class 1 and 4 proteins but good recognition of lipooligosaccharide (LOS) and H8 antigen. Empigen BB had no effect on renaturation of the class 1 protein. When 0.1% SDS was incorporated in the same buffer all of the proteins were removed from the gel, and although the major proteins bound to nitrocellulose other proteins did not. There was weak antibody recognition of the class 1 and 4 proteins, stronger reaction to the class 5 protein, but no recognition of the class 2 protein, LOS or H8 antigen, Empigen BB slightly enhanced antibody recognition of the class 1 protein. After transfer in Tris-glycine buffer, all the major proteins were transferred and bound to nitrocellulose and, other than the class 2 protein, were recognised by antibody, both in the presence or absence of Empigen BB, as were LOS and the H8 antigen. Differences existed in the patterns of antibody recognition between the lithium and the Sarkosyl extracts; additional proteins were recognised in the lithium extracts. The surface-labelling studies indicated, however, that some of these proteins were not surface-exposed. Some minor proteins appeared to be more highly immunogenic than the major proteins.

Acetates↗
PubMed1990

Metronidazole resistant Bacteroides fragilis infection of a prosthetic hip joint.

A case of infection involving a prosthetic joint in a patient with adult Still's Disease is described. The causative organism was a strain of Bacteroides fragilis which was resistant to metronidazole. The rarity of this occurrence is emphasised. Diagnostic difficulties which arose are described and the problems encountered with therapy discussed.

Administration, Oral↗
PubMed1990

The 70 kilodalton iron regulated protein of Neisseria meningitidis is not the human transferrin receptor.

Neisseria meningitidis is able to chelate iron from human transferrin (HTF), the main sequestrator of extracellular iron in vivo. Previous workers have reported that a ca. 70 kilodalton (kDa) iron regulated outer membrane protein (FeRP-70) is a highly specific receptor for HTF. We have examined the interaction between the iron regulated outer membrane proteins (OMP's) and HTF, using HTF and rabbit anti HTF, as well as gold labelled HTF (Au-HTF) to blot OMP's of various serogroups and serotypes of N. meningitidis. Also, we used monospecific rabbit anti FeRP-70 in competitive experiments to determine the role of FeRP-70 in HTF-binding. Single proteins (molecular weights range ca. 60 to ca. 90 kDa) were identified in the OMP's from each strain which reacted with HTF. HTF failed to block the reaction between FeRP-70 and the OMP's, conversely anti FeRP-70 failed to block the HTF-binding reaction. We believe that the 70 kDa iron regulated protein of N. meningitidis is not a human transferrin receptor.

Adolescent↗
PubMed1990

Immunogenicity and cross-reactivity of the 70-Kda iron-regulated protein of Neisseria meningitidis in man and animals.

The immune response to different serogroups and serotypes of N. meningitidis has been examined in acute and convalescent sera from patients with meningococcal diseases. The focus of the study was the c. 70-Kda iron-regulated outer-membrane protein (FeRP-70). FeRP-70 was demonstrated on all strains of different serogroups and serotypes examined by sodium dodecylsulphate-polyacrylamide gel electrophoresis or Western blots of outer-membrane proteins (OMPs). Immunoblotting experiments demonstrated the presence of considerable amounts of anti-FeRP-70 IgG antibodies in the acute and convalescent sera of six patients; the antibodies reacted with homologous and heterologous strains. However, sera from two patients who died of severe meningococcal septicaemia had no antibodies against FeRP-70 or any other OMPs demonstrable by immunoblotting. Absorbed rabbit hyperimmune sera reacted with FeRP-70 of their homologous strains, but, unlike human sera, with only a few of the heterologous strains. We believe that FeRP-70 is strongly immunogenic in vivo, cross-reactive amongst different strains, and that man and animals differ considerably in their response to similar meningococcal antigens. The functional attribution of human antibody response against this protein requires further exploration.

Animals↗
PubMed1989

Epitopes of serogroup B Neisseria meningitidis analysed in vitro and directly from cerebrospinal fluid.

Two type B15 P1.16 strains of Neisseria meningitidis were examined by immunogold electron microscopy for accessibility of two outer membrane protein (OMPs) to monoclonal antibodies. Both strains exhibited cell-to-cell variation of one epitope of the Class 3 OMP (P3.15) and one of the Class 1 OMPs (P1.16) when grown in vitro. One strain, a nasopharyngeal isolate revealed this variation to be growth-phase independent and double labelling of both epitopes showed independent variation. CSF containing N. meningitidis was stored in liquid nitrogen without laboratory processing at the time of isolation of the second strain. Direct analysis of the organisms showed no cell-to-cell variation and immunoglobulin G on the surface. However, while there were similar labelling densities of the Class 1 epitope in vivo compared with either strain grown in vitro, there was a lower labelling density of the Class 3 epitope in vivo that was not caused by freeze-thawing. This reduction may be due to decreased expression of this epitope in vivo which casts doubts on the use of the Class 2/3 OMP as a vaccine candidate.

Adult↗
PubMed1989

Clonal and variable properties of Neisseria meningitidis isolated from cases and carriers during and after an epidemic in The Gambia, West Africa.

A representative collection of meningococci was isolated from cases and healthy carriers in The Gambia between 1982 and 1988, during and after an epidemic of meningococcal meningitis. These bacteria were subjected to a clonal analysis. All serogroup A bacteria from both cases and carriers were of one clone (A IV-1). Several unrelated clones were observed among serogroup 29E and serogroup Y carrier strains. The serogroup A strains were uniform for serotype and subtype antigens (serotype 4, subtype P1.7) and antibiotic sensitivity pattern. Occasional strains varied in their lipopolysaccharide (LPS), DNA fingerprint pattern, and/or the quantitative expression of the class 1 protein. A high degree of strain-specific variation was found for the expression of class 5 proteins, pili, and sulfonamide sensitivity. The frequency of strains expressing reduced amounts of the class 1 protein, altered LPS, and/or increased amounts of capsular polysaccharide rose among case strains obtained after the epidemic had ceased. These strains seem to be generally resistant to antibody-mediated bactericidal activity.

Antibodies, Monoclonal↗
PubMed1988

2-Phenylpyridine and 3-phenylpyridine, constituents of tea, are unlikely to cause idiopathic Parkinson's disease.

Idiopathic Parkinson's disease (PD) is likely to be caused by one or more unidentified neurotoxins, present in the environment or formed endogenously, which progressively damage dopaminergic nigrostriatal neurons. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is an experimental neurotoxin which produces biochemical and neuropathological changes in lower primates and mice and in humans inadvertently exposed to it that closely resemble those found in PD. 2-Phenylpyridine (2-PP) and 3-phenylpyridine (3-PP), both of them present in tea, are the only MPTP analogues that are known to be present in the human diet. We exposed C57 black mice, animals very sensitive to the dopaminergic neurotoxicity of MPTP, to prolonged parenteral and oral administration of large doses of 2-PP, and to prolonged parenteral administration of the N-methylated tetrahydro derivatives of 2-PP and 3-PP. The latter are closer chemical analogues of MPTP than are 2-PP and 3-PP themselves. None of these MPTP analogues lowered the contents of dopamine and its metabolites in the striatum of mice. We speculate that the neurotoxins which cause PD are unlikely to resemble MPTP structurally, and we suggest that the search for chemical causes of PD should be directed to a wider variety of compounds encountered by humans.

3,4-Dihydroxyphenylacetic Acid↗