Biomedical subjects
A G Wilson
Publications and source records attributed to A G Wilson.
A tiered approach to pharmacokinetic studies.
Studies of absorption, distribution, metabolism, and elimination (ADME) have long been recognized as important in the evaluation of the pharmacological efficacy of pharmaceutical agents. In recent years, the importance of ADME studies in toxicology also has become increasingly apparent. In realization of the importance of ADME studies, regulatory agencies have established guidelines governing the conduct of these studies. To be of maximum utility, it is desirable that ADME and pharmacokinetic studies be closely integrated with the toxicity testing protocol. However, in many instances this is not the case, which results in ADME and pharmacokinetic studies that are often chronologically and philosophically remote from the toxicity testing protocols. An inevitable consequence of this approach is that it frequently leads to the generation of ADME data that are of limited use in the process of toxicity evaluation and risk assessment. Recently, there has been increased focus on developing testing strategies that would result in the development of ADME data with greater application to toxicity testing and risk assessment. An example of such an approach is the concept of a tiered approach to the conduct of ADME studies. An important aspect of the tiered approach is generating ADME data at an earlier stage during the toxicity testing of a chemical. This could be effected by acceptance of the concept of a minimum experimental data set for a chemical. This minimum data set could be conducted in a timely and economic manner and would develop data addressing three fundamental questions: Is the chemical absorbed? Is the chemical metabolized? Does the chemical persist?(ABSTRACT TRUNCATED AT 250 WORDS)
An allelic polymorphism within the human tumor necrosis factor alpha promoter region is strongly associated with HLA A1, B8, and DR3 alleles.
The tumor necrosis factor (TNF) alpha gene lies within the class III region of the major histocompatibility complex (MHC), telomeric to the class II and centromeric to the class I region. We have recently described the first polymorphism within the human TNF-alpha locus. This is biallelic and lies within the promoter region. Frequency analysis of the TNF-alpha polymorphism, using the polymerase chain reaction and single-stranded conformational polymorphism, in HLA-typed individuals, reveals a very strong association between the uncommon TNF allele and HLA A1, B8, and DR3 alleles. This is the first association between TNF-alpha and other MHC alleles and raises the possibility that the uncommon TNF-alpha allele may contribute to the many autoimmune associations of the A1,B8,DR3 haplotype.
No independent association between a tumor necrosis factor-alpha promotor region polymorphism and insulin-dependent diabetes mellitus.
Several studies have implicated tumor necrosis factor (TNF)-alpha in the pathogenesis of insulin-dependent diabetes mellitus (IDDM). In the present study we analyzed the first reported TNF-alpha gene polymorphism in relation to IDDM. We have made frequence analysis and tested in vitro lipopolysaccharide (LPS)-induced TNF-alpha secretion. A significant difference in allele frequency was observed between patients and controls (p = 0.03). However, a very strong association of the uncommon TNF2 allele was observed with the HLA-B8, -DR3 alleles. The relative risk (RR) of TNF2 was 2.2 compared to a RR of 3.1 for DR3. One reason for this difference was the identification of the TNF1 allele on the otherwise strongly IDDM-associated HLA-DR3 haplotype: DQB1*0201, DQA1*0501, DRB1*0301, TNFc2, TNFB*2, TNFa1, TNFb5, B18. Thus, the IDDM-associated TNF2 allele had no DR3-independent value as a disease marker. The LPS-induced TNF-alpha production by human monocytes in relation to genotypes demonstrated that TNF1/2 heterozygous individuals had higher, though not statistically significantly (p = 0.08) levels than TNF1-homozygous subjects. However, this difference was rather small, unlikely to be of biological significance and based on the present material we cannot establish the functional importance of this polymorphism.
Immunoblotting of streptococcal antigens in guttate psoriasis.
Guttate psoriasis may be precipitated by acute streptococcal infection, usually of the upper respiratory tract. We have studied the immune response to streptococci in 26 patients presenting with a first or recurrent episode of acute guttate psoriasis (AGP), using immunoblotting. Eighteen of 26 patients studied had a demonstrable response to a wide range of streptococcal antigens using this approach, compared with 14 of 26 patients who demonstrated a response using more conventional antistreptococcal antibody tests. Patients with AGP had a significantly higher antibody detection score using immunoblotting than did control subjects (P < 0.005). We conclude that immunoblotting is a useful technique in studying this condition and may be of benefit in exploring the immunopathogenesis of AGP.
A physiologically based model for gastrointestinal absorption and excretion of chemicals carried by lipids.
Pharmacokinetic models which incorporate independently measured anatomical characteristics and physiological flows have been widely used to predict the pharmacokinetic behavior of drugs, anesthetics, and other chemicals. Models appearing in the literature have included as many as 18, or as few as 5 tissue compartments. With the exception of the multiple-compartment delay trains used by Bischoff to model the delays inherent to the appearance of drug metabolites in bile and segments of the intestinal lumen, very little effort has been made to incorporate the available information on gastrointestinal anatomy and physiology into more accurate gastrointestinal absorption/enterohepatic recirculation submodels. Since several authors have shown that the lymphatic system is the most significant route of absorption for highly lipophilic chemicals, we have constructed a model of gastrointestinal absorption that emphasizes chylomicron production and transport as the most significant route of absorption for nonvolatile, lipophilic chemicals. The absorption and distribution of hexachlorobenzene after intravenous vs. oral dosing are used to demonstrate features of this model.
Lung abscess: a neglected cause of life threatening haemoptysis.
Three cases who presented with life threatening haemoptysis are reported, all of whom required surgery to control the bleeding. In all three patients chronic lung abscess was responsible for the haemoptysis. Even in the absence of typical clinical or radiographic features of an abscess this diagnosis should be considered in any patient presenting with life threatening haemoptysis.
Clearance of recombinant tissue factor pathway inhibitor (TFPI) in rabbits.
The pharmacokinetics of recombinant tissue factor pathway inhibitor (TFPI) after an intravenous bolus injection was studied in rabbits. Clearance of TFPI was followed by measurement of the radioactivity of the 125I-labelled compound in the whole plasma or the trichloroacetic acid precipitate and by quantitation of the functional TFPI activity of the unlabelled compound using a tissue factor-induced coagulation assay. When iodinated TFPI was used, the ratios of the trichloroacetic acid precipitable counts vs. that of the whole plasma was about 1 in the first 10 min after TFPI injection, but this ratio gradually decreased to less than 0.5 after 2 h. This result suggested that the iodinated TFPI in the plasma was partially degraded after prolonged circulation in the animal. When unlabelled TFPI was used, the clearance of TFPI activity from the plasma exhibited bi-exponential elimination kinetics with a rapid alpha phase half-life (t1/2 alpha) of 2.3 min, and a terminal beta phase half-life (t1/2 beta) of 79 min. The plasma clearance was 4.2 ml kg-1 min-1. The tissue distribution of intravenously administered 125I-TFPI in the rabbit was studied using whole-body autoradiography. At 3 min after dosing, significant levels of TFPI were apparent in the liver, kidney, and other highly blood perfused tissues. Significant levels of 125I-TFPI-derived radioactivity were also apparent in the liver and kidney at 30 min after intravenous administration. The localization within the liver demonstrated a mottled appearance, suggesting regions of higher uptake within the liver. In the kidney, the outer cortex consistently revealed the highest activity.
Toxicity of calcium sodium metaphosphate fiber. I. In vitro and in vivo degradation and clearance studies.
In an experiment to ascertain the degradability of calcium sodium metaphosphate (CSM) fiber in vitro, 32P-labeled CSM fiber was incubated in media with or without rat lung epithelial cells (LEC) or rat alveolar macrophages (RAM). The amount of radioactivity appearing in the filtrate of the media in the presence of cells minus the radioactivity in the media in the absence of cells was considered to reflect cell-aided dissolution of the fiber. LEC and RAM cells increased the degree of dissolution two- and sevenfold, respectively, compared to their respective media controls in a 7-day time period. In a separate experiment, male Fischer rats were given 32P-labeled CSM fiber either by intraperitoneal injection or by intratracheal instillation and the amount of radioactivity appearing in the urine and feces was measured over a period of 60 days. Selected animals from this experiment were also subjected to whole-body autoradiography 0, 1, 5, 15, 30, and 60 days postexposure. After intraperitoneal injection, approximately 0.9% of the administered dose appeared in the urine. A similar percentage of the dose was eliminated in the urine when the fibers were administered by intratracheal instillation; however, the amount of radioactivity in the feces after intratracheal instillation, i.e., 11.6% of the administered dose, was much higher than that after intraperitoneal dose, i.e., 0.24% of the administered dose. Whole-body autoradiographs showed a time-related increase in radioactivity at a site other than the site of administration, and the location of this radioactivity appeared to be exclusively associated with mineralized tissue. The clearance of nonradiolabeled CSM fiber (approximately 200,000 fibers) from rat lung after intratracheal inhalation (IH) and intratracheal instillation (IT) was monitored. Approximately 93% of the initial fiber load after IH and approximately 84% of the initial fiber load after IT was cleared from the lung in 6 months. Histological and biochemical evaluation of the rat lungs did not reveal any indication of fibrosis up to a period of 6 months. All the studies discussed indicate that CSM is degradable in biological systems and is cleared from the lung after IT and IH administration. These attributes of CSM fiber should reduce the potential for chronic adverse effects in the lung after inhalation.
Biochemical toxicology and disposition of Therminol 66 heat transfer fluid after inhalation or after dietary administration to male Sprague-Dawley rats.
The objectives of this study were to determine the disposition of Therminol 66 in rats and to determine the effects of this heat-transfer fluid on liver and kidney microsomal drug-metabolizing enzymes. Therminol 66 was administered to male Sprague-Dawley rats at various doses as either a single oral administration at 0, 100, or 300 mg/kg, or as a single 6-h inhalation exposure at 0 or 350 mg/m3. Animals were killed 48 h after gavage or after termination of inhalation exposure. Additional groups of animals were exposed to Therminol 66 via the diet at 0, 100, 500, or 5000 ppm for 14 d, or via repeated inhalation exposure at 0, 25, 250, or 1200 mg/m3 for 6 h/d for 14 d. These exposure scenarios represent approximately equivalent doses of Therminol 66 by the different routes of administration. No change in body weight was observed after acute oral or inhalation exposure, and little change in body weight was observed in animals administered Therminol 66 via the diet except at the highest dose. There was no change in kidney weight, and liver weights were increased only at the higher doses of Therminol 66. The body weight gain of animals exposed to Therminol 66 via inhalation decreased in a dose-dependent manner over the 2-wk exposure period. Results from the disposition study indicated that Therminol 66 did not appear to accumulate in the tissues examined and did not appear to be extensively absorbed after a single oral dose of 300 mg/kg. The whole-body elimination half-life was approximately 14 h and occurred primarily via the feces. There was no significant induction of hepatic aryl hydrocarbon hydroxylase (AHH) activity after single oral or inhalation exposures to Therminol 66. Ethoxycoumarin O-deethylase (ECOD) was significantly induced only in animals exposed to 350 mg/m3 via inhalation. Repeated dietary and inhalation exposures resulted in AHH and ECOD induction only at the highest doses, and the kidney appeared to be less sensitive than the liver. Animals exposed via inhalation demonstrated a greater hepatic inductive effect than did animals exposed via the diet, which may be due to absorption differences.(ABSTRACT TRUNCATED AT 400 WORDS)
Single base polymorphism in the human tumour necrosis factor alpha (TNF alpha) gene detectable by NcoI restriction of PCR product.
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Microalbuminuria in systemic sclerosis.
A prospective study was performed to determine urinary albumin excretion in a group of 28 patients with systemic sclerosis. At the initial screen one patient had proteinuria and three had microalbuminuria. One year later these abnormalities persisted and in two of of the patients serum creatinine had significantly increased. In addition, a further three patients had developed microalbuminuria. In a control group of 10 patients with primary Raynaud's disease none had microalbuminuria. In a second control group of 16 patients with unrelated skin diseases one patient had microalbuminuria and one proteinuria, but both these patients had a history of hypertension. It is concluded that microalbuminuria is more common in patients with systemic sclerosis than in patients of equivalent age with other dermatological conditions but no vascular disease.
Heredofamilial deficiency of monocyte esterase in patients with rheumatoid arthritis.
Deficiency of the monocyte ectoenzyme non-specific esterase is described in a heredofamilial pattern in four patients with rheumatoid arthritis. No association with HLA status or rheumatoid factor seropositivity was found.
Mycosis fungoides in childhood: an unusual presentation.
Mycosis fungoides, a cutaneous T cell lymphoma, is rare in childhood and adolescence. We report a case of mycosis fungoides in a 9-year-old boy initially at a site of benign reactive lymphoid hyperplasia.
Lichen planus and mesalazine.
Lichen planus is a recognized complication of sulfasalazine therapy. Two patients developed typical oral and cutaneous lichen planus on sulfasalazine and their skin lesions recurred when they were subsequently changed to mesalazine. Lichen planus only resolved on withdrawal of both drugs. It seems likely that the aminosalicylic acid moiety is responsible for this reaction and that lichen planus is a true complication of mesalazine therapy.
Comments on incorporating mechanistic data into quantitative risk assessment.
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Echogenic focus in gastric ulceration.
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Successful pregnancy in a woman with systemic sclerosis while taking nifedipine.
The case is reported of successful conception and pregnancy in a woman with systemic sclerosis while receiving continuous treatment with nifedipine 30 mg/day, after a previously poor obstetric record and involuntary secondary infertility.