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Biomedical subjects

J S Dixon

Publications and source records attributed to J S Dixon.

At least 19 recordsLinked to original sources
PubMed1995

Flexible ligand docking using a genetic algorithm.

Two computational techniques have been developed to explore the orientational and conformational space of a flexible ligand within an enzyme. Both methods use the Genetic Algorithm (GA) to generate conformationally flexible ligands in conjunction with algorithms from the DOCK suite of programs to characterize the receptor site. The methods are applied to three enzyme-ligand complexes: dihydrofolate reductase-methotrexate, thymidylate synthase-phenolpthalein and HIV protease-thioketal haloperidol. Conformations and orientations close to the crystallographically determined structures are obtained, as well as alternative structures with low energy. The potential for the GA method to screen a database of compounds is also examined. A collection of ligands is evaluated simultaneously, rather than docking the ligands individually into the enzyme.

Algorithms↗
PubMed1995

Immunohistochemical localization of neuromarkers and neuropeptides in human fetal and neonatal urinary bladder.

OBJECTIVE: To use immunohistochemical techniques to determine the spatial and temporal distribution of a variety of neuropeptides in the human fetal and neonatal urinary bladder. MATERIALS AND METHODS: Thirteen pre-natal specimens ranging in gestational age from 17 to 35 weeks were acquired following abortion or miscarriage. In addition two post-natal specimens aged 8 and 12 weeks were obtained at post-mortem and were included in this study. The overall innervation of each specimen was visualized using the general nerve marker protein gene product 9.5 (PGP). Localization of dopamine-beta-hydroxylase (DBH) and tyrosine hydroxylase (TH) revealed putative noradrenergic nerves. The neuropeptides studied included neuropeptide Y (NPY), vasoactive intestinal polypeptide (VIP), substance P (SP), and calcitonin gene-related peptide (CGRP). RESULTS: At 17 weeks a rich plexus of PGP and NPY-containing nerves was present throughout the detrusor muscle coat. As gestational age increased, VIP, SP and CGRP-containing nerves were observed with increasing frequency although SP and CGRP were mainly confined to perivascular nerve plexuses. TH- and DBH-containing nerves were first observed in the intramural ureters at 30 weeks and the detrusor muscle at 35 weeks and were relatively numerous in the intramural ureters and muscle of the superficial trigone in the two post-natal specimens. PGP-containing nerves were first observed beneath the bladder epithelium at 23 weeks and gradually became more numerous with increasing age. Occasional NPY, VIP, SP and CGRP-containing nerves were observed in the submucosa but TH- and DBH-immunostained nerves were especially numerous in the mucosa of the trigone in the two post-natal specimens, many such nerves being unrelated to the vascular supply. CONCLUSIONS: The bladder detrusor possesses a rich autonomic innervation by 17 weeks of gestation and this presumptive cholinergic innervation is associated with NPY immunoreactivity. Presumptive noradrenergic nerves appear relatively late in pre-natal development and mainly supply the intramural ureters and superficial trigone. A submucosal plexus of nerves has been demonstrated, the functional significance of which remains uncertain.

Calcitonin Gene-Related Peptide↗
PubMed1995

Development of peptide-containing nerves in the human fetal vas deferens and seminal vesicle.

OBJECTIVE: To use immunohistochemical methods to study the developing autonomic innervation of the human fetal vas deferens and seminal vesicle. MATERIAL AND METHODS: Thirteen pre-natal specimens ranging in gestational age from 13 to 30 weeks were acquired following abortion or miscarriage. The overall innervation of each specimen was visualized using protein gene product 9.5 (PGP), a general nerve marker, while the onset and development of specific neuropeptide-containing sub-populations were investigated using antisera to neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene related peptide (CGRP), bombesin (BOM), somatostatin (SOM), and met-enkephalin (ENK). In addition the occurrence and distribution of presumptive noradrenergic nerves was studied using antisera to dopamine-beta-hydroxylase (D beta H) and tyrosine hydroxylase (TH). RESULTS: At 13 weeks numerous PGP, D beta H, TH, NPY and ENK immunoreactive (-IR) nerve trunks were present in the adventitia of the vas deferens and seminal vesicle but at this stage nerve fibres were not present in the smooth muscle coat of either organ. By 17 weeks, fine PGP-, D beta H, and TH-IR nerve fibres had penetrated the outer aspect of the muscle coat of the seminal vesicle but not the vas deferens. At 20 weeks a branching network of PGP-, D beta H- and TH-IR nerve fibres occurred throughout the full thickness of the muscle coat of the seminal vesicle while similar nerves were present only in the outer half of the muscle coat of the vas deferens. At 23 weeks the full thickness of the muscle coat of the vas deferens was richly innervated by a branching plexus of PGP-IR nerves. Many of these adventitial and intramuscular nerves were immunoreactive for D beta H or TH while some were immunoreactive for either NPY or ENK. Occasional adventitial nerves were immunoreactive for SP or CGRP, these being first observed at 20 weeks. VIP-IR nerves were extremely rare in the muscle coat of either organ, being first observed at 17 weeks in the seminal vesicle and at 20 weeks in the vas deferens where they mainly formed perivascular plexuses. PGP-IR nerves were first observed in the submucosa of the seminal vesicle at 20 weeks and in the vas deferens at 21 weeks. Some of these nerves were perivascular in location while other formed a subepithelial plexus which increased in density with increasing gestational age. At 22 weeks of gestation some of the submucosal nerves were immunoreactive for SP or NPY, while at 30 weeks NPY-IR nerves formed the majority of subepithelial nerves. Occasional VIP-IR subepithelial nerves were first observed at 26 weeks but were extremely rare even at 30 weeks. Submucosal nerves immunoreactive for CGRP, D beta H, TH or ENK did not occur in any of the specimens examined. CONCLUSION: (i) From 13 weeks gestation autonomic nerves develop in the muscle coat of the fetal seminal vesicle and vas deferens, being denser in the seminal vesicle than the vas deferens up to 23 weeks gestation. (ii) The majority of the intramuscular nerves in either organ contain D beta H, TH, NPY and ENK and are presumably noradrenergic in type. (iii) A subepithelial nerve plexus develops around 20 weeks gestation and contains NPY but not VIP, unlike the adult organs. (iv) Scattered neuroendocrine cells immunoreactive for SOM are present in the mucosa of the seminal vesicle from 23 weeks of gestation.

Autonomic Nervous System↗
PubMed1995

Development of peptide-containing nerves in the human fetal prostate gland.

Immunohistochemical methods were used to study the developing peptidergic innervation of the human fetal prostate gland in a series of specimens ranging in gestational age from 13 to 30 wk. The overall innervation of each specimen was visualised using protein gene product 9.5 (PGP), a general nerve marker. The onset and development of specific neuropeptide-containing subpopulations were investigated using antisera to neuropeptide Y (NPY), vasoactive intestinal peptide (VIP), substance P (SP), calcitonin gene-related peptide (CGRP), bombesin (BOM), somatostatin (SOM), leu-enkephalin (l-ENK) and met-enkephalin (m-ENK). In addition the occurrence and distribution of presumptive noradrenergic nerves was studied using antisera to dopamine-beta-hydroxylase (D beta H) and tyrosine hydroxylase (TH). At 13 wk numerous branching PGP-immunoreactive (-IR) nerves were observed in the capsule of the developing prostate gland and surrounding the preprostatic urethra but the remainder of the gland was devoid of nerves. The majority of nerves in the capsule contained D beta H and TH and were presumed to be noradrenergic in type while other nerves (in decreasing numbers) contained NPY, l-ENK, SP and CGRP. Nerves associated with the preprostatic urethra did not contain any of the neuropeptides under investigation. At 17 wk the density of nerves in the capsule had increased and occasional m-ENK-, VIP- and BOM-IR nerve fibres were also observed. In addition PGP, D beta H-, TH-, NPY- and l-ENK-IR nerves occurred in association with smooth muscle bundles which at 17 wk were present in the outer part of the gland. Occasional PGP-IR nerves were also present at the base of the epithelium forming some of the prostatic glands. At 23 wk some of the subepithelial nerves showed immunoreactivity for NPY, VIP or l-ENK. At 26 wk smooth muscle bundles occurred throughout the gland and were richly innervated by PGP, D beta H and TH-IR nerves while a less dense plexus was formed by NPY- and l-ENK-IR nerves together with a few m-ENK-IR nerves. Occasional smooth muscle-associated varicose nerve fibres showed immunoreactivity for SP, CGRP, VIP or BOM although the majority of these types of nerve formed perivascular plexuses. Also at 26 wk numerous varicose nerve fibres were observed in association with the prostatic acini, the majority of such nerves containing NPY with a few showing immunoreactivity to VIP, l-ENK, SP or CGRP.(ABSTRACT TRUNCATED AT 400 WORDS)

Bombesin↗
PubMed1994

A shape- and chemistry-based docking method and its use in the design of HIV-1 protease inhibitors.

The program DOCK [1,2] has been used successfully to identify molecules which will bind to a specified receptor [3]. The original method ranks molecules based on their shape complementarity to the receptor site and relies on the chemist to bring the appropriate electrostatic or hydrogen bond properties into the molecular skeletons obtained in the search. This is useful when screening a small database of compounds, where it is not likely that molecules with both the correct shape and electrostatic properties will be found. As large databases are more likely to have redundant molecular shapes with a variety of functionality (e.g., members of a congeneric series), it would be useful to have a method which identifies molecules with both the correct shape and functionality. To this end we have modified the DOCK 1.0 method to target user-specified atom types to selected positions in the receptor site. The target sites can be chosen based on structural evidence, calculation or inspection. Targeted-DOCK improves the ability of the DOCK method to find the crystallographically determined binding mode of a ligand. Additionally, targeted-DOCK searches a database of small molecules at 100-1000 times the rate of DOCK 1.0, allowing more molecules to be screened and more sophisticated scoring schemes to be employed. Targeted-DOCK has been used successfully in the design of a novel non-peptide inhibitor of HIV-1 protease.

Binding Sites↗
PubMed1994

The effect of renal function on the pharmacokinetics of ranitidine.

This open study evaluated the influence of renal function on the pharmacokinetics of ranitidine (50 mg i.v. infusion given over 6 min). Five groups, each of 8 subjects, 1 with normal renal function and 4 with different degrees of renal impairment were studied. Renal function was assessed in each patient by 51Cr-EDTA (glomerular filtration rate, GFR), creatinine clearance (GFR) and N-methylnicotinamide clearance (reflecting glomerular and tubular function). Sixteen blood samples (5 ml) taken up to 48 h post dose from each subject were analysed for plasma ranitidine concentrations by reversed phase HPLC. Patient groups with renal impairment had significantly increased AUC infinity and t1/2 with corresponding decreases in CLp and lambda z when compared with normal subjects. There was also a significant increase in tmax but not in Cmax. There was a high linear correlation between the degree of renal impairment and ranitidine clearance. In patients with GFR < or = 20 ml min-1, the AUC infinity mean ratio (compared with normal subjects) was up to 4.6 while for patients with GFR 20-50 ml min-1, the average AUC infinity ratio was 2.6. It is recommended that the dose of ranitidine is halved in patients with GFR < or = 20 ml min-1.

Adult↗
PubMed1994

The intramural innervation of the human vas deferens and seminal vesicle in infants and children.

Immunohistochemical methods were used to study the autonomic innervation of the vas deferens and seminal vesicle in a series of human postnatal specimens ranging in age from 1 month to 3 years. The occurrence and distribution of nerves immunoreactive for the neuropeptides vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY) substance P (SP) and calcitonin gene-related peptide (CGRP) were investigated. In addition immunoreactivity to tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH) and to protein gene product (PGP 9.5), a general nerve marker were also studied. A neurohistochemical method was used to localise acetylcholinesterase. The results obtained from either organ were similar. Regardless of age, a rich plexus of nerve fibres immunoreactive for PGP 9.5 was present both within the muscle coat and also beneath the epithelium of the vas deferens and seminal vesicle. Some acetylcholinesterase containing nerves occurred in the muscle coat but the majority were found under the epithelium in the connective tissue of the mucosa. TH and DBH-containing nerves (presumably noradrenergic in type) formed dense intramuscular plexuses but none occurred subepithelially. In contrast NPY-containing nerves formed a less dense intramuscular plexus and were also observed beneath the epithelium. Thus while NPY may occur in some of the intramuscular noradrenergic nerve fibres it is clearly not confined to this type of nerve in either the vas deferens or the seminal vesicle. SP- and CGRP-containing nerves were extremely infrequent and, when observed, were confined to the muscle coat.(ABSTRACT TRUNCATED AT 250 WORDS)

Autonomic Nervous System↗
PubMed1992

Proteolysis of an active site peptide of lactate dehydrogenase by human immunodeficiency virus type 1 protease.

The muscle and heart lactate dehydrogenase (LDHs) of rabbit and pig are specifically cleaved at a single position by HIV-1 protease, resulting in the conversion of 36-kDa subunits of the oligomeric enzymes into 21- and 15-kDa protein bands as analyzed by SDS-PAGE. While the proteolysis was observed at neutral pH, it became more pronounced at pH 6.0 and 5.0. The time courses of the cleavage of the 36-kDa subunits were commensurate with the time-dependent loss of both quaternary structure and enzymatic activity. These results demonstrated that deoligomerization of rabbit muscle LDH at acidic pH rendered its subunits more susceptible to proteolysis, suggesting that a partially denatured form of the enzyme was the actual substrate. Proteolytic cleavage of the rabbit muscle enzyme occurred at a decapeptide sequence, His-Gly-Trp-Ile-Leu*Gly-Glu-His-Gly-Asp (scissile bond denoted throughout by an asterisk), which constitutes a "strand-loop" element in the muscle and heart LDH structures and contains the active site histidyl residue His-193. The kinetic parameters Km, Vmax/KmEt, and Vmax/Et for rabbit muscle LDH and the synthetic decapeptide Ac-His-Gly-Trp-Ile-Leu*Gly-Glu-His-Gly-Asp-NH2 were nearly identical, suggesting that the decapeptide within the protein substrate is conformationally mobile, as would be expected for the peptide substrate in solution. Insertion of part of this decapeptide sequence into bacterial galactokinase likewise rendered this protein susceptible to proteolysis by HIV-1 protease, and site-directed mutagenesis of this peptide in galactokinase revealed that the Glu residue at the P2' was important to binding to HIV-1 protease. Crystallographic analysis of HIV-1 protease complexed with a tight-binding peptide analogue inhibitor derived from this decapeptide sequence revealed that the "strand-loop" structure of the protein substrate must adopt a beta-sheet structure upon binding to the protease. The Glu residue in the P2' position of the inhibitor likely forms hydrogen-bonding interactions with both the alpha-amide and gamma-carboxylic groups of Asp-30 in the substrate binding site.

Amino Acid Sequence↗
PubMed1992

Computer-aided drug design: getting the best results.

There are two major stages in the design of drug molecules: lead-molecule development and lead-molecule optimization. Whereas a variety of computational chemistry and molecular modeling (CC/MM) techniques are now routinely and successfully applied to the optimization stage of drug design, the generation of initial lead compounds has proven a more difficult problem for the CC/MM approach. Only recently has the design of lead molecules by this route become a subject of active research. This article looks at the factors which must be considered carefully when incorporating CC/MM methods into different aspects of drug-design strategies.

Computers↗
PubMed1992

Increase in presumptive sensory nerves of the urinary bladder in idiopathic detrusor instability.

The density of subepithelial, presumptive sensory nerves in the bladder wall was assessed in 21 women with idiopathic detrusor instability and compared with the density of these nerves in 21 asymptomatic women, using a point-counting technique on sections of bladder biopsies stained for acetylcholinesterase activity. The mean value (+/- S.E.) for the amount of such nerves in patients with detrusor instability (91 +/- 13/mm2) was significantly greater than that from the control group (61 +/- 7/mm2). This suggests that a relative abundance of subepithelial sensory nerves may serve to increase the appreciation of bladder filling, giving rise to the frequency and urgency of micturition which are characteristic of patients with detrusor instability.

Adult↗
PubMed1992

An immunohistochemical study of human postnatal paraganglia associated with the urinary bladder.

Histological and immunohistochemical methods were used to study pelvic paraganglia in a series of human postnatal specimens ranging in age from 1 month to 6 y. Up to 5 months of age, many of the encapsulated paraganglia contained small pacinian-like sensory corpuscles which occurred either singly or in small clusters, implying an unknown functional interrelationship during this period. In older specimens, this intimate association was not observed since pacinian corpuscles and small nonencapsulated clusters of paraganglion cells were observed only as separate structures. It is suggested that the paraganglion cells may induce the formation of the pacinian corpuscles during fetal development. Immunohistochemistry using the nerve marker protein gene product (PGP 9.5) demonstrated a rich plexus of varicose nerve fibres within the paraganglia which may directly innervate the paraganglion cells and/or be associated with the profuse vascular supply. A similar density of vasoactive intestinal polypeptide-containing nerves was also demonstrated while some of the nerves contained calcitonin gene related peptide or substance P. The paraganglion cells stained positively for tyrosine hydroxylase, dopamine-beta-hydroxylase and neuropeptide Y, but not for phenylethanolamine N-methyltransferase. This combination of immunostaining confirms them as a rich source of noradrenaline.

Age Factors↗
PubMed1991

Interactions between non-steroidal anti-inflammatory drugs and H2-receptor antagonists or prostaglandin analogues.

Published pharmacokinetic studies investigating possible interaction between H2-receptor antagonists (n = 22) or prostaglandin analogues (n = 6) and nonsteroidal anti-inflammatory drugs (NSAIDs) have been reviewed. With two exceptions the studies were carried out in young, healthy male volunteers rather than in arthritis patients. In addition some of the studies were poorly designed and inadequately described. Cimetidine appeared to increase the area under the plasma concentration-time curve, and hence to decrease the apparent oral clearance, of several NSAIDs including piroxicam, indomethacin, flurbiprofen, sulindac, oxaprozin and aspirin, while ranitidine co-administration resulted in similar changes for oxyprozin alone. The data currently available for prostaglandin analogues are insufficient to draw firm conclusions. It therefore remains a possibility that clinically relevant pharmacokinetic interactions may occur in elderly arthritic patients, and this issue needs to be addressed.

Adult↗
PubMed1991

Ranitidine in the treatment of duodenal ulcer disease: relationship between antisecretory effect and ulcer healing rate.

The relationship between drug-induced suppression of intragastric acidity and the rate of duodenal ulcer healing was examined using data for a single drug, ranitidine, from 156 clinical trials involving 16,362 patients together with data on acid suppression from 37 studies of intragastric acidity in 630 subjects. In these studies ranitidine was given in doses ranging from 150 mg to 1200 mg per day administered in 9 different dosage regimens. The overall percentage of patients whose duodenal ulcers healed at 2 and 4 weeks on the different regimens was highly correlated with the percentage suppression of 24-hour intragastric acidity induced by different regimens. Thus the therapeutic benefit of a given ranitidine dosage regimen in healing duodenal ulcers relates directly to its antisecretory effect.

Drug Administration Schedule↗
PubMed1991

The pharmacokinetics and pharmacodynamics of nifedipine at steady state during concomitant administration of cimetidine or high dose ranitidine.

Ranitidine may be used at doses of up to 300 mg twice daily in the healing of duodenal ulcers, and this study investigated the potential for a pharmacokinetic or pharmacodynamic interaction between nifedipine 10 mg three times daily and ranitidine 300 mg twice daily compared with cimetidine 800 mg daily and placebo in a randomised crossover study in 18 healthy male subjects. Twelve blood samples were taken on the fifth day in each treatment period and assayed for nifedipine by h.p.l.c. Pulse, blood pressure and ECG recordings were also taken. Cimetidine, but not ranitidine, produced significant changes in the pharmacokinetics of nifedipine at steady state. Mean +/- s.d. values of AUC were 105 +/- 40 micrograms l-1 for placebo treatment, 111 +/- 45 micrograms l-1 h for ranitidine and 211 +/- 64 micrograms l-1 h for cimetidine (P less than 0.001), and Cmax values were 33 +/- 14, 39 +/- 27 and 76 +/- 40 micrograms l-1 (P less than 0.001), respectively. Neither ranitidine nor cimetidine produced statistically significant changes in the pharmacological response to nifedipine.

Adult↗
PubMed1991

Relationship between bladder morphology and long-term outcome of treatment in patients with high pressure chronic retention of urine.

A group of 32 men undergoing bladder outflow surgery for high pressure chronic retention (HPCR) of urine were studied prospectively. At the time of treatment marked morphological changes in the bladder wall were demonstrated histologically, but after a mean follow-up of 42.9 months residual urine had decreased significantly and renal function had improved or stabilised in 28 patients (84%). Four patients deteriorated but in 3 of these another potential cause for loss of renal function was present. The majority of patients have a good long-term prognosis following treatment for HPCR.

Adult↗
PubMed1991

Cystometric, physiological and morphological studies after relief of bladder outflow obstruction in the pig.

Experimental bladder outflow obstruction was relieved in 18 pigs between 2 and 15 months after the creation of partial urethral obstruction. Cystometric, physiological and morphological studies were performed 2 to 6 months after relief of the obstruction. An increase in average voiding flow rates from 2.8 +/- 1.0 ml/s to 6.8 +/- 1.2 ml/s was recorded in the Landrace pigs and from 2.2 +/- 0.9 ml/s to 7.4 +/- 1.4 ml/s in the Göttingen mini-pigs. There was a concomitant decrease in the voiding detrusor pressures from 52 +/- 11 cm H2O to 32 +/- 8 cm H2O and from 78 +/- 12 cm H2O to 33 +/- 6 cm H2O respectively. A return towards control values of the physiological responses to exogenously applied agonists (acetylcholine and potassium) and to electrical field stimulation was observed. There was an increase in neuronal innervation in the morphological studies which was more marked in the animals with a shorter period of obstruction. The implications for patient care are discussed.

Acetylcholine↗
PubMed1990

A lack of pharmacokinetic interaction between ranitidine and piroxicam.

The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects. In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (Cmax) was 467 ng.ml-1 for ranitidine alone and 466 ng.ml-1 in the presence of piroxicam: mean area under the plasma concentration vs time curve (AUC) was 2460 h.ng ml-1 and 2551 h.ng ml-1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively. In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean Cmax was 2.1 micrograms.ml-1 in the presence of placebo and 2.0 micrograms.ml-1 in the presence of ranitidine respectively; mean AUC was 133 h.microgram ml-1 and 137 h.microgram ml-1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.

Adolescent↗