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Biomedical subjects

G G Thompson

Publications and source records attributed to G G Thompson.

At least 55 records · Page 3Linked to original sources
PubMed1987

The Harderian gland, its secretory duct and porphyrin content in the woodmouse (Apodemus sylvaticus).

The Harderian gland of the woodmouse (Apodemus sylvaticus) consists of tubules lined by a single layer of epithelial cells with a surrounding layer of myoepithelial cells. The epithelium contains two cell types, one with numerous small, clear, lipid vacuoles (Type I), the other with large electron-dense ones (Type II). Each type is further subdivided into cells where the smooth endoplasmic reticulum exhibits pronounced vacuolation (Ia and IIa). The lipid vacuoles frequently coalesce and are released by exocytosis. They possess a multilamellar cap; similar multilamellar whorls (without a vacuole) are also seen. Polytubular complexes are a feature of Type II cells; tubules are in continuity with the smooth endoplasmic reticulum. Peroxisomes are also present. Fenestrated capillaries occur frequently in the interstitium, and (where no myoepithelial cell intervenes) the basal surface of the gland epithelial cell is covered with microvilli. There is no morphologically distinct duct system within the gland. The extraglandular duct is lined by columnar epithelium except at the opening on to the nictitating membrane where there is stratified squamous epithelium, with melanocytes and nests of mucus-secreting cells. The porphyrin content of the gland is low and solid intraluminal deposits are not seen.

Animals↗
PubMed1986

Verapamil potentiates carbamazepine neurotoxicity: a clinically important inhibitory interaction.

Verapamil (120 mg three times a day) was given as adjunctive therapy to six patients with refractory partial epilepsy who were receiving carbamazepine (CBZ). Within a few days symptoms of CBZ neurotoxicity developed in all six patients. There was a mean rise of 46% in total and 33% in free plasma CBZ concentrations in five of these patients (p less than 0.01), and a simultaneous fall of 36% in the ratio of the principal metabolite, CBZ-10,11-epoxide, to CBZ (p less than 0.001). Two patients with mild symptoms were rechallenged with a lower verapamil dosage (120 mg twice a day) and showed similar rises in CBZ concentration and recurrent neurotoxic symptoms. Verapamil increased the area under the CBZ concentration/time curve during a dose interval by 42% in another patient. Withdrawal of verapamil was associated with a decline in circulating CBZ concentration from 12 mg/l to 7 mg/l and seizure breakthrough in a further patient who was receiving both drugs long term. These results suggest that verapamil inhibits the metabolism of CBZ to an extent likely to have important clinical repercussions.

Adult↗
PubMed1986

The effect of verapamil on the pharmacokinetics of adriamycin.

The concurrent administration of adriamycin (intravenous) and verapamil (oral) is of considerable interest because of experimental data suggesting that resistance to adriamycin may be overcome by this means. The potential for a pharmacokinetic interaction between the two drugs has therefore been investigated in five patients with small cell lung cancer treated with combination chemotherapy comprising adriamycin, VP16, vincristine and cyclophosphamide. The data indicate that a significant interaction takes place. Adriamycin peak levels, terminal half-life and the volume of distribution at steady state are higher, whereas plasma drug clearance and the volume of the central compartment are lower with co-administration of verapamil. There was no evidence of enhanced drug toxicity in this study; however, the data should be considered in the interpretation of clinical trials in which adriamycin and verapamil are used together, both in terms of toxicity and tumour response.

Administration, Oral↗
PubMed1986

The prevention of porphyrin loss from tissues during routine histological processing: quantitative studies on the Harderian gland.

The rodent Harderian gland is an important site of porphyrin biosynthesis and storage. Porphyrins are visible at the light and electron microscope level as large intraluminal accretions, as large interstitial accretions surrounded by foreign body giant cells, or as small interstitial deposits within free macrophages. Since porphyrins are soluble in a wide range of solvents, it is important to employ histological routines which minimize porphyrin loss during processing in addition to giving good tissue preservation. In this quantitative investigation, these requirements were optimally achieved with fixation in 3% buffered glutaraldehyde and the use of amyl acetate as a clearing agent.

Animals↗
PubMed1986

Quantitative studies on the effects of hormones on structure and porphyrin biosynthesis in the harderian gland of the female golden hamster. II. The time course of changes after ovariectomy.

The Harderian gland of the golden hamster is an important model of porphyrin biosynthesis. In the female, ovariectomy leads to changes in porphyrin production and gland structure. The present study demonstrates that these changes are progressive and independent of age and environmental factors which may have similar effects. Porphyrinogenic enzyme activity decreases with time after ovariectomy while tubule wall degeneration and neutrophilic infiltration increase. Tubule degeneration leads in turn to porphyrin stores (normally intraluminal) occurring increasingly in the interstitial tissue of the gland, either as large accretions surrounded by foreign body giant cells or as small deposits inside individual free macrophages. Between 20-30 weeks after ovariectomy, the frequency of mitotic figures begins to increase accompanied by a transient rise in porphyrinogenic enzyme activity. Mast cell numbers (both in the gland and its capsule) increase markedly with time after ovariectomy.

5-Aminolevulinate Synthetase↗
PubMed1986

Hemodialysis-related porphyria cutanea tarda--treatment failure with charcoal hemoperfusion.

A 56-yr-old man presented with a photosensitive bullous dermatosis 1 yr after commencing hemodialysis. Urinary porphyrin levels were normal and fecal porphyrin levels only minimally increased, but the plasma uroporphyrin concentration was markedly elevated, being higher than that normally occurring in porphyria cutanea tarda. The high plasma uroporphyrin level was thought to result from the combined effects of increased porphyrin production and failure of adequate clearance by hemodialysis. Chronic alcohol ingestion, methyldopa therapy and elevated iron and aluminum levels may have contributed to the porphyrin overproduction. Charcoal hemoperfusion proved unhelpful in lowering the plasma uroporphyrin concentration.

Charcoal↗
PubMed1985

Chester porphyria: biochemical studies of a new form of acute porphyria.

A previously unrecognised form of acute porphyria has been identified in a large family in Chester, UK. Patients presented with attacks of neurovisceral dysfunction and none had experienced cutaneous photosensitivity. Biochemically, the excretion pattern of haem precursors varied between individuals; some had a pattern typical of acute intermittent porphyria, others showed that of variegate porphyria, and some had an intermediate pattern. Studies of the enzymes of haem biosynthesis in peripheral blood cells showed a dual enzyme deficiency, with reduced activity of both porphobilinogen deaminase, as seen in acute intermittent porphyria, and protoporphyrinogen oxidase, as seen in variegate porphyria. The genetic basis of this dual form of acute porphyria and its relation to the other acute porphyrias are not clear.

5-Aminolevulinate Synthetase↗
PubMed1985

The Harderian gland, its secretory duct and porphyrin content in the Plains mouse (Pseudomys australis).

The Harderian gland of the Australian Plains mouse (Pseudomys australis) consists of tubules lined by a single layer of epithelial cells with a surrounding meshwork of myoepithelial cells. The epithelium contains three types of cell. Type I cells, characterised by their many large apical lipid vacuoles, are comparable with cells reported in other rodents. Secretion is exocytotic and, to a lesser extent, apocrine. Type II cells are highly distinctive with extremely large mitochondria arranged in stacks and whorls. Unusually for Harderian glands, these cells possess prominent conventional Golgi complexes and lysosomes. Cytoplasmic 'slashes', possible vacuole-precursors, are also present. Type III cells have few distinguishing features and may be resting cells. They are occasionally binucleate and mitotic figures occur. The gland contains stored porphyrins, chiefly protoporphyrin, in the form of solid intraluminal accretions. There is a marked sex difference, with females having higher levels of porphyrin than males. Among the components of the interstitial tissue are mast cells, plasma cells and porphyrin-containing macrophages. The secretory duct contains large quantities of cell debris, including nuclei, and is lined by columnar cells with single large apical vacuoles. The outer opening of the duct is lined by mucus-secreting cells and stratified squamous epithelium.

Animals↗
PubMed1984

Effect of stanozolol on delta-aminolaevulinic acid synthase and hepatic monooxygenase activity in man and rat.

Stanozolol is an anabolic steroid which is used in the treatment of aplastic anaemia and has been recently advocated for the prophylaxis of vascular thrombosis. Similar steroid substances stimulate the activity of delta-aminolaevulinic acid synthase (ALA S), the rate limiting enzyme of haem biosynthesis, in rat hepatocytes and chick embryo liver cell cultures and activate acute hepatic porphyria. In the present study stanozolol (10 mg daily for 14 days) has been shown to increase significantly leucocyte ALA S activity in 9 healthy male subjects. There was a concomitant rise in urinary ALA and total porphyrin excretion but no change in antipyrine kinetics or urinary 6 B hydroxycortisol excretion. In a complementary study in male Sprague Dawley rats, stanozolol administered intraperitoneally, produced a dose-dependent increase in hepatic ALA S activity without changing hepatic cytochrome P 450 content. Stanozolol has been clearly shown to elevate ALA S activity, probably directly, and thereby, porphyrin production without affecting hepatic monooxygenase activity. This porphyrinogenic effect may be relevant to the successful treatment of aplastic anaemia with anabolic steroids. Leucocyte ALA S activity may provide a human system for the study of drug porphyrinogenicity in vivo.

5-Aminolevulinate Synthetase↗
PubMed1984

Sex differences in haem biosynthesis and porphyrin content in the Harderian gland of the golden hamster.

Methods are described for the measurement of seven haem biosynthetic enzymes in Harderian gland tissue from male and female golden hamsters. Sex differences were found in five of the seven enzymes. In each case, female tissue exhibited higher activity than male tissue. These differences in enzyme activity are sufficient to account for the major sex difference in porphyrin content in the Harderian gland of this species.

5-Aminolevulinate Synthetase↗
PubMed1984

Effects of cimetidine on carbamazepine auto- and hetero-induction in man.

The effect of cimetidine (CMT; 400 mg twice daily) and matching placebo on the enzyme-inducing properties of carbamazepine (CBZ; 200 mg at night for 15 days) was studied in seven healthy male volunteers. CMT alone had no significant effect on antipyrine kinetics, urinary 6 beta-hydroxycortisol excretion or leucocyte delta-aminolaevulinic acid synthase (ALA.S) activity. CBZ increased leucocyte ALA.S activity by 204% following 1 week's treatment (P less than 0.001). Thereafter, ALA.S activity fell despite continued CBZ administration. Concomitant CMT did not influence this response. Antipyrine clearance and urinary 6 beta-hydroxycortisol excretion were both increased by CBZ after 2 weeks' treatment (P less than 0.01). CMT blocked CBZ induction of antipyrine metabolism but the rise in urinary 6 beta-hydroxycortisol excretion was unaffected. Plasma CBZ concentrations 10, 14 and 18 h following the 8th and 15th doses were higher when CMT was taken concurrently (P less than 0.05). CBZ half-life fell by 36% and clearance rose by 29% (both P less than 0.001) with placebo and by 10% and 7% (both NS) when CMT was taken concurrently. CMT inhibits CBZ auto- and hetero-induction in man. Epileptic patients receiving CBZ chronically may be at risk of toxicity if CMT is also prescribed.

5-Aminolevulinate Synthetase↗
PubMed1984

Effect of carbamazepine on haem biosynthesis in man.

The effects of the enzyme-inducing anticonvulsant carbamazepine on haem biosynthesis in healthy male subjects is reported. A dose-dependent increase in the activity of leucocyte delta-aminolaevulinic-acid synthase, the rate-limiting enzyme of haem biosynthesis, was noted following 400 and 600 mg carbamazepine daily in the same eight subjects. This rise was maximal after 1 week's treatment (400 mg: 509% +/- 285 of baseline; 600 mg: 1062% +/- 170 of baseline; P less than 0.01). Values fell from this peak during the second week despite continuing carbamazepine administration. This pattern was confirmed in a further six subjects taking carbamazepine 400 mg daily for 3 weeks in whom more frequent enzyme measurements were made. The activity of uroporphyrinogen-1-synthase in the erythrocyte fell by 10-15% during the treatment periods (P less than 0.01). Uroporphyrin and penta-, hexa- and hepta-carboxylic porphyrins appeared in the urine of all subjects during CBZ therapy. Changes in daily urinary porphyrin and precursor excretion were inconsistent. CBZ is a porphyrinogenic drug which mimics the changes in enzyme activities and urinary porphyrin ester profile found in patients with latent acute intermittent porphyria, who have a genetic deficiency in uroporphyrinogen-1-synthase activity. Leucocyte delta-aminolaevulinic-acid synthase may provide a suitable in vivo system for testing the porphyrinogenicity of drugs in man.

5-Aminolevulinate Synthetase↗
PubMed1983

Charcoal haemoperfusion and haemodialysis in acute intermittent porphyria.

Charcoal haemoperfusion has been advocated as a means of removing delta aminolaevulinic acid, which accumulates in attacks of acute intermittent porphyria. A woman presented with acute intermittent porphyria unresponsive to conventional treatment and with pain that was difficult to control. Charcoal haemoperfusion was performed in series with haemodialysis for two hours daily on four consecutive days. Although during this treatment serum and urinary concentrations of delta aminolaevulinic acid and porphobilinogen were considerably reduced, they had returned to pretreatment values 24 hours after the end of treatment. Abdominal pain was not relieved. Although a longer course of treatment might have had a more favourable outcome, this seems unlikely in view of the rapid rebound of serum concentration of delta amino-laevulinic acid after each haemoperfusion.

Acute Disease↗
PubMed1983

Carbamazepine-induced non-hereditary acute porphyria.

Acute intermittent porphyria has hitherto been recognised as an autosomal dominant inborn error of haem metabolism characterised by a depressed activity of the enzyme uroporphyrinogen I synthase (URO.S). A case of non-hereditary acute porphyria, similar to acute intermittent porphyria, following treatment of epilepsy with carbamazepine is reported. Subsequent measurements of erythrocyte URO.S activity in a group of epileptic patients treated with various combinations of anticonvulsant drugs suggest that carbamazepine exerts a direct suppressant effect on URO.S in addition to its indirect enzyme-inducing properties.

5-Aminolevulinate Synthetase↗
PubMed1983

Plasma protein-binding and CSF concentrations of valproic acid in man following acute oral dosing.

Simultaneous cerebrospinal fluid (CSF), total and free plasma valproic acid (VPA) concentrations were measured in 17 patients receiving two weight-adjusted VPA doses as seizure prophylaxis prior to diagnostic myelography or cisternography. Free drug concentrations were similar when measured by equilibrium dialysis (ED) at 37 degrees C for 24 h (Dianorm) or by a novel ultrafiltration (UF) method (EMIT freelevel system 1, SYVA) (ED:2.3-35.5 mg-1; UF:1.3-33.6 mg-1; r = 0.78, P less than 0.002). There was wide variation in total VPA concentration (39-154 mg-1) and in free fraction (ED: 3.3-25.6%; UF: 5.9-24%). Concentration dependent protein binding was not demonstrated. CSF VPA varied between 4.2 and 25.6 mg-1 and was accurately reflected by free plasma VPA concentrations (ED: r = 0.75, P less than 0.005: UF: r = 0.93, P less than 0.001). CSF concentration also correlated with the total plasma VPA (r = 0.76, P less than 0.005). The Emit freelevel system 1 provides a rapid measure of unbound VPA in the plasma which may be suitable for routine clinical use.

Adolescent↗
PubMed1983

Hepatic enzyme induction and leucocyte delta-aminolaevulinic acid synthase activity: studies with carbamazepine.

Antipyrine metabolism, daily urinary 6-beta-hydroxycortisol excretion, carbamazepine (CBZ) half-lives and leucocyte delta-aminolaevulinic acid synthase (ALA.S) activities were measured following 2 weeks' treatment with CBZ 400 mg and 600 mg once daily in eight healthy male volunteers. Dose-dependent induction of antipyrine metabolism was demonstrated but cortisol hydroxylation appeared maximally induced by the 400 mg dose. CBZ half-lives fell significantly in both studies (P less than 0.01 in each case) but a greater fall was seen with the higher dose (P less than 0.01). Plasma CBZ concentrations were higher following the eighth doses (P less than 0.01) in both studies. Leucocyte ALA.S activity increased by a mean of 657% following 1 week's treatment with 400 mg CBZ and 1145% on the 600 mg dose. In both studies ALA.S activities fell towards baseline during the second week of treatment. CBZ possesses potent dose-dependent hetero- and auto-inducing properties. Leucocyte ALA.S activity may represent a novel in vivo index of extrahepatic enzyme induction in man.

5-Aminolevulinate Synthetase↗
PubMed1983

The Harderian gland, its secretory duct and porphyrin content in the mongolian gerbil (Meriones unguiculatus).

The Harderian gland, its secretory duct and porphyrin content were examined in the mongolian gerbil (Meriones unguiculatus). The gland consisted of tubules lined by a single layer of epithelial cells and a myoepithelial network. The tubule cells were often binucleate and possessed lipid vacuoles in the apical half of the cell, a corona of granular endoplasmic reticulum surrounding the nucleus, and cytoplasmic 'slashes'. The latter are probably derived from dense membranous couplets and may be precursors of the lipid vacuoles. Holocrine and merocrine secretion was observed. Interstitial cells included plasma cells, mast cells and (predominantly) melanocytes which render the gland black. The gland was surrounded by a collagen capsule and an outer layer of highly attenuated (possibly endothelioid) cells. Within the gland, the secretory duct was lined by a single layer of normal tubule cells. Outside the gland, the duct enlarged to form an ampulla, from which clefts led off to deep crypts. The ampulla and clefts were lined by cells with small dense apical granules and stubby microvilli; some possessed lipid vacuoles. The crypts were lined by serous cells with active Golgi regions. At the duct opening, ampullary cells became squamous and goblet cells occurred. Geometric crystalloid deposits (with a layered structure of 7.6 nm periodicity) occurred at cleft-crypt junctions. Islets of extra-glandular ductal tissue were occasionally found within the gland. Porphyrins were detectable both by chemical assay and fluorescence microscopy. There was a trend for female glands to have a higher content than males. Solid intraluminal accretions of porphyrin and/or lipid were present.

Animals↗