The metabolism of the hypolipidaemic drug sultosilic acid in rat, dog and man

1. Single oral doses of the hypolipidaemic drug [35S]sultosilic acid to rats (40 mg/kg), dogs (40 mg/kg) and man (7 mg/kg) were well absorbed. During three days, means of 59.2%, 58.8% and 61.8% in urine and 37.7%, 31.9% and 19.7% in faeces, were excreted by these species respectively. Most of the dose was excreted during the first 24 h. 2. Peak plasma levels of 35S were generally reached during 1-2 h after oral doses in rats (12 micrograms equiv./ml), dogs (45 micrograms equiv./ml) and two human subjects (15.2 and 10.3 micrograms equiv./ml). In humans, peak plasma levels of unchanged drug (at 1-1.5 h) were 10.5 and 6.3 micrograms/ml. Plasma concentrations of 35S increased almost proportionately to dose in rats following oral doses of 400 and 1200 mg/kg, although in dogs, concentrations were similar at these two dose levels but several times higher than at 40 mg/kg. 3. Tissue concn. of 35S were generally higher in rats than in dogs. Highest concn. occurred at 3 h in rats and 1 h in dogs. Apart from those in the liver and kidneys, tissue concn. were appreciably lower than the corresponding plasma levels. 4. The major radioactive component in dog urine was sultosilic acid. Rat and human urine contained sultosilic acid and also two more polar major metabolites. In male and female rat urine, the proportions of these excretory products differed and the proportions in male rat urine were similar to those in human urine. Sultosilic acid was also the only component detected in dog plasma, whereas rat and human plasma also contained the two urine metabolites. Dog bile contained a conjugate of sultosilic acid. 5. The two metabolites have been identified by mass spectrometry and nuclear magnetic resonance spectroscopy as products resulting from oxidation of the methyl in the p-toluenesulphonyl group. The structures assigned are the corresponding carboxylic acid and the hydroxymethyl derivatives.     

Bertiellosis in man: a review of cases

To study the cognitive effects of diphenylhydantoin (PTH), 17 patients of simple partial or generalised tonic clonic seizure, who were on PTH monotherapy for at least 6 months were included. None of them had a seizure in last one month and their CT scans were normal. Serum PTH levels of these patients were in the therapeutic range (10.2-17.7 micrograms/ml). The clinical signs of PTH toxicity in the form of gingival hyperplasia and cerebellar ataxia were present in 1 patient only. In 3 patients memory quotient (MQ) and Benton visual retention test (BVRT) scores were marginally abnormal but the group difference in the clinical psychometric tests were not significant. P3 latency was also normal in all the patients. In the therapeutic range, PTH does not seem to produce significant cognitive dysfunction.     

Folic acid metabolism in normal, folate deficient and alcoholic man

Folate metabolism was studied in normal, folate-deficient and alcoholic man by tracer measurements of plasma clearance, urinary excretion, tissue storage and release of folate using both [3H]pteroylglutamic acid (3H-PteGlu) and 14C-methyl-H4PteGlu. Alcohol ingestion did not adversely affect tissue uptake of folates. Whether in normal or folate deficient subjects, the relative clearance rates of 3H-PteGlu and 14C-methyl-H4PteGlu were maintained in the face of alcohol ingestion and there was no evidence of increased urinary loss of intact vitamin or labelled breakdown products. As measured by the flushing technique, the rate of storage or tissue binding of 3H-PteGlu was not influenced by folate deficiency, folate store depletion or alcohol ingestion. However, alcohol may retard the release of methyl-H4PteGlu from tissue stores to plasma. A significantly greater recovery of 14C-methyl-H4PteGly with flush was observed in those normal subjects who ingested alcohol for 6 d. A partial block in the rate of release of tissue folate stores would be a possible mechanism behind the rapid depression in serum methyl-H4PteGlu levels and early induction of megaloblastic erythropoiesis which has been observed following acute alcohol ingestion.     

The oxidative metabolism of catecholamines in the brain: a review

The EBI (BARD-XT, C.R. Bard, Murray Hill, NJ) stent is a new radiopaque balloon expandable coronary stent with high resistance to external radial forces. It does not shorten significantly with expansion and allows stent implantation in bifurcation lesions. A total of 28 EBI stents were implanted in 23 lesions in 21 patients. Indications for stent implantation were acute closure in 1, threatened closure in 15, and electively in 7 lesions. In 2 cases, the lesion involved a bifurcation where a stent was implanted in both vessels. All patients received aspirin and ticlopidine. No anticoagulant therapy was given. The stenting procedure was successful in 22 of 23 lesions. No complications occurred with the exception of 1 patient with a thrombotic reocclusion within 1 hr after stent implantation and 1 patient with a temporary occlusion of a side branch. The mean minimal luminal diameter (MLD) increased from 0.74+/-0.46 mm before balloon dilatation to 1.27+/-0.62 mm before stent implantation and 2.32+/-0.57 mm after stent implantation. Percent stenosis decreased from 71+/-19% before angioplasty to 46+/-25% after angioplasty to 5+/-8% after stent implantation. MLD at the time of follow-up angiography after 4 months was 1.98+/-0.77 mm and percent stenosis was 26+/-21%. Restenosis of more than 50% occurred in 2 lesions. In these lesions, a second percutaneous transluminal coronary angioplasty was performed. Advantages of this stent are its flexibility together with an acceptable radial strength as well as enabling radiopacity without obscuring the arterial lumen. Stenting of bifurcation lesions is possible.     

Modulation of fatty acid metabolism by glucagon in man. IV. Effects of a physiologic hormone infusion in normal man

This study was done to explore the role of physiologic elevations of glucagon concentration in plasma ketone body concentration in normal man. During the period of hormone elevation, plasma free fatty acids were pharmacologically elevated to ensure adequate free fatty acid substrate delivery to the liver to support hepatic ketogenesis. Eighty-minute infusions of glucagon resulted in a plasma hormone concentration of approximately 300 pg./ml. During the infusion, ketone bodies declined from their basal concentration and remained below basal for the duration of the infusion. An acute heparin-induced pharmacologic elevation of plasma free fatty acid concentration resulted in a transient rise in plasma ketone body concentration, but at no time did it attain the concentration observed during the control saline infusion. Plasma glucose concentration was not altered by glucagon infusion, but plasma insulin concentration rose by approximately 2.5 muU./ml. These results suggest that glucagon is not ketogenic in normal man as has been previously reported in insulin-deficient diabetics. The glucagon-induced rise in plasma insulin concentration may participate in the observed reduction in plasma ketone body concentration.     

Propoxyphene: pathways of metabolism in man and laboratory animals

Through the combined use of stable isotope labeling and gas chromatographic mass spectrometric analysis, the metabolic patterns for propoxyphene have been determined in laboratory animals and man. The rat and dog eliminated propoxyphene and its metabolites principally via the bile, while the rabbit more closely resembled man in excreting the metabolic products into urine. Metabolites in rat and rabbit existed as conjugates, whereas in dog and man the metabolites were excreted as a mixture of the free and unconjugated forms. The primary route of metabolism in all species studied was N-demethylation. However, the rat and rabbit extensively hydroxylated propoxyphene and its metabolites prior to elimination. Metabolites arising from ester hydrolysis were found in rat and man. N-acetylated products were identified in all four species. A metabolite formed from cyclization and dehydration of dinorpropoxyphene was isolated in urine and was further identified as a circulating metabolite in dog plasma.     

Enflurane metabolism in rats and man

A-patterns have been treated by various techniques, with variable results. A desinsertion of the superior oblique at its insertion temporal to the superior rectus has proved to be a satisfactory treatment. This is combined with horizontal surgery. The results of this surgery in 137 cases are analysed and the complications outlined.     

Gender and fat metabolism during exercise: a review

We examined the evidence for greater fat utilization by women during exercise and the potential gender differences in specific cellular processes. Results from well-controlled studies show that, compared to men, women oxidize more fat during submaximal exercise, resulting in the relative sparing of muscle glycogen. Mature female rats use less muscle glycogen during running and can run longer than male counterparts. Circulating estrogen is critical to these observations, as shown by studies where male rats were treated with estrogen. Estrogen-treated male rats use less muscle glycogen during exercise and can run longer than untreated males. The cellular mechanisms and factors underlying these findings are unknown and certainly multifactorial. We offer some information that, unfortunately, does not lead to any natural conclusion. However, this area is certainly ripe for research.     

Ketoconazole and other imidazole derivatives are potent inhibitors of peroxisomal phytanic acid alpha-oxidation

Twelve young adults were treated with either melatonin, 3 mg or 6 mg, or placebo, at two different times before an early evening nap (18.00-20.00 h) according to a balanced double-blind Latin square design. Polysomnographic monitoring revealed that both dosages of melatonin significantly shortened sleep latency and increased total sleep time in comparison to placebo, irrespective of the time of administration. Subjects also tended to assess their sleep as 'deeper' after melatonin treatment. Based on previous data and the present results, it was concluded that exogenous melatonin exerts hypnotic effects only when circulating levels of endogenous melatonin are low.     

Chenodeoxycholate: the bile acid. The drug. a review

Chenodeoxycholate (3 alpha, 7 alpha-dihydroxy-5 beta-cholanic acid) is a primary bile acid directly synthesized from cholesterol. It is an amphipathic molecule, possessing both a hydrophobic side and a polar hydrophilic side, giving it the ability to solubilize lipids in a water environment. Bile acids are necessary for the absorption of fats and fat soluble vitamins. Chenodeoxycholate inhibits the rate-limiting step of cholesterol synthesis, the formation of hydroxymethyl-glutaryl-coenzyme A. It was first reported to be useful in the dissolution of cholesterol gallstones in 1972. Today, chenodeoxycholate has other medicinal uses and is used for the management of cerebrotendinous xanthomatosis, hypertriglyceremia, congenital liver diseases, rheumatoid arthritis, and constipation. This article details some finer points of chenodeoxycholate biochemistry and physiology and discusses in some detail the current and past clinical uses of chenodeoxycholate. This is not an exhaustive discussion on gallstone dissolution therapies, but an overview of some of the lesser-known uses for this drug.     

Mathematical models of purine metabolism in man

The tachykinin NK1 receptor is widely distributed in both the central and peripheral nervous system. In the CNS, NK1 receptors have been implicated in various behavioural responses and in regulating neuronal survival and degeneration. Moreover, central NK1 receptors regulate cardiovascular and respiratory function and are involved in activating the emetic reflex. At the spinal cord level, NK1 receptors are activated during the synaptic transmission, especially in response to noxious stimuli applied at the receptive field of primary afferent neurons. Both neurophysiological and behavioural evidences support a role of spinal NK1 receptors in pain transmission. Spinal NK1 receptors also modulate autonomic reflexes, including the micturition reflex. In the peripheral nervous system, tachykinin NK1 receptors are widely expressed in the respiratory, genitourinary and gastrointestinal tracts and are also expressed by several types of inflammatory and immune cells. In the cardiovascular system, NK1 receptors mediate endothelium-dependent vasodilation and plasma protein extravasation. At respiratory level, NK1 receptors mediate neurogenic inflammation which is especially evident upon exposure of the airways to irritants. In the carotid body, NK1 receptors mediate the ventilatory response to hypoxia. In the gastrointestinal system, NK1 receptors mediate smooth muscle contraction, regulate water and ion secretion and mediate neuro-neuronal communication. In the genitourinary tract, NK1 receptors are widely distributed in the renal pelvis, ureter, urinary bladder and urethra and mediate smooth muscle contraction and inflammation in response to noxious stimuli. Based on the knowledge of distribution and pathophysiological roles of NK1 receptors, it has been anticipated that NK1 receptor antagonists may have several therapeutic applications at central and peripheral level. At central level, it is speculated that NK1 receptor antagonists could be used to produce analgesia, as antiemetics and for treatment of certain forms of urinary incontinence due to detrusor hyperreflexia. In the peripheral nervous system, tachykinin NK1 receptor antagonists could be used in several inflammatory diseases including arthritis, inflammatory bowel diseases and cystitis. Several potent tachykinin NK1 receptor antagonists are now under evaluation in the clinical setting, and more information on their usefulness in treatment of human diseases will be available in the next few years.     

The metabolism of carbohydrates by extremely halophilic bacteria: identification of galactonic acid as a product of galactose metabolism

Cell-free extracts prepared from the extremely halophilic bacterium Halobacterium saccharovorum oxidize galactose and accumulate a product which reacts as if it were a lactone. The product does not act as a reducing sugar and contains all six of the carbon atoms initially present in galactose. The product was jugged to be galactonic acid, based on the behavior of the acetylmethyl ester derivative of the product and the pentaacetyl derivative of the galactonic methyl ester during gas chromatography.     

Calcium metabolism, osteoporosis and essential fatty acids: a review

Essential fatty acid (EFA)-deficient animals develop severe osteoporosis coupled with increased renal and arterial calcification. This picture is similar to that seen in osteoporosis in the elderly, where the loss of bone calcium is associated with ectopic calcification of other tissues, particularly the arteries and the kidneys. Recent mortality studies indicate that the ectopic calcification may be considerably more dangerous than the osteoporosis itself, since the great majority of excess deaths in women with osteoporosis are vascular and unrelated to fractures or other bone abnormalities. EFAs have now been shown to increase calcium absorption from the gut, in part by enhancing the effects of vitamin D, to reduce urinary excretion of calcium, to increase calcium deposition in bone and improve bone strength and to enhance the synthesis of bone collagen. These desirable actions are associated with reduced ectopic calcification. The interaction between EFA and calcium metabolism deserves further investigation since it may offer novel approaches to osteoporosis and also to the ectopic calcification associated with osteoporosis which seems to be responsible for so many deaths.     

Bioavailability and first-pass metabolism of oral pentazocine in man

The bioavailability of oral pentazocine was studied in 5 healthy volunteers. Plasma concentrations were determined from 30 min up to 6 hr following oral administration (two 50-mg tablets) and, at other occasions, after intravenous injection of 30 mg pentazocine. The average bioavailability was found to be 18.4 +/- 7.8% (SD, n = 5). It is shown that this low bioavailability depend almost entirely on the first-pass metabolism of pentazocine following oral administration by application of intravenous clearance concepts. The average beta-phase half-life was about the same following intravenous administration, 203 +/- 71 (SD, n = 5) min as following oral administration, 177 +/- 34 (SD, n = 5) min, with a total volume of distribution of 5.56 +/- 1.63 (SD, n = 5) L/kg. It is suggested that the variations in bioavailability of orally administered pentazocine have the potential to contribute to variations in pharmacologic effects in patients.     

Arachidonic acid metabolism: a primer for head and neck surgeons

The arachidonic acid metabolites, or eicosanoids, are a large series of lipid-derived mediators capable of producing a multitude of physiologic effects in the local environment. They play important roles in a variety of signaling pathways in endocrinology, immunology, and oncology. A significant body of work in this area has occurred in squamous cell carcinomas of the head and neck over the past 15 years. This review will attempt to familiarize the head and neck surgical oncologist with the basic biochemical steps in the formation of these compounds, newer developments in the field of eicosanoid biochemistry, and related experimental evidence of the roles of these substances in head and neck cancer.