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Biomedical subjects

D R Knapp

Publications and source records attributed to D R Knapp.

At least 55 records · Page 3Linked to original sources
PubMed1985

Pharmacologic characterization of human and canine thromboxane A2/prostaglandin H2 receptors in platelets and blood vessels: evidence for different receptors.

The present study was undertaken to characterize thromboxane A2/prostaglandin H2 (TXA2/PGH2) receptors in platelets and blood vessels. Both human and canine platelet aggregation and saphenous vein contractions were induced by the stable TXA2/PGH2 mimetics (15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z, 13E-dienoic acid (U46619) and 9,11-epithio-11,12-methano-TXA2 (ONO-11113). ONO-11113 was a more potent agonist than U46619 in the human saphenous vein but less potent in the platelet. These agonists were equipotent in the canine platelet but ONO-11113 was more potent in the saphenous vein. Platelet aggregation and saphenous vein contraction induced by U46619 were blocked in a dose-dependent manner by the TXA2/PGH2 receptor agonists 9,11-dimethylmethano-11,12-methano-16-phenyl-13,14-dehydro-13-aza- 15 alpha beta-omega-tetranor-TXA2 (ONO-11120), 9,11-dimethylmethano-11,12-methano-16-(4-hydroxyphenyl)-13,14-d ihy dro-13-aza-15 alpha beta-omega-tetranor-TXA2 (PTA-OH), 9,11-dimethylmethano-11,12-methano-16-(4-methoxyphenyl)-13,14-d ihy dro-13-aza-15 alpha beta-omega-tetranor-TXA2 (PTA-OM), 9,11-dimethylmethano-11,12-methano-16-(3-iodo-4-hydroxyphenyl-13,1 4-dihydro-13- aza-15 alpha beta-omega-tetranor-TXA2 (I-PTA-OH) and 9,11-dimethylmethano-11,12-methano-15-phenyl-13,14-dihydro-13-aza- 15 alpha beta-omega-pentanor-TXA2 [PTA-(omega-1)].(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Calvarial cells synthesize 1 alpha,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3.

A metabolite of vitamin D has been isolated in pure form from incubation of 25-hydroxyvitamin D3 with embryonic chick calvarial cells that had been grown on Cytodex 1 microcarrier beads. The isolation involved dichloromethane extraction of the cells and incubation medium, followed by Sephadex LH-20 column chromatography and high-performance liquid chromatography of the extract. The metabolite was identified as 1 alpha,25-dihydroxyvitamin D3 by means of ultraviolet absorption spectroscopy, mass spectrometry, and sensitivity to oxidation by periodate. This metabolite was not produced by cell-free medium or by cells from embryonic chick liver, skin, or heart. In conclusion, (1) kidney cells are not unique in having 25-hydroxyvitamin D3:1 alpha-hydroxylase activity as previously believed and (2) vitamin D target tissues such as the skeleton may play a direct role in mediating the metabolism of 25-hydroxyvitamin D3 to 1 alpha,25-dihydroxyvitamin D3, a vitamin D metabolite active at those sites.

Animals↗
PubMed1983

Synthesis and chromatographic separation of the glucuronides of (R)- and (S)-propranolol.

One of the major metabolites of propranolol (Inderal) is the O-glucuronide. In order to further study its disposition, possible metabolism, and contribution to the antihypertensive effect of propranolol, we have synthesized and separated the two diastereomeric propranolol O-beta-D-glucuronides (9a,b). These compounds were prepared by reaction of naphthol with epichlorohydrin and treatment of the resulting (2RS)-1'-(2,3-epoxypropoxy)naphthalene (2) with sodium azide to give (2RS)-1-(1'-naphthoxy)-3-azido-2-propanol (3). Alkylation of 3 with methyl (2,3,4-tri-O-acetyl-1-bromo-1-deoxy-alpha-D-glucopyranosid)uronate (4) gave methyl (2RS)-[1-(1'-naphthoxy)-3-azido-2-propyl-2",3",4"-tri-O-acetyl-beta-D- glucopyranosid]uronate (5a,b). Reductive alkylation, followed by HPLC separation of the diastereomers, gave methyl (2R)- and (2S)-[1-(1'-naphthoxy)-3-(isopropylamino)-2-propyl-2",3",4"-tri-O-acetyl- beta-D-glucopyranosid]uronate (6a,b). Hydrolytic removal of the acetyl and methyl protecting groups gave the free glucuronides, which were then converted to the sodium salts, 9a,b. The stereochemistry of the glycoside linkage was deduced from the 400-MHz 1H NMR spectra. The absolute configuration of the aglycon portion was determined after Glusulase hydrolysis by derivatization with (R)-(+)- or -(-)-alpha-methylbenzyl isocyanate and comparison of the HPLC retention volumes with those of derivatized reference (R)- and (S)-propranolols.

Chromatography, High Pressure Liquid↗
PubMed1982

Gall-stone dissolution and recurrence: are we being misled?

Oral cholecystography repeated at six-months intervals is the standard method for determining reduction in size of gall stones (partial success) and complete dissolution of stones (complete success). In a comparative study of oral cholecystography and cholecystosonography six out of 14 patients with gall stones achieving complete success by oral cholecystographic criteria had stones still detectable by ultrasonography. Repeat oral cholecystography in a further 11 patients receiving post-dissolution maintenance treatment detected stones in two, whereas ultrasonography detected stones in seven. In future complete dissolution of gall stones should be reported only if both oral cholecystography and ultrasonographic studies give negative results and the progress of patients receiving post-dissolution maintenance treatment is monitored by ultrasonography rather than serial oral cholecystography.

Chenodeoxycholic Acid↗
PubMed1982

Outcome of endoscopy and barium radiography for acute upper gastrointestinal bleeding: controlled trial in 1037 patients.

A study was conducted to find whether the higher diagnostic yield of endoscopy compared with barium radiography improves management or survival in patients with acute upper gastrointestinal bleeding. A total of 1037 patients were entered into a randomised study comparing the outcomes after each investigation. The diagnostic yield in patients who underwent endoscopy was 73% (382 of 526 cases) and in those examined by radiography 55% (280 of 511 cases). A fifth of the patients in the radiology group and a tenth of those in the endoscopy group subsequently underwent the alternative investigation; in most cases, however, no additional diagnostic information was obtained. Operation rates were similar in two groups, though patients in the endoscopy group were generally operated on sooner. Mortality rates were also similar in the two groups, though postoperative mortality was higher in the endoscopy group. Endoscopy may be a more accurate means of diagnosis than radiography, but it offers no short-term benefits in management.

Clinical Trials as Topic↗
PubMed1982

Glucagon and infusion cholangiography.

It has been previously suggested that glucagon improves the bile duct and gall-bladder opacification obtained by infusion cholangiography. One hundred and ninety consecutive patients referred for intravenous cholangiography were entered into a double-blind study designed to see if glucagon would in fact significantly improve bile duct opacification. All patients received a one hour intravenous infusion of iotroxamide at a rate of 3.15 mg/kg body weight/min. Glucagon did not enhance bile duct opacification, the mean post-injection scores for the two groups being 2.47 +/- 1.11 and 2.29 +/- 1.15 respectively. On the basis of the present study we cannot recommend the routine use of glucagon following infusion cholangiography.

Bile Ducts↗
PubMed1981

Intraductal infusion of mono-octanoin: experience in 24 patients with retained common-duct stones.

Mono-octanoin (glyceryl-l-mono-octanoate), 2-4 ml/h, was instilled into the bile or hepatic ducts of twenty-four patients with retained gallstones after cholecystectomy and choledochotomy. After treatment, fifteen patients no longer had stones. In five the stones were smaller or reduced in number; and in four of these the stones were extracted mechanically via the T-tube tract. Mechanical extraction was also possible in one of the four patients with unaltered stones. With a battery-operated pump or hand injection, mono-octanoin can be safely infused as early as the 8th postoperative day and some patients can continue the treatment outside hospital.

Adolescent↗
PubMed1981

The two types of pyelosinus extravasation.

There are two types of extravasation into the renal sinus from the fornices of the calyces; one due to transudation through an intact mucosa and the other due to an actual defect in the calyx. It is suggested that extravasation from the fornices into the renal sinus can occur spontaneously in the absence of obstruction and without a rise in pressure. Truly spontaneous extravasation can occur whether ureteric compression is used or not.

Adult↗
PubMed1981

Ring-hydroxylated propranolol: synthesis and beta-receptor antagonist and vasodilating activities of the seven isomers.

Propranolol (Inderal; 1) is extensively metabolized in man. Metabolites of interest pharmacologically include ring-hydroxylated propranolols (1a-g). In order to identify these ring-oxidized products and to study the effect of hydroxyl position on biological activity, we have synthesized all seven isomers. With the exception of 1b and 1g, the desired compounds were prepared by alkylation of the respective methoxy-1-naphthols with epichlorohydrin and reaction of the resulting epoxide with isopropylamine. Cleavage og the methyl group in fused pyridine hydrochloride afforded 1a,c-f. 1g was prepared by the direct alkylation of 1,8-naphthalenediol (17) with epichlorohydrin, followed by reaction with isopropylamine. 1b was synthesized by treating 2-naphthol (9) with chlorine gas and then treating the resulting 1,1-dichloronaphthalen-2(1H)-one (10) with sodium allyl oxide. Acetylation of the hydroxy function and epoxidatrion of the allyl group, followed by relation with isopropylamine, gave 3'-hydroxy-4'-chloropropranolol (15). Dechlorination gave 1b. All of the racemic hydroxylated propranolols produced beta blockade and direct vasodilation in anesthetized dogs. The potency is strongly dependent upon the position of the hydroxyl group, i.e., 1e is 4 times as potent as 1 as a beta receptor antagonist, whereas 1a, 1b, and 1g are all significantly less potent than 1. For direct vasodilation, 1a and 1g are equipotent to 1, while 1b-f are much less potent. The potencies of the compounds were also compared with their 1-octanol/pH 7.4 buffer distribution coefficients; the direct vasodilating potency was found to increase with increasing lipophilicity, while the beta-adrenergic antagonist potency decreased.

Adrenergic beta-Antagonists↗
PubMed1981

Essential fatty acid deficient rats: a new model for evaluating arachidonate metabolism in shock.

Essential fatty acid deficient (EFAD) rats are significantly more resistant to the lethal effects of S. enteritidis endotoxin (20 mg/kg, IV) than normal control rats. Compared to endotoxin-treated normal rats, EFAD rats also manifested less severe alterations of hepatic and lysosomal integrity and became less hypoglycemic. Administration of the ethyl ester of the essential fatty acid, arachidonic acid (100 mp, IP) two days prior to challenge with S. enteritidis endotoxin (20 mg/kg) in EFAD rats restored their sensitivity to endotoxin, as denoted by a 100% mortality compared to a 24% mortality (P less than 0.01) in EFAD rats. Treatment of EFAD rats with the fatty acid docosahexaenoic acid, a non-prostaglandin and thromboxane precursor, (100 mg, IP) produced significantly less (less than 0.01) mortality than ethyl-arachidonate-treated groups (ie, 40% vs 100%). The arachidonate metabolite, thromboxane B2 (TxB2), increased from nondetectable plasma levels (less than 200 pg/ml) to 2285 +/- 449 pg/ml (N = 10) at 30 min and remained elevated for 180 minutes after endotoxin administration in nondeficient rats. However, plasma TxB2 was not detectable in endotoxin-treated EFAD rats and was only slightly elevated in groups supplemented with docosahexaenoic acid (273 +/- 104 pg/ml, N = 6) after 30 minutes. In ethyl arachidonate (100 mg, IP) supplemented EFAD rats, plasma TxB2 rose to 873 +/- 204 pg/ml (N = 8), 30 min after endotoxin. Pretreatment of the ethyl-arachidonate-supplemented EFAD group with a specific thromboxane synthetase inhibitor, 7-(1-imidazolyl)-heptanoic acid (30 mg/kg, IV), significantly reduced mortality 100% to 50% (P less than 0.05) from endotoxic shock. These observations suggest a deleterious role for arachidonic acid and its conversion to TxA2 in the pathogenesis of endotoxic shock.

Acid Phosphatase↗
PubMed1980

Vasopressin-stimulated water flow is decreased by thromboxane synthesis inhibition or antagonism.

The time course of vasopressin stimulation of water flow and immunoreactive thromboxane B2 (iTXB2) and prostaglandin E (iPGE) biosynthesis was studied in the isolated toad urinary bladder. Vasopressin (25 mU/ml) significantly stimulated iTXB2 synthesis within 8 min, synthesis reaching a maximum rate by 17 min. iPGE synthesis was significantly stimulated within 8 min, remaining unchanged for 24 min. Maximum vasopressin-stimulated water flow was reached between 16 and 24 min. 7-(1-Imidazolyl)-heptanoic acid (7IHA), a thromboxane synthetase inhibitor, inhibited both vasopressin-stimulated water flow and iTXB2 synthesis in a dose-dependent fashion, but did not affect iPGE synthesis. Vasopressin-stimulated water flow and iTXB2 synthesis were significantly correlated (r = 0.75, n = 24, P less than 0.001). 13-Azaprostanoic acid (13APA), a thromboxane antagonist, inhibited vasopressin-stimulated water flow in a dose-dependent fashion. Inhibition of arachidonic acid metabolism abolished the effects of 7IHA and 13APA on vasopressin-stimulated water flow. 7IHA and 13APA had no effect on cAMP-stimulated water flow. These results confirm that vasopressin stimulates TXA2 and PGE synthesis and support the hypothesis that TXA2 is a positive modulator of vasopressin-stimulated water flow in the toad urinary bladder.

Animals↗