Biomedical subjects

I Setnikar

Publications and source records attributed to I Setnikar.

At least 19 recordsLinked to original sources

PubMed1992

Antireactive properties of "chondroprotective" drugs.

The medicinal therapy of osteoarthritis is based on the use of analgesics, NSAIDs and corticosteroids to relieve pain and inflammation. In addition, "chondroprotective" agents (CPA) are used to stop the evolution of the disease. In this review the biochemical and pharmacological activities of some of the most widely used CPAs are described. All of these show more or less marked antiinflammatory activities, which for some of them are the result of an inhibition of cyclo-oxygenase and of prostaglandin biosynthesis, in which case they should be more properly classified as mild NSAIDs. Only two of the CPAs reviewed, diacerein and D-glucosamine sulfate, elicit antiinflammatory and antireactive effects without significant inhibition of the prostaglandin biosynthesis. These agents have also remarkable chondroprotective effects, and only these two agents should be classified as true CPAs. In particular glucosamine sulfate, which naturally occurs in the human body and is almost devoid of toxicity, is suitable for long-term therapeutic use. This, with its chondrometabolic, antireactive and antiarthritic properties, represents the pharmacological rationale for the use of glucosamine sulfate as a disease-modifying agent in osteoarthritis.

Animals↗

PubMed1992

Sodium fluoride-induced gastric mucosal lesions: comparison with sodium monofluorophosphate.

In a randomized double-blind study with two parallel groups of 10 male healthy volunteers each the response of gastric mucosa after a 7 days ingestion of sodium fluoride tablets (NaF) or sodium monofluorophosphate tablets (MFP) was compared. Gastroscopic evaluations were performed before treatment, day 1 and day 7. Simultaneously blood samples were collected for determination of laboratory data and serum fluoride values. In the MFP-group no severe gastric lesions were observed, whereas in the NaF-group in 7 of the 10 subjects significant gastric mucosal lesions including acute hemorrhages and free blood in the gastric lumen were found. The differences of the lesions scores in both groups were statistically significant (p = 0.0015). The serum fluoride content was comparable in both treatment groups. Possible adverse drug reactions were reported in 4 subjects with NaF and in 1 subject with MFP. In summary, under the experimental conditions used MFP is well tolerated by the stomach while NaF produces significant gastric mucosal lesions.

Adult↗

PubMed1991

Antireactive properties of glucosamine sulfate.

Glucosamine (CAS 3416-24-8) is an aminomonosaccharide naturally occurring in the human body. It was tested for antiinflammatory activities and it showed to protect against the edema provoked in the rat paw by carrageenin, dextran, formalin, but not against the edema provoked by specific inflammation mediators, such as bradykinin, serotonin, histamine. Glucosamine protected against pleurities provoked in the rat by carrageenin, but not against that provoked by bradykinin. Furthermore glucosamine protected against peritonitis provoked in the rat by formalin and in the mouse by acetic acid. Glucosamine did not show antinoceptive properties against writings provoked by i.p. phenylquinone in the mouse. Glucosamine did not show inhibiting activities on cyclooxygenase or on the proteolytic enzymes in the inflamed paw of the rat, but it was able to inhibit in vitro superoxide generation and lysosomial enzymes of the liver. The potency of glucosamine on the antiinflammatory tests was lower than that of acetylsalicylic acid and much lower than that of indomethacin. Its acute toxicity, however, and notably the toxicity on the gastrointestinal tract is very low, practically absent. The pharmacological therapeutic index of glucosamine with regard to the antiinflammatory activities seems therefore comparable or superior to that of the known non-steroidal anti-inflammatories.

Analgesics↗

PubMed1991

Antiarthritic effects of glucosamine sulfate studied in animal models.

The antireactive activity of glucosamine sulfate (GS) (CAS 29031-19-4) was tested in the rat in experimental models of subacute inflammation (sponge granuloma and croton oil granuloma), on subacute mechanical arthritis (kaolin arthritis) and in immunological-reactive arthritis and generalized inflammation (adjuvant arthritis). On these models GS was found effective in oral daily doses of 50-800 mg/kg. Tne potency of GS in comparison of that of indometacin used in the same tests as reference substance was found 50-300 times lower. Since, however, the toxicity of indometacin in chronic toxicity experiments is 1000-4000 times larger, the therapeutic margin with regard to prolonged treatments of inflammatory disorders results 10-30 times more favourable for GS than for indometacin. GS can therefore be considered as a drug of choice for prolonged oral treatment of rheumatic disorders.

Animals↗

PubMed1990

Effect of loxiglumide on gallbladder contractile response to cerulein and food in humans.

The present study investigated the effect of loxiglumide, a new selective cholecystokinin-receptor antagonist, on the gallbladder contractile responses to caerulein and to food in humans. In 6 healthy men, the gallbladder emptying driven by intravenous infusion of stepwise increasing doses of cerulein (10-80 ng/kg . h) and that induced by a 550-cal standard meal were monitored by ultrasonography. In both sets of experiments, the effect of loxiglumide was tested at various infusional rates against a control infusion of saline. An infusional rate of 2.5 mg/kg . h of loxiglumide abolished the gallbladder response even to maximal doses of cerulein, whereas a rate of 1.0 mg/kg . h counteracted the cholecystokinetic activity of cerulein up to the dose of 20 ng/kg . h. In postprandial experiments, the cholecystokinin antagonist dose-dependently inhibited the physiologic gallbladder contraction. The maximal gallbladder emptying, which always occurred 85 min after the meal, was 71.1% +/- 3.3% of basal volume in control studies, 39.2% +/- 1.8% during infusion of 2.5 mg/kg . h of loxiglumide, and 17.3% +/- 5.9% when 5.0 mg/kg . h were infused. A dose of 7.5 mg/kg . h of loxiglumide was able to prevent any postprandial emptying of the gallbladder. The present study shows that a selective cholecystokinin receptorial blockade competitively antagonizes cerulein-induced gallbladder contraction and dose-dependently inhibits postprandial gallbladder emptying.

Adult↗

PubMed1990

Effects of a cholecystokinin receptor antagonist on intestinal phase of pancreatic and biliary responses in man.

The present study was designed (a) to characterize the activity of loxiglumide as a peripheral cholecystokinin (CCK) antagonist in healthy human subjects, and (b) to determine whether CCK is a physiologic regulator of the intestinal phase of meal-stimulated exocrine pancreatic and biliary secretions in man. Intravenous loxiglumide (22 mumol/kg per h) was highly potent in antagonizing CCK8-induced pancreatic enzyme and bile acid secretion as well as pancreatic polypeptide release. The potency and selectivity of loxiglumide as an antagonist of CCK provides the tool for evaluating the role of CCK as a physiological mediator of meal-induced pancreatic and biliary responses in humans. Infusion of a liquid test meal into the duodenum evoked an immediate response of pancreatic enzyme and bilirubin outputs, respectively. Intravenous loxiglumide significantly inhibited the meal-induced pancreatic amylase output by 63% (P less than 0.05), lipase output by 43% (P less than 0.05), and bilirubin output by 59% (P less than 0.05). These data suggest that CCK is a physiological mediator of the intestinal phase of meal-stimulated pancreatic and biliary responses.

Adult↗

PubMed1990

Bioequivalence of sodium monofluorophosphate with sodium fluoride and compatibility with calcium.

The study was conducted in a triple cross-over on 12 healthy Caucasian volunteers (4 males and 8 females) of an age between 23 and 44 years. The following products were given in a single oral dose in fasting state. 1. Solution of 29.18 mg of sodium fluoride in 80 ml of water (reference NaF solution). 2. Solution of 100 mg sodium monofluorophosphate (CAS 10163-15-2) in 80 ml of water (Na2FPO3 solution). 3. Tablets with 100 mg sodium monofluorophosphate and 1250 mg calcium carbonate (Na2FPO3 + Ca tablets). The three products were equivalent in fluorine content (13.2 mg). The bioavailability of fluorine was evaluated on the basis of the plasma levels and of the urinary excretion of fluoride. After administration of the products, fluoride appeared in blood with a lag time smaller than 0.05 h and invaded the blood with a t1/2 from 0.07 to 0.12 h. The Cmax of fluoride in plasma was 412-466 ng/ml at a tmax of 0.5-0.7 h. The AUCs of fluoride after Na2FPO3 solution and after Na2FPO3 tablets were within the 0.80-1.20 bioequivalence limits with regard to the AUC after NaF solution. The three products can therefore be considered bioequivalent according to the Westlake criteria. In the 24 h following the administration, the urinary excretion of fluoride accounted for 51 +/- 10%, 46 +/- 6% and 47 +/- 8% of the administered dose, respectively for NaF solution, Na2FPO3 solution and Na2FPO3 + Ca tablets. The difference between the three products was statistically not significant and confirms their bioequivalence.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

Relative bioavailability of fluoride from monofluorophosphate tablets after single oral administration.

The study was conducted on 12 healthy male Caucasian volunteers of an average age of 27.8 +/- 4.0 years with single oral doses of the following products: 1. sodium monofluorophosphate tablets (MFP-tablets, Mono-Tridin); 2. aqueous solution of 23.2 mg of sodium fluoride (NaF solution-reference); 3. aqueous solution of sodium monofluorophosphate (MFP solution). The three products were equivalent in fluorine content with 10.5 mg F. The bioavailability was evaluated on the basis of the plasma levels and of the urinary excretion of fluoride. The study was designed as a triple latin-square crossover and each subject received the three products in three different periods, at empty stomach. After administration of the products, fluoride appeared quickly in blood (lag time between 0.07 and 0.13 h) and invaded rapidly the blood (invasion t1/2 from 0.04 to 0.15 h). The Cmax of fluoride in plasma was 439 ng/ml at tmax of 1.08 h after MFP tablets, 430 ng/ml at a tmax of 0.51 h after NaF solution and 403 ng/ml at tmax of 0.62 h after MFP solution. The differences for the Cmax were not statistically significant. The relative bioavailability of fluoride from MFP tablets, estimated from the AUC, was 1.35, and significantly larger than that from the reference NaF solution. Fluoride was eliminated from plasma with an initial fast rate (t1/2 from 0.68 to 1.03 h) and a terminal slower rate (t1/2 from 4.71 to 7.37 h). The plasma levels of fluoride were consistent with a two-compartment open pharmacokinetic model after extravascular administration. In the 24 h following the administration the urinary excretion of fluoride accounted for 50-53% of the administered dose, without significant difference between the three products. The three products were well tolerated and no systemic or gastric adverse reaction was recorded.

Adult↗

PubMed1989

Antispasmodic activity of tiropramide.

Tiropramide hydrochloride and some of its metabolites were studied in vivo for their antispasmodic activities on the following models: gastric emptying in the mouse retarded by cholecystokinin octapeptide (CCK-8) or morphine, progression of intestinal contents in the mouse, spontaneous motility of the colon in the anesthetized rabbit, diarrhea induced by castor oil in the rat, spasm of the sphincter of Oddi provoked by morphine in the guinea pig, contractions of the urinary bladder in the anesthetized rat. On these models tiropramide had an antispasmodic activity at doses of 4-40 mg/kg i.p. or i.v. and of 50-90 mg/kg orally. The potency was greater on "pathological" contractions or spasms and smaller on "physiological" movements. Tiropramide may therefore be regarded as a "eukinetic" antispasmodic agent. Tiropramide in general was more potent than reference agents such as papaverine or flavoxate and was active also after oral administration. The metabolites of tiropramide, i.e. CR 1034, CR 1098 and CR 1166 showed similar pharmacodynamic effects, but their potency was smaller than that of tiropramide. Large doses of tiropramide have depressive actions on the cardiovascular system, which can be seen especially if tiropramide is administered i.v. and are less pronounced after oral administration. The circulatory effects are therefore probably the limiting factor for increasing the parenteral doses of tiropramide in human therapy. Tiropramide was found less toxic than papaverine (LD50). The metabolites of tiropramide were less toxic than the parent compound. The toxicity of the chiralic forms of tiropramide does not differ significantly from that of the racemic substance.

Animals↗

PubMed1989

Pharmacological characterisation of the smooth muscle antispasmodic agent tiropramide.

(+/-) Tiropramide hydrochloride, its D and L optical isomers and some of its metabolites were characterized in a number of in vitro pharmacological tests. Tiropramide showed broad spectrum antispasmodic activities on the isolated stomach of guinea pig electrically stimulated; on the longitudinal muscles of the ileum of guinea pig stimulated by electrical impulses, BaCl2, acetylcholine, histamine, serotonin, substance P and cholecystokinin octapeptide (CCK-8); on the spontaneous contractions and on the electrical inhibition of the jejunum of rabbit; on the spontaneous contractions and on the contractions provoked by BaCl2 and acetylcholine of the ascending colon of the rat; on the contractions provoked by BaCl2, acetylcholine, histamine and cerulein of the circular muscles of the gall bladder of the guinea pig; on the spontaneous contractions of the pyel-ureter preparation of the guinea pig; on the contractions of the uterus of the rat provoked by oxitocin, serotonin, acetylcholine, PGF2; on the spontaneous contraction of the portal vein of the rat; on the constriction of the tail artery of the rat provoked by electrical stimulation, epinephrine and ergotamine; on the contractions of the aortic strip of the rabbit stimulated by norepinephrine; on the contractions of the strip of bovine coronary artery depolarized by HCl. In general tiropramide had antispasmodic effect at 5-60 mumol/l concentration. It was more potent than papaverine on contractions provoked by electrical or chemical stimuli, and was less potent or ineffective on spontaneous and "physiological" contractions of the different smooth muscle preparations. Tiropramide had small effects on vascular smooth muscles and showed very small calcium channel blocking activity.

Animals↗

PubMed1989

Pharmacokinetics and tolerance of repeated oral doses of loxiglumide.

The study was conducted on 6 adult healthy subjects (5 males and 1 female) in order to investigate the pharmacokinetics and tolerance of repeated b.i.d. oral administration for 7 days of tablets containing 400 mg of loxiglumide (CR 1505). The pharmacokinetics of loxiglumide in plasma after the first single dose of 400 mg is characterized by a lag time of 16 +/- 4 min, a rapid invasion (kinv = 10 h-1), a Cmax of 11.9 +/- 5.1 mg/l at tmax of 2.3 +/- 0.8 h, a mean residence time (MRT) of 6.9 +/- 1.1 h and an AUC of 60.6 +/- 16.3 (mg/l) x h. After the last dose of 400 mg the lag time was 17 +/- 6 min, the Cmax 12.7 +/- 3.8 mg/l at tmax of 2.1 +/- 0.8 h, a MRT of 11.0 +/- 1.9 h and an AUC of 109.8 +/- 39.9 (mg/l) x h. The increases of the AUC and of MRT were statistically significant and are probably due to an accumulation of loxiglumide which occurs during the repeated dose course and reaches the steady state within 48 h of repeated administration. Due to this accumulation the Cmax increased by 7%. The increase was not statistically significant or clinically relevant. No dose adjustment seems required during a repeated dose dosing schedule with 400 mg b.i.d. In the urine loxiglumide and 3 metabolites were found, which were called Metabolite (Met.) 11.2, Met. 12.0 and Met. 12.8. Met. 12.0 was the most abundant, accounting for 45% of the loxiglumide related substances excreted in the urine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1989

Metabolism and excretion of 14C-tiropramide after single intravenous or peroral administration to the rat.

The study was performed with 14C-tiropramide hydrochloride, i.e. O-(2-diethylamino-ethyl)-N-benzoyl-[DL-(U-14C)tyrosyl]-dipropylamide+ ++ hydrochloride, with a specific activity of 466.16 microCi/mmol. For the study of pulmonary, urinary and fecal excretion the substance was administered in single intravenous (i.v.) doses of 4 mg/kg to 4 rats (2 males and 2 females) and in single peroral (p.o.) doses of 10 mg/kg to other 4 rats (2 males and 2 females). For the study of biliary excretion 4 mg/kg of 14C-tiropramide hydrochloride were administered in single i.v. doses to 4 rats (2 males and 2 females) anesthetized with urethane and the bile was collected from the choledocus in the 8 h following administration. The radioactivity in the expired CO2, urine feces and bile was measured by scintillometry. The radioactive substances were extracted, separated by TLC and identified by comparison of their Rf values with those of putative metabolites with known chemical structure. The following results were obtained. Radioactivity in the expired CO2: No radioactivity was found, either after i.v. or p.o. administration. Radioactivity in urine: In the 48 h after administration 37% of the i.v. administered radioactivity and 31% of the p.o. administered radioactivity was recovered in the urine. Six basic substances could be identified. In order of decreasing abundance these were CR 1166, CR 1098, tiropramide, CR 1034, CR 1919 and CR 1938. Radioactivity in feces: In the 120 h after administration 60% of the i.v. administered radioactivity and 56% of the p.o. administered radioactivity was recovered in the feces.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1989

Distribution of tiropramide and metabolites after single intravenous or peroral administration of 14C-tiropramide to the rat.

The study was performed with 14C-tiropramide hydrochloride, i.e. O-(2-diethylamino-ethyl)-N-benzoyl-[DL-(U-14C)tyrosyl]-dipropylamide+ ++ hydrochloride, with a specific activity of 466.16 microCi/mmol. The substance was administered in single intravenous (i.v.) doses of 4 mg/kg to 16 rats (8 males and 8 females) and in single peroral (p.o.) doses of 10 mg/kg to other 16 rats (8 males and 8 females). The radioactivity in plasma, in several organs and tissues and in gastrointestinal contents was measured by scintillometry. After i.v. administration the radioactivity is rapidly found in all investigated organs and tissues and also in the stomach contents. The radioactivity is concentrated in the liver and kidney, and also in other organs, as the pancreas and the salivary glands. After 120 h the radioactivity is small in the organs but still appreciably present in the colon content. The radioactivity crosses the blood-brain barrier. Deep compartments were not found. After p.o. administration the radioactivity is rapidly found in the organs and is particularly concentrated in the liver, showing a rapid absorption from the gastrointestinal tract. Besides the obvious higher concentration of radioactivity in the stomach and small intestine in the initial times after p.o. administration, the distribution and elimination pattern from the organs do not substantially differ from those found after i.v. administration. The distribution pattern found using the scintillographic method were confirmed by an autoradiographic study made on 12 non-pregnant rats (10 males and 2 females) and on 7 rats at the 13th day of pregnancy and 7 rats at the 18th day of pregnancy.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗

PubMed1988

Identification of metabolites of tiropramide in human urine.

The metabolites of tiropramide were extracted from the urine of healthy volunteers given tiropramide hydrochloride orally. Eight metabolites of tiropramide were found by gas chromatography/mass spectrometry. Three were identified on the basis of their mass spectra, retention times and comparison with synthetic standards. For the others a probable structure is proposed on the basis of their mass spectra.

Adult↗

PubMed1988

Tiropramide and metabolites in blood and plasma after intravenous or peroral administration of 14C-tiropramide to the rat.

The study was performed with 14C-tiropramide hydrochloride (O-(2-diethylamino-ethyl)-N-benzoyl-[DL-U-14C-tyrosyl]-dipropyl-amide hydrochloride) with a specific activity of 466.16 muCi/mmol. The substance was administered in single i.v. doses of 4 mg/kg to 18 male and 18 female rats or p.o. doses of 10 mg/kg to 16 male and 16 female rats. The radioactivity in blood and plasma was measured by scintillometry. The radioactive substances were extracted, separated by TLC and identified by comparison of their Rf values with those of putative metabolites with known chemical structure. After i.v. administration the parent substance tiropramide and 5 metabolites were identified in plasma. Tiropramide was the most abundant substance with an AUC equal to 51% of the AUC of total radioactivity. After p.o. administration the parent tiropramide and 5 metabolites were identified. Tiropramide was the most abundant substance till the 1st h. Then the metabolite CR 1098 ((+-)a-benzoylamino-4-(2-ethylamino-ethoxy)-N, N-dipropyl-benzenepropanamide) prevailed. The Cmax of tiropramide was reached at 0.5 h with 1183 nmol/l. The AUC of tiropramide was 19% of the AUC of total radioactivity. It appears that after p.o. administration the biotransformation of tiropramide is more intense than after i.v. administration. The absolute bioavailability of total radioactivity calculated on the ratio between the p.o. and i.v. AUC was 0.67, that of tiropramide was 0.23. The difference between the absolute bioavailability of total radioactivity and that of tiropramide is probably due to a first-pass effect and a more intense biotransformation of the substance after p.o. administration.

Administration, Oral↗

PubMed1988

Chemical stability and mode of gastrointestinal absorption of sodium monofluorophosphate.

Sodium monofluorophosphate, an agent used for the fluorine therapy of osteoporosis, is chemically stable in aqueous environment in the range from pH 13 to 2. At pH lower than 1.5 the monofluorophosphate ion (MFP) hydrolyzes to fluoride and orthophosphate. At these pH values fluoride forms undissociated hydrofluoric acid which damages the gastric mucosa. Therefore, to prevent the formation of hydrofluoric acid, sodium monofluorophosphate should always be combined with buffering agents, preferably calcium salts, because calcium is compatible with MFP and is an aid for osteoporosis. MFP is stable in the intestinal environment. It is absorbed from the gastrointestinal lumen and is then hydrolyzed into fluoride and orthophosphate. Hydrolysis is provided by MFPases of the intestinal mucosa and of the liver. Alkaline phosphatase has MFPase activity, whereas acid phosphatase has not. In conclusion, if buffered with an appropriate calcium salt, MFP is stable in the gastrointestinal environment and does not release fluoride which could damage the gastrointestinal mucosa and be sequestrated by calcium ions of the diet or given as medicaments.

Alkaline Phosphatase↗

PubMed1988

Pharmacokinetics of loxiglumide after single intravenous or oral doses in man.

Loxiglumide (D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylam ino)-5-oxo-pentanoic acid, CR 1505) was given intravenously to 8 male healthy volunteers in a single dose of 2 mg/kg body weight (b.w.) or orally in a single dose of 5 mg/kg b.w. Loxiglumide was measured in plasma and in urine by HPLC during 48 h following the administration. After i.v. infusion the plasma levels were consistent with an open two-compartment pharmacokinetic model represented by the equation C (mg/l) = 43.791 x e-2.652 x h + 2.657 x e-0.139 x h. In the urine, besides loxiglumide, two metabolites were found and in the 48 h following the i.v. administration the urinary excretion of loxiglumide and of its metabolites accounted for 11.13% of the administered dose. After oral administration loxiglumide appeared in plasma with a lag time of 14 min, reached the peak 34 min after administration, being eliminated with an initial fast and a terminal slow elimination rate. The plasma levels were consistent with an open two-compartment pharmacokinetic model represented by the equation C (mg/l) = -46.72 x e-8.765 x (h-0.23) + 40.660 x e-1.383 x (h-0.23) + 6.057 x e-0.120 x (h-0.23). In the urine, besides loxiglumide, two metabolites were found and in the 48 h following the oral administration the excretion of loxiglumide and of its metabolites accounted for 7.67% of the administered dose. The absolute bioavailability of loxiglumide was calculated comparing the AUC(0-inf) found after oral and after i.v. administration and was estimated as 0.967, with p = 0.05 fiducial limit of 0.656-1.278.

Administration, Oral↗

PubMed1987

Biological effects of a proglumide derivative as cholecystokinin antagonist in conscious dogs.

In conscious dogs we studied the effects of a new cholecystokinin (CCK) antagonist (coded CR 1505) on CCK8-stimulated exocrine pancreatic secretion and release of pancreatic polypeptide (PP). Graded doses of CCK8 (25-400 ng kg-1h-1) were infused i.v. Experiments were repeated against a background infusion of CR 1505 at different doses (0.1, 1 and 10 mg kg-1h-1). The lowest dose of CR 1505 had no biological effects. However, at the upper two doses the compound significantly inhibited the CCK8-stimulated PP release. Furthermore, a significant inhibition of exocrine pancreatic protein secretion was observed with 10 mg kg-1h-1 of CR 1505 (P less than 0.05). The results suggest that CR 1505 could be a useful tool in defining the physiological role of CCK in vivo.

Animals↗