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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

Anticholecystokinin activities of loxiglumide.

The anticholecystokinin activities of loxiglumide, (D,L-4-(3,4-dichloro-benzoylamino)-5-(N-3-methoxypropyl-pentylamino++ +)-5-oxo- pentanoic acid, CR 1505) are described. Loxiglumide antagonizes in vivo the contractions of the gall bladder of guinea pig induced or mediated by cholecystokinin-8 (CCK-8) (i.v. ED50 = 0.24 mumol/kg), the emptying of the gall bladder of the mouse induced by CCK-8 (i.v. ED50 = 29 mumol/kg, oral ED50 = 42 mumol/kg), the retardation of gastric emptying of the rat induced by CCK-8 (i.p. ED50 = 13 mumol/kg), the retardation of the pyloric transit in the mouse induced by CCK-8 (i.v. ED50 = 3.7 mumol/kg, oral ED50 = 11 mumol/kg), the hypermotility of the ileum of the rabbit induced by CCK-8 (i.v. ED50 = 1.2 mumol/kg) and the contractions of the gall bladder of the non-anesthetized dog induced by caerulein (i.v. ED50 ca. 11 mumol/kg). Loxiglumide also antagonizes the satiety behaviour of the rat elicited by CCK-8 (i.p. ED50 = 0.65 mumol/kg) and the exocrine pancreatic hypersecretion in the anaesthetized dog induced by CCK-8 (i.v. ED50 ca. 0.35 mumol/kg). Loxiglumide has a simple, non-polypeptidic chemical structure and is active after parenteral and after oral administration.

Anesthesia↗
PubMed1987

Loxiglumide protects against experimental pancreatitis.

Loxiglumide (D,L-4-(3,4-dichloro-benzoylamino)- 5-(N-3-methoxypropyl-pentylamino)-5-oxo-pentanoic acid, CR 1505) is a derivative of pentanoic acid and belongs to a newly discovered class of agents with cholecystokinin antagonistic activities. Loxiglumide has preventive effects on different types of experimental pancreatitis, induced e.g. by ceruletide (i.p. ED50 ca. 9 mumol/kg), by intrapancreatic taurocholate (i.p. ED50 ca. 80 mumol/kg) or by choline-deficient ethionine-supplemented diet (i.p. ED50 ca. 45 mumol/kg). Loxiglumide has a simple, non-polypeptidic chemical structure and may be a candidate for clinical investigations in man, e.g. for pancreatitis.

Animals↗
PubMed1987

Pharmacological properties of lorglumide as a member of a new class of cholecystokinin antagonists.

Derivatives of 5-(dipentylamino)-5-oxo-pentanoic acid are a new class of non-peptide cholecystokinin (CCK) antagonists. The most potent compound, D,L-4-(3,4-dichlorobenzoylamino)-5-(dipentylamino)-5-oxo-pen tanoic acid (lorglumide, CR 1409), has a great affinity for the pancreatic CCK receptors and is a competitive, specific and potent CCK antagonist on the smooth muscles of the gall bladder and ileum of the guinea pig and on the CCK-induced amylase secretion of isolated pancreatic acini. In vivo lorglumide antagonizes the contraction of the gall bladder of the guinea pig and of the dog provoked by i.v. CCK-8 or ceruletide (caerulein). It antagonizes the satiety effect of CCK-8 in the rat and is protective against ceruletide-, taurocholate- and diet-induced pancreatitis. Lorglumide is therefore a useful pharmacological tool to study the functions of CCK. For its pharmacological properties, its relatively low toxicity and because it is active also after oral administration, lorglumide is a candidate for diagnostic or therapeutic use in man when an involvement of CCK is suspected.

Animals↗
PubMed1978

Treatment of gastric ulcer. The randomized clinical trials from 1964 to 1974 and their impact.

Twenty-nine randomized clinical trials (RCTs) from the decade 1964-74 evaluating treatments of gastric ulcer have been analyzed. None of them ful-filled all criteria for an ideal RCT. The most frequent shortcomings were: short treatment or follow-up periods, incomplete description of the patients included, small patient samples, suboptimal experimental design, lack of double-blind testing, high number of drop-outs, less precise or less relevant types of evaluation of the treatment effect, uncontrolled ancillary treatment, or lack of statistical evaluation of the results. The most frequently tested drug was carbenoxolone, which has been shown to be clearly effective. Judged by the effect on the recommendations in standard medical textbooks the impact of the best RCTs have been small. This situation emphasizes the need for more well-planned and performed RCTs on treatments of gastric ulcer.

Adult↗
PubMed1987

Pharmacological characterisation of a new potent and specific nonpolypeptidic cholecystokinin antagonist.

D,L-4-(3,4-Dichloro-benzoylamino)-5-(N-3-methoxypropyl- pentylamino)-5-oxo-pentanoic acid (CR 1505) belongs to a newly discovered class of agents with cholecystokinin (CCK) antagonistic activity. CR 1505 displaces CCK-8 from the central CCK receptors at concentrations of 9.1 mumol/l, and from the peripheral CCK receptors at concentrations of 0.33 mumol/l. CR 1505 antagonizes in vitro the contractant effects of CCK-8 on gall bladder strips of the guinea pig at 0.79 mumol/l and those on the small intestine at 1.6 mumol/l. These antagonistic effects are dose dependent and of competitive type. The antagonistic activities of CR 1505 against contractions of smooth muscles elicited by CCK-8 are at least 1000 times more potent than those against the contractions elicited by acetylcholine, BaCl2, histamine, serotonin, Substance P, bradykinin or dimethylphenylpiperazine. CR 1505 is also practically ineffective against the contractions of the small intestine of the guinea pig elicited by electrical field stimulations either as "cholinergic twich" (0.05 Hz), or as "cholinergic contractions" (trains of 10 min at 1 Hz), or as "non-cholinergic contractions" (200 impulses at 5 Hz in presence of atropine). CR 1505 is therefore a potent, specific, competitive and reversible CCK antagonist.

Animals↗
PubMed1985

New glutaramic acid derivatives with potent competitive and specific cholecystokinin-antagonistic activity.

New glutaramic acid derivatives were evaluated for anti-cholecystokinin (CCK) activity in vitro on guinea pig gallbladder. The compounds are competitive and specific CCK-antagonists, causing a parallel right shift of the cumulative dose-response curve of the agonist. The affinity for the binding site of the CCK-receptor for some of these compounds was hundreds of times higher than that of pro-glumide, the model compound.

Acetylcholine↗
PubMed1980

Responses of goat ruminal musculature to bradykinin and serotonin in vitro and in vivo.

Concentration-response curves obtained for contraction of goat rumen strips indicated that both bradykinin (BK) and serotonin (5-hydroxytryptamine creatinin sulphate; 5-HT) are potent agents. Sodium meclofenamate antagonized the smooth muscle-stimulating action of BK; the 5-HT blocking agents xylamidine and methysergide diminished the contractile effects of 5-HT. The results indicated that the antagonisms are noncompetitive in nature. In vivo, both BK and 5-HT caused a dose-dependent inhibition of the rumen contraction sequences. The BK was the more potent of the two compounds. This inhibition was probably due to an increase in ruminal smooth muscle tone, resulting in reflex inhibition of the normal cyclical contraction sequences. In conscious goats, BK induced tachycardia, whereas 5-HT produced only minor changes in heart rate. Treatment with sodium meclofenamate or phenylbutazone prevented the BK-induced inhibition of rumen motility. Treatment with the 5-HT blocking agents only partly reduced the 5-HT-induced effects.

Animals↗