Satiety effects of the type A CCK receptor antagonist loxiglumide in lean and obese women.

Several studies have demonstrated that administration of cholecystokinin (CCK) reduces food intake in several species, including humans. In animal studies CCK-receptor antagonists have been reported to increase food intake, suggesting a physiological satiety effect of CCK in these animals. In a double-blind, placebo-controlled study, we investigated the effect of the specific CCK-A receptor antagonist loxiglumide on food intake (carbohydrate-rich meal) and on subjective hunger feelings scored with visual analogue scales and food selection lists in seven healthy obese women and in seven healthy lean women. Loxiglumide was administered intravenously in a dose of 10 mg/kg ideal weight/h. For the whole group, food intake during loxiglumide (359 +/- 39 g) was not significantly different from food intake during saline infusion (333 +/- 31 g). Also, when the lean and obese subgroups were analyzed separately, no significant influence of loxiglumide on food intake was found. In addition, no significant differences in satiety scores were seen using the food selection lists or visual analogue scales. In conclusion, in the present study during infusing the CCK-A receptor antagonist loxiglumide we found no increase in preprandial satiety nor in food intake of a carbohydrate-rich meal nor in postprandial satiety in lean and obese women.

Proglumide potentiates morphine analgesia for acute postsurgical pain.

Proglumide, an antagonist of cholecystokinin, has been shown to potentiate morphine analgesia in animal and human experimental pain models. This study was undertaken to determine whether proglumide enhances morphine analgesia for patients experiencing postoperative pain. At onset of pain after the removal of impacted third molars, patients (n = 60) received intravenously either 4 mg morphine, 8 mg morphine, or 4 mg morphine plus proglumide (0.05, 0.5, or 5 mg). The administration of 8 mg morphine significantly reduced pain, in comparison with baseline and 4 mg morphine, for the first 30 minutes. The addition of 0.05 mg proglumide resulted in a significant increase in the magnitude and duration of the analgesic activity of 4 mg morphine; 0.5 and 5.0 mg proglumide did not produce this effect. No difference was seen in respiratory rate or in the frequency of side effects among the various forms of treatment. These data indicate that a low dose of proglumide potentiates both the magnitude and the duration of morphine analgesia in a clinical model of acute pain, without any detectable increase in side effects.

Clinical evaluation and safety of loxiglumide (CCK-A receptor antagonist) in nonresectable pancreatic cancer patients. Italian Pancreatic Cancer Study Group.

The effects and safety of loxiglumide, a cholecystokinin-A (CCK-A) receptor antagonist, on advanced pancreatic cancer were investigated in humans. A perspective, controlled (2.4 g/day vs. placebo), randomized, double-blind, parallel-group study was performed in 64 patients affected by nonresectable histologically diagnosed pancreatic cancer. The patients were stratified according to sex and stage (A, T3/N0-N1/M0; B, T1-T2-T3/N0-N1/M1; C, relapse after surgical exeresis). Tumor size (by computed tomography scan) and mortality rate were evaluated as efficacy criteria. Clinical symptoms and physical signs, laboratory tests, and adverse reactions were checked every 6 weeks as efficacy/tolerability criteria. Forty-two male and twenty-two female patients were considered. A homogeneous distribution of the patients was demonstrated in the two treatment groups. Group C was not statistically evaluated for survival and tumor evolution because of its small number. Three patients dropped out for causes not related to the therapy. No toxic reactions to the drug were reported. Tumor size monitoring within groups A and B demonstrated a similar increase in both the loxiglumide and the placebo group. Survival in group A was higher than in group B (p = 0.0003). In group B, survival was lower in females (F) than in males (M) (F = 61.00 +/- 6.47 days, M = 140.44 +/- 22.15 days; p = 0.012), while survival by sex was similar in group A and in global analysis. Survival by treatment was similar for groups A and B. Survival by surgery was higher (p = 0.049) for surgical palliation than for nonoperated patients. The tumor grade affected survival but it did not vary by therapy. In conclusion, sure efficacy of loxiglumide in advanced pancreatic cancer was not demonstrated by our results. In consideration of its documented tumor growth inhibiting action, we suggest that loxiglumide be tested for recurrence prevention after resective surgery.

Double-blind clinical comparison between a gastrin-receptor antagonist, proglumide, and a histamine H2-blocker, cimetidine.

A double-blind trial was carried out in 30 patients with peptic ulcers to assess the effects of treatment with a gastrin-receptor antagonist, proglumide, compared with a histamine H2-blocker, cimetidine. Patients received either 1200 mg proglumide or 1200 mg cimetidine per day for 28 days. The results showed that both drugs significantly reduced clinical symptoms and gastric secretion. In patients treated with cimetidine there was a significant increase in blood gastrin levels and marked hypertrophy and hyperplasia of the antral mucosa was observed in almost all patients. No such changes were found in the patients treated with proglumide.

A pilot randomized control trial of proglumide (a gastrin receptor antagonist) in advanced colorectal cancer.

Forty-one patients with advanced colorectal cancer were entered into a randomized controlled trial of treatment with proglumide--a gastrin receptor antagonist. There was no difference in survival between the treated and the untreated groups of patients, although there was a trend towards increased survival in those treated patients with hepatic metastases alone. Proglumide does not cause regression in advanced colorectal cancer but larger studies would be required to detect an effect on tumour growth.

Plasma cortisol levels in captive wild felines after chemical restraint.

Eight Panthera onca (Po), 13 Felis concolor (Fc), 7 Felis yagouaroundi (Fy), 7 Felis tigrina (Ft) and 5 Felis pardalis (Fp) specimens from São Paulo State zoos were used. All animals were restrained with darts containing 10 mg/kg ketamine and 1 mg/kg xylazine. Venous blood samples were collected as soon as possible (within 15-20 min) and serum was frozen until the time for cortisol quantification. Cortisol was determined using a solid phase radioimmunoassay with an intra-assay coefficient of 8.51%. Data were analyzed statistically by the Kruskal-Wallis test, followed by Dunn's multiple comparisons test, and the one-sample t-test, with the level of significance set at P < 0.05. Data are reported as means +/- SEM. Cortisol levels differed among the captive felines: Po = 166 +/- 33a, Fc = 670 +/- 118b, Fy = 480 +/- 83b, Ft = 237 +/- 42ab, Fp = 97 +/- 12a nmol/l (values followed by different superscript letters were significantly different (P < 0.001)). Since most of the veterinary procedures on these species involve chemical restraint, these results show the necessity of preventive measures in order to minimize the effect of restraint stress on more susceptible species.

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.

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)

Plasma cortisol levels in captive wild felines after chemical restraint

Eight Panthera onca (Po), 13 Felis concolor (Fc), Felis yagouaroundi (Fy) 7 Felis tigrina (Ft) and 5 Felis pardalis (Fp) specimens from SÒo Paulo State zoos were used. All animals were restrained with darts containing 10 mg/kg ketamine and 1 mg/kg xylazine. Venous blood samples were collected as soon as possible (within 15-20 min) and serum was frozen until the time for cortisol quantification. Cortisol was determined using a solid phase radioimmunoassay with and intra-assay coefficient of 8.51 percent. Data were analyzed statistically by the Kruskal-Wallis test, followed by Dunn´s multiple comparisons test, and the one-sample t-test, with the level of significance set at P<0.05. Data are reported as means + SEM. Cortisol levels differed among the captive felines: Po = 166 + 33a, Fc = 670 + 118b, Fy = 480 + 83b, Ft = 237 + 42ab, Fp = 97 + 12a nmol/l (values followed by different superscript letters were significantly different (P<0.001). Since most of the veterinary procedures on these species involve chemical restraint, these results show the necessity of preventive measures in order to minimize the effect of restraint stress on more susceptible species.