Comparative Cardiovascular Effects of the Angiotensin II Type 1 Receptor Antagonists ZD 7155 and Losartan in the Rat

Binding experiments show that ZD 7155 is a potent angiotensin II type 1 receptor antagonist. In this study this novel substance was studied in normotensive and hypertensive rats. The relative potency and duration of the antihypertensive effects of ZD 7155 were compared with those of the reference substance, losartan. The inhibitory effects of both compounds on angiotensin II-induced pressor actions were studied in the conscious normotensive Sprague-Dawley (SD) rat and in the conscious, spontaneously hypertensive rat (SHR). Arterial blood pressure and heart rate (HR) were obtained by direct intraarterial recording. Angiotensin II infusion was administered intravenously in the dose range 53.3 ng—12.8 μg kg^?1 min^?1 to the conscious rats. ZD 7155 was administered in a bolus dose of 1.082 μmol kg^?1 (0.51 mg kg^?1) and losartan in bolus doses of 2.165 and 6.495 μmol kg^?1 (1.0 and 3.0 mg kg^?1). In conscious SD rats, ZD 7155 and losartan behaved as competitive antagonists and the pressor response curve to angiotensin II was shifted to the right. Experiments in conscious SD rats also showed that ZD 7155 was approximately ten times as potent as losartan in suppressing the angiotensin II-induced pressor response (240 ng kg^?1; 10 min infusion). In addition, experiments with conscious rats demonstrated that ZD 7155 could suppress the angiotensin II-induced pressor response for approximately 24 h when ZD 7155 was administered intravenously in a 1.082 μmol kg^?1 bolus dose and angiotensin II was given at 240 ng kg^?1 (in a 10?min infusion). Experiments in conscious SHRs using ZD 7155 (1.082 μmol kg^?1) and losartan (6.495 μmol kg^?1) as intravenous boluses indicated that both ZD 7155 and the reference compound losartan exhibited a significant antihypertensive effect. These results demonstrate that ZD 7155 is a potent angiotensin II-type 1 antagonist which is approximately ten times as potent as losartan in suppressing the angiotensin II-induced pressor response. Furthermore, ZD 7155 may suppress the angiotensin II-induced pressor response for 24 h and in the SHR ZD 7155 induces a pronounced and persistent antihypertensive effect.     

Lack of interaction between metoclopramide and morphine in vitro and in mice

1.?This study examined interactions via common metabolism or via common pharmacodynamic pathways between frequently co-prescribed metoclopramide (a prokinetic) and morphine (an opioid analgesic).

2.?In human liver microsomes, morphine 3-glucuronide and morphine 6-glucuronide formation had V_max estimates of 6.2 ± 0.07 and 0.75 ± 0.01 (nmole min^?1 mg^?1 protein) and K_m estimates of 1080 ± 37 and 665 ± 55 (µM), respectively. The in vitro K_i for morphine 3-glucuronide formation in the presence of metoclopramide in human liver microsomes or recombinant uridine diphosphoglucuronosyltransferase 2B7 predicted a lack of in vivo interaction.

3.?Morphine (2 mg kg^?1 subcutaneously) delayed gastrointestinal meal transit in mice, metoclopramide (10 mg kg^?1 subcutaneously) had no effect on meal transit, and metoclopramide did not alter this effect of morphine.

4.?Morphine (2 or 5 mg kg^?1 subcutaneously) was antinociceptive in mice (hot plate test) and metoclopramide (10 mg kg^?1 subcutaneously) did not alter the antinociceptive effects of morphine.

5.?Together, the data suggest a lack of interaction between morphine and metoclopramide.     

Morphine intake from poppy seed food

Morphine was determined in commercially available poppy seed and seed cake as well as in urine from healthy normal human adults 3 and 15 h after ingestion of poppy seed cake. The following morphine concentrations were determined: between 374 ±51 and 9.4 ± 1.0 μmol kg^?1 poppy seed of different brands, 290 ± 11 μmol kg^?1 poppy seed paste, 1.43 ± 0.07 and 0.53 ± 0.15 μmol litre^?1 urine sampled 3 and 15 h, respectively, after ingestion of two cakes and 0.67 ± 0.17 and 0.30 ± 0.06 μmol litre^?1 urine sampled 3 and 15 h, respectively, after ingestion of one cake. It is concluded that a positive finding of morphine in the urine from a person suspected of heroin abuse calls on some attention due to possible accidental morphine intake from poppy seed food.     

Interactions of opioids with caffeine: evaluation by ambulatory activity in mice

Abstract— Morphine (up to 10 mg kg^?1), buprenorphine (up to 0·1 mg kg^?1), pentazocine (30 mg kg^?1) and caffeine (up to 10 mg kg^?1), significantly increased mouse ambulation. The combination of morphine, buprenorphine and pentazocine with caffeine generally enhanced the effect. Dopamine D₁- and D₂-receptor bockade, depletion of stored dopamine, and inhibition of dopamine synthesis could reduce the ambulation increased by single administration of morphine, buprenorphine and caffeine, and by combined administration of morphine and buprenorphine with caffeine. Although naloxone (0·1–3 mg kg^?1) itself did not change mouse ambulation, at 3 mg kg^?1, it reduced the effect of caffeine. The repeated administration of morphine (10 mg kg^?1) induced a sensitization to the ambulation-increasing effect, and was inhibited by the combination of caffeine (10 mg kg^?1) in the repeated administration schedule. The repeated administration of caffeine (10 mg kg^?1) with buprenorphine (0·3 mg kg^?1) resulted in a decrease in the effect to the level of caffeine alone. The development of cross-sensitization to morphine (10 mg kg^?1) by the repeated treatment with buprenorphine (0·3 mg kg^?1) was inhibited by caffeine (10 mg kg^?1). Our results suggest that the dopaminergic systems are involved in the enhanced interaction of opioids having agonistic action on μ- or σ-receptors with caffeine. However, it is also considered that, following the repeated administration, caffeine acts to reduce the sensitivity to the ambulation-increasing effect of opioids, probably inducing up-regulation of adenosinergic systems.     

Pharmacokinetics and Tissue Distribution of (±)-3′-Azido-2′,3′-dideoxy-5′-O-(2-bromomyristoyl)thymidine,a Prodrug of 3′-Azido-2′,3′-dideoxythymidine (AZT) in Mice

The in-vivo biodistribution and pharmacokinetics in mice of 3′-azido-2′,3′-dideoxythymidine ( 1 , AZT), 2-bromomyristic acid ( 2 ) and their common prodrug, (±)-3′-azido-2′,3′-dideoxy-5′-O-(2-bromomyristoyl)thymidine ( 3 ) are reported. The objectives of the work were to enhance the anti-human immunodeficiency virus and anti-fungal effects of 1 and 2 by improving their delivery to the brain and liver. The pharmacokinetics of AZT (βt1/2 (elimination, or beta-phase, half-life) = 112.5 min; AUC (area under the plot of concentration against time) = 29.1 ± 2.9 μmol g^?1 min; CL (blood clearance) = 10.5 ± 1.1 mL min^?1 kg^?1) and its ester prodrug ( 3 , βt1/2 = 428.5 min; AUC = 17.3 ± 4.7 μmol g^?1 min; CL = 17.6 ± 4.8 mL min^?1 kg^?1) were compared after intravenous injection of equimolar doses (0.3 mmol kg^?1) via the tail vein of Balb/c mice (25.30 g). The prodrug was rapidly converted to AZT in-vivo, but plasma levels of AZT (peak concentration 0.17 μmol g^?1) and AUC (12.3 μmol min g^?1) were lower than observed after AZT administration (peak concentration 0.36 μmol g^?1; AUC 29.1 μmol min g^?1). The prodrug also accumulated rapidly in the liver immediately after injection, resulting in higher concentrations of AZT than observed after administration of AZT itself (respective peak concentrations 1.11 and 0.81 μmol g^?1; respective AUCs 42.5 and 12.7 μmol min g^?1). Compared with doses of AZT itself, 3 also led to significantly higher brain concentration of AZT (25.7 compared with 9.8 nmol g^?1) and AUCs (2.8 compared with 1.4 μmol min g^?1). At the doses used in this study the antifungal agent 2-bromomyristic acid was measurable in plasma and brain within only 2 min of injection. Hepatic concentrations of 2-bromomyristic acid were higher for at least 2 h after dosing with 3 than after dosing with the acid itself. In summary, comparative biodistribution studies of AZT and its prodrug showed that the prodrug led to higher concentrations of AZT in the brain and liver. Although the prodrug did not result in measurably different concentrations of 2-bromomyristic acid in the blood and brain, it did lead to levels in the liver which were higher than those achieved by dosing with the acid itself.     

Antinociceptive Effect of the Hydroalcoholic Extract of Bauhinia splendens Stems in Mice

The analgesic effect of the hydroalcoholic extract of the stems of Bauhinia splendens (Leguminosae) has been investigated in chemical and thermal models of nociception in mice. The hydroalcoholic extract of B. splendens, 3–60 mg kg^? intraperitoneally or 50–400 mg kg^? orally, caused dose-related, and long-lasting (up to 3 h) inhibition of acetic acid-induced abdominal constriction in mice, with ID50 values of 3.2 and 177.6 mg kg^? and maximum inhibition of 95 ± 2 and 61 ± 6%, respectively. In the formalin test, the extract given intraperitoneally (1.60 mg kg^?) or orally (50–400 mg kg^?) caused graded inhibition of both phases of formalin-induced pain, being about 5- to 6-fold more potent in attenuating the second phase of pain. The calculated mean ID50 values for the first and the second phases were 11.5 and 2.5 mg kg^?, respectively, for intraperitoneal administration and > 200 and 70 mg kg^?, respectively, for oral administration; the percentages of maximum inhibition for the first and the second phases were 68 ± 6 and 99 ± 1, respectively, for intraperitoneal administration and 37 ± 6 and 69 ± 9, respectively, for oral administration. However, at the same doses the extract did not significantly affect the oedematogenic response induced by formalin. The treatment of animals with naloxone (5 mg kg^?, i.p.) completely reversed the analgesic effect caused by morphine (5 mg kg^?, s.c), but had no effect against the antinociceptive effect of the hydroalcoholic extract of B. splendens (60 mg kg^?, i.p.) when assessed against acetic acid-induced abdominal constrictions. Furthermore, the extract, in contrast with morphine, had no analgesic effect in the hot-plate test. These data show that the hydroalcoholic extract of B. splendens has significant analgesic action when assessed against several models of pain. The mechanism underlying its analgesic effect still remains unknown, but seems to be unrelated to interaction with opioid systems.     

Pharmacokinetics of a novel retinoid AGN 190168 and its metabolite AGN 190299 after intravenous administration of AGN 190168 to rats

The pharmacokinetics of AGN 190168, a novel synthetic retinoid, and its major metabolite, AGN 190299, in rat blood after intravenous administration was investigated. Approximately 4.4 mg kg^?1 (high dose) or 0.49 mg kg^?1 (low dose) of AGN 190168 was administered to rats via the femoral vein. Blood was collected from the femoral artery at various time points during an 8 h period. Blood concentrations of AGN 190168 and AGN 190299 were determined by a specific and sensitive high-pressure liquid chromatographic (HPLC) method. AGN 190168 was rapidly metabolized in rats. The only detectable drug-related species in the blood was AGN 190299. Therefore, only pharmacokinetics of AGN 190299 were calculated. Elimination of AGN 190299 appeared to be non-linear after administration of the high dose, and linear after administration of the low dose. The maximum elimination rate (V_max) and the concentration at half of the V_max (k_m), as estimated by a Michaelis—Menten one-compartment model, were 7.58 ± 2.42 μg min^?1 (mean ± SD) and 6.10 ± 1.58 μg mL^?1, respectively. The value of the area under the blood concentration time curve (AUC) was 9.54 ± 1.68 μg h mL^?1 after administration of the high dose and 0.594 ± 0.095 μg h mL^?1 after administration of the low dose. The clearance value was 7.79 ± 1.20 mL min^?1 kg^?1 after the high dose, statistically significantly different from that after the low dose (p < 0.05), 14.0 ± 2.2 mL min^?1 kg^?1. The terminal half-life (t_1/2) was 1.25 ± 0.74 h for the high-dose group and 0.95 ± 0.16 h for the low-dose group. Study results demonstrate rapid systemic metabolism of AGN 190168 to AGN 190299, non-linear pharmacokinetics of AGN 190299 after the 4.4 mg kg^?1 dose, and the lack of difference in disposition profiles between sexes after intravenous administration of AGN 190168 to rats.     

Plasma pharmacokinetics and urinary and biliary excretion of a new potent tripeptide HIV-1 protease inhibitor,KNI-272, in rats after intravenous administration

The pharmacokinetic (PK) characteristics of KNI-272, a potent and selective HIV-1 protease inhibitor, were evaluated in rats after intravenous (IV) administration. The effect of dose on KNI-272 plasma kinetics, and the urinary and biliary elimination kinetics of KNI-272, were examined. After IV administration of 10.0 mg kg^?1 KNI-272, the mean terminal elimination half-life, t_1/2λz, was 3.49 ± 0.19 (SE) h, the total plasma clearance, CL_tot, was 15.1 ± 1.2 mL min^?1 and the distribution volume at steady state, V_d,ss, was 3790±280 mL kg^?1. On the other hand, after 1.0mg kg^?1 IV administration, t_d,ss, was 3.04±0.11 h, CL_tot was 15.9±0.2mL min^?1, and V_d,ss was 6950±600 mL kg^?1. The PK parameters of KNI-272 after IV administration showed that the disposition of KNI-272 in the rat plasma is linear within the dose range from 1.0 to 10.0mg kg^?1. Using an equilibrium dialysis method, the plasma binding of KNI-272 was measured in vitro. The free fractions were 17.7 ± 0.6%, 12.1±1.5%, and 13.8 ± 1.4% at the total concentration ranges of 9.898 ± 0.097 μg mL^?1, 0.888 ± 0.008 μg mL^?1, and 0.470±0.55 μg mL^?1, respectively. The percentages of the dose excreted into the urine and bile as the unchanged form were 1.20 ± 1.06% and 1.61 ± 0.32% at 1.0mg kg^?1 dose, and 0.164 ± 0.083% and 1.42 ± 0.26% at 10.0 mg kg^?1 dose, respectively. The renal clearance (CL_R) and the biliary clearance (CL_B) were calculated to be 0.191 and 0.256mL min^?1 for 1.0mg kg^?1, and 0.0248 and 0.215 mL min^?1 for 10.0 mg kg^?1, respectively. When comparing these values with the CL_tot values, the urinary and biliary excretion of KNI-272 are minor disposition routes.     

Dependency of salivary excretion of mexiletine on the plasma concentration in rats

Abstract— The effect of steady-state plasma concentrations on the salivary excretion of mexiletine was investigated following simultaneous bolus intravenous injection of the loading dose (2·7 or 16·1 mg kg^?1) and constant-rate intravenous infusion of the maintenance dose (15 or 102 μg min^?1 kg^?1) in male Wistar rats. Parotid and mandibular saliva was collected separately by stimulating salivation with a constant-rate infusion of pilocarpine (50 μg kg^?1 min^?1) in each rat. The low and high steady-state levels of mexiletine in blood plasma were attained at 0·259 + 0·123 and 1·616 ± 0·475 μg mL^?1, respectively, within the first 1–2 h after drug administration. Similarly, the two different steady-states in both parotid and mandibular saliva were attained. Although the mexiletine levels in both types of saliva were lower than that in plasma, the drug level in parotid saliva was always higher than that in mandibular saliva at any steady-state (P < 0·001 or 0·01). In parotid saliva, the high steady-state produced greater saliva to plasma drug concentration ratios (S/P ratio, 0·475 + 0·160) than that (0·386±0·131) at the low steady-state (P < 0·05). The S/P ratio for mandibular saliva at the high (0·204 ± 0·060) steady-state was also greater than that at the low (0·158 ± 0·050) steady-state (P < 0·01). These changes in the S/P ratio could not be explained by the pH for either parotid or mandibular saliva, but partially by the change in the unbound fraction of the drug which tended to be consistent with that in the ratio for both salivary glands. These findings suggest that the salivary excretion of mexiletine may be dependent on the plasma unbound concentration in rats.     

The Disposition of Morphine and Its Metabolites in the In-situ Rat Isolated Perfused Liver

A specific HPLC method with UV detection was used to investigate the disposition of morphine and its metabolites in the in-situ rat isolated perfused liver preparation. Livers of male Sprague-Dawley rats (n = 4) were perfused under single pass conditions with protein-and erythrocyte-free perfusate, containing 2·66 μm morphine, for up to 90 min. The concentration of morphine, normorphine and morphine-3-glucuronide (M3G) in outflow perfusate, and the biliary excretion of M3G and normorphine glucuronide, all reached steady-state levels within 15–20 min after commencing perfusion. At steady-state, the mean (± s.d.) extraction ratio of morphine was 0·87 ± 0·06 and clearance (26·0 ± 1·7 mL min^?1) approached perfusate flow rate (30 mL min^?1). Although M3G was the main metabolite, accounting for 72·8 ± 12·7% of eliminated morphine, a significant proportion (21·6 ± 13·5%) was N-demethylated to normorphine and was recovered as unchanged normorphine in outflow perfusate and normorphine glucuronide in bile. The biliary extraction ratio of hepatically-formed M3G was 0·61 ± 0·31. Results from an additional six experiments, in which livers were perfused with 1·33 and 2·66 μm of morphine for 30 min each in a balanced cross-over manner, indicated that the disposition of morphine and its metabolites was approximately linear within this concentration range.     

Pharmacokinetics: The Effect of the Mode of Administration on the Hypolipidaemic Activity of Niacin: Continuous Gastrointestinal Administration of Low-dose Niacin Improves Lipid-lowering Efficacy in Experimentally-induced Hyperlipidaemic Rats

The effect of different routes and modes of administration of niacin (nicotinic acid) on its hypolipidaemic activity has been evaluated. Our working hypothesis was that the major sites of niacin action are located presystemically (i.e. in the gut wall or the liver, or both) which would make niacin a gastrointestinal drug. For such drugs continuous administration to the gastrointestinal tract is expected to augment their efficacy compared with bolus oral administration or parenteral administration. The hypothesis was examined in two rat models of experimentally induced hyperlipidaemia—Model A, based on a cholesterol-enriched diet, and Model B, in which acute hyperlipidaemia is induced by intraperitoneal administration of triton (225 mg kg^?1). Continuous administration of niacin into the duodenum at 1.66 mg h^?1 (total dose 40 mg kg^?1 day^?1) for up to 7 days (Model A) or at 2.22 mg h^?1 over 18 h (Model B) had significantly greater lipid-reducing effects both on total cholesterol and on triglyceride levels (15–25%) and elevation of high-density lipoprotein (HDL) cholesterol levels than did bolus oral administration of the same dose. Continuous duodenal infusion of niacin also had an even greater lipid-reducing effect than continuous intravenous infusion of the drug at the same rate and dose. The results indicate that the site(s) of action are located presystemically and that continuous duodenal administration of a low dose of niacin (40 mg kg^?1) has a greater lipid-lowering effect than a higher dose (200 mg kg^?1) administered by peroral bolus administration. These conclusions were validated by administration of a specially designed niacin sustained-release matrix tablet formulation that was non-invasively administered to hyperlipidaemic rats. The hypolipidaemic activity of the sustained-release tablet was of similar magnitude to that resulting from continuous duodenal administration, thus providing a pharmacodynamic rationale for this mode of administration.     

Effect of Cholecystokinin-B/Gastrin Receptor Blockade on Gastric Acid Secretion in Conscious Rats

Abstract: Gastrin, histamine and acetylcholine are physiological stimuli of gastric acid secretion. The cholecystokinin-B/gastrin receptor antagonists YM022 and RP73870 were used to study the effect of gastrin receptor blockade on acid secretion. Gastrin, histamine, insulin or bethanechol were administered to conscious gastric fistula rats with or without the concomitant intravenous infusion of YM022 or RP73870. Other rats were subjected to pylorus ligation. YM022 and RP73870 inhibited the gastrin-induced acid secretion in a dose- and time- dependent manner; maximal inhibition was observed at a dose of 0.3 μmol·kg^?1 · hr^?1 for both YM022 and RP73870, the ID₅₀ values being 0.02 μmol · kg^?1 · hr^?1 and 0.05 μmol · kg^?1 · hr^?1 for YM022 and RP73870, respectively. At a dose of 0.3 μmol · kg^?1 · hr^?1 YM022 and RP73870 failed to inhibit basal and histamine-, bethanechol-, and insulin-evoked secretion. They also failed to affect the secretion evoked by infusion of a cocktail of maximally effective doses of gastrin-17, histamine and bethanechol. YM022 and RP73870, finally, were without effect on the acid response to pylorus ligation. We suggest that endogenous gastrin in the conscious rat does not contribute to the basal acid secretion and does not participate in the acid response to histamine or to vagus stimulation.     

Further Studies on the Antinociceptive Action of the Hydroalcoholic Extracts from Plants of the Genus,Phyllanthus

The analgesic effects of the hydroalcoholic extracts (HEs) of Phyllanthus urinaria, P. tenellus, P. niruri and P. sellowianus have been investigated in several models of nociception in mice. The HE of four species of Phyllanthus (1–90 mg kg^?1, i.p.) caused a dose-related inhibition of acetic acid-induced abdominal constriction in mice with ID50 values of 5·4, 8·5, 18·2 and 53·0 mg kg^?1 and maximal inhibition (%) of 80 ± 2, 67 ± 8, 63 ± 8 and 50 ± 4 for P. urinaria, P. niruri, P. tenellus and P. sellowianus, respectively. In the formalin test, the HE of all Phyllanthus species (0·3–60 mg kg^?1, i.p.) caused graded inhibition of both phases of formalin-induced pain, but they were, however, more potent in relation to the second phase of the pain. The ID50 values (mg kg^?1) for the first phase were 20·0, 23·0, > 60, and > 60 for the P. urinaria, P. tenellus, P. niruri and P. sellowianus, respectively, and percentages of maximal inhibition were 63 ± 2, 70 ± 2,41 ± 3 and 46 ± 4, respectively. The ID50 values (mg kg^?1) for the second phase were 0·71, 4·87, 7·7, 33·0, with maximal inhibition (%) of 91 ± 6, 97 ± 3, 97 ± 3 and 92 ± 6, respectively. Given orally, the HEs of species of Phyllanthus caused a significant antinociceptive profile, but they were about one-tenth to one-twentieth as potent when given intraperitoneally. However, the HEs of Phyllanthus failed to affect formalin-induced paw oedema and did not interfere with the performance of animals in the rota-rod test. Naloxone (5 mg kg^?1) completely reversed the analgesic effect caused by morphine (5 mg kg^?1), but had no effect against the analgesic effect of the HE of Phyllanthus. Furthermore, the HEs of Phyllanthus in contrast to morphine had no analgesic effect in either tail-flick or hot-plate tests. Taken together, these findings confirm and extend our previous results and indicate that all studied HE of species of plant belonging to the genus Phyllanthus exhibit potent and long-lasting antinociceptive activity in several models of pain, including the neurogenic algesic component of the formalin test. The mechanism underlying their analgesic profile is presently unknown.     

The Disposition of Morphine and Morphine-3-glucuronide in the Isolated Perfused Rat Liver: Effects of Altered Perfusate Flow Rate

The rat single-pass isolated perfused liver preparation was used to study the effects of altered perfusate flow rate on the hepatic disposition of morphine and its polar metabolite morphine-3-glucuronide (M3G). Using a balanced, cross-over design, livers of female Sprague-Dawley rats (n = 6) were perfused at 15 and 30 mL min^?1 with erythrocyte- and protein-free perfusion medium containing a constant concentration of morphine (2.7 μM). After reaching steady-state, inflow and outflow perfusate and bile samples were collected and morphine and M3G were measured by HPLC. Doubling of perfusate flow rate was associated with a significant increase (P < 0.05) in the availability of morphine (mean ±s.d. of 0.19± 0.06 at 15 mL min^?1 and 0.29 ± 0.08 at 30 mL min^?1). The magnitude of the change in morphine availability was consistent with the predictions of the well-stirred model of hepatic elimination. The fate of hepatically generated M3G was assessed by the biliary extraction ratio of M3G; alterations in perfusate flow rate had no significant effect on this ratio (mean ± s.d. of 0.49 ± 0.14 at a perfusate flow rate of 15 mL min^?1 and 0.47 ± 0.22 at 30 mL min^?1). A physiologically-based mathematical model, in which the vascular and intracellular spaces of the liver were represented by two well-mixed compartments, was utilized to derive an equation for the biliary extraction ratio of M3G. According to the model, the value of this extraction ratio will become insensitive to changes in perfusate flow rate when the permeability for M3G of the membrane separating the intracellular and vascular compartments is low compared with perfusate flow rate. Hence, the experimental results are consistent with the concept that the hepatic sinusoidal membrane represents a diffusional barrier to M3G.     

Gastrointestinal Effects of Diazepam-withdrawal are Linked to Activation of Central Cholecystokinin-ergic Pathways in Rats

Abstract— The influence of flumazenil-precipitated diazepam withdrawal on intestinal myoelectric activity and colonic transit was evaluated, in diazepam-dependent rats. Administered intraperitoneally, flumazenil (15 mg kg^?1) induced a strong stimulation of the duodenal spiking activity lasting 197 ± 20 min, and accelerated colonic transit corresponding to a significantly (P < 0·05) increased value of the geometric centre (3.52 ± 0.23 vs 2·44 ± 0·1 for the control). Both devazepide and L365260 administered intracerebroventricularly at a dose of 10 μg kg^?1 abolished the flumazenil-induced withdrawal effect on the duodenum, whereas at a lower dose (1 μg kg^?1) only L365260 was able to antagonize this effect. In the same way, devazepide, loxiglumide and L365260 suppressed the effect of precipitated withdrawal on colonic transit when administered intracerebroventricularly at a dose of 10 μg kg^?1, whereas similar blockade was obtained at a dose of 5 μg kg^?I with L365260, and 10 ng kg^?1 with PD135–158. It is concluded that in rats precipitated diazepam-withdrawal altered intestinal motility and colonic transit and that these effects are mediated by central release of cholecystokinin (CCK) or activation of CCK-ergic neurons.     

Pharmacokinetics of 14C-DMPS (sodium-1,3 14C-2,3-dimercaptopropane-l-sulphonate) in beagle dogs

The pharmacokinetics of labelled DMPS (sodium-1,3 ¹⁴C-2,3-dimercaptopropane-1-sulphonate) have been studied in four beagle dogs following bolus intravenous injection (65-7 μmolkg^?1) and oral administration (197μmol kg^?1). Following intravenous injection the main kinetic parameters were t_1/2 = 43min, V_β = 160 ml kg^?1, and plasma clearance Cl_p = 2.6ml min^?1 kg^?1. Following oral administration ¹⁴C-DMPS is rapidly absorbed with peak concentrations (478 ± 25 umol 1^?1) measured after 30–45 min. About 60 per cent of the oral dose was absorbed. Estimates of t_1/2, V_β, and Cl_p after oral administration were in close agreement with the values obtained in the intravenous study. ¹⁴C-DMPS is eliminated from the body by the kidneys. About 70 per cent of ¹⁴C-DMPS in dog plasma are bound to proteins. Binding is even higher in plasma from rat and man.     

Comparative effects of calcium channel blockers and indomethacin on insulin secretion and blood pressure increase derived from α1-adrenoceptor stimulation in the rabbit

1 In conscious, fasted rabbits the intravenous infusion of the α₁-adrenoceptor agonist, amidephrine (3 and 10 μg kg^?1 min^?1) induced a dose related increase in insulin plasma levels. This effect was accompanied by a minor hypo- or hyperglycaemic response, depending on the dose of agonist infused. 2 A dose related increase in mean arterial pressure and reduction in heart rate were also found after amidephrine administration. 3 The insulin secretory response to amidephrine was not prevented in rabbits previously treated with atropine (5.26 μg kg^?1 min^?1). However, in the presence of muscarinic receptor blockade the bradycardic effect of amidephrine was either suppressed or attenuated. 4 Pretreatment with the calcium channel antagonist elgodipine (35 ng kg^?1 min^?1) or with indomethacin (0.66 mg kg^?1 min^?1) clearly blocked the effect of amidephrine on insulin secretion. 5 The haemodynamic changes induced by amidephrine were preserved in the presence of either verapamil (0.17 μg kg^?1 min^?1) or indomethacin, whereas the hypertensive response was antagonized by elgodipine. 6 Our results suggest that the metabolic and haemodynamic changes mediated by amidephrine are two independent effects, insulin secretion requiring the presence of extracellular calcium and the synthesis of arachidonic acid metabolites.     

Pharmacokinetics of Terbutaline and Theophylline in Guinea Pigs when Administered Simultaneously

Abstract: Simultaneous administration of terbutaline and theophylline to guinea pigs did not cause significant alterations of the pharmacokinetic properties of any of the drugs. Terbutaline sulphate 24 μg kg^?1 and aminophylline 52 mg kg^?1 (7.42.10^?8 and 2.37.10^?4 mol kg^?1 respectively) were given by a bolus intravenous injection, producing plasma concentrations in the range 0–15 ng terbutaline sulphate per ml (0–46 nanomol 1^?1) and 10–85μg theophylline per ml (50–429 μmol 1^?1). Pharmacokinetic analyses of time courses of plasma concentrations of intact drugs and investigations of tissue distribution 1 hour after the administration were performed. The results showed a weak, statistically insignificant trend of the peripheral compartment of the 2-compartment model to sequester a larger fraction of the drugs when these were administered simultaneously.     

Selective effect of fentanyl on group III and IV somatosympathetic reflexes

The effect of fentanyl on sympathetic reflexes evoked by supramaximal electrical stimulation of the radial nerve, and the subsequent reversal of its effects by naloxone, have been observed in 10 dogs anaesthetized with α-chloralose, paralysed with suxamethonium and artiflcally ventilated. During infusions of 5 μg/kg^?1 min^?1 the late, long-latency, sympathetic response evoked by unmyelinated fibres was abolised at a mean dose of 27 μg/kg^?1 (SD 12.6 μg/kg^?1) after which the early, short-latency response evoked by small myelinated fibres was eliminated at a mean dose of 90.3 μg/kg^?1 (SD 54.6 μg/kg^?1) so that there was no longer any response to stimulation of the radial nerve. During a subsequent infusion of naloxone (200 μg/kg^?1) the late response returned to control values at a mean dose of 0.5mg and subsequently the early response reappeared to return to control values at a total dose of 1.6 mg. In 2 preparations phrenic nerve activity was abolished after 6.1 and 17.4 μg/kg^?1 of fentanyl and returned immediately before the late response, during the infusion of naloxone. In 2 preparations, induced tolerance occurred so that the early response could not be eliminated.     

Anti-ulcer Activity of Cromakalim (BRL 34915), a Potassium-channel Opener,Against Experimentally Induced Gastric and Duodenal Ulcers in Rats and Guinea-pigs

The effect of cromakalim, a potassium-channel opener, was studied on pylorus ligation-induced, aspirin-induced and water-immersion plus restraint stress-induced gastric ulcers in rats and on histamine-induced duodenal ulcer in guinea-pigs. Pretreatment with cromakalim (50–500 μg kg^?1, p.o.) resulted in a significant reduction in the incidence of gastric and duodenal ulceration in each model. The anti-ulcer activity of cromakalim was comparable with that of cimetidine. Cromakalim at 100, 250 and 500 μg kg^?1 caused a reduction in the volume of the gastric content in pylorus-ligated rats, and a dose of 250 μg kg^?1 resulted in a significant reduction in total acidity (28.81 ± 11.73 mEq L^?1, P < 0.02) in the pylorus ligation model. A significant reduction in total acid output was observed at doses of 250 μg kg^?1 (84.27 ± 22.33 mEqH+, P < 0.02) and 500 μg kg^?1 (120.17 ± 24.49 mEq H+, P < 001) in pylorus-ligated rats. A significant reduction in the ulcer index in pylorus-ligated rats was observed at all cromakalim doses: 50 μg kg^?1 (0.23 ± 009, P < 0.05), 100 μg kg^?1 (0.15 ± 0009, P < 0.02), 250 μg kg^?1 (0.12 ± 0.05, P < 0.01) and 500 μg kg^?1 (0.14 ± 0.03, P < 0.02). A significant reduction in the ulcer index of aspirin-treated rats was also observed at all cromakalim dose levels: 50 μg kg^?1 (0.39 ± 0.03. P < 0.01), 100 μg kg^?1 (0.28 ± 0.06, P < 0.01), 250 μg kg^?1 (0.22 ± 0.04, P < 0.001) and 500 μg kg^?1 (0.28 ± 0.03, P < 0.01). In the water-immersion plus restraint stress-induced gastric ulcer model, cromakalim significantly reduced gastric ulceration at all the dose levels: 50 μg kg^?1 (28.2 ± 2.12, P < 0.001), 100 μg kg^?1 (20.24 ± 1.71, P < 0.01), 250 μg kg^?1 (19.95 ± 1.46, P < 0.001) and 500 μg kg^?1 (21.61 ± 3.00, P < 0.001) but there was no consistent reduction of gastric bleeding. In addition to gastric ulcers, duodenal lesions were also reduced by pretreatment with cromakalim at all dose levels: 50 μg kg^?1 (97.87 ± 20.03 mm², P < 0.02). 100 μg kg^?1 (70.72 ± 12.82 mm², P < 0.02), 250 μg kg^?1 (48.32 ± 8.42 mm², P < 0.01) and 500 μg kg^?1 (55.50 ± 12.50 mm², P < 0.01). Cromakalim at a dose of 100 μg kg^?1 also reduced total acidity (99.36 ± 9.12 mEq L^?1, P < 0.02) and total acid output (172.22 ± 45.33 mEq of H+, P < 0.05) in this model. These findings demonstrate the anti-ulcer activity of cromakalim in different experimental models and suggest its potential use in ulcer therapy.