Responses to arachidonic acid and other dilator agonists and their modification by inhibition of prostaglandin synthesis in the canine hindlimb

The influence of indomethacin, in doses that completely inhibit the response to arachidonic acid, has been examined on canine hindlimb vascular responses to intra-arterial administration of bradykinin, histamine, nitroglycerin, isoprenaline and papaverine. The hindlimb was perfused at constant flow. Dose-response curves to intra-arterial administration of arachidonic acid (12 to 200 microgram kg-1), bradykinin (0.4 to 100 ng kg-1), histamine (1.8 to 120 ng kg-1), nitroglycerin (15 to 100 ng kg-1), isoprenaline (12 to 100 ng kg-1) and papaverine (1.2 to 160 microgram kg-1) (all n = 4) were compared before and 30 min after indomethacin (5 mg kg-1 i.v.). All the drugs produced dose-related decreases in hindlimb perfusion pressure. After indomethacin, responses for all dilator agonists except arachidonic acid, were significantly greater than control (P less than 0.05), both in terms of absolute (mmHg) or percent change. Dose-response curves after indomethacin had a left upward shift compared with control. Arachidonic acid responses were completely blocked by indomethacin. These findings suggest that indomethacin produces a non-specific increase in responsiveness of the hindlimb vascular bed to dilator substances, except arachidonic acid. The data presented do not support the hypothesis that the peripheral vasodilatation produced by bradykinin, nitroglycerin and histamine could be mediated by endogenous prostaglandin release.     

U-46619-induced Ischaemic Electrocardiographic Changes in Rats: Preventive Effects of Prostacyclin and Nitroglycerin

Abstract— The anti-anginal effect of nitroglycerin and prostacyclin was examined using, as an index, the ischaemic electrocardiogram (ECG) change (ST elevation) induced by intracoronary arterial injection of 9,11-dideoxy-11α,9α-epoxymethano-PGF_2α (U-46619), a stable thromboxane A₂ agonist, in anaesthetized rats. The ST elevation induced by U-46619 (5–20 μg kg^?1, i.c.a.) was dose-dependent and reproducible. U-46619-induced ST elevation was markedly prevented by the pretreatment of intravenous administration of prostacyclin (0·01 μg kg^?1), and to a lesser extent by nitroglycerin (0·3 mg kg^?1). Simultaneously, platelet count decreased significantly in the coronary arterial blood which indicated that platelet aggregation was enhanced by U-46619. The decrease of platelet count in coronary arterial blood at the time of ST elevation was significantly suppressed by prostacyclin (0·1 μg kg^?1, i.v.), but not by nitroglycerin (0·3 mg kg^?1, i.v.). These results suggest that the ST elevation induced by intracoronary arterial injection of U-46619 may be derived from spasm of coronary artery and platelet aggregation in the intracoronary artery in rats.     

Catecholamine uptake blockade in anaesthetized dogs: influence on cardiovascular responses

The effects of differential and combined catecholamine uptake antagonism on cardiovascular responses of anaesthetized dogs to isoprenaline, noradrenaline, and electrical stimulation of the left ansa subclavia nerve have been studied. Uptake 1 inhibition by cocaine HCl (5 mg kg^?1 and 1 mg kg^?1 every 45 min) enhanced responses to noradrenaline (0·1 to 2·0 μg kg^?1 i.v.) and sympathetic nerve stimulation (1 to 20 Hz), but did not affect those to isoprenaline. Uptake 2 inhibition by metanephrine (40 μg kg^?1 min^?1) enhanced cardiac responses to isoprenaline (0·05 to 1·0 μg kg^?1 i.v.), but did not significantly alter those to noradrenaline or nerve stimulation. Responses to all agonist interventions were increased by the combined administration of cocaine and metanephrine. Cocaine preferentially enhanced the positive chronotropic cardiac response to noradrenaline, but metanephrine did not differentiate between heart rate and contractility. These results have been discussed in the light of the mechanism of drug action involved.     

Rolipram inhibits airway microvascular leakage induced by platelet-activating factor,histamine and bradykinin in guinea-pigs

Abstract— Rolipram (0·1–1000 μg kg^?1, i.v.) reduced the increase in microvascular permeability induced by platelet-activating factor (PAF; 50 ng kg^?1, i.v.) at different sites of the guinea-pig airways. Rolipram (1–100μg kg^?1, i.v.) inhibited histamine (30μg kg^?1, i.v.)-and bradykinin (0·3 μg kg, i.v.)-induced airway microvascular leakage. These effects of rolipram were obtained at doses which inhibit histamine (7–20 μg kg^?1 min^?1)-induced bronchoconstriction (IC50 = 3 ± 1 μg kg, i.v.) without depressing arterial blood pressure in the guinea-pig. Aminophylline (50 mg kg^?1) did not change the effect of PAF. The anti-exudative effect of rolipram is of potential therapeutic value in asthma.     

Pharmacokinetics and Cardiovascular Effects of YM-21095, a Novel Renin Inhibitor,in Dogs and Monkeys

Abstract— The pharmacokinetics and cardiovascular effects of YM-21095 ((2 RS), (3S)-3-[N^α-[1,4-dioxo-4-morpholino-2-(1-naphthylmethyl)-butyl]-l-histidylamino]-4-cyclohexyl-1-[(1-methyl-5-tetrazolyl)thio]-2-butanol), a potent renin inhibitor, have been studied in beagle dogs and squirrel monkeys. Plasma levels of YM-21095 after 3 mg kg^?1 intravenous dosing to dogs declined biphasically and fitted a two-compartment model. Kinetics were as follows: t½α = 4·9±0·2 min, t½β = 2·76±0·79 h, Vd_ss = 3·86±1·04 L kg^?1, plasma clearance = 2·22 ± 0·39 L kg^?1, and AUC= 1445 ± 266 ng h mL^?1. After 30 mg kg^?1 oral dose, maximum plasma concentration, t_max and AUC of YM-21095 were 28·8 ± 9·6 ng mL^?1, 0·25 h and 23·6 ± 7·7 ng h mL^?1, respectively. Systemic bioavailability as determined on the basis of the ratio of AUC after intravenous and oral dose was 0·16 ± 0·04%. In conscious, sodium-depleted monkeys, YM-21095 at an oral dose of 30 mg kg^?1 lowered systolic blood pressure and inhibited plasma renin activity without affecting heart rate and plasma aldosterone concentration. Maximum plasma concentration of YM-21095 after 30 mg kg^?1 oral dose to monkeys was 71·8 ± 41·5 ng mL^?1, which was reached 0·5 h after the dose. At equihypotensive doses, captopril and nicardipine increased plasma renin activity markedly and slightly, respectively. These results suggest that oral absorption of YM-21095 is low in dogs and monkeys, and YM-21095 shows a blood pressure lowering effect by inhibiting plasma renin activity in sodium-depleted monkeys.     

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.     

Reversal of corticosterone-induced supersensitivity of vascular smooth muscle to noradrenaline by arachidonic acid and prostacyclin

In the isolated perfused hindlimb preparation of rats treated with corticosterone (2 × 20 mg/kg daily for 2 days), the dose-response curve to noradrenaline was shifted to the left, indicating supersentivity of the vascular bed to noradrenaline. Perfusion with arachidonic acid (10^?5 M) and prostacyclin (10^?9 M) for 5 min reversed the supersensitivity induced by corticosterone. The metabolite of prostacyclin, 6-keto PGF_1α(10^?9 M), was ineffective in this respect. In rats which had received desoxycorticosterone acetate (2 × 5 mg/kg daily for 7 days), there was supersenstivity of the hindlimb preparation to noradrenaline similar to that in corticosterone-treated rats. In that case, however, administration of arachidonic acid not reverse the leftward shift of the dose-response curve. Administration of indomethacin (2 × 2.5 mg/kg for 7 days) prior to the perfusion experiment also resulted in a shift of the noradrenaline dose-response curve to the left, which was less pronounced than the shift induced by cortiscosterone. Combined administration of corticosterone and indomethacin caused the same increase in noradrenaline sensitivity as did corticosterone alone. Since glucocorticoids inhibit the release of arachidonic acid from phospholipids, it is concluded that corticosterone may enhance the sensitivity to noradrenaline by affecting the biosynthesis of prostaglandins.     

Buspirone and 1-(2-pyrimidinyl)-piperazine attenuate xylazine-induced antinociception in the mouse

Abstract— The effects of subcutaneous pretreatment with buspirone and its major metabolite 1-(2-pyrimidinyl)-piperazine (1-PP) on the antinociceptive effect of xylazine were examined using the mouse acetic acid assay. Both buspirone and 1-PP dose-dependently attenuated the antinociceptive action of subcutaneously administered xylazine (0·8 mg kg^?1), with ED50 values of 7·3 mg kg^?l for buspirone and 3·4 mg kg^?1 for 1-PP. Pretreatment with either buspirone (8 mg kg^?1) or 1-PP (4 mg kg^?1) increased the antinociceptive ED50 of xylazine 3–4-fold. These data support the involvement of α₂-adrenoceptor and 1-PP in the pharmacological activity of buspirone.     

Do antidiarrhoeal opiates accumulate in the rat intestinal lumen?

Abstract— The opiate antidiarrhoeal drugs loperamide (0·6 mg kg^?1, i.p.) or difenoxin (0·77 mg kg^?1, s.c), were administered in an anaesthetic mixture (pentobarbitone 60 mg kg^?1) to rats. A length of jejunum (approx. 30 cm) was cannulated, washed and then perfused with iso-osmotic saline for 20 min. The perfusion commenced 50 min after drug administration and continued for 20 min. The perfusates were collected for analysis of fluid transport rates and antidiarrhoeal drug content. These doses of the antidiarrhoeals caused marked inhibition of intestinal fluid secretion induced by intra-arterial infusion of vasoactive intestinal peptide. However, neither of the antidiarrhoeal drugs were detected in the intestinal perfusates (< 0·5 ng by HPLC). The results indicate that loperamide and difenoxin have a different pharmacokinetic profile compared with that previously found for morphine under the same conditions.     

Pharmacokinetic behaviour in polymorphonuclear leucocytes of N,N-dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]benzopyrano[2,3-b]-pyridine-7-acetate (Y-23023), a new prodrug type of antiinflammatory agent,and indomethacin after oral administrations in rats

Abstract— N,N-Dimethylcarbamoylmethyl α,2-dimethyl-5H-[1]-benzopyrano[2,3-b]pyridine-7-acetate (Y-23023) is a prodrug developed as a new non-steroidal anti-inflammatory drug (NSAID). Y-23023 is rapidly hydrolysed to an active metabolite, α,2-dimethyl-5H-[1]benzopyrano[2,3-b]pyridine-7-acetic acid (M₁) following its absorption and then exhibits a strong anti-inflammatory activity. We have examined the pharmacokinetic behaviour in polymorphonuclear leucocytes (PMNs) of M₁ and of indomethacin after oral administration to rats of Y-23023 and indomethacin, respectively. Y-23023 was rapidly absorbed, producing a mean C_max (1·13 μg mL^?1) of M₁ after 1 h in plasma. Indomethacin was less rapidly absorbed, producing a mean C_max (3·38 μg mL^?1) after 3 h in plasma. The mean AUC of M₁ and indomethacin in plasma were 5·45 μg h mL^?1 and 22·49 μg h mL^?1, respectively. The mean t_max, C_max and AUC of M1 in PMNs were 1 h, 11·1 ng (41 pmol)/10⁸ cells and 58·6 ng (164 pmol) h/10⁸ cells, respectively. The same parameters for indomethacin in the PMNs were 3 h, 15·4 ng (57 pmol)/10⁸ cells and 95·2 ng (266 pmol) h/10⁸ cells, respectively. The PMNs/plasma ratio of M₁ was about 2·8 times that of indomethacin. These results indicate that the association of M₁, an active metabolite of Y-23023, from blood to the PMNs is greater than that of indomethacin.     

Potent Antinociceptive Activity of a Hydroalcoholic Extract of Phyllanthus corcovadensis

Abstract— This study analyses the analgesic effect of a hydroalcoholic extract (HE) from Phyllanthus corcovadensis in several models of pain in mice. HE (3–60 mg kg^?1, i.p.) or (100–500 mg kg^?1, p.o.) caused a graded and potent analgesic effect against the abdominal constriction response caused by acetic acid and acetylcholine with an ID50 of about 3 and 100 mg kg^?1, respectively. In the tail-flick model HE (up to 500 mg kg^?1, p.o.) was without effect, while morphine (1–10 mg kg^?1, s.c.) caused a graded increase in pain latency (ID50, 3 mg kg^?1). HE (1–300 mg kg^?1) given both intraperitoneally and orally caused a potent and graded inhibition of the second phase of formalin-induced persistent pain in mice with an ID50 of 1 and 80 mg kg^?1, respectively. In contrast, morphine (1–5 mg kg^?1, s.c.) inhibited both phases of formalin-induced pain with an ID50 of 2·5 mg kg^?1. Indomethacin (1–10 mg kg^?1, i.p.) only inhibited the second phase of formalin-induced pain with an ID50 of about 3 mg kg^?1. The analgesic effect of indomethacin, but not that caused by morphine and HE was accompanied by a graded inhibition of formalin-induced mouse paw oedema. In addition, HE up to 1 g kg^?1 failed to prevent carrageenan- and dextran-induced rat hindpaw oedema. It is concluded that HE exhibits a potent antinociceptive profile, either when given intraperitoneally or orally. The mechanisms that underly its analgesic effect are unclear at present, but appear to be unrelated to inhibition of synthesis of arachidonic acid via cyclo-oxygenase or to activation of opioid receptors.     

Pharmacokinetics and Absolute Bioavailability of Cyclosporin Following Intravenous and Abomasal Administration to Sheep

Abstract— Cyclosporin A pharmacokinetics were studied following intravenous and abomasal dosing in an open, crossover study in healthy, merino ewes. Five different doses of cyclosporin A were dispersed in milk and administered into the abomasum through a surgically inserted fistula which simulates oral administration. Cyclosporin A was well tolerated. Whole blood concentrations of cyclosporin A were measured by HPLC and mean clearance (0·45 ± 0·05 L h^?1 kg^?1), distribution volume (4·4 ± 2·0 L kg^?1), mean residence time (9·6 ± 4·1 h) and half-life (12·1 ± 3·1 h) were calculated. Negligible cyclosporin A was excreted in urine or bile. Area under the curve increased proportionally with doses up to 26·3 mg kg^?1, but was curvilinear above this dose. Abomasal bioavailability at 6·4 mg kg^?1 was 0·26 ± 0·09, and mean absorption time was 4·7 ± 11·1 h. Considerable pharmacokinetic variability was observed, particularly after abomasal administration. Cyclosporin A pharmacokinetics in sheep lie within the values reported in man after renal, bone marrow and cardiac transplantation.     

Femoral Vasodilation to Cromakalim is Blocked by U37883A,a Non-sulphonylurea that Selectively Inhibits KATP Channels

The purpose of the present study was to determine the effects of U37883A, a non-sulphonylurea inhibitor of K_ATP channels, in the femoral vascular bed of the anaesthetized dog. Administration of U37883A, 4-morpholinecarboxamidine-N-1-adamentyl-N-cyclohexyl hydrochloride (2·5 mg kg^?1, i.v.), significantly inhibited the femoral vasodilator response to intra-femoral arterial injection of cromakalim, an activator of K_ATP channels. In contrast, U37883A had no effect on the femoral vasodilator responses to nitroglycerin, isoprenaline, 5-HT, or 5-carboxamidotryptamine, suggesting this agent is a novel and selective inhibitor of hindlimb vasodilation induced by K_ATP-channel activation. Since U37883A did not significantly alter baseline femoral blood flow and femoral vascular resistance, the present data suggest that K_ATP channels do not contribute, in large measure, to regulating the canine femoral vascular bed under resting conditions in-vivo.     

Dopamine Antagonists Can Inhibit Methamphetamine Sensitization,But Not Cocaine Sensitization,When Assessed by Ambulatory Activity in Mice

Abstract— The repeated subcutaneous administration of methamphetamine (2 mg kg^?1) and cocaine (10 mg kg^?1) at 3–4 day intervals induced sensitization to their ambulation-increasing effects in mice. Subcutaneous administration of SCH 23390 (R-(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0·003–0·03 mg kg^?1) and YM-09151–2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide; 0·003–0·03 mg kg^?1), the selective dopamine D₁ and D₂ antagonists, respectively, reduced dose-dependently the acute ambulation-increasing effect of methamphetamine. The development of methamphetamine sensitization was inhibited when it was administered in combination with either SCH 23390 or YM-09151–2 in the repeated administration schedule. Although SCH 23390 (0·01–0·1 mg kg^?1) and YM-09151–2 (0·01–0·1 mg kg^?1) also reduced the ambulation-increasing effect of cocaine (10 mg kg^?1), neither drug inhibited the cocaine sensitization. Mice given cocaine with SCH 23390 (0·03 mg kg^?1) or YM-09151–2 (0·03 and 0·1 mg kg^?1) showed higher sensitivity than those given cocaine alone. The present results suggest that, although both the dopamine D₁ and D₂ antagonists reduce the acute stimulant effects of both methamphetamine and cocaine, they are only effective for inhibition of the methamphetamine sensitization. Mechanisms other than the dopaminergic system appear to be involved in the cocaine sensitization.     

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.     

Increased ex-vivo colonic generation of PAF induced by diphenylmethane stimulant laxatives in rats,mice, guinea-pigs and rabbits

Abstract— The effects of in-vivo treatment with bisacodyl, phenolphthalein, picosulphate, sulphosuccinate, mannitol and lactulose laxatives were examined on the ex-vivo formation of platelet-activating factor (PAF) by duodenum and colon of rat, mouse, guinea-pig and rabbit. Bisacodyl (10 mg kg^?1), phenolphthalein (20 mg kg^?1) and picosulphate (10 mg hg^?1), but not sulphosuccinate (40 mg kg^?1), mannitol (50 mg kg^?1) or lactulose (50 mg kg^?1), at doses that all caused laxation, markedly increased PAF in the colon (P < 0·01) but not in the duodenum. Intraluminal release of acid phosphatase was also significantly increased in the colon of rats treated with bisacodyl, phenolphthalein and picosulphate, but not in colons of animals treated with sulphosuccinate, mannitol or lactulose. The data show that enhanced generation of PAF is associated with the colonic damage induced by diphenylmethane laxatives, but do not show whether this is a cause or a consequence of the pathophysiological changes.     

The Adenosine Agonist NECA Inhibits Intestinal Secretion and Peristalsis

Abstract— This study aimed to determine whether the antidiarrhoeal effect of the mixed A₁/A₂ adenosine agonist NECA (5′-N-ethylcarboxamido adenosine) is due to inhibition of intestinal fluid transport or to contractility. Intestinal secretion was stimulated in anaesthetized rats by intra-arterial infusions of PGE₂ (4 μg min^?1) or vasoactive intestinal peptide (0·8 μg min^?1). NECA reversed PGE₂-induced secretion in the jejunum (ED50 16 μg kg^?1) and ileum (ED50 21 μg kg^?1, i.v.) and inhibited VIP-induced secretion in the jejunum (ED50 21·5 μg kg^?1). NECA inhibited twitch responses (0·1 Hz, 1 ms, IC50 11·2Nm ) but not tetanic contractions at 10 Hz of the transmurally stimulated guinea-pig ileum. Likewise, NECA (10 μm ) did not inhibit frequency-related contractions over the range of 2·5 to 40 Hz of rat jejunum or ileum. However, NECA was shown to be a potent inhibitor (30 Nm ) of the peristaltic reflex in the rat ileum. The results indicate that adenosine receptors are involved in modulating peristalsis as well as the secretory activity of the mucosa in the rat small intestine.     

Effects of opiate antagonists and of morphine on chlordiazepoxide-induced hyperdipsia in the water-deprived rat

The effects of naloxone hydrochloride (0.01–10 mg·kg^?1), naltrexone hydrochloride (0.01–10 mg·kg^?1), and morphine sulphate (0.01–10 mg·kg^?1) on the increased water consumption provoked by administration of chlordiazepoxide (10 mg·kg^?1) were investigated in male rats which had been adapted to a 22 hr water-deprivation schedule. As previously reported, both naloxone and naltrexone dose-relatedly reduced water ingestion. Naloxone at 1 mg·kg^?1 and naltrexone at 0.1 mg·kg^?1 completely blocked the chlordiazepoxide-induced hyperdipsia. Since both opiate antagonists removed the chlordiazepoxide-induced effects in small doses, their effect can plausibly be attributed to opiate receptor blockade. Hence, chlordiazepoxide-induced hyperdipsia may depend upon the activation of endogenous opioid mechanisms. Morphine had little effect on drinking, unless a large dose (10 mg·kg^?1) was used, when the thirst-induced and chlordiazepoxide-induced drinking were attenuated. The data provided no evidence that morphine, a μ opiate agonist, enhanced chlordiazepoxide-induced water consumption. The results are considered in relation to other relevant behavioural and biochemical findings.     

Dose Regimen Adjustment for Milrinone in Congestive Heart Failure Patients with Moderate and Severe Renal Failure

This study was designed to test a proposed dose modification for intravenous milrinone in congestive heart failure patients (CHF, NYHA I-II) with either moderate or severe renal impairment. All the patients were administered an intravenous loading dose of drug at 50 μg kg-1 over 10 min. This was followed by an 18 h maintenance infusion of milrinone at 0·45 or 0·35 μg kg^?1 min^?1 for the moderate (chromium-EDTA clearance of 31–75 mL min^?1, n = 10) and severe renally impaired subjects (chromium-EDTA of clearance 10–30 mL min^?1, n = 11), respectively. Plasma and urine samples were collected for up to 34 h and analysed for parent drug by validated HPLC methods. The mean (± s.d.) steady-state plasma concentrations of milrinone were within the therapeutic range (100–300 ng mL^?1) for both groups, with values of 239 ± 71 ng mL^?1 and 269 ± 32 ng mL^?1 for the moderate and severe patients, respectively. No statistical differences were observed between the steady-state values for the two groups. With the exception of two patients per group, individual steady-state levels were also within the therapeutic range. Those outside the nominal range showed steady-state levels, ranging between 308 and 353 ng mL^?1, that were not associated with any serious adverse events. As predicted for this highly renally cleared drug, there were differences (P < 0·001) in the total plasma clearance (CL_P), renal clearance (CL_r), and plasma terminal half-life (t1/2) of drug, with values in the severe group being 44% lower, 75% lower, and about 134% longer respectively, when compared with the moderate group. High (correlation coefficient > 0·8) and significant correlations (P < 0·001) were observed between CL_P and CL_r and the degree of renal impairment (chromium-EDTA clearance). The apparent volume of distribution was approximately 40% higher (P < 0·01) in the severe group compared with that for the moderate group (moderates were 0·443 ± 0·155 L kg^?1). This volume difference suggests a decrease in the plasma protein-binding of milrinone because of the renal disease. The fraction of drug excreted in the urine was 0·705 ± 0·100 for the moderate group and 0·320 ± 0·089 for the severe group (P < 0·001). These results may suggest an increase in non-renal clearance of the compound, representing a partial compensation mechanism for the reduced renal function. In conclusion, this study has confirmed that the current dose reductions recommended for the use of intravenous milrinone in CHF patients with impaired renal function will yield plasma concentrations of the drug within the therapeutic range.     

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.