Pharmacokinetics and pharmacodynamics of the acetylcholinesterase inhibitor 2,2,2-trifluoro-1-(3-trimethylsilylphenyl) ethanone in dog. Potential for transdermal patch delivery.

MDL 73,745 (2,2,2-trifluoro-1-(3-trimethylsilylphenyl) ethanone, CAS 132236(18-1) is a novel tight-binding inhibitor of acetylcholinesterase (AChE), which is in development as a potential therapeutic compound in the symptomatic treatment of Alzheimer's disease. Pharmacokinetics and pharmacodynamics of the compound were studied in the dog after single intravenous (i.v. 2 mg/kg), oral p.o. 10 mg/kg) and sub-cutaneous (s.c., 10 mg/kg) administrations of [14C]-MDL 73,745. Plasma concentrations of total radioactivity were much higher than those of parent drug after i.v., p.o. and s.c. administration, indicating extensive metabolism of the compound, although this was less after, s.c. administration than after p.o. administration. The bioavailability (F) was 34% after s.c. administration, compared with 4% after p.o. administration. The low bioavailability after p.o. administration was not due to poor drug absorption, as over 64% of the dose was absorbed. Pharmacokinetic parameters, calculated after i.v. administration, showed a terminal elimination half-life of 24 h, total body plasma clearance of around 70 ml/min/kg and apparent volume of distribution of 150 l/kg. AChE activity was almost 100% inhibited after i.v. administration, and over 80% inhibited 1 h after p.o. administration. In both cases, AChE activity returned to baseline levels by 12 h. AChE was around 80% inhibited 4 h after s.c. administration, and did not return to baseline levels until 36 h after drug administration. A combined pharmacokinetic-pharmacodynamic (PK-PD) effect model demonstrated that the extent of AChE inhibition could be correlated with plasma levels of the parent compound. As s.c. administration increased F, and led to longer AChE inhibition, transdermal (t.d.) delivery was assessed in the same animals. Patches, corresponding to a dose of 50 mg/kg, were applied to the shaved lateral abdominal skin for a period of 96 h. Sustained plasma concentrations of the parent drug were observed over the 96 h period of t.d. application. Mean (+/- SD) maximum plasma concentrations (Cmax) of 26.9 +/- 4.3 ng/ml were found 3.7 +/- 2.5 h after t.d. patch application und F was around 13%. AChE inhibition reached a maximum of 72% at 6 h after t.d. application and was still 35% at 96 h. The rate of release from the delivery system, per unit surface area, (ko) was calculated to be 7.7 micrograms/cm2. Transdermal delivery of MDL 73,745 thus decreased the important hepatic first-pass effect, and led to sustained plasma concentrations of drug, thus avoiding peaks and troughs which could lead to side-effects or poor efficacy.

Are the cardiovascular effects and '5-HT syndrome' induced by MDL 73,975 and flesinoxan in the dog mediated by 5-HT1A receptors?

The cardiovascular effects of the 5-HT1A receptor agonists MDL 73,975 (8-[2-(2,3-dihydro-8-methoxy-1,4-benzodoxin-2-yl)methylaminol++ +]-ethyl]-8- azaspiro[4,5]decane-7,9-dione hydrochloride) and flesinoxan (10-300 micrograms/kg subcutaneously, s.c.), the 5-HT1A receptor antagonist NAN 190 (2-[4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl]-1H-isoindole-1,3(2H)- dione,1,2-ethanedioate), and the alpha 1-adrenoceptor antagonist prazosin have been investigated in conscious normotensive and renal hypertensive dogs. In normotensive dogs the increases in heart rate and respiratory rate induced by both agonists were dose-related, as were the decreases in systolic and diastolic blood pressure induced by MDL 73,975. Both compounds caused a dose-related increase in the intensity of the '5-HT syndrome'. After pretreatment with NAN 190 (100 micrograms/kg s.c.) the increases in heart rate, respiratory rate and symptoms of the '5-HT syndrome' were significantly reduced but the decreases in systolic and diastolic pressure were additive. Pretreatment with prazosin (100 micrograms/kg s.c.) antagonized the '5-HT syndrome' and the increase in respiratory rate. Similar responses were evident in renal hypertensive dogs. Tolerance did not develop to the increases in heart rate, respiratory rate and manifestations of the '5-HT syndrome' in normotensive dogs during 5 days of treatment with MDL 73,975 or flesinoxan. In conclusion, MDL 73,975 and flesinoxan induced a 5-HT1A receptor-mediated fall in blood pressure but the changes in heart rate, respiratory rate and the '5-HT syndrome' are probably mediated by alpha 1-adrenoceptors.

The cardiovascular effects of centrally administered taurine in anaesthetised and conscious rats.

The effects of pentobarbitone anaesthesia on the cardiovascular changes induced by centrally administered taurine have been investigated in spontaneously hypertensive (SHR) and normotensive rats. Administration of taurine (100-400 micrograms) into the lateral cerebral ventricle (i.c.v.) of anaesthetised SHR and normotensive rats induced a dose-related fall in systemic blood pressure and heart rate, which tended to be of a greater magnitude in the SHR. In anaesthetised rats attached to a ventilator, taurine was not as potent at inducing a fall in systemic blood pressure, approximately double the dose being required to produce the same cardiovascular changes as that which occurred in anaesthetised rats without a ventilator. In conscious normotensive rats taurine had no effect on blood pressure until a dose of 800 micrograms was administered i.c.v., whereas in conscious SHR, a small, but significant depressor response was evident with 400 micrograms. These findings demonstrate that pentobarbitone anaesthesia sensitises the rats to the cardiovascular effects of taurine, partially through a mechanism which involves respiratory depression. Conversely in conscious rats a much higher dose of taurine is required to induce a fall in arterial pressure and heart rate per se.

Comparison between the cardiovascular effects of 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and clonidine in the conscious sino-aortic denervated rat.

1. The purpose of this study was to investigate the role of an intact baroreceptor reflex mechanism in the expression of the cardiovascular response to 8-OH-DPAT and to determine whether there are any differences between the activation of central alpha 2-adrenoreceptors and 5-HT1A receptors in this respect. To this end, the effects of 8-OH-DPAT and clonidine have been assessed on blood pressure, heart rate, ECG and cardiac contractility indices in conscious sino-aortic baroreceptor denervated (SAD) rats and their sham-operated controls. 2. In both sham-operated and SAD rats, intravenous (i.v.) administration of 8-OH-DPAT (32 micrograms kg-1) and clonidine (8 micrograms kg-1) produced falls in systemic blood pressure, left ventricular systolic pressure and dP/dtmax. 3. 8-OH-DPAT produced similar bradycardia in each group of rats; in contrast, clonidine had a greater effect in the SAD animals. Increases of the PQ interval mirrored the heart-rate changes with both compounds. 4. No significant changes in end diastolic blood pressure or in the myocardial contractility indices dP/dtmax/P and Vmax were evident. 5. This study provides support for the view that i.v. 8-OH-DPAT lowers blood pressure and heart rate through a central mechanism. The effects occur independently of an intact baroreceptor reflex and are not associated with effects on myocardial contractility. 8-OH-DPAT shows close qualitative similarities to clonidine in this model.

Antihypertensive effects of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) in conscious dogs.

Low doses of 8-OH-DPAT (10 and 25 micrograms/kg) administered subcutaneously (s.c.) to renal hypertensive mongrel dogs caused decreases in systolic blood pressure which persisted for 3 h. Mild salivation and hyperventilation were observed with both doses. A short-lasting (less than 60 min) depressor response was seen with 100 micrograms/kg s.c. Prominent hyperventilation and salivation accompanied this response. A still higher dose (250 micrograms/kg s.c.) induced tremor, signs of anxiety and occasional vomiting in addition to the hyperventilation and salivation. Paradoxically, no cardiovascular activity was noted at this dose.

Comparison between the effects of MDL 72567 and nifedipine on various cardiovascular parameters in conscious sinoaortic-denervated rats and sham-operated controls.

In this study the effects of a new calcium entry blocking agent, 2,6-dimethyl-3-methoxycarbonyl-4-(2-nitrophenyl)-5-(2-furoyl)-1, 4-dihydropyridine (MDL 72567), were compared with those of nifedipine on blood pressure, heart rate, ECG, and cardiac contractility indices in conscious sinoaortic baroreceptor-denervated (SA-denervated) rats and their sham-operated controls. In sham-operated rats, the calcium-entry blocking agents (0.1-2 mg/kg i.v.) produced equivalent falls in blood pressure. However, nifedipine caused a much greater reflex tachycardia which was accompanied by a negative inotropic effect, and with the highest dose (2 mg/kg), a prolongation of the PQ interval. MDL 72567 induced an increase in myocardial contractility. In SA-denervated rats, both drugs produced an enhanced fall in blood pressure accompanied by a negative inotropic effect. Nifedipine did not change heart rate in SA-denervated rats, whereas MDL 72567 caused bradycardia. Thus, in these experiments, MDL 72567 caused less reflex tachycardia for a given fall in blood pressure than nifedipine and was less likely to cause myocardial depression. These effects of MDL 72567 may represent valuable, clinically relevant advantages over nifedipine.

Hemodynamic profile of N-(2,5-dimethyl-1H-pyrrol-1-yl)6-(4-morpholinyl)-3-pyridazinamine hydrochloride in conscious dogs.

The effects of N-(2,5-dimethyl-1H-pyrrol-1-yl)6-(4-morpholinyl)-3-pyridazinamine hydrochloride (MDL-899) on systemic, pulmonary, renal and coronary circulation and on myocardial contractility have been investigated in conscious dogs treated orally. The compound induced a decrease in systemic arterial blood pressure, slow in onset (peak effect at 4 h) and long-lasting (more than 7 h), by reducing total peripheral resistance, while the heart rate, cardiac output, cardiac work and myocardial contractility increased because of the reflex increase in sympathetic drive evoked by the blood pressure fall. Coronary and renal blood flows were increased for a long time. Pulmonary resistance was markedly decreased, but the pulmonary pressure was increased, probably due to the hyperkinetic activity triggered by the increases of cardiac output and heart rate. The hemodynamic changes induced by MDL-899 are qualitatively similar to those induced by hydralazine. The results suggest that the compound belongs to the class of vasodilators that act primarily on systemic arterioles to produce arteriolar dilation.

Pharmacological studies of N-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride (MDL-899), a new long-acting antihypertensive vasodilator.

N-(2,5-Dimethyl-1H-pyrrol-1-yl)-6-(4-morpholinyl)-3-pyridazinamine hydrochloride (MDL-899) is a new long-acting antihypertensive vasodilator which reduces the blood pressure of conscious hypertensive rats and dogs to normal levels. The oral doses that reduce blood pressure by 50 mmHg are: 4.4 mg/kg in conscious spontaneously hypertensive rats (SHR), 18 mg/kg in conscious Milan hypertensive strain (MHS) and 1.7 mg/kg in conscious renal hypertensive dog (RHD). The i.v. doses are 1.26, 3.2 and 0.9 mg/kg. The reduction in blood pressure is slow (peak effect at 3 h) and long-lasting (more than 7 h) after p.o. or i.v. administration. Tolerance to MDL-899 is seen to develop in hypertensive dogs, whereas in hypertensive rats this phenomenon never occurs. The compound antagonizes the development of hypertension when given to SHR between days 25 and 88. The haemodynamic study in conscious normotensive rats (labelled microspheres) demonstrated that the fall in blood pressure is accompanied by increases in heart rate and cardiac output and a decrease in total peripheral resistance. The lack of alpha-blocking activity, in the rat caudal artery "in vitro"; beta 2-stimulating activity, in SHR pretreated with propranolol, and prostaglandin (PG) release activity, in SHR pretreated with indomethacin, excludes the possibility that the hypotension is due to one of these mechanisms. MDL-899 given orally to rats has no important depressant effects on the CNS at hypotensive or higher doses and induces no adrenergic system stimulation symptoms (midriasis, exophthalmus). In comparison with hydralazine, it is slower in onset and longer lasting, devoid of adrenergic system stimulation, less toxic and nonmutagenic. They are equipotent after p.o. treatment.

Positive inotropic effect of K-canrenoate: an investigation in anaesthetized dogs, untreated or treated with digitalis.

Potassium canrenoate (KCR) is widely used in cardiac patients as an aldosterone antagonist, antiarrhythmic and diuretic drug. According to experimental and clinical studies it can also elicit an inotropic action. It is not clear, however, whether this inotropic activity occurs in the absence of any treatment or after the myocardial contractility has already been improved with digitalis. In order to evaluate a possible interaction of this drug with digitalis we administered KCR intravenously to 41 anaesthetized dogs either untreated or treated with digitalis, in which aortic and left ventricular pressures were recorded and myocardial contractility was evaluated by calculating in real time the first derivative of ventricular pressure (Formula: see text) max and two other contractility indexes (Formula: see text) max and V.max. The results obtained showed that KCR given at doses of 10, 20 and 30 mg/kg i.v. did not elicit any inotropic effect in dogs not previously digitalized. 100 mg/kg i.v. first depressed cardiac contractility and then increased it. After cardiac performance had been improved by digitalis, KCR further increased all contractility indexes significantly. These results could explain previous observations that no inotropic effect was observed in human subjects not treated with digitalis after treatment with KCR.

Hemodynamic profile of a new cerebral vasodilator, vincamine and of one of its derivatives, apovincaminic acid ethylester (RGH-4405).

The hemodynamic modifications induced by vincamine and by one of its derivatives, apovincaminic acid ethylester (RGH-4405), have been studied in anesthetized and conscious dogs. The two alkaloids induced peripheral vasodilatation in all the experimental models, but their action on systemic blood pressure and heart rate was clearly influenced by anesthesia and was different according to the anesthetic used. In the conscious animals an increase of both heart rate and systemic blood pressure was observed, concomitantly with an increase in femoral and vertebral blood flow and a decrease in renal blood flow. In the renal vascular bed a subsequent decrease in resistance was shown, when all the other measured hemodynamic parameters had returned to control values. The greater increase of vertebral blood flow than of femoral blood flow for the same increment of cardiac output was taken as an indirect demonstration of the selectivity of the two drugs for the cerebral circulation.