In vivo muscarinic cholinergic mediated effects of Lu 25-109, a M1 agonist and M2/M3 antagonist in vitro.

Lu 25-109 [5-(2-ethyl-2H-tetrazol-5-yl)-1,2,3,6-tetrahydro-1-methylpyridine] , has M agonistic and M2/M3 antagonistic effects at muscarinic receptors in vitro; a pharmacological profile that may be beneficial in treatment of Alzheimer's disease. In the present study, we compare functional in vivo effects of Lu 25-109 and reference compounds in animal models of muscarinic cholinergic function. Lu 25-109 substituted completely for the discriminative stimulus effects of (-)-7-methyl-3-(2-propynyloxy)-4,5,6,7-tetrahydroisothiazolo -[4, 5-c]pyridine (Lu 26-046), a partial M1/M2 agonist, but only weakly for the effects of the non-selective M1/M2/M3 agonist 3-methoxy-4,5,6,7-tetrahydro-isoxazolo[4, 5-c] pyridine (O-Me-THPO). Lu 25-109 did not reverse O-Me-THPO-induced discriminative stimulus. Tacrine did not substitute for any of the training drugs. Lu 25-109 did not substitute in (-)-nicotine trained rats. Lu 25-109 did not antagonize oxotremorine-induced hypothermia, tremor and salivation in mice and antagonized physostigmine-induced lethality with low potency. Unlike non-selective muscarinic agonists and acetylcholinesterase inhibitors, Lu 25-109 did not induce hypothermia, tremor or salivation in mice. Spontaneous locomotor activity and motor co-ordination were inhibited only at high doses. Lu 25-109 had no effect on mean blood pressure in anaesthetized rats. Lu 25-109 and O-Me-THPO produced a significant increase in heart rate. The maximum increase was 37%. In anaesthetized cats, increasing i.v. doses of Lu 25-109 were without effect on the mean blood pressure, except for a short lasting (<2 min) depressor effect following the IV injection. Furthermore, Lu 25-109 did not attenuate the reflex mechanisms restoring blood pressure following orthostasis in cats. In conclusion, the drug discrimination studies suggest a unique activity profile of Lu 25-109, and the in vivo profile suggests none or a very low frequency of unwanted cholinergic mediated effects.

[Survival in ovarian cancer treated in a gynecological department of a central hospital]. / Overlevelsen ved ovariecancer behandlet og efterbehandlet i en gynaekologisk afdeling på et centralsygehus.

The characteristics of 73 patients with all stages of epithelial ovarian cancer were retrospectively analysed with emphasis on prognostic factors and survival. The patients underwent total hysterectomy, bilateral oophorectomy and infracolic omentectomy. Efforts were made to reduce the tumor burden as much as possible without endangering the general health status of the patient. Postoperative treatment was cisplatin 60 mg/m2 body surface and cyclophosphamide 50 mg/m2 every four weeks (CP). Patients with low general health status were offered either treosulphane 1 g daily for four weeks alternating with four weeks without treatment, or no treatment. Patients in FIGO stage IA and B generally received no postoperative chemotherapy treatment. Fifteen percent were in FIGO stage I, 7% in stage II, 5% in stage III and 23% in stage IV. Fifteen patients could be radically operated, however, only three patients who were in stage III. Fifty-four patients were treated with CP, 11 with treosulphane and eight patients did not receive postoperative treatment. In 28 patients second look laparotomy was performed. Only six patients had a complete pathological response, two of these in stage III. Stage and tumour grade could be identified as prognostic factors. Three-year survival was 70% in stage I, 67% in stage II, 28% in stage III and 0% in stage IV. Survival in 43 patients in stage III and IV was statistically compared to 265 patients from a prospective, randomized study by the Danish Ovarian Cancer Group (DACOVA), comparing cyclophosamide and cisplatin with and without doxorubicin. We found no statistical difference in survival between patients in our material and the DACOVA-material except in patients with low grade tumours whose survival in the CAP-arm of the DACOVA-study was superior. The rate of complete pathological response was significantly better in the DACOVA-study.

The antipsychotic drug sertindole is a specific inhibitor of alpha1A-adrenoceptors in rat mesenteric small arteries.

We have investigated the adrenergic antagonist effect of the antipsychotic sertindole in rat resistance vessels and in membranes of HEK293 cells transfected with alpha1-adrenoceptors. Segments of rat mesenteric small arteries or rat aorta were mounted on a myograph for isometric tension recording. In mesenteric small arteries, specific alpha1A-adrenoceptor antagonists (5-methyl urapidil and WB-4101 (2-(2,6-dimethoxyphenoxyethyl) aminomethyl-1,4-benzodioxane)) inhibited phenylephrine responses with high affinity (pA2 9.1 and 9.5, respectively). Chlorethylclonidine (alpha1B- and alpha1D-adrenoceptor antagonist) and BMY7378 (8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro [4,5] decane-7,9-dione dihydrochloride, alpha1D-adrenoceptor antagonist) had little effect. This indicated that the adrenoceptor subtype in the mesenteric small arteries was of the alpha1A subtype. Sertindole inhibited the phenylephrine response of mesenteric small arteries (pA2 9.0), but had little effect on the phenylephrine response of aorta (which lacks alpha1A-adrenoceptors). The specific action of sertindole on alpha1A-adrenoceptors was supported by experiments with membranes of HEK293 (human embryonic kidney) cells transfected with the alpha1A-, alpha1B- and alpha1D-adrenoceptors. Here, with concurrent incubation, sertindole showed selective competitive inhibition of BE2254 (2-beta(4-hydroxyphenyl)-ethylaminomethyl)-tetralone) binding to alpha1A-adrenoceptors (Ki 8.9), compared to alpha1B-adrenoceptors (Ki 7.1) and alpha1D-adrenoceptors (Ki 6.8). Despite the apparent competitive action sertindole, it was not possible to wash out its antagonist effect within 6 h in the functional phenylephrine concentration-response experiments. Furthermore, in the membranes of HEK293 cells transfected with the alpha1A-adrenoceptors, binding of [125I]BE2254 was reduced by 45% following preincubation with sertindole (1 nM). We conclude that the alpha-adrenoceptors of rat mesenteric small arteries are of the alpha1A-type, and that sertindole is a specific pseudo-irreversible competitive antagonist of this adrenoceptor subtype.

Peripheral and central blood flow in man during cold, thermoneutral, and hot water immersion.

Cardiovascular reflexes were studied during immersion in water to the chest. Cardiac output (CO) was determined by acetylene rebreathing; forearm muscle and subcutaneous blood flow by 133Xe-clearance; and cutaneous blood flow by laser Doppler. Measurements were taken in a) control situation (CTR) (subject sitting dry); b) immersed in thermoneutral (NWI); c) in cold (CWI); and d) in hot water (HWI). The overall trend was that water immersion per se increased stroke volume (SV), but mostly during NWI and CWI, where heart rate (HR) was decreased by 15%; during HWI, HR increased by 32%, the temperature effect evidently overriding the immersion effect. Insignificant increases in CO were seen in NWI and HWI (18% and 44%), and no effect in CWI. Arterial pressure and total peripheral resistance (TPR) increased significantly in CWI due to an increase in peripheral vascular resistance, while significant decreases in TPR and CPR were observed in HWI and tendencies to decreases were found in NWI.