Potentiation of analgesia and reversal of tolerance to morphine by calcium channel blockers.

Effect of four calcium channel blockers (CCBs) belonging to different chemical classes, alone and in combination with morphine was investigated on two models of pain sensitivity, i.e. formalin and tail flick tests in mice. All the studied CCBs, i.e. diltiazem, flunarizine, nimodipine and verapamil inhibited formalin-induced pain responses; however, with verapamil, though there was a trend towards a reduction of paw-licking response to formalin, it was not found to be statistically significant. In contrast, none of the CCBs affected the tail flick latency at any of the doses studied. Morphine, a mu-receptor agonist exerted a significant analgesic effect in formalin as well in tail flick tests. Pretreatment with all CCBs significantly enhanced the analgesic effect of morphine in both tests of nociception. Further, concomitant administration of one of the CCBs, diltiazem with morphine prevented the development of tolerance to the latter. However, combination of diltiazem with morphine, like morphine alone was found to be ineffective in morphine tolerant animals. Results, thus, show that CCBs produced an analgesic effect of their own in formalin-induced tonic pain and potentiated the analgesic activity of morphine. They also modulated opioid-induced tolerance.

Effects of flunarizine on dopamine dependent behaviours in rats.

1. Radio-ligand binding study has demonstrated that flunarizine has a high affinity for the rat striatal D 2 dopamine (DA) receptors. 2. In the present behavioural study conducted in rats it was observed that flunarizine, unlike the postsynaptic striatal D 2 DA receptor agonist apomorphine, did not induce stereotyped behaviour (SB) in rats. This indicates that flunarizine does not act as an agonist at the postsynaptic striatal D 2 DA receptors. 3. Flunarizine however, like the postsynaptic striatal D 2 DA receptor antagonist haloperiodal, inhibited the conditioned avoidance response, induced catalepsy and antagonized the SB induced by the DA agonists apomorphine and methamphetamine. 4. Our findings indicate that flunarizine acts as a postsynaptic striatal D 2 DA receptor antagonist.

Synergistic effect of flunarizine and sodium valproate on seizure thresholds elicited by cortical stimulation in conscious rats.

The effect of flunarizine (FLU) and sodium valproate (SV) alone and in combination were examined for their effects on seizure thresholds elicited by cortical stimulation in conscious rats. Two different pharmacodynamic parameters could be distinguished viz, the threshold for localised seizures (TLS) defined as the current (mu A) required to elicit forelimb clonus and the threshold for generalised seizure (TGS), defined as the current (mu A) required to elicit vigorous clonic activity without a tonic component. In preliminary neuro-behavioral studies on rats, the most favourable combination was FLU 10 mg/kg i.p. and SV 200 mg/kg i.p., which produced anticonvulsant efficacy with minimal neurotoxicity. With FLU alone, SV alone and the combination of FLU and SV, the mean % change +/- SEM from baseline values over a period of 6 h were for TLS: 3.8 +/- 0.8, 23.9 +/- 3.7, and 29.8 +/- 2.1; and for TGS 5.5 +/- 0.7, 15.6 +/- 2.7 and 190.9 +/- 22.7 respectively, indicating that FLU alone had no effect on TLS or TGS, SV significantly elevated TLS but had no effect on TGS and the combination of FLU plus SV produced a synergistic elevation of both TLS and TGS-the intensity of effect being more on TGS than on TLS. This model provides a new dimension to the profiling of two anticonvulsant agents with different mechanisms of anticonvulsant activity and offers predictive criteria for protective effects on clinical manifestations of partial or generalised tonic clonic seizure.

Effects of ca2+ entry blockers and an intracellular ca2+ antagonist on glucose tolerance and insulin secretion in rats

The effects of Ca2+ entry blockers: Isradipine [5 mg/kg i.p.] and flunarizine HCl [10 mg/kg i.p.] as well as the intracellular Ca2+ antagonist, dantrolene Na [5 mg/kg i.p.] were studied on blood glucose levels, insulin secretion and liver glycogen content during an oral glucose tolerance test in rats. Isradipine markedly increased plasma glucose and significantly reduced plasma insulin levels, which was accompanied by a marked increase in liver glycogen content. Isradipine-induced glucose intolerance was associated with a decreased pancreatic secretory activity as evidenced by lowered insulinogenic indices. Flunarizine HCl produced significant increase in plasma glucose level 1 hour after drug administration which was associated with decreased insulinogenic index, while the drug had no effect on plasma insulin levels or liver glycogen content. Dantrolene Na increased plasma glucose level 1 hour after drug treatment, but it failed to significantly alter plasma insulin level, insulinogenic index or liver glycogen content. In conclusion, the data suggested that the calcium entry blockers [isradipine and flunarizine] impair glucose tolerance in rats and confirm the in vitro results on the isolated perfused rat pancreas. Studies have also shown that isradipine is more potent hyperglycemic agent than flunarizine. Also, it is a potent inhibitor of insulin secretion under glucose-stimulated conditions

A study on the action of two calcium channel blockers (verapamil and flunarizine) upon an experimental model of tardive dyskinesia in rats

A discinesia tardia (DT) é complicaçäo decorrente do uso prolongado de neurolépticos. Até o presente, nenhum tratamento provou ser eficaz na DT. Evidências indiretas apontam para a açäo de drogas bloqueadoras de canais de cálcio (BCC) em algumas vias neurais. A açäo de duas dessas drogas, varapamil e flunarizina, foi testada em modelo experimental de DT em rato, neste estudo. O haloperidol foi administrado por 21 dias e induçäo de movimentos estereotipados era obtida no 24§ dia, com a injeçäo de apomorfina. As drogas BCC foram administradas por uma vez no 28§ dia (experimento agudo) e por 8 dias, após o 25§ dia (experimento crônico). A flunarizina näo induziu modificaçäo no padräo de estereotipia dos animais, mas o verapamil levou a aumento no experimento agudo e a diminuiçäo no experimento crônico. Estes achados indicam que as drogas BCC podem ter alguma açäo sobre a DT e que ensaios clínicos devem ser feitos para se comprovar se tal açäo ocorre no homem

Tratamento das labirintopatias infantis com flunarizina / Treatment of infantile labyrinthopaties with flunarizine

O uso de flunarizina revelou-se extremamente eficaz no tratamento de distúrbios vestibulares infantis de várias causas. A remissäo parcial ou total de vertigens e outros tipos de tonturas, tinnitus e náuseas ocasionadas por síndromes vestibulares periféricas irritativas ou deficitárias ocorreu na maioria das crianças tratadas. A única reaçäo adversa relatada com a administraçäo da flunarizina foi discreta a moderada sonolência, mais intensa ao início do tratamento e que näo obrigou a suspensäo do medicamento em nenhuma criança

Flunarizine and verapamil inhibit chloroquine-resistant Plasmodium falciparum growth in vitro.

Using pharmacological properties in relation to the biochemistry of P. falciparum, verapamil, flunarizine, and chlorpromazine which are calcium blockers were selected to test for their antimalarial activity against P. falciparum in vitro. Results revealed that the drugs inhibited parasite population growth in the following order of IC50: verapamil 1 X 10(-6) M, chlorpromazine 3.5 X 10(-6) M, and flunarizine 5 X 10(-6) M. These three calcium blockers have antimalarial effects on chloroquine resistant parasite (alone T9/94) but are less potent when compared with the efficacy of quinine or mefloquine in vitro.