flunarizine and Pain

Potassium (K(+)) channels are membrane proteins expressed in most living cells that selectively control the flow of K(+) ions. More than 80 genes encode the K(+) channel subunits in the human genome. The TWIK-related K(+) channel (TREK-1) belongs to the two-pore domain K(+) channels (K2P) and displays various properties including sensitivity to physical (membrane stretch, acidosis, temperature) and chemical stimuli (signaling lipids, volatile anesthetics). The distribution of TREK-1 in the central nervous system, coupled with the physiological consequences of its opening and closing, leads to the emergence of this channel as an attractive therapeutic target. We review the TREK-1 channel, its structural and functional properties, and the pharmacological agents (agonists and antagonists) able to modulate its gating.

Topics: Arrhythmias, Cardiac; Depression; Epilepsy; Humans; Inflammation; Models, Molecular; Molecular Structure; Neuroprotective Agents; Pain; Potassium Channels, Tandem Pore Domain; Structure-Activity Relationship

The effect of flunarizine in the treatment of post-phlebitic syndrome (PPS) and venous leg ulcers was studied in 42 patients in a double-blind, placebo-controlled trial over a period of 3 months. During the first month the dose of flunarizine or the matching placebo was 1 capsule of 5 mg twice-daily, and during the following 2 months 1 capsule of 5 mg once-daily. Most of the subjective symptoms such as heaviness in the legs, pain, paraesthesia, cramps at night, and swelling of the ankles considerably improved during treatment with flunarizine and were slightly improved in the placebo group. The ulcer surface area decreased after 3 months' treatment with flunarizine by 68.3% (p < 0.001), and after treatment with placebo by 20.5% (p > 0.05). In 15 patients treated with flunarizine and 1 with placebo the ulcers vanished completely. An improvement in the photoplethysmographic record of the lower legs in the flunarizine group was observed, as shown by increase in the index recovery time, while there were no significant changes in the placebo group. The results show that the favorable effect of flunarizine in the treatment of PPS and venous leg ulcers might be due largely to an improvement in subcutaneous circulation of the lower legs. Flunarizine may be an important adjunct to the conservative management of the complications caused by chronic venous insufficiency.

Topics: Adult; Aged; Aged, 80 and over; Double-Blind Method; Edema; Female; Flunarizine; Humans; Leg Ulcer; Male; Middle Aged; Pain; Phlebitis; Photoplethysmography

Flunarizine, a calcium channel blocker is considered useful in migraine prophylaxis. We report the first Indian trial with this drug. Fifteen patients with migraine were studied in a 6 months double-blind, placebo-controlled crossover trial. Flunarizine was superior to placebo in reducing the severity and duration of the individual attacks though there was no statistically significant effect on frequency of migraine attacks. The side effects most frequently caused by flunarizine were weight gain and daytime sleepiness.

Topics: Adult; Drug Evaluation; Female; Flunarizine; Humans; Male; Migraine Disorders; Pain

Flunarizine, a Ca-antagonist with demonstrated antimigraine properties, and indoprofen, an anti-inflammatory non-steroidal agent, were used in the treatment of daily chronic headache. Forty-two migraineurs with interval headache (MIH) were treated with flunarizine in a 6-month open trial, while indoprofen was administered to 23 patients with MIH and 7 with chronic tension headache (CTH) in a 2-month, double-blind, cross-over placebo-controlled study. Flunarizine was found effective in over 65% of the patients, while indoprofen was able to improve headache severity in only 30% of the subjects. In the responder patients, the effectiveness of both drugs is more pronounced in MIH, and seems to be ascribable to the ability of the treatments to reduce number and severity of attacks. A higher incidence of previous affective disturbances is found in non-responsive cases. The analysis of factors converting episodic into chronic headache shows slight but not significant differences between responders and non-responders. An impairment of plasma beta-endorphin levels, in the presence of normal ACTH, cortisol and nociceptive RIII threshold values, characterizes daily chronic headache (DCH) patients. Moreover, indoprofen does not significantly affect these biological and neurophysiological parameters independently of the therapeutic response.

Topics: Adult; Anti-Inflammatory Agents; Calcium Channel Blockers; Cinnarizine; Endorphins; Female; Flunarizine; Headache; Humans; Indoprofen; Male; Migraine Disorders; Pain; Phenylpropionates; Piperazines; Sensory Thresholds

The therapeutic agents flunarizine and lomerizine exhibit inhibitory activities against a variety of ion channels and neurotransmitter receptors. We have optimized their scaffolds to obtain more selective N-type calcium channel blockers. During this optimization, we discovered NP118809 and NP078585, two potent N-type calcium channel blockers which have good selectivity over L-type calcium channels. Upon intraperitoneal administration both compounds exhibit analgesic activity in a rodent model of inflammatory pain. NP118809 further exhibits a number of favorable preclinical characteristics as they relate to overall pharmacokinetics and minimal off-target activity including the hERG potassium channel.

Topics: Analgesics; Animals; Binding Sites; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Calcium Channels, T-Type; Disease Models, Animal; Drug Design; Pain; Pain Measurement; Pain Threshold; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship