SELECTIVE EFFECTS OF LOMERIZINE, A NOVEL DIPHENYLMETHYLPIPERAZINE Ca<sup>2+</sup> CHANNEL BLOCKER, ON CEREBRAL BLOOD FLOW IN RATS AND DOGS

Hara, Hideaki; Shimazawa, Masamitsu; Sasaoka, Masaaki; Yamada, Chieko; Iwakura, Yasushi; Sakai, Takanori; Maeda, Yu; Yamaguchi, Takafumi; Sukamoto, Takayuki; Hashimoto, Munehiro

doi:10.1046/j.1440-1681.1999.03154.x

Cited by 23 publications

(13 citation statements)

References 28 publications

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“…Hara et al (1999) have studied in anesthetized rats the effects of lomerizine, a CCB of the piperazine group, on cerebral blood flow by laser Doppler flowmetry and on vertebral blood flow in anesthetized beagle dogs with an electromagnetic flowmeter. They observed that lomerizine (2.5 and 5 mg/kg, intraduodenally) dose-dependently increased vertebral blood flow in dogs without significantly changing BP or HR.…”

Section: Acute Hemodynamic Effects Of Ccbsmentioning

confidence: 99%

Discovery and Development of Calcium Channel Blockers

2017

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In the mid 1960s, experimental work on molecules under screening as coronary dilators allowed the discovery of the mechanism of calcium entry blockade by drugs later named calcium channel blockers. This paper summarizes scientific research on these small molecules interacting directly with L-type voltage-operated calcium channels. It also reports on experimental approaches translated into understanding of their therapeutic actions. The importance of calcium in muscle contraction was discovered by Sidney Ringer who reported this fact in 1883. Interest in the intracellular role of calcium arose 60 years later out of Kamada (Japan) and Heibrunn (USA) experiments in the early 1940s. Studies on pharmacology of calcium function were initiated in the mid 1960s and their therapeutic applications globally occurred in the the 1980s. The first part of this report deals with basic pharmacology in the cardiovascular system particularly in isolated arteries. In the section entitled from calcium antagonists to calcium channel blockers, it is recalled that drugs of a series of diphenylpiperazines screened in vivo on coronary bed precontracted by angiotensin were initially named calcium antagonists on the basis of their effect in depolarized arteries contracted by calcium. Studies on arteries contracted by catecholamines showed that the vasorelaxation resulted from blockade of calcium entry. Radiochemical and electrophysiological studies performed with dihydropyridines allowed their cellular targets to be identified with L-type voltage-operated calcium channels. The modulated receptor theory helped the understanding of their variation in affinity dependent on arterial cell membrane potential and promoted the terminology calcium channel blocker (CCB) of which the various chemical families are introduced in the paper. In the section entitled tissue selectivity of CCBs, it is shown that characteristics of the drug, properties of the tissue, and of the stimuli are important factors of their action. The high sensitivity of hypertensive animals is explained by the partial depolarization of their arteries. It is noted that they are arteriolar dilators and that they cannot be simply considered as vasodilators. The second part of this report provides key information about clinical usefulness of CCBs. A section is devoted to the controversy on their safety closed by the Allhat trial (2002). Sections are dedicated to their effect in cardiac ischemia, in cardiac arrhythmias, in atherosclerosis, in hypertension, and its complications. CCBs appear as the most commonly used for the treatment of cardiovascular diseases. As far as hypertension is concerned, globally the prevalence in adults aged 25 years and over was around 40% in 2008. Usefulness of CCBs is discussed on the basis of large clinical trials. At therapeutic dosage, they reduce the elevated blood pressure of hypertensive patients but don't change blood pressure of normotensive subjects, as was observed in animals. Those active on both L- and T-type channels are efficient in nephropat...

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Section: Acute Hemodynamic Effects Of Ccbsmentioning

confidence: 99%

Discovery and Development of Calcium Channel Blockers

2017

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“…2,34 The resultant increase in cytoplasmic calcium concentrations activates intracellular calcium-dependent signaling processes 35 that may lead to secondary death by apoptotic or necrotic processes. 36 -38 The relatively newly synthesized calcium channel blocker lomerizine, also known as KB-2796, is a diphenylmethylpiperazine compound currently marketed as an antimigraine drug 39 and is in phase II clinical trials for glaucoma. 40,41 Lomerizine is highly selective for L-type channels in the CNS and cerebral arteries and therefore has few peripheral side effects.…”

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confidence: 99%

Secondary Retinal Ganglion Cell Death and the Neuroprotective Effects of the Calcium Channel Blocker Lomerizine

Fitzgerald

Payne

Bartlett

et al. 2009

Invest. Ophthalmol. Vis. Sci.

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“…Oral or intraduodenal administration of this drug induced a dose-dependent and continuous increase in both CBF in rats and VBF in dogs, largely without affecting BP or HR (30). The values obtained for the plasma concentration of lomerizine (free base) in anesthetized rats at 30 and 60 min after the initial administration of 5 mg/kg, p.o.…”

Section: Selective Effects Of Lomerizine On Cerebral Blood Flowmentioning

confidence: 86%

“…Lomerizine has been investigated for its effects on cerebral cortical blood flow (CBF) in anesthetized rats (by laser Doppler flowmetry) and on vertebral blood flow (VBF) in anesthetized beagle dogs (by electromagnetic flowmetry). Oral or intraduodenal administration of this drug induced a dose-dependent and continuous increase in both CBF in rats and VBF in dogs, largely without affecting BP or HR (30). The values obtained for the plasma concentration of lomerizine (free base) in anesthetized rats at 30 and 60 min after the initial administration of 5 mg/kg, p.o.…”

Section: Selective Effects Of Lomerizine On Cerebral Blood Flowmentioning

confidence: 86%

Clinical Potential of Lomerizine, a Ca²⁺ Channel Blocker as an Anti‐Glaucoma Drug: Effects on Ocular Circulation and Retinal Neuronal Damage

Hara

Toriu

Shimazawa

2004

Cardiovascular Drug Reviews

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Glaucoma is defined as an optic neuropathy with characteristic changes in the optic nerve head and ultimate loss of visual field. Previous studies have suggested that (a) mechanical damage due to raised intraocular pressure and (b) a compromised tissue circulation in the optic nerve head play significant roles in the development of glaucomatous damage in the optic nerve head. Recently, we found that lomerizine, a new Ca(2+) channel blocker, increased ocular circulation and protected neuronal cells against retinal neurotoxicity both in vitro and in vivo with minimal cardiovascular side effects. We examined the effect of lomerizine on the ocular circulation and compared it with those of other Ca(2+) channel blockers in normal rabbits and in rabbits with an endothelin-1-disturbed circulation in the optic nerve head. In anesthetized rabbits, lomerizine and the other Ca(2+) channel blockers increased the ocular circulation and also inhibited the hypoperfusion induced in optic nerve head tissue by an intravitreous injection of endothelin-1. Whereas the other Ca(2+) channel blockers produced changes in blood pressure and heart rate, the effects of lomerizine on these parameters were slight. In healthy humans, lomerizine increased blood velocity in the optic nerve head, without significantly altering blood pressure or heart rate. Moreover, lomerizine reduced retinal damage in rats both in vitro and in vivo, presumably through a Ca(2+) channel blocking effect via an action that may involve a direct protection of retinal neurons as well as an improvement in the ocular circulation. These results indicate that lomerizine may be useful as a therapeutic drug against ischemic retinal diseases (such as glaucoma and retinal vascular occlusive diseases) that involve a disturbance of the ocular circulation.

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SELECTIVE EFFECTS OF LOMERIZINE, A NOVEL DIPHENYLMETHYLPIPERAZINE Ca²⁺ CHANNEL BLOCKER, ON CEREBRAL BLOOD FLOW IN RATS AND DOGS

Cited by 23 publications

References 28 publications

Discovery and Development of Calcium Channel Blockers

Discovery and Development of Calcium Channel Blockers

Secondary Retinal Ganglion Cell Death and the Neuroprotective Effects of the Calcium Channel Blocker Lomerizine

Clinical Potential of Lomerizine, a Ca²⁺ Channel Blocker as an Anti‐Glaucoma Drug: Effects on Ocular Circulation and Retinal Neuronal Damage

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SELECTIVE EFFECTS OF LOMERIZINE, A NOVEL DIPHENYLMETHYLPIPERAZINE Ca2+ CHANNEL BLOCKER, ON CEREBRAL BLOOD FLOW IN RATS AND DOGS

Cited by 23 publications

References 28 publications

Discovery and Development of Calcium Channel Blockers

Discovery and Development of Calcium Channel Blockers

Secondary Retinal Ganglion Cell Death and the Neuroprotective Effects of the Calcium Channel Blocker Lomerizine

Clinical Potential of Lomerizine, a Ca2+ Channel Blocker as an Anti‐Glaucoma Drug: Effects on Ocular Circulation and Retinal Neuronal Damage

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Product

Resources

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SELECTIVE EFFECTS OF LOMERIZINE, A NOVEL DIPHENYLMETHYLPIPERAZINE Ca²⁺ CHANNEL BLOCKER, ON CEREBRAL BLOOD FLOW IN RATS AND DOGS

Clinical Potential of Lomerizine, a Ca²⁺ Channel Blocker as an Anti‐Glaucoma Drug: Effects on Ocular Circulation and Retinal Neuronal Damage