Pharmacological Effects in Protective and Resuscitative Models of Brain Hypoxia

Wauquier, A.; Ashton, David; Hermans, Carlo; Clinke, G.

doi:10.1007/978-3-642-69175-1_13

Cited by 12 publications

(10 citation statements)

References 15 publications

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“…and in the potassium cyanide hypoxic test in rats (1.77 mg/kg s.c.). In comparison with reference substances, those shown here as well as those described earlier [Wauquier et al, 1983, R 58 735 is hitherto the most potent antihypoxic compound experimentally available. Its potential as a resuscitative agent (i.e., efficacy of the compound when given after an hypoxic insult) is currently being investigated in models of cerebral ischemia.…”

Section: Discussionmentioning

confidence: 91%

“…Thus, the development of drugs that antagonize brain hypoxia may lead to many clinical applications, as in migraine [Amery et al, 19841. Therefore, we undertook to investigate new antihypoxic agents by means of tests capable of detecting potential antihypoxic drugs [e.g., Wauquier et al, 1981Wauquier et al, , 1983 In addition, we investigated the anticonvulsant activity of these compounds for the reasons mentioned above. Finally, taking into account that cognitive disturbances are often the first sign of hypoxic injury, we studied antagonism of memory deficits caused by hypoxia.…”

Section: Introductionmentioning

confidence: 99%

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R 58 735: A new antihypoxic drug with anticonvulsant properties and possible effects on cognitive functions

Wauquier

Clincke

Ashton

et al. 1986

Drug Development Research

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R 58 735, a benzthiazole derivative, is a potent antihypoxic agent with anticonvulsant properties. As an antihypoxic drug, it was more potent than any other reference substance in hypobaric hypoxia in mice and in histotoxic dysoxia and nitrogen hypoxia in rats. In the nitrogen hypoxia test, R 58 735 was equipotent in males and females, and the p.0.li.v. ratio varied from 2.8 to 2.6. The antihypoxic activity of orally administered R 58 735 lasted more than 8, but less than 24 hr. The anticonvulsant profile of R 58 735 resembled that of flunarizine, i.e., blockade of the tonic convulsions induced by pentylenetetrazol, allylglycine, or bicuculline, but not of clonic convulsions, except those seen in audiogenic seizureprone mice. In the allylglycine or bicuculline tests, it was more potent than any other reference anticonvulsant. In the bicuculline test, there were no sex-related differences in activity, and the p.o./s.c. activity ratio was 2.01 in males and 1.74 in females. Following oral administration, the duration of anticonvulsant activity in the bicuculline test was more than 8, but less than 24 hr. In guinea pigs, R 58 735 completely antagonized hypoxiainduced amnesia at a dose of 2.5 mglkg S.C. Furthermore, it enhanced acquisition of a two-way avoidance task over a broad dose range (0.63-20 mglkg) in rats.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

R 58 735: A new antihypoxic drug with anticonvulsant properties and possible effects on cognitive functions

Wauquier

Clincke

Ashton

et al. 1986

Drug Development Research

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“…Post-ischaemic flunarizine treatment preserved neurological function in rats [4], and prevented the reduction in canine cerebral cortical blood flow which was seen in untreated animals subjected to 20 min complete cessation of perfusion [5], Van Reempts et al [6] have reported that flunarizine reduced the mor phologically quantified cerebral cortical damage in rats subjected to a 24-hour hypoxic-ischaemic insult. Karasawa et al [7] compared the protective effects of flunari zine, cinnarizine, verapamil and pentobarbitone in four models of cerebral hypoxic anoxia in rodents; they used cytotoxic anoxia by KCN injection, hyperbaric hypoxia and normobaric hypoxia in mice, and hypercapnic anoxia induced by stopping artificial ventilation in rats.…”

Section: Discussionmentioning

confidence: 99%

Variable Results of Calcium Blockade in Post-Ischaemic Renal Failure

Jm²,

Rb³

1988

Eur Urol

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“…In pathologic conditions, brain hypoxia and ischemia will rapidly lead to cerebral dysfunction or necrosis (47,126,132). Experimentally, the brain can be protected from the deleterious effects of hypoxia and its functional state maintained or restored by treatment with flunarizine (121,124,126,127). Such protection is observed in the rat during histotoxic dysoxia produced by potassium cyanide and hypoxia caused by exposure to 100% nitrogen.…”

Section: Brain Hypoxiamentioning

confidence: 99%

Flunarizine

Nueten

Vanhoutte

1984

Cardiovascular Drug Reviews

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Flunarizine, (E)-1 -[bis(4-fluorophenyl)methyl]-4-( 3-phenyl-2-propenyl) piperazine ( Fig. 1), belongs to the chemically heterogenous group of calcium-entry blockers (16,101,113). Chronic treatment with flunarizine provides symptomatic relief of peripheral (arterial and venous) and cerebral circulatory disorders (23,27,31,50,(52)(53)(54)59,60,72,80,81,(83)(84)(85)(86)92,93,120,133). The drug is also used for the treatment of vestibular disorders (12,52,65,128) and may be beneficial in the prophylactic treatment of migraine (1,2,26,29,63,64,82). Ongoing studies have demonstrated the effectiveness of this compound in therapy-resistant forms of epilepsy ( 17,74). The suggestion has been made that flunarizine may be helpful in some cases of urinary incontinence (75,87). The therapeutic effects may be due, at least in part, to its ability to inhibit the entry of calcium ions (Ca2+) into tissue cells, thereby preventing cellular intoxication due to an overload of Ca2+ (15,113). In particular, the compound affects the function of vascular smooth muscle cells, endothelial cells, myocardial cells, erythrocytes, and brain cells (13,15,16,35,36,76,103,104,114). F FIG. 1. Three-dimensional representation of the chemical structure of flunarizine based on the crystal structure conformation of cinnarizine (J. Tollenaere and H. Moereels, unpublished data). 245 246 120 ~ 100z I-2 80-V < n t 60-I 1 I I 8 I I -15 -10 -5 0 5 10 20 30 $0 50 60 70 80 90 MIN FIG. 2. Depression of K+-induced contractions of canine basilar arteries by increasing concentrations (M) of flunarizine. Means 5 SE; N = 5.

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Pharmacological Effects in Protective and Resuscitative Models of Brain Hypoxia

Cited by 12 publications

References 15 publications

R 58 735: A new antihypoxic drug with anticonvulsant properties and possible effects on cognitive functions

R 58 735: A new antihypoxic drug with anticonvulsant properties and possible effects on cognitive functions

Variable Results of Calcium Blockade in Post-Ischaemic Renal Failure

Flunarizine

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