Improved short-term neurological recovery with flunarizine in a canine model of cardiac arrest

Edmonds, Harvey L.; Wauquier, A.; Melis, W.; Broeck, W.A.E. Van Den; Loon, J. Van; Janßen, Paul

doi:10.1016/0735-6757(85)90040-3

Cited by 43 publications

(11 citation statements)

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“…Recently published papers report beneficial effects of this drug in models of global ischemia 8 " 10 and graded hypoxia-oligemia." The presently used dose of flunarizine was selected according to its absorption and tissue distribution characteristics in rats 12 and with respect to its activity in other ischemia studies.…”

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confidence: 99%

Flunarizine reduces cerebral infarct size after photochemically induced thrombosis in spontaneously hypertensive rats.

Reempts

Deuren

Ven

et al. 1987

Stroke

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The cerebroprotective effect of flunarizine was studied in a minimally invasive model of photochemically induced cerebral infarction in spontaneously hypertensive rats. Intravenous administration of the photosensitizing dye rose bengal and intense focal illumination of the brain produced a deep cortical infarction that resulted from singlet oxygen-induced peroxidative injury to the endothelial membrane, subsequent platelet adhesion, and eventual thrombus formation. The infarct size was calculated from area measurements on consecutive histologic sections prepared from the brain cortex 4 hours after the onset of the insult. Oral treatment with 40 mg/kg flunarizine 3 hours before photoexcitation resulted in a significant reduction of the median infarct size from 11.75 mm 3 in the untreated group to 6.40 mm 3 in the treated group (a = 13, p<0.001). At this dose, flunarizine had no effect on systemic blood pressure. In a separate experiment the area of thrombotic obstruction was quantified 30 minutes after the onset of light exposure. Flunarizine did not significantly reduce early thrombus formation (2.28 mm 3 in the untreated and 1.78 mm 3 in the treated group) (n = 12, p = 0.2). The infarcted area at 4 hours was considerably larger than the initial thrombotic area. Protection with flunarizine against development of cortical infarction has been unequivocally shown. Although some effect may already be present at the early stage of lesion formation, the major protective action admittedly occurred in the later postinsult period when the lesion was expanding. The observed beneficial effects may be attributed to preservation of the integrity of endothelial cell membranes (reduction of platelet adhesion and vasogenic edema formation), of neuronal cell membranes (inhibition of toxic Ca 2+ overload), and of glial cell membranes (prevention of cytotoxic edema formation). The results indicate that flunarizine may be of clinical use for the suppression of thrombotic stroke.

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confidence: 99%

Flunarizine reduces cerebral infarct size after photochemically induced thrombosis in spontaneously hypertensive rats.

Reempts

Deuren

Ven

et al. 1987

Stroke

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“…Further, improved neurological recovery after ischemic spinal cord injury in rabbits is observed following pretreatment with flunarizine [19]. In a canine model of cardiac arrest, flunarizine improves cerebral oxygen consumption and blood flow, and reduces neurological deficits when given after cardiac arrest but before resuscitation [9]. Thus, flunarizine is potentially beneficial both as a treatment and a pretreatment.…”

Section: Introductionmentioning

confidence: 83%

“…The effective dose of flunarizine appears to be independent of species. For example, in rats [11,16], dogs [9], and rabbits [19] an i.v. dose of 0.1 mg/kg, and in fetal sheep 1 mg/kg [2], protect against insults to the microvasculature.…”

Section: Discussionmentioning

confidence: 99%

Flunarizine pretreatment attenuates hyperthermia-induced extravasation in rats

Matthew

Sils

2000

Pflügers Arch - Eur J Physiol

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Previous work has established that there is an increase in endothelial permeability in hyperthermic rats. This work assessed the potential of the calcium channel blocker (E)-1-bis(4-fluorophenyl)methyl-4-(3-phenyl-2-propenyl)piperazine dihydrochloride (flunarizine) as a pretreatment to ameliorate this extravasation. Five groups of male rats (n=12 rats per group, 400-500 g) were given 0, 0.3, 1, 2, or 3 mg/kg flunarizine (FL0, FL0.3, FL1, FL2, and FL3, respectively) by gavage 30 min prior to induction of hyperthermia. Hyperthermia was achieved by placing unrestrained animals in their own cages in a chamber maintained at 41.5 degrees C until a core temperature (Tc) of 42.6 degrees C was attained. Then, 25 mg/kg of Evans blue in saline was administered via a jugular cannula. After 15 min the animals were anesthetized, exsanguinated, tissues removed and washed in saline, and Evans blue extracted with formamide. As the dose of flunarizine was increased, there was a significant (P<0.05) reduction of Evans blue recovered from the liver, kidney, lung, spleen, and intestinal tissue. Endurance time in the heat to reach a Tc of 42.6 degrees C increased significantly from 194+/-39 min (mean+/-SD) with FL0 to 275+/-33 min with FL1, but decreased again with FL2 (206+/-42) and FL3 (199+/-60). Thus, flunarizine pretreatment attenuated hyperthermia-induced extravasation, and 1 mg/kg flunarizine markedly increased the tolerance time to heat exposure.

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“…1983;Smith et al 1983;Steen et al 1983Steen et al , 1984Steen et al , 1985Mabe et al 1986;Newberg et al 1986;Ment el al. 1987); lidoflazine (Winegar et al 1983, Vaagenes et al 1984, Dean et al 1984, Fleischer et al 1987, Thiringer et al 1987; flunarizine (White et al 1982, Hossmann et al 1983, Newberg et al 1984, Edmonds et al 1985, Silverstein et al 1986); verapamil (White et al 1983a, b;Berger et al 1984) and nicardipine (Sakabe et al 1986).…”

Section: Discussionmentioning

confidence: 99%

“…The concept of cerebral protection by pharmacological agents following global cerebral injury is now widely accepted as a promising method for the clinical management of this condition. Calciumchannel blockers have been singled out for evaluation by a number of research groups, using various animal models (Takenaka and Handa 1979;Harper et al 1981;Harris et al 1982;White et al 1982;Haws and Heistad 1983;Hossmann et al 1983;Kagstrom et al 1983;Smith et al 1983;Steen et al 1983Steen et al , 1984Steen et al , 1985White et al 1983a, 6;Winegar et al 1983;Berger et al 1984;Dean et al 1984;McCalden et al 1984;Mohamed et al 1984Mohamed et al , 1985Newberg et al 1984Newberg et al , 1986Vaagenes et al 1984;Edmonds et al 1985;Forsman et al 1986;Mabe et al 1986;Sakabe et al 1986;Fleischer et al 1987). This group of drugs has at least three potentially important actions: protection of the neuron from the effect of calcium ion (Ca+ +) entry; prevention of post-ischaemic cerebral arteriolar vasoconstriction; and improvement of myocardial function (White et al 1983a, b).…”

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confidence: 99%

The Use Of A Calcium‐Channel Blocker, Nicardipine, For Severely Asphyxiated Newborn Infants

Levene

Gibson

Fenton

et al. 1990

Develop Med Child Neuro

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SUMMARY A continuous infusion of nicardipine was given to four severely asphyxiated fullterm infants who were at high risk for adverse outcome and had abnormal cerebral Doppler haemodynamic studies. The heart rate increased in all four infants and mean arterial blood pressure (MAP) fell in three. Two infants had a sudden and marked fall in MAP, together with severe impairment of skin blood‐flow and a concurrent fall in cerebral blood‐flow velocity. The serum level of nicardipine was <40ng/mL in all cases. The use of nicardipine, and possibly other calcium‐channel blockers, may be associated with marked hypotension, and if there is no cerebral autoregulation, may cause further cerebral hypoperfusion, so use of these drugs in asphyxiated newborn infants should only be attempted if blood pressure is carefully monitored. RéSUMé La nicardipine chez les nouveaux‐nés présentant une asphyxie sévère Une perfusion continue de nicardipine a été administrée chez quatre nouveaux‐nés a terme avec asphyxie sévére qui présentaient un risque élevé de devenir pathologique et avaient présenté des résultats anormaux aux études hémodynamiques cérébrales avec doppler. Le rythme cardiaque s'accrût chez les quatres nouveaux‐nés et la pression artérielle moyenne (MAP) diminua dans trois cas. Deux nourrissons avaient présenté une chute soudaine et marquée de la MAP, ainsi qu'une altération grave de la circulation sanguine cutanée et une chute simultanée de la vitesse de circulation sanguine cérébrale. Le taux sérique de nicardipine était <40ng/mL dans tous les cas. L'utilisation de nicardipine et éventuellement d'autres bloqueurs des canaux calciques peut étre associée avec une hypotension marquée et s'il n'y a pas d'auto‐régulation cérébrale, cela peut créer une hypo‐perfusion ultérieure; aussi l'utilisation de ces médications ne doit être tentée que si la pression sanguine est soigneusement contrôlée. ZUSAMMENFASSUNG Nicardipin bei Kindern mit schwerer Asphyxie Vier reife Kinder mit schwerer Asphyxie, die hinsichtlich ihrer Entwicklung hochgradig gefährdet waren und die abnorme cerebrale hämodynamische Doppler‐Untersuchungen aufwiesen, bekamen Nicardipin‐Infusionen. Die Herzfrequenz stieg bei allen vier Patienten an und der mittlere arterielle Druck (MAP) fiel bei drei Patienten ab. Zwei Kinder hatten einen plötzlichen, starken Abfall des MAP, einhergehend mit schweren Hautdurchblutungsstörungen und einem Abfall der cerebralen Strömungsgeschwindigkeit. Der Serumspiegel des Nicardipin betrug in allen Fällen 40ng/mL. Die Anwendung von Nicardipin, und vielleicht auch anderer Kalziumantagonisten, kann eine schwere Hypotonic zur Folge haben, und wenn keine cerebrale Autoregulation eintritt, resultiert daraus eine verstärkte cerebrale Mangeldurchblutung. Die Gabe dieser Medikamente sollte bei Neugeborenen mit Asphyxie daher nur erwogen werden, wenn der Blutdruck sorgfältig überprüft werden kann. RESUMEN Nicardipina en recien nacidos con asfixia grave Un gota a gota continuo de Nicardipina se administró a cuatro recién nacidos a término con un...

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Improved short-term neurological recovery with flunarizine in a canine model of cardiac arrest

Cited by 43 publications

References 11 publications

Flunarizine reduces cerebral infarct size after photochemically induced thrombosis in spontaneously hypertensive rats.

Flunarizine reduces cerebral infarct size after photochemically induced thrombosis in spontaneously hypertensive rats.

Flunarizine pretreatment attenuates hyperthermia-induced extravasation in rats

The Use Of A Calcium‐Channel Blocker, Nicardipine, For Severely Asphyxiated Newborn Infants

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