Dose-escalation study of intravenous nicardipine in patients with aneurysmal subarachnoid hemorrhage

Flamm, Eugene S.; Adams, Harold P.; Beck, David; Pinto, Richard S.; Marler, John R.; Walker, Michael D.; Godersky, John C.; Loftus, Christopher M.; Biller, José; Boarini, David J.; O’Dell, Chris; Banwart, Karla; Kongable, Gail L.

doi:10.3171/jns.1988.68.3.0393

Cited by 100 publications

(38 citation statements)

References 40 publications

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“…The details of this study are described elsewhere. 7 In all cases, blood in the subarachnoid space was evident on either computed tomography (CT) or nontraumatic lumbar puncture. Cerebral angiography to demonstrate the presence of a saccular aneurysm and the absence of vasospasm was performed before patients were entered into the study.…”

Section: Methodsmentioning

confidence: 94%

Combination of aminocaproic acid and nicardipine in treatment of aneurysmal subarachnoid hemorrhage.

Beck

Adams

Flamm

et al. 1988

Stroke

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Antifibrinolytic drags reduce the risk of rebleeding during the first 2 weeks after aneurysmal subarachnoid hemorrhage. However, they do not lower overall mortality, largely because of an increased incidence of cerebral ischemia. The usefulness of antifibrinolytic drugs might be increased if a method to prevent or control vasospasm in patients were to be developed. We recently completed late Phase I and Phase II studies of the calcium ion blocking drug nicardipine in 67 patients treated within 1 week of subarachnoid hemorrhage. Of these 67 patients, 42 had delayed operations and were treated concomitantly with the antifibrinolytic drug aminocaproic add (1.5 g/hr) for an average of 6 days before surgery. The outcome of these 42 patients is the subject of this report. T he use of antifibrinolytic drugs in the management of aneurysmal subarachnoid hemorrhage (SAH) is controversial. 1 " 3 Recently two large multicenter trials showed that the risk of rebleeding was substantially reduced in patients receiving antifibrinolytic drugs compared with a comparable group of patients not receiving antifibrinolytic drugs. 45 However, the overall mortality rate at 3 months between the groups was similar. The reduction of mortality due to rebleeding was negated by increased mortality due to cerebral ischemia among the patients given antifibrinolytic drugs.4 " 6 Antifibrinolytic drugs could become a useful preoperative therapy in patients with recent SAH if the risks of vasospasm and cerebral ischemia could be reduced.We recently performed a prospective dosage escala- Received June 3, 1987; accepted July 14, 1987. tion study of nicardipine, a dihydropyridine calcium ion entry blocking agent that preferentially binds to cerebrovascular smooth muscle, in 67 patients with recent SAH. Forty-two patients had delayed operations planned for the treatment of the aneurysm and were given aminocaproic acid before surgery. These 42 patients were studied for any effect on the incidence and severity of symptomatic vasospasm by the concomitant administration of nicardipine and aminocaproic acid. Subjects and MethodsPatients between the ages of 18 and 75 admitted to University of Iowa Hospitals or to New York University Medical Center within 7 calendar days of SAH from a documented cerebral aneurysm were included in the study. The details of this study are described elsewhere. 7 In all cases, blood in the subarachnoid space was evident on either computed tomography (CT) or nontraumatic lumbar puncture. Cerebral angiography to demonstrate the presence of a saccular aneurysm and the absence of vasospasm was performed before patients were entered into the study. Patients were excluded if they were deeply comatose, if they had a large intracerebral hemorrhage, or if arterial narrowing was found on the initial arteriogram. Patients were also excluded if they were taking a calcium ion blocking

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Section: Methodsmentioning

confidence: 94%

Combination of aminocaproic acid and nicardipine in treatment of aneurysmal subarachnoid hemorrhage.

Beck

Adams

Flamm

et al. 1988

Stroke

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“…Studies demonstrated that nicardipine, a Ca 2+ -channel blocker, could improve the impaired cerebral circulation (33,34). The ocular vasculature anatomically and functionally resembles the cerebral vasculature.…”

Section: Discussionmentioning

confidence: 99%

Intravenously Administered Vasodilatory Prostaglandins Increase Retinal and Choroidal Blood Flow in Rats

et al. 2007

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Abstract. We established an experimental system for measuring blood flow in the rat fundus and examined whether intravenously administered vasodilatory prostaglandins (PGE 1 , PGE 2 , and PGI 2 ), 8-(4-chlorophenylthio)-cAMP (a cAMP analogue), and nicardipine (a Ca 2+ -channel blocker) increase fundus blood flow (FBF). Under artificial ventilation, rats were injected with tetrodotoxin (50 µg / kg, i.v.) to eliminate any nerve activity and prevent movement of the eye.After tetrodotoxin, the rats were infused with norepinephrine (0.3 -0.5 µg ⋅ kg) and) simultaneously to maintain adequate systemic circulation.We found that intravenous infusion of PGE 1 (2 -10 µg ⋅ kg), and PGI 2 (1 -10 µg ⋅ kg −1 ⋅ min −1 ) increased the FBF in a dose-dependent manner. The vasodilatory PGs decreased arterial pressure, whereas they did not affect heart rate. Like vasodilatory PGs, 8-(4-chlorophenylthio)-cAMP (30 µmol / kg, i.v.) increased FBF and decreased arterial pressure. While infusion of nicardipine (0.3 -3 µg ⋅ kg −1 ⋅ min −1 ) produced comparable depressor responses with those to vasodilatory PGs and the cAMP analogue, it did not increase FBF. These results suggest that vasodilatory PGs and cAMP act more selectively than Ca 2+ -channel blockers on retinal / choroidal blood vessels. Therefore, the vasodilatory PGs might be considered to be possible candidates for the therapeutics to treat disorders of retinal / choroidal circulation.

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“…In addition, the marked degradation of contractile and cytoskeletal proteins also contributes to the development of vasospasm, and this probably occurs by severe uncoupling of the contractile units from the cytoskeleton. Flamm, et al, 18 reported that the intravenous infusion of high doses of nicardipine had significantly beneficial effects on development of delayed cerebral ischemia after aneurysmal SAH. In our clinic similar results have been reported in early treatment with high doses of nicardipine as early as possible within 24 hours after SAH, 44 suggesting that the therapeutic reduction of intracellular Ca ++ is an important measure to prevent development of vasospasm.…”

Section: The Continuous Increase In Intracellular Camentioning

confidence: 99%

Molecular mechanisms involved in development of cerebral vasospasm

Tani

2002

FOC

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Object Although the agents responsible for production of vasospasm have not yet been clearly identified, the author reviews the molecular mechanisms involved in development of vasospasm mainly based on the experimental data in a canine two-hemorrhage model. Methods The blood products after subarachnoid hemorrhage most likely stimulate many cell membrane receptors, such as G protein–coupled receptors and receptor tyrosine kinases, to activate the tyrosine kinase pathway of the vascular smooth muscle cells. The activation of the tyrosine kinase pathway is associated with continuous elevation of intracellular Ca++ levels and activation of μ-calpain; the former may result mainly not from Ca++ release but from Ca++ influx from outside the cells. The increased intracellular Ca++ concentrations stimulate Ca++/calmodulin (CaM)–dependent myosin light chain kinase to phosphorylate myosin light chain continuously during vasospasm. A topical application of genistein, ethylene-glycol-bis(β-aminoethylether) N,N'-tetraacetic acid, or various L-type Ca++ channel blockers likely induces reversal of vasospasm as a result of a decrease in intracellular Ca++ levels. The blood products also activate the rho/rho-associated kinase pathway during vasospasm most likely via G protein–coupled receptors, and the activated rho-associated kinase inhibits myosin phosphatase through phosphorylation at its myosin-binding subunit to induce Ca++-independent development of vasospasm. The enhanced generation of arachidonic acid during vasospasm may also contribute to inhibition of myosin phosphatase, at least in part, through the rho/rho-associated kinase pathway. The activity of myosin phosphatase in vasospam can also be inhibited by activated protein kinase C independently of the rho/rho-associated kinase pathway, but the inhibition may play a minor and transient role in contractile regulation. The protein levels of thin filament–associated proteins, calponin and caldesmon, are progressively decreased in vasospasm, whereas their phosphorylation levels are increased. Both changes probably contribute to the enhancement of smooth muscle contractility. Contractile and cytoskeletal proteins appear to be degraded in vasospasm by proteolysis with activated μ-calpain, suggesting that the intracellular devices responsible for smooth-muscle contraction are severely degraded in vasospasm. Conclusions It remains to be determined the extent to which Ca++-dependent and -independent contractile regulations, proteolysis and phosphorylation of thin filament–associated proteins, and degradation of contractile and cytoskeletal proteins are involved in the development of vasospasm.

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Dose-escalation study of intravenous nicardipine in patients with aneurysmal subarachnoid hemorrhage

Cited by 100 publications

References 40 publications

Combination of aminocaproic acid and nicardipine in treatment of aneurysmal subarachnoid hemorrhage.

Combination of aminocaproic acid and nicardipine in treatment of aneurysmal subarachnoid hemorrhage.

Intravenously Administered Vasodilatory Prostaglandins Increase Retinal and Choroidal Blood Flow in Rats

Molecular mechanisms involved in development of cerebral vasospasm

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