sildenafil-citrate and Vasospasm--Intracranial

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Blood Pressure; Cardiovascular Diseases; Coronary Circulation; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Isoenzymes; Organ Specificity; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Pulmonary Circulation; Purines; Sildenafil Citrate; Sulfones; Vasospasm, Intracranial

Studies show that phosphodiesterase-V (PDE-V) inhibition reduces cerebral vasospasm (CVS) and improves outcomes after experimental subarachnoid hemorrhage (SAH). This study was performed to investigate the safety and effect of sildenafil (an FDA-approved PDE-V inhibitor) on angiographic CVS in SAH patients.. A2-phase, prospective, nonrandomized, human trial was implemented. Subarachnoid hemorrhage patients underwent angiography on Day 7 to assess for CVS. Those with CVS were given 10 mg of intravenous sildenafil in the first phase of the study and 30 mg in the second phase. In both, angiography was repeated 30 minutes after infusion. Safety was assessed by monitoring neurological examination findings and vital signs and for the development of adverse reactions. For angiographic assessment, in a blinded fashion, pre- and post-sildenafil images were graded as "improvement" or "no improvement" in CVS. Unblinded measurements were made between pre- and post-sildenafil angiograms.. Twelve patients received sildenafil; 5 patients received 10 mg and 7 received 30 mg. There were no adverse reactions. There was no adverse effect on heart rate or intracranial pressure. Sildenafil resulted in a transient decline in mean arterial pressure, an average of 17% with a return to baseline in an average of 18 minutes. Eight patients (67%) were found to have a positive angiographic response to sildenafil, 3 (60%) in the low-dose group and 5 (71%) in the high-dose group. The largest degree of vessel dilation was an average of 0.8 mm (range 0-2.1 mm). This corresponded to an average percentage increase in vessel diameter of 62% (range 0%-200%).. The results from this Phase I safety and proof-of-concept trial assessing the use of intravenous sildenafil in patients with CVS show that sildenafil is safe and well tolerated in the setting of SAH. Furthermore, the angiographic data suggest that sildenafil has a positive impact on human CVS.

Topics: Administration, Intravenous; Adult; Aged; Aged, 80 and over; Arterial Pressure; Cerebral Angiography; Dose-Response Relationship, Drug; Female; Humans; Magnetic Resonance Angiography; Male; Middle Aged; Prospective Studies; Sildenafil Citrate; Subarachnoid Hemorrhage; Treatment Outcome; Vasodilator Agents; Vasospasm, Intracranial

Cerebral vasospasm following subarachnoid hemorrhage (SAH) is the most important complication that effects the mortality and morbidity of patients with intracranial aneurysm. Today, the mechanisms of vasospasm are not understood in spite of experimental and clinical researches. The aim of our study was to investigate the effects of curcumin on vasospasm following SAH.. In this study, 64 rats (200-250 g weight) were divided into 7 groups. Group 1: having no treatment after SAH; Group 2: treatment with nimodipine after SAH; Group 3: treatment with nicorandil after SAH; Group 4: treatment with sildenafil citrate after SAH; Group 5: treatment with 150 mg/kg curcumin after SAH; Group 6: treatment with 300 mg/kg curcumin after SAH, Group 7: treatment with 600 mg/kg curcumin after SAH. The experimental SAH was induced by injection of autologous blood into the cisterna magna. After medical treatment, in the first hour, blood was taken for quantified the levels of TNF-α, IL-1β and IL-6. Then, cerebrum and cerebellum were removed for analysis. Basilar artery luminal diameter was measured and apoptotic cell count was performed with tissue samples.. Histopathological findings showed that, in sufficient dose, curcumin dilated the basilar artery beside anti-oxidant effect.. Curcumin can be used for the treatment of vasospasm as a new medical drug.

Topics: Animals; Apoptosis; Basilar Artery; Cerebellum; Cerebral Cortex; Curcumin; Interleukin-1beta; Interleukin-6; Male; Nicorandil; Nimodipine; Rats; Sildenafil Citrate; Subarachnoid Hemorrhage; Tumor Necrosis Factor-alpha; Vasodilator Agents; Vasospasm, Intracranial

The phosphodiesterase-5 inhibitor sildenafil has been shown to attenuate delayed cerebral ischemia (DCI) and improve neurologic function in experimental subarachnoid hemorrhage (SAH). We recently demonstrated that it could improve cerebral vasospasm (CVS) in humans after SAH. However, successful therapies for DCI must also restore cerebral blood flow (CBF) and/or autoregulatory capacity. In this study, we tested the effects of sildenafil on CBF in SAH patients at-risk for DCI.. Six subjects with angiographically confirmed CVS received 30-mg of intravenous sildenafil (mean 9 ± 2 days after aneurysmal SAH). Each underwent (15)O-PET imaging to measure global and regional CBF at baseline and post-sildenafil.. Mean arterial pressure declined by 10 mm Hg on average post-sildenafil (8 %, p = 0.01), while ICP was unchanged. There was no change in global CBF (mean 34.5 ± 7 ml/100g/min at baseline vs. 33.9 ± 8.0 ml/100g/min post-sildenafil, p = 0.84). The proportion of brain regions with low CBF (<25 ml/100g/min) was also unchanged after sildenafil infusion.. Infusion of sildenafil does not lead to a change in global or regional perfusion despite a significant reduction in cerebral perfusion pressure. While this could reflect the ineffectiveness of sildenafil-induced proximal vasodilatation to alter brain perfusion, it also suggests that cerebral autoregulatory function was preserved in this group. Future studies should assess whether sildenafil can restore or enhance autoregulation after SAH.

Topics: Administration, Intravenous; Adult; Aged; Cerebrovascular Circulation; Female; Homeostasis; Humans; Male; Middle Aged; Outcome Assessment, Health Care; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Subarachnoid Hemorrhage; Vasospasm, Intracranial

Topics: Eating; Humans; Sildenafil Citrate; Vasospasm, Intracranial

Cerebral vasospasm is an independent predictor of poor outcome after subarachnoid hemorrhage (SAH). The nitric oxide-cyclic guanosine monophosphate (NO-cGMP) vasodilatory pathway is strongly implicated in its pathophysiology. Preliminary studies suggest that phosphodiesterase 5 (PDE5), an enzyme that degrades cGMP, may play a role because the PDE5 inhibitor sildenafil was found to reduce vasospasm after SAH. However, several questions that are critical when considering translational studies remain unanswered.. To elucidate the mechanism of action of sildenafil against vasospasm and to assess whether sildenafil attenuates SAH-induced neuronal cell death, improves functional outcome after SAH, or causes significant physiological side effects when administered at therapeutically relevant doses.. SAH was induced via endovascular perforation in male C57BL6 mice. Beginning 2 hours later, mice received sildenafil citrate (0.7, 2 or 5 mg/kg orally twice daily) or vehicle. Neurological outcome was assessed daily. Vasospasm was determined on post-SAH day 3. Brain PDE5 expression and activity, cGMP content, neuronal cell death, arterial blood pressure, and intracranial pressure were examined.. We found that PDE5 activity (but not expression) is increased after SAH, leading to decreased cGMP levels. Sildenafil attenuates this increase in PDE5 activity and restores cGMP levels after SAH. Post-SAH initiation of sildenafil was found to decrease vasospasm and neuronal cell death and markedly improve neurological outcome without causing significant physiological side effects.. Sildenafil, a US Food and Drug Administration-approved drug with a proven track record of safety in humans, is a promising new therapy for vasospasm and neurological deficits after SAH.

Topics: Animals; Blood Pressure; Cell Death; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme-Linked Immunosorbent Assay; Extremities; In Situ Nick-End Labeling; Intracranial Pressure; Male; Mice; Mice, Inbred C57BL; Motor Activity; Movement; Neurons; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Recovery of Function; Severity of Illness Index; Sildenafil Citrate; Subarachnoid Hemorrhage; Sulfones; Vasospasm, Intracranial

The therapeutic effect of sildenafil citrate on cerebral vasospasm after experimental subarachnoid hemorrhage (SAH) was studied in a rat model.. We used four groups of seven rats were as follows: no SAH, no treatment; SAH only; SAH plus 2 days of peroral sildenafil citrate 5mg/kg treatment and SAH plus 2 days of peroral sildenafil citrate 15 mg/kg treatment. Three different parameters were evaluated including the diameter of the basilar artery, the level of lipid peroxidation and the degree of the apoptosis 48 hours following SAH.. The results showed that sildenafil citrate attenuated SAH-induced cerebral vasospasm in the treatment groups in terms of the diameter of the basilar artery and lipid peroxidation in the two treatment groups, but there was no difference in terms of the level of apoptosis.. This study indicates that further research on the therapeutic effect of sildenafil citrate can be combined with the use of any apoptosis-blocking agent for the treatment of cerebral vasospasm following experimental subarachnoid hemorrhage.

Topics: Animals; Apoptosis; Disease Models, Animal; Immunohistochemistry; In Situ Nick-End Labeling; Lipid Peroxidation; Male; Piperazines; Purines; Rats; Rats, Sprague-Dawley; Sildenafil Citrate; Subarachnoid Hemorrhage; Sulfones; Vasodilator Agents; Vasospasm, Intracranial; Vertebrobasilar Insufficiency

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Cerebrovascular Circulation; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Hypercapnia; Models, Biological; Nitric Oxide; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Subarachnoid Hemorrhage; Sulfones; Vasodilation; Vasodilator Agents; Vasospasm, Intracranial

One of the phosphodiesterase isoenzymes, Type V (PDE V), specifically hydrolyzes cyclic guanosine monophosphate to cause vasoconstriction. This study analyses the effect of PDE V inhibition with sildenafil citrate (SC) on cerebral vasospasm and its effect on apoptotic changes of the vascular endothelium.. Twenty-four rabbits were divided into four groups. The first group was composed of sham-surgery animals. The second group was the subarachnoid hemorrhage (SAH) group, in which cerebral vasospasm was induced. In the third group, sham-surgery rabbits were treated with SC. In the fourth group, animals were treated with SC after SAH. SC was administered for 48 hours, 0.7 mg/kg, three times per day in Groups 3 and 4. Basilar artery lumen circumferences were measured in all groups by computerized image analysis. The terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling (TUNEL) method was used to evaluate the rate of apoptosis between SAH and SC-treated SAH groups. Results were compared by analysis of variance and paired t tests, and P values less than 0.05 were considered significant.. Basilar artery circumferences between groups were significantly different (P < 0.001). SC (0.7 mg/kg, three times per d) significantly dilated the basilar arteries in both the sham-surgery group (2370 +/- 233 microm; P = 0.039) and the SAH group (2142 +/- 195 microm; P = 0.006) after 48 hours of treatment. The TUNEL method for apoptosis revealed that actual numbers of the apoptotic endothelial cells per cross section after SAH in the control (no treatment) (73 +/- 2) and SC-treated (0.7 mg/kg) groups(76 +/- 3) were not significantly different (P > 0.05).. The vasodilatory effect of SC was observed to be significant on normal cerebral vessels and after SAH-induced vasospasm. SC did not prevent apoptosis of the endothelium in our study, which suggests that prevention of apoptosis is not necessary in the treatment of cerebral vasospasm.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Administration, Oral; Animals; Basilar Artery; Blood Flow Velocity; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dose-Response Relationship, Drug; Male; Phosphodiesterase Inhibitors; Piperazines; Purines; Rabbits; Sildenafil Citrate; Subarachnoid Hemorrhage; Sulfones; Treatment Outcome; Vasodilation; Vasodilator Agents; Vasospasm, Intracranial

Cyclic GMP (cGMP) mediates smooth muscle relaxation in the central nervous system. In subarachnoid hemorrhage (SAH), decreases in intrinsic nitric oxide (NO) cause cerebral vasospasms due to the regulation of cGMP formation by NO-mediated pathways. As phosphodiesterase type V (PDE V) selectively hydrolyzes cGMP, we hypothesized that PDE V may function in the initiation of vasospasm. This study sought to identify the altered PDE V expression and activity in the vasospastic artery in a canine SAH model. We also used this system to examine possible therapeutic strategies to prevent vasospasm. Using a canine model of SAH, we induced cerebral vasospasm in the basilar artery (BA). Following angiographic confirmation of vasospasm on day 7, PDE V expression was immunohistochemically identified in smooth muscle cells of the vasospastic BA but not in cells of a control artery. The isolation of PDE enzymes using a sepharose column confirmed increased PDE V activity in the vasospastic artery only through both inhibition studies, using the highly selective PDE V inhibitor, sildenafil citrate, and Western blotting. Preliminary in vivo experiment using an oral PDE V inhibitor at 0.83 mg kg(-1) demonstrated partial relaxation of the spastic BA. PDE V activity was increased from control levels within the BA seven days after SAH. PDE V expression was most prominent in smooth muscle cells following SAH. These results suggest that clinical administration of a PDE V inhibitor may be a useful therapeutic tool in the prevention of vasospasm following SAH.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Blotting, Western; Cerebral Angiography; Cerebral Arteries; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Disease Models, Animal; Dogs; Immunohistochemistry; Male; Myocytes, Smooth Muscle; Phosphodiesterase Inhibitors; Phosphoric Diester Hydrolases; Piperazines; Purines; Sildenafil Citrate; Subarachnoid Hemorrhage; Sulfones; Time Factors; Vasospasm, Intracranial