Inhaled therapy for the management of perioperative pulmonary hypertension.

Patients with pulmonary hypertension (PH) are at high risk for complications in the perioperative setting and often receive vasodilators to control elevated pulmonary artery pressure (PAP). Administration of vasodilators via inhalation is an effective strategy for reducing PAP while avoiding systemic side effects, chiefly hypotension. The prototypical inhaled pulmonary‑specific vasodilator, nitric oxide (NO), has a proven track record but is expensive and cumbersome to implement. Alternatives to NO, including prostanoids (such as epoprostenol, iloprost, and treprostinil), NO‑donating drugs (sodium nitroprusside, nitroglycerin, and nitrite), and phosphodiesterase inhibitors (milrinone, sildenafil) may be given via inhalation for the purpose of treating elevated PAP. This review will focus on the perioperative therapy of PH using inhaled vasodilators.

Assessment of ocular surface toxicity after topical instillation of nitric oxide donors / Avaliação da toxicidade na superfície ocular após instilação tópica de doadores de óxido nítrico

PURPOSE: To evaluate the ocular surface toxicity of two nitric oxide donors in ex vivo and in vivo animal models: S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylcysteine (SNAC) in a hydroxypropyl methylcellulose (HPMC) matrix at final concentrations 1.0 and 10.0 mM. METHODS: Ex vivo GSNO and SNAC toxicities were clinically and histologically analyzed using freshly excised pig eyeballs. In vivo experiments were performed with 20 albino rabbits which were randomized into 4 groups (5 animals each): Groups 1 and 2 received instillations of 150 µL of aqueous HPMC solution containing GSNO 1.0 and 10.0 mM, respectively, in one of the eyes; Groups 3 and 4 received instillations of 150 µL of aqueous HPMC solution-containing SNAC 1.0 and 10.0 mM, respectively, in one of the eyes. The contralateral eyes in each group received aqueous HPMC as a control. All animals underwent clinical evaluation on a slit lamp and the eyes were scored according to a modified Draize eye test and were histologically analyzed. RESULTS: Pig eyeballs showed no signs of perforation, erosion, corneal opacity or other gross damage. These findings were confirmed by histological analysis. There was no difference between control and treated rabbit eyes according to the Draize eye test score in all groups (p>0.05). All formulations showed a mean score under 1 and were classified as "non-irritating". There was no evidence of tissue toxicity in the histological analysis in all animals. CONCLUSION: Aqueous HPMC solutions containing GSNO and SNAC at concentrations up to 10.0 mM do not induce ocular irritation.

OBJETIVO: Avaliar a toxidade na superfície ocular de dois compostos doadores de óxido nítrico em modelos ex vivo e in vivo: S-nitrosoglutationa (GSNO) e S-nitroso-N-acetilcisteína (SNAC), em uma matriz de hidroxipropil metilcelulose (HPMC) nas concentrações finais de 1,0 and 10,0 mM. MÉTODOS: As toxicidades de GSNO e SNAC foram avaliadas clinicamente e histologicamente em modelo ex vivo usando globos oculares porcinos recém excisados. Experimentos in vivo foram realizados com 20 coelhos albinos que foram randomizados em 4 grupos (5 animais em cada): Os grupos 1 e 2 receberam instilações de 150 µL de solução aquosa de HPMC contendo GSNO 1,0 e 10,0 mM, respectivamente, em um dos olhos; Os grupos 3 e 4 receberam instilações de 150 µL de solução aquosa de HPMC contendo SNAC 1,0 and 10,0 mM, respectivamente, em um dos olhos. Os olhos contralaterias em cada grupo receberam solução aquosa de HPMC como controle. Todos os animais foram clinicamente avaliados em lâmpada de fenda e os olhos foram pontuados de acordo com o teste de Draize modificado e analisados histologicamente. RESULTADOS: Os globos oculares porcinos não apresentaram sinais de perfuração, erosão, opacidade da córnea ou outros danos graves. Esses resultados foram confirmados pela análise histológica. Não houve diferença entre os olhos dos coelhos tratados e controles de acordo com a pontuação do teste de Draize em todos os grupos (p>0,05). Todas as formulações apresentaram um escore médio menor do que 1 e foram classificadas como "não-irritantes". Não houve evidência de toxicidade tecidual nas análises histológicas em todos os animais. CONCLUSÃO: Soluções aquosas de HPMC contendo GSNO e SNAC em concentrações até 10,0 mM não induzem irritação ocular.

Effectiveness of oral route isosorbide 5-mononitrate on peritoneal solute and fluid transports in CAPD patients.

BACKGROUND: Addition of sodium nitroprusside (NaNTP), a nitric oxide (NO) donor to peritoneal solution could enlarge the effective peritoneal surface area and the peritoneal pore size. This would be leading to increased clearance of all solutes. Generalized clinical usage of NaNTP in CAPD patients however is not practical because it has a very short half-life and needs a specific route of administration. Organic nitrate, another NO donor, has a longer half-life and could be more easily absorbed via many routes. OBJECTIVE: The present study was conducted to determine the effect and mechanism of oral active nitrate (isosorbide 5-mononitrate: ISMN) on solute andfluid transports in stable CAPD patients. MATERIAL AND METHOD: A prospective randomized placebo control with a crossover study was performed in nine stable CAPD patients. In group I (n = 4), the treatment included 1) oral ISMN at the dose of 20 mg bid for 5 days 2) wash out period for 7 days, and 3) placebo for 5 days. In group 2 (n = 5), the treatment regimens were placebo, wash out, and ISMN periods. RESULTS: The MTACs of low molecular weight (LMW) solutes in the ISMN period were greater than the placebo period: median urea, 16.7 vs 13.8 ml/min; creatinine (Cr), 7.9 vs 6.9 ml/min; and urate, 6.1 vs 5.5 ml/min (p < 0.05 for all except MTAC of urea). Administration of ISMN could also enhance the clearances of high molecular weight (HMW) solute with a magnitude of increase as follows: 10% for beta2-microglobulin, 50% for albumin, and 15% for immunoglobulin G (p < 0.05 for all). However, the values of restrictive coefficient of LMW as well as HMW solutes of both groups were not different, indicating that the increased solute transports are not due to alteration in the peritoneal membrane permeability. Despite the increased peritoneal solute clearance, net ultrafiltration (UF) was unchanged after drug administration, 110 (ISMN group) vs 120 ml (placebo group), (NS). CONCLUSION: ISMN has a similar effect as NaNTP in enhancing peritoneal clearances of both LMW and HMW solutes. The effect of ISMN, however, is mediated only via expansion of peritoneal surface area without significant change in pore size. As such, administration of oral ISMN to stable CAPD patients would be practically beneficial in enhancing the achievement of target solute clearances suggested by NKF- DOQI Guidelines.

Clinical efficacy of 0.2% glyceryl trinitrate ointment for anal fissures

To validate the clinical efficacy of 0.2% glyceryl trinitrate ointment, a nitric oxide donor, in the management of anal fissures. A prospective clinical study conducted on consecutive patients with anal fissures presented to the surgical clinic of Jinnah Hospital and Allama Iqbal Medical College Complex Lahore. These patients were treated with topical 0.2% glyceryl trinitrate paste in soft white paraffin three times a day. Patients were examined at regular intervals to evaluate the fissure status, adverse reactions, symptomatic control and recurrence. All subjects were followed-up until they were pronounced cured or treatment terminated. 121 patients comprised this study group. 6 cases were lost to follow-up and 109 [94.7%] of the remaining 115 subjects were cured. Of those cured, 13 [11.3%] presented with acute and 102 [88.7%] chronic fissures. There were 98 male and 17 female patients with median age of 41 years [range, 14-70 years]. Complete symptomatic relief w as achieved in all patients within one month of therapy. Treatment had to be terminated in 6 [5.2%] patients: 5 [4.3%] experienced intolerable adverse effects and 1 [0.8%] patient failed to respond. All these cases were successfully treated with lateral internal sphincterotomy. There was no change of continence in this series. Glyceryl trinitrate ointment produces healing of the anal fissures and adequate symptomatic relief and should be considered as the first line treatment for anal fissures

Intraventricular sodium nitroprusside therapy: a future promise for refractory subarachnoid hemorrhage-induced vasospasm.

A prospective study was carried out to evaluate the efficacy of intraventricular sodium nitroprousside (SNP) in the reversal of refractory vasospasm secondary to aneurysmal subarachnoid hemorrhage (SAH). Ten patients of aneurysmal SAH with symptomatic vasospasm, corroborated on Transcranial Doppler (TCD) and/or angiography, were included in the study. The mean age distribution of the patients was 50.8 years (range 33-65 years) with an equal number of males and females. Once vasospasm was refractory even after 12 hours of SAH therapy, intraventricular SNP was instilled in an escalating dose and the reversal of vasospasm was monitored on TCD and/or angiography. All patients showed improvement in TCD velocity on day 0 through day 3. Partial to complete reversal of vasospasm was demonstrated on angiography in all the patients, though not in all the vessels. Two patients who had weakness of limbs due to vasospasm improved following intraventricular SNP therapy. Vomiting was the commonest adverse effect (7/10). Three patients had mild fluctuation in blood pressure. The overall outcome was good in 6 out of 10 patients. The study suggests that intraventricular SNP therapy is effective in reversing the changes even in established cases of SAH-induced vasospasm.

Role of nitric oxide on insulin induced seizures in mice.

The role of nitric oxide (NO) on acute hypoglycemia-induced seizures in mice was investigated using insulin as the hypoglycemic agent. The NO precursor L-arginine in the doses of 150, 500 and 750 mg/kg exhibited a dose-dependent protective effect against seizures induced by 8 mu/kg insulin. The NO synthase inhibitor (L-NMMA) at the doses of 50 and 100 mg/kg potentiated the subconvulsive doses of insulin (2 mu/kg). The onset, duration, number of seizures and the mortality were noted in a 2 hr study period. The results of this study suggest than NO plays an important protective role in acute hypoglycemia induced seizures which are known to occur through the activation of NMDA receptors.