Meta-analysis of the risks of hypertension and QTc prolongation in patients with advanced non-small cell lung cancer who were receiving vandetanib.

BACKGROUND: A meta-analysis of published data was conducted to investigate the overall risks of hypertension and QTc prolongation in patients with advanced non-small cell lung cancer (NSCLC) who were receiving vandetanib. METHODS: A computerized search through electronic databases, including PubMed and Embase (until Dec 2014), was performed to obtain eligible randomized controlled trials (RCTs) that compared hypertension and/or QTc prolongation profile of vandetanib alone or plus chemotherapy with control groups (placebo, single targeted therapy, chemotherapy, or a combination of them) in patients with advanced NSCLC. The outcome measures were the overall risks of hypertension and QTc prolongation. Relative risk (RR) and 95% confidence interval (CI) were calculated and pooled using a random effects model. RESULTS: A total of nine RCTs, which involved 4813 patients, were enrolled in the present study. A significant increase in risk was observed for all-grade hypertension (RR 5.58; 95% CI 4.16 to 7.48; P < 0.00001) and grade ≥3 hypertension (RR 4.79; 95% CI 2.31 to 9.93; P < 0.0001) in advanced NSCLC patients who were receiving vandetanib compared with the controls. Moreover, vandetanib significantly prolonged all-grade QTc interval (RR 7.90; 95% CI 4.03 to 15.50; P < 0.00001) and grade ≥3 QTc interval (RR 3.12; 95% CI 1.01 to 9.63; P = 0.05). CONCLUSIONS: Current evidence showed that significant risks in developing hypertension and QTc prolongation exist in advanced NSCLC patients who were receiving vandetanib. Thus, appropriate monitoring and management of these events are recommended.

[Preliminary screening of nocturnal sleep breathing disturbance in patients with ischemic cerebral stroke].

OBJECTIVE: To investigate nocturnal sleep breathing disturbance in patients with ischemic cerebral stroke. METHODS: Forty-one patients with cerebral infarction undertook all-night screening of sleep breathing. The clinical features between cerebral infarction concomitant with mild and severe sleep breathing disturbance were compared, and the effects of different infarcted sites and sizes, the infarction history and symptoms on the breathing disorders were analyzed. RESULTS: The history of cerebral infarction was significantly shorter in patients with AHI greater than 20 (P < 0.01) whose breathing frequencies were also significantly lower (P = 0.043). Breathing disturbance was remarkably severe in patients with brainstem involvement (P = 0.045), with larger infarctions and with abnormalities of ingestion, pharyngeal reflex, speech, tongue thrust, consciousness, and motion coordination. CONCLUSIONS: Newer cerebral infarctions are commonly accompanied with relatively severe breathing disturbance. The occurrence of hypopnea would increase when brainstem is involved, and more severe breathing disturbance is associated with larger infarctions. The functioning abnormalities of tissues surrounding the upper airways resulted from infarctions are considered to be involved in the exacerbation of sleep disturbance.

[Effect of endothelin-1 on voltage-gated K+ current in the pulmonary artery smooth muscle cells of chronic hypoxic rats].

AIM: To investigate the effect of endothelin-1 (ET-1) on voltage-gated K+ current in the pulmonary artery smooth muscle cells (PASMCs) of chronic hypoxic rats. METHODS: Twelve male Wistar rats matched with age and body weight were randomly divided into control and chronic hypoxic groups. Single PASMCs were obtained with acute enzyme (collagnase plus papain) dispersing method. Using the whole cell patch clamp technique in freshly isolated PASMCs from normoxic and hypoxic rats, the effects of ET-1 on voltage-gated K+ current were recorded. RESULTS: The resting membrane potential (Em) in PASMCs from chronic hypoxic rats was significantly depolarized to (-32.6 +/- 1.3) mV compared with (-42.1 +/- 2.8) mV in PASMCs from normoxic rats (P < 0.01, n = 20). In chronic hypoxic rats, the IKv was smaller than that in normotensive rats [+50 mV, the peak current density of control group reduced from (136 +/- 24) pA/pF to (98 +/- 12) pA/pF, percent inhibition was (28.4 +/- 2.4)%, P < 0.01, n = 6]. Application of ET-1 (1 x 10(-8) mol x L(-1)) also depolarized PASMCs of chronic hypoxic rats from (-32.6 +/- 1.3) mV to (-21.5 +/- 1.7) mV (P < 0.05, n = 20) compared with the ET-1 induced depolarization from (-42.1 +/- 2.8) mV to (-22.6 +/- 1.4) mV (P < 0.05, n = 20). The change in membrane potential induced by ET-1 was not significantly different between PASMCs from normoxic and hypoxic rats. ET-1 (1 x 10(-10) to 1 x 10(-7) mol x L(-1)) caused concentration-dependent inhibition of K+ current in PASMCs both from normoxic and hypoxic rats. At higher concentration (1 x 10(-8) - 1 x 10(-7) mol x L(-1)), the effect of ET-1 on K+ current in PASMCs from hypoxic rats was greater than that of normoxic rats [+50 mV, the peak current density of control group reduced from (136 +/- 24) pA/pF to (40 +/- 10) pA/pF, percent inhibition was (71 +/- 7)%, that of hypoxic group was (98 +/- 6) pA/pF to (16 +/- 3) pA/pF, percent inhibition was (85 +/- 10)% at 1 x 10(-7) mol x L(-2), n = 6, P < 0.01]. CONCLUSION: Chronic hypoxia did not change the effect of ET-1 on the passive electrical properties of PASMCs. In both normotensive and chronic hypoxic hypertensive PASMCs, exogenous ET-1 could cause concentration-dependent inhibition of voltage-gated K+ current, and the inhibition of K+ current in PASMCs from chronic hypoxic rats was greater than that from normoxic rats at higher concentration (1 x 10(-8) - 1 x 10(-7) mol x L(-1)). Chronic hypoxia might alter the sensitivity of PASMCs to ET-1, perhaps PASMCs exposed to chronic hypoxia were more susceptible to ET-1 mediated IKv inhibition.

[Inhibition of voltage-gated K+ current in rat intrapulmonary arterial smooth muscle cells by endothelin-1].

AIM: To investigate the role of endothelin-1 (ET-1) in the physiological and pathophysiological regulating mechanisms of voltage-gated K+ current (IKV) inhibition in rat intrapulmonary arterial smooth muscle cells (PASMCs). METHODS: Single PASMCs were obtained with acute enzyme (collagnase plus papain) dispersing method. Using whole cell patch-clamp technique in freshly isolated rat PASMCs, the effect of ET-1 on voltage-gated K+ current was recorded. RESULTS: ET-1 (1 x 10(-9) mol.L-1) and the voltage-dependent K+ (KV)-channel antagonist 4-aminopyridine (4AP), but not the Ca(2+)-activated K(+)-channel antagonist tetraethylammonium (TEA), caused membrane depolarization. The effect of ET-1 on membrane potential persisted in cells in which intracellular Ca2+ was buffered with 1,2-bis (2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid (BAPTA). ET-1 (1 x 10(-9) mol.L-1) caused a significant reversible inhibition of KV current, which began 4.0 s after application of ET-1, was much earlier than the effect of membrane depolarization of PASMCs (15s). ET-1 (1 x 10(-10) to 1 x 10(-7) mol.L-1) caused a concentration-dependent inhibition of K+ current ( mV, from 136 to 40 pA/pF). The percent inhibition was 71% at 1 x 10(-7) mol.L-1 (n = 6). The effect of ET-1 (1 x 10(-9) mol.L-1) on K+ current was weaker under conditions free of Ca2+ than containing Ca2+. At a test potential of mV, free of Ca2+ conditions reduced the maximum inhibitory effect of ET-1 from 71% to 50%. CONCLUSION: ET-1 modulated pulmonary vascular reactivity by depolarizing membrane potential and inhibiting the K+ current of PASMCs. The effect of ET-1 on PASMCs membrane potential and the inhibition of K+ current were independent of Ca2+, but the inhibition of K+ current was much greater under conditions containing Ca2+ than free of Ca2+.