星状神经节阻滞对心率变异性影响的实验研究

目的：探讨在家兔清醒状态下,以第7颈椎横突为标志,经皮行星状神经节阻滞的可行性和有效性．及其对心率变异性的影响。方法：健康新西兰大耳白兔16只被随机均分为左侧星状神经节阻滞组（LSGB组）、右侧星状神经节阻滞组（RSGB组）。白兔均在清醒状态下四肢固定,仰卧于动物手术台,胸前及四肢连接十二导动态心电图分析系统,稳定30min后,以第七颈椎横突为骨性标志,垂直进针,给予0．5％布比卡因1ml,行星状神经节阻滞。观察眼睑下垂程度、耳廓温度、心率变异性指标[24h正常RR间期标准差（SDNN）、低频功能（LF）、高频功能（HF）、LF／HF]。另取9只家兔同法向星状神经节处推注亚甲蓝溶液后暴露星状神经节,以其是否蓝染判断注射阻滞部位的精确程度。结果：两组动物均完成星状神经节阻滞操作,术后即刻及饲养1周均未发现并发症。阻滞10min后两组动物阻滞侧均出现上睑下垂和眼裂变小。与对侧及阻滞前相比．阻滞侧耳廓温度明显升高（P〈0．05）。两组动物阻滞前后心率无明显差异,LSGB组,阻滞前、后SDNN、LF、HF、LF/HF无显著差异。RSGB组．LF和HF值在阻滞后较阻滞前显著减小（P〈0．05）．但LF／HF、SDNN无明显改变。9只家兔行亚甲蓝注射后．解剖发现8只星状神经节被染色,精确程度为88．9％（8／9）。结论：以第7颈椎横突为标志,经皮行星状神经节阻滞建立动物模型的方法切实可行,眼睑、眼裂及耳廓温度是较好的阻滞成功判断指标。星状神经节阻滞对自主神经功能有调节作用,可能就是其阻滞治疗各种疾病的作用机制之一。     

Stability-Indicating RP-HPLC Method for the Simultaneous Determination of Prazosin, Terazosin, and Doxazosin in Pharmaceutical Formulations

The current study was carried out with an attempt to separate similarly structured title drugs by liquid chromatography. Spectrophotometric techniques were generally insufficient under these conditions because of the spectral overlapping of drugs with similar functional groups. The pharmaceutical drugs prazosin, terazosin, and doxazosin contain the same parent quinazoline nucleus, thus making it especially difficult to separate the former two drugs because of their very similar structures. A simple and sensitive method for the routine determination of these drugs in pharmaceutical formulations was attempted. We found that the mobile phase consisting of A: ACN–diethylamine (0.05 ml), B: methanol, and C: 10 mM Ammonium acetate separated these drugs effectively. Separations were carried out on a new Kromasil C18 column (250 × 4.6 mm, 5.0 μm) at 254 nm wavelength. The calibration curve was found to be linear in the range of 2–500 μg/ml. The stated method was then validated in terms of specificity, linearity, precision, and accuracy. Additionally, the proposed method reduced the duration of the analysis.     

Poor effectiveness of proton pump inhibitors in non‐erosive reflux disease: the truth in the end!

Despite acid secretion being normal in the majority of patients with gastro‐esophageal reflux disease (GERD) or Barrett’s esophagus, acid inhibition represents the mainstay of treatment for both these conditions, with the aim of reducing the aggressive nature of the refluxate toward the esophageal mucosa. Proton pump inhibitors (PPIs) represent, therefore, the first choice medical treatment for GERD, in that they are able to provide an 80–85% healing rate for esophageal lesions, a 56–76% symptom relief and also reduce the incidence of complications, such as strictures as well as dysplasia and adenocarcinoma in Barrett’s esophagus. According to a widely quoted systematic review, compared to patients with erosive esophagitis, patients with non‐erosive reflux disease (i.e., NERD) display a reduced symptom relief with PPIs, with about 20% reduction of therapeutic gain. In this issue of NeuroGastroenterology & Motility, Weijenborg et al. address for the first time the PPI efficacy in subpopulations of patients with NERD. The study shows clearly that, when the diagnosis is accurately made by including a functional test, NERD patients respond to PPI therapy in a similar way to those with erosive disease. Although not as frequent as previously suggested, however, PPI‐refractory heartburn does exist. Some 20% (range: 15–27%) of correctly diagnosed and appropriately treated patients do not respond to PPI treatment at standard doses. Although the pathophysiology underlying PPI failure in GERD is complex and likely multifactorial, acid (be it the sole component of refluxate or not) still remains a major causative factor. A better and more predictable form of acid suppression should therefore be pursued.     

Insulin Resistance and Cardiovascular Drugs

Under certain circumstances the effect of insulin to promote glucose uptake in peripheral tissues is reduced because of a resistance to insulin action. This insulin resistance and the resulting hyperinsulinaemia are now recognised as common background factors that may be responsible for hypertension, hyperlipidaemia, decreased thrombolysis and also impaired glucose tolerance and diabetes. Hyperinsulinaemia has also been identified as an independent risk factor for coronary heart disease and promotes smooth muscle cell growth and plaque formation.

A series of studies have now demonstrated that treatment with selective beta-blockers as well as thiazide diuretics impair insulin sensitivity by 15–30% and causes a compensatory increase in insulin concentrations. Furthermore, lipoprotein concentrations are affected in an unfavourable way. This is in contrast to the drugs belonging to ACE-inhibitors, calcium-channel blockers and α₁-blocker classes that are either neutral or may have the opposite effects in these respects.     

Of Steeplejacks and Bureaucrats

Readers are invited to submit questions relating to problem cases. Inquiries will be answered by qualified consultants and replies forwarded by mail promptly. Selected problems and solutions are published every month in this section.     

Hypertrophic cardiomyopathy in childhood and adolescence – strategies to prevent sudden death

Clinically overt hypertrophic cardiomyopathy is the most common cause of sudden unexpected death in childhood and has significantly higher sudden death mortality in the 8‐ to 16‐year age range than in the 17‐ to 30‐year age range. A combination of electrocardiographic risk factors (a limb‐lead ECG voltage sum >10 mV) and/or a septal wall thickness >190% of upper limit of normal for age (z‐score > 3.72) defines a paediatric high‐risk patient with great sensitivity. Syncope, blunted blood pressure response to exercise, non‐sustained ventricular tachycardia and a malignant family history are additional risk factors. Of the medical treatments used, only beta‐blocker therapy with lipophilic beta‐blockers (i.e. propranolol, metoprolol or bisoprolol) have been shown to significantly reduce risk of sudden death, with doses ≥6 mg/kg BW in propranolol equivalents giving around a tenfold reduction in risk. Disopyramide therapy is a very useful adjunct to beta‐blockers to improve prognosis in those patients that have dynamic outflow obstruction in spite of large doses of beta‐blocker, and its use in patients with hypertrophic cardiomyopathy is not associated with significant pro‐arrhythmia mortality. Calcium‐channel blockers increase the risk of heart failure‐associated death in hypertrophic cardiomyopathy (HCM) patients with severe generalized hypertrophy and should be avoided in such patients. Amiodarone does not protect against sudden death, and long‐term use in children usually has to be terminated because of side effects. Therapy with internal cardioverter defibrillator implantation has high paediatric morbidity, 27% incidence of inappropriate shocks, and does not absolutely protect against mortality but is indicated as secondary prevention or in very high‐risk patients.     

Ongoing clinical trials in systemic hypertension

Hypertension was identified as a cardiovascular risk factor in the late fifties and still remains a public health issue. The number of patients treated reaches only half of those diagnosed and, of those treated, half fail to reach target blood pressure. Furthermore, the number of antihypertensive drugs reaching the market has increased exponentially in the last few years, however, the impact on treatment and on attaining target blood pressure levels remains to be seen. The high percentage of treated patients who do not reach target blood pressure, combined with the high number of patients requiring more than one antihypertensive drug, have triggered a series of long-term morbidity and mortality trials comparing different therapeutic approaches (‘new’ pharmacological classes vs. ‘old’ pharmacological classes). These are described in this paper.     

Mortality Amongst Patients of the Glasgow Blood Pressure Clinic was High in the 1970s and 80s but has Fallen Since,Why?

Established in 1968 the Glasgow Blood Pressure Clinic has over 11,000 patients on its computer record. Up to 1980, mortality from all-causes and from cardiovascular causes was high: relative risks compared with two local control populations were greater than 2.0. Since 1980, all-cause mortality has decreased to 1.31 (859 deaths, CI 1.23–1.39). Lower mortality from cardiovascular causes, particularly coronary heart disease, contributes to the decrease. Reasons for the decrease are under investigation currently. Referral of patients with slightly lower blood pressure contributes, as may better blood pressure control with newer antihypertensive drugs. ACE inhibitors and calcium channel blockers were introduced in 1980 and during the 16-year period to 1995, all-cause mortality has decreased most in patients taking ACE inhibitor. A decrease also occurred in patients taking antihypertensive drugs other than ACE inhibitor.     

Nitrosamine Contamination in Pharmaceuticals: Threat,Impact, and Control

Nitrosamine-contaminated medicinal products have raised safety concerns towards the use of various drugs, not only valsartan and all tetrazole-containing angiotensin II receptor blockers, but also ranitidine, metformin, and other medicines, many of which have been recalled and prone to shortage. At any stages, from drug substance synthesis throughout each product's lifetime, these impurities may evolve if an amine reacts with a nitrosating agent coexisting under appropriate conditions. Consequently, drug regulatory authorities worldwide have established stringent guidelines on nitrosamine contamination for all drug products in the market. This review encompasses various critical elements contributing to successful control measures against current and upcoming nitrosamine issues, ranging from accumulated knowledge of their toxicity concerns and potential root causes, precise risk evaluation, as well as suitable analytical techniques with sufficient sensitivity for impurity determination. With all these tools equipped, the impact of nitrosamine contamination in pharmaceuticals should be mitigated. An evaluation aid to tackle challenges in risk identification, as well as suitable industry-friendly analytical techniques to determine nitrosamines and other mutagenic impurities, are among unmet needs that will significantly simplify the risk assessment process.