柳酚咖敏片含量及有关物质的UFLC测定

目的建立UFLC法测定柳酚咖敏片中盐酸去氧肾上腺素、对乙酰氨基酚、无水咖啡因、水杨酰胺和马来酸溴苯那敏的含量及有关物质。方法采用Kinetex C18色谱柱,以0.5%三乙胺溶液(磷酸调节pH至3.0)和甲醇为流动相,梯度洗脱,流速为1mL.min-1。结果盐酸去氧肾上腺素、马来酸溴苯那敏、咖啡因对乙酰氨基酚和水杨酰胺分别在0.10~10.33,0.05~4.82,0.04~4.10,0.30~30.50和0.30~30.44μg范围内线性关系良好。各组分平均回收率为99.7%~100.7%,RSD为0.24%~0.67%(n=9)。结论该方法简单、快速、准确,可用于柳酚咖敏片的含量及有关物质检测。     

Drug-excipient compatibility testing-Identification and characterization of degradation products of phenylephrine in several pharmaceutical formulations against the common cold

Different pharmaceutical preparations against the common cold containing phenylephrine (PHE) and saccharose were studied. New impurities were discovered in these preparations after exposure using isocratic ion-pair chromatography separation on a C18 column. LC-MS and NMR techniques were employed to identify and to fully characterize these new compounds. The products were identified as 1-[5-(hydroxymethyl)-2-furyl]-2-methyl-1,2,3,4-tetrahydroisochinolin-4,8-diol and 1-[5-(hydroxymethyl)-2-furyl]-2-methyl-1,2,3,4-tetrahydroisochinolin-4,6-diol. Identification of these degradation products allowed to understand and to confirm their formation mechanism. The developed HPLC method separates of all known impurities and impurities originated from PHE as well.     

小剂量去氧肾上腺素、甲氧明、麻黄素和输注羟乙基淀粉对腰硬联合麻醉剖宫产术中低血压的预防

目的比较预注小剂量去氧肾上腺素、甲氧明及麻黄素和输注羟乙基淀粉对腰-硬联合麻醉(CSEA)下产妇心血管系统的影响。方法 120例择期行剖宫产手术的产妇,随机分为4组,入手术室后先开放静脉,输注乳酸钠林格注射液200～300mL,行麻醉穿刺,在蛛网膜下腔注入0.5%布比卡因1.5mL后,产妇转为平卧位时,从静脉分别给予去氧肾上腺素10μg,甲氧明3mg,麻黄素6mg,羟乙基淀粉300mL,所有患者经上述处理后仍出现低血压时,给予麻黄素6～12mg;当心率低于60次/min时,给予阿托品0.5～1.0mg记录腰麻前、腰麻后(预注后)5、10、15min及手术结束后的血压、心率,比较两组间患者低血压、心动过缓的发生率,恶心呕吐的发生情况及麻黄素(不包括预注量)、阿托品用量,两组反应性高血压次数。结果甲氧明组低血压发生率稍高于麻黄素组,但差异无统计学意义(P>0.05)。与麻黄素组比较,甲氧明组心动过缓的发生率稍增多,但差异无统计学意义(P>0.05)。去氧肾上腺素组低血压发生率低于甲氧明组和麻黄素组,羟乙基淀粉组低于甲氧明组和麻黄素组,恶心呕吐发生率比较差异无统计学意义(P>0.05)。麻黄素用量(不包括预注量)差异无统计学意义(P>0.05)。结论去氧肾上腺素10μg,甲氧明3mg,或麻黄素6mg羟乙基淀粉术前输注均能有效地预防CSEA下产妇血压下降,并且对新生儿无不良影响。     

Changes in the subcellular distribution of NADPH oxidase subunit p47phox in dendrites of rat dorsomedial nucleus tractus solitarius neurons in response to chronic administration of hypertensive agents

NADPH oxidase-generated superoxide can modulate crucial intracellular signaling cascades in neurons of the nucleus tractus solitarius (NTS), a brain region that plays an important role in cardiovascular processes. Modulation of NTS signaling by superoxide may be linked to the subcellular location of the mobile NADPH oxidase p47(phox) subunit, which is known to be present in dendrites of NTS neurons. It is not known, however, if hypertension can produce changes in the trafficking of p47(phox) in defined NTS subregions, particularly the preferentially barosensitive dorsomedial NTS (dmNTS), or preferentially gastrointestinal medial NTS (mNTS). We used immunogold electron microscopy to determine if p47(phox) localization was differentially affected in dendritic profiles of neurons from these NTS subregions of the rat in response to distinct models of hypertension, namely chronic 7-day subcutaneous administration of angiotensin II (AngII), or phenylephrine. In small (<1 microm) dendritic processes, both AngII and phenylephrine produced a decrease in intracellular p47(phox) labeling selectively in dmNTS neurons. In intermediate-size (1-2 microm) dendritic profiles in the dmNTS region only, there was an increase in p47(phox) labeling in response to each hypertensive agent, although these changes occurred in different subcellular compartments. There was an increase in non-vesicular labeling in response to AngII, but an increase in surface labeling with phenylephrine. Moreover, each of the changes in p47(phox) targeting mentioned above occurred in dendritic profiles with, or without immunoperoxidase labeling for the AngII AT-1A receptor subtype (AT-1A). These results indicate that chronic administration of agents that induce hypertension can also produce changes in the subcellular localization in p47(phox) in dmNTS neurons. Thus, systemic hypertension may produce alterations in the trafficking of proteins associated with superoxide production in central autonomic neurons, thus revealing a potentially important neurogenic component of free radical production and systemic blood pressure elevation.     

Vasomodulation of Tumor Blood Flow: Effect on Perfusion and Thermal Ablation Size

Blood flow is a key factor in the efficacy of radiofrequency (RF) ablation treatment of solid tumors. We hypothesized that vasoactive drugs can modulate tumor blood flow and thereby improve the outcome of this thermal ablation approach. To verify this hypothesis, we measured the tumor perfusion changes in response to phenylephrine (PE) and hydralazine (HYZ) using a CT perfusion method in a rat subcutaneous tumor model. The coagulation sizes induced by RF ablation alone, RF ablation with PE and RF ablation with HYZ were compared. Results demonstrated that HYZ produced a marked decrease in entire tumor and tumor rim blood flow of 31.1 and 29.1%; while PE insignificantly change tumor blood flow (5.1% decrease in whole tumor and 6.0% decrease in tumor rim). A markedly greater coagulation area (0.59 cm² ± 0.24) was observed when HYZ was administered before RF ablation. No difference was noted in the coagulation area induced by RF ablation alone or the combination of PE injection followed by RF ablation (0.29 cm² ± 0.13 vs. 0.30 cm² ± 0.18). Results suggest that HYZ decreases subcutaneous tumor blood flow and enhances the coagulation size induced by RF ablation. PE has little influence on tumor blood flow and does not improve ablation.     

Towards safer treatments for benign anorectal disease: the pharmacological manipulation of the internal anal sphincter

INTRODUCTION

The internal anal sphincter (IAS) is an important structure that is responsible for the majority of resting tone of the sphincter complex. It has a central role in continence and damage to the muscle has serious implications. Injury is most frequently from obstetric trauma though iatrogenic injury from proctological surgery is also common. This review expands on how developments in understanding of the pharmacology of IAS might identify drug treatments as alternatives for proctological conditions such as anal fissure, avoiding the risk of sphincter injury. It also examines the role of pharmacology in treatment of those patients with established incontinence.

RESULTS

Much of the basic physiology and pharmacology of the IAS has been established through in vitro analysis, particularly in the superfusion organ bath. Further analysis has been undertaken using animal models such the pig. Clinical trials have established the efficacy of a number of agents for reducing IAS tone including glyceryl trinitrate and botulinum toxin. These drugs are probably safer, but less effective, than surgery for sphincter spasm, as is seen in anal fissure, though surgery alone or in combination with drug treatment may be appropriate for some patients. In vitro analysis and small-scale clinical trials suggest that phenylephrine and methoxamine may have a role in treating patients with incontinence primarily attributable to inadequate IAS function.

CONCLUSIONS

The pharmacology of IAS has been extensively studied in the laboratory, both in vitro and in animal models. In a short time, this laboratory work has been applied to clinical problems after testing in clinical trials. It is likely, however, that the best drugs and the optimal targets for manipulation have not yet been identified.     

Modulation of the cardiac baroreflex following reversible blockade of the parabrachial nucleus in the rat

The parabrachial nucleus (PBN) has a prominent anatomical connection with the nucleus of the solitary tract as well as other central baroreflex centres which suggests a role for the PBN in the regulation of this cardiovascular reflex. This study examined the effects of a reversible, bilateral blockade of the PBN on the cardiac baroreflex. Male Sprague-Dawley rats were anesthetized with sodium butabarbitol and instrumented to monitor blood pressure and heart rate and for the intravenous administration of drugs. The cardiac baroreflex was evoked using bolus intravenous injections of phenylephrine (PE) and sodium nitroprusside (NaNp) at various doses and a graph of baroreflex sensitivity was constructed. Bilateral microinjections of the reversible anesthetic, lidocaine (5%, 300 nl), into the PBN did not significantly change baseline blood pressure or heart rate when compared to microinjections of saline (0.9%, 300 nl) into the PBN. The pressor or depressor responses evoked by bolus injections of PE or NaNp, respectively, were not significantly affected by the bilateral pretreatment of the PBN with lidocaine when compared to saline controls. However, approximately 30 min following lidocaine injection, the amplitudes of both the evoked-reflex bradycardia and reflex tachycardia were significantly increased by approximately 98%. The cardiovascular responses to various doses of PE and NaNp were graphed and baroreflex sensitivity curves were constructed. This graph showed an increased slope of the baroreflex sensitivity curve following lesions of the PBN. Reflex changes in heart rate returned to pre-lidocaine injection levels after approximately 2 h. The results of the present investigation suggest that the PBN participates in the modulation of the cardiac baroreflex which in turn suggests a role for this nucleus in the central integration of cardiovascular reflex function.     

短时间诱导高血压对急性脑缺血再灌注大鼠梗死体积的影响

目的探讨在不同缺血时间诱导高血压对急性局部脑缺血再灌注大鼠梗死体积的影响。方法61只年龄30～40周的SD大鼠,随机分为假手术组、缺血组、缺血再灌注组和升压组。通过静脉滴注新福林对升压组动物进行诱导高血压治疗。结果(1)缺血再灌注组的梗死体积大于相应的缺血组。(2)升压组的梗死体积小于缺血再灌注组和缺血4h组。(3)在缺血4h再灌注2h升压组中,再灌注前15min升压组的梗死体积小于再灌注后30min升压组。结论(1)诱导高血压治疗能有效地减少急性脑缺血再灌注大鼠梗死体积。(2)再灌注前升压疗效优于再灌注后升压。     

Adrenergic receptor systems and unscheduled DNA synthesis in the rat brain

Two experiments were carried out in the albino rat to investigate the role of brain adrenergic systems in DNA remodeling. Adult maw Sprague-Dawley rats were given an intraventricular micreoinjection of an adronergic drug or vehicle followed 2 h later by the intraventricular injection of 50 μCi of [³H-methyl]tinymkline. The rats were sacrificed 0.5 h after the injection of the radioactive tracer. The rate of DNA synthesis was determined by measuring the amount of radioactive precursor incorporated into the DNA extracted from homogenates of several brain areas. In Experiment 1, at time 0 rats received the alpha-adrenergic antagonist phentolamine (5 μg), the beta antagonist propranolol (10 μg), the alpha agonist phenylephrine (1 μg), the beta agonist isoproterenol (12.5 μg), or the vehicle. The latter decreased UBDS in neocortex, and increased it in the septum, neostriaturn, hypothalamus, cerebellum, and rest of the brain. The alpha and beta agonists and antagonists induced several significant effects, depending on the brain region. In Experiment 2, rats were bilateraly lesioned in the dorsal noradrenergic bundle (DNB) by injection or 8-hydroxydopamine or were sham lesioned. One week later, at time 0 they were given the alpha agonist phenylephrine (1 μg), the beta agonist isoproterenol (12.5 μg), or the vehicle. The DNB-lesionsd rats showed a higher UBDS in the hippocampus, neocortex, and hypothalamus, which was reversed by the alpha or time beta agonist The results suggest an influence of the DNB, probably as a tonic Inhibitor of UBDS in time hippocampus and the hypothalamus which, in turn, are likely to be mediated by beta- and alpha-adrenergic receptors. In addition, a phasic inhibitory effect seems to be mediated by beta and alpha receptors in the neocortex, and by beta receptors in the cerebellum. A modulatory role of central adrenergic systems on unscheduled brain DNA synthesis may be inferred from these findings.     

Ocular absorption and disposition of phenylephrine and phenylephrine oxazolidine

The ocular bioavailability of phenylephrine oxazolidine (PO), a prodrug intended for rapid corneal penetration, was micronized and suspended in sesame oil (1 and 10 per cent) and compared in bioavailability to phenylephrine HC1 (PE) dissolved (10 per cent) in a buffered (pH 5.75), viscous (30 centipoise) vehicle. Cornea and aqueous humor of New Zealand rabbits were measured over time following 10 microliter instillation to the eye. Based upon AUC measurements, corneal and aqueous humor levels were approximately 6 and 8 times greater for 10 per cent PO versus 10 per cent PE, respectively. In addition, the ocular pharmacokinetic values were determined for PE applied in a constant concentration (1 per cent) to the cornea over 180 min to anesthetized rabbits. Cornea and aqueous humor were measured for drug content over time. Using moment analysis and an initial slope method, the absorption rate constant, ka, the steady state volume of distribution in the eye, Vss, and ocular clearance, Qe, were calculated. Values obtained for PE were 4.15 x 10(-5) min-1, 0.423 ml and 14.6 microliter min-1, respectively. The half-life for drug elimination ranged from 63-83 min depending on the tissue or route of administration.