ACEI——阻断RAS系统的领跑者

自第一个肾素血管紧张素转化酶抑制剂（ACEI）问世以来,ACEI便以卓越的疗效活跃于降压药物的舞台,拥有大量的循证医学证据,其适应证也在不断扩展。即便在RAS系统抑制剂的其他成员的挑战下,其光环依旧,王者地位尚不可动摇。     

Catalepsy Induced by Manidipine,a Calcium Channel Blocker,in Mice

Manidipine, a calcium channel blocker, is a piperazine derivative similar to flunarizine or cinnarizine, which are known to induce parkinsonism. Since it has been reported that manidipine can worsen parkinsonian symptoms in a patient with Parkinson's disease, we have evaluated catalepsy in manidipinetreated mice and compared this with flunarizine-and haloperidol-induced catalepsy. The minimum dose at which manidipine induced catalepsy was 200 times higher than that of haloperidol whereas for flunarizine, the minimum dose was 50 times higher than that for haloperidol. Manidipine, flunarizine and haloperidol occupied both dopamine D₁ and D₂ receptors, and D₂-receptor occupancy was higher than D₁-receptor occupancy. These results suggest that the blockade of dopamine D₁ and D₂ receptors by drugs and the drug-induced catalepsy are related to the structure (piperazinyl substituent) of the drugs.     

尼卡地平治疗心绞痛

冠心病心绞痛７４例，其中４６例（男性３２例，女性１４例；年龄６５±ｓ８ａ）采用尼卡地平４０ｍｇ，ｐｏ，ｂｉｄ为治疗组；另２８例（男性１５例，女性１３例；年龄６２±９ａ）采用丹参舒心胶囊２粒，ｐｏ，ｔｉｄ为对照组。１２ｗｋ后，临床与心电图总有效率，治疗组依次为９１％和７２％，对照组为６８％和４３％，治疗组优于对照组（Ｐ均＜０．００１）。尼卡地平尚有减慢心率。降低血压及改善左室收缩功能等作用，不良反应轻微。     

In-vitro Negative Chronotropic and Inotropic Effects of a Novel Dihydropyridine Derivative,CD-832, in the Guinea-pig: Comparison with Calcium-channel Antagonists

The effects of CD-832 (4R-(-)-2-(nicotinoylamino)ethyl-3-nitroxypropyl-1,4-dihydro-2,6-dimethyl-4,3-nitrophenyl, 3,5-pyridine dicarboxylate), a novel dihydropyridine derivative, on guinea-pig isolated myocardial preparations have been compared with those of Ca²⁺-channel antagonists. All ten compounds induced concentration-dependent negative chronotropic effects on preparations of isolated right atria and negative inotropic effects on isolated right ventricular papillary muscles. The order of potency for the negative chronotropic effect was CD-832 > nicardipine = gallopamil > clentiazem > nifedipine = efonidipine > amlodipine = semotiadil > verapamil > diltiazem; that for the negative inotropic effect was nicardipine = gallopamil > nifedipine > verapamil > CD-832 > diltiazem > clentiazem > efonidipine = semotiadil > amlodipine. The ratio of the EC50 (the concentration of Ca²⁺ antagonist having 50% of the maximum effect) for the negative inotropic effect divided by the EC50 for the negative chronotropic effect, considered to be an index of selectivity for negative chronotropic effect, was higher for CD-832, amlodipine, efonidipine and semotiadil than for the other Ca²⁺ antagonists. The ratio for CD-832, nifedipine, nicardipine, efonidipine, amlodipine, verapamil, gallopamil, diltiazem, clentiazem and semotiadil was 11·4, 0·29, 0·87, 35·4, 37·1, 0·65, 0·87, 0·92, 7·11 and 30·0, respectively. These findings indicate that CD-832 and the newly developed Ca²⁺ antagonists including amlodipine, efonidipine, semotiadil and clentiazem were selective for a negative chronotropic effect rather than for a negative inotropic effect. This ‘chrono-selective’ effect of these drugs might be of benefit in the treatment of cardiovascular disorders.     

Nicardipine, a calcium antagonist, does not aggravate intracerebral haemorrhage in an intracerebral haemorrhage model in rats

Despite controversy over their safety in patients with intracerebral haemorrhage, calcium antagonists are widely used in the treatment of hypertensive emergencies. Here, we investigated the effects of nicardipine on haematoma size and neurological deficit in a rat model of collagenase-induced intracerebral haemorrhage. Injection of collagenase (0.014 U) into the striatum induced haematoma (19.9+/-3.4 mm(3)) in the striatum and brain oedema. Drugs were infused from 30 min after collagenase injection for 3 h under conscious conditions. Nicardipine intravenously at 0.1, 1 and 10 microg kg(-1) min(-1) affected neither haematoma size nor the degree of brain oedema. Nicardipine at these doses provided a stable and dose-dependent decrease in mean blood pressure of 6%, 13% and 33%, respectively, with an increase in heart rate that was apparently caused reflexively. Further, nicardipine did not aggravate the neurological deficits in these intracerebral haemorrhage rats, primarily forearm flexion behaviour on suspension by the tail and circling behaviour. These results indicate that nicardipine infusion stably decreased blood pressure without affecting intracerebral haemorrhage in an intracerebral haemorrhage model in rats.     

尼卡地平注射液治疗主动脉瓣返流

目的 :评价尼卡地平注射液对主动脉瓣返流的影响。方法 :主动脉瓣返流的病人 2 0例 [男性1 3例 ,女性 7例 ,年龄 (5 6±s 1 2 )a],应用尼卡地平注射液 2 0mg+氯化钠注射液 2 5 0mL ,iv,gtt,治疗前后进行彩色多普勒超声心动图检查 ,检测返流指标。结果 :在给病人静脉滴注尼卡地平注射液 1h后 ,主动脉瓣返流束的长度、宽度、面积、返流分数及返流频谱的下降斜率与治疗前比较均显著减小或降低 [(6.3± 0 .8)cmvs (2 .6± 0 .5 )cm ;(0 .80±0 .1 1 )cmvs(0 .40± 0 .1 4)cm ;(9.4± 0 .8)cm2 vs(4 .6± 0 .6)cm2 ;(0 .60± 0 .2 3 )vs (0 .40± 0 .1 2 ) ;(2 2 2± 2 0 )cm·s-2 vs (94± 5 )cm·s-2 ;均P <0 .0 1 ) ];主动脉瓣返流频谱的压差半降时间显著延长 [(2 41± 1 6)msvs (3 80± 1 8)ms,P <0 .0 1 ) ]。结论 :尼卡地平注射液可以明显减轻主动脉瓣返流的程度     

PhTx3-4, a Spider Toxin Calcium Channel Blocker,Reduces NMDA-Induced Injury of the Retina

The in vivo neuroprotective effect of PhTx3-4, a spider toxin N-P/Q calcium channel blocker, was studied in a rat model of NMDA-induced injury of the retina. NMDA (N-Methyl-d-Aspartate)-induced retinal injury in rats reduced the b-wave amplitude by 62% ± 3.6%, indicating the severity of the insult. PhTx3-4 treatment increased the amplitude of the b-wave, which was almost equivalent to the control retinas that were not submitted to injury. The PhTx3-4 functional protection of the retinas recorded on the ERG also was observed in the neuroprotection of retinal cells. NMDA-induced injury reduced live cells in the retina layers and the highest reduction, 84%, was in the ganglion cell layer. Notably, PhTx3-4 treatment caused a remarkable reduction of dead cells in the retina layers, and the highest neuroprotective effect was in the ganglion cells layer. NMDA-induced cytotoxicity of the retina increased the release of glutamate, reactive oxygen species (ROS) production and oxidative stress. PhTx3-4 treatment reduced glutamate release, ROS production and oxidative stress measured by malondialdehyde. Thus, we presented for the first time evidence of in vivo neuroprotection from NMDA-induced retinal injury by PhTx3-4 (-ctenitoxin-Pn3a), a spider toxin that blocks N-P/Q calcium channels.     

尼卡地平用于支撑喉镜手术的观察

目的 :评价尼卡地平用于支撑喉镜手术时预防应激反应的效果。方法 :30例择期行支撑喉镜术的患者 ,随机分为常规组 (C组 )和尼卡地平组 (N组 ) ,每组15例。C组常规麻醉用药 ;N组常规用药 +尼卡地平10μg/kg 静脉注射 ,继之1～2μg/(kg·min)静脉滴注 ,监测患者围术期血压 (BP)、心率 (HR )和血糖 (Glu)等。结果 :两组从插管时到拔管时各检测点MBP和HR均增加 ,但与基础值比较 ,C组有统计学意义 (P<0 05) ,N组无统计学意义 ;两组同时点比较 ,有显著性差异 (P<0 05) ;各时点血糖 ,C组较N组高 (P<0 05)。结论 :尼卡地平能有效地预防支撑喉镜术中心血管的应激反应 ,在支撑喉镜术中应用有积极的临床意义     

Synthesis and Biological Activity of Two New Calcium-channel Blockers,Mebudipine and Dibudipine

Dihydropyridine derivative calcium-channel blockers are widely used in the therapy of hypertension, angina pectoris and other cardiovascular diseases. Because the prototype of dihydropyridine derivatives, nifedipine, does not have the optimum pharmacokinetic and pharmacodynamic characteristics, attempts have been made to synthesize other drugs in this class with improved properties. The synthesis and biological activity of two new calcium-channel blockers, non-symmetrical (mebudipine) and symmetrical (dibudipine) analogues of nifedipine, is described herein. The pharmacological potencies of the compounds were evaluated by studying their effects on the contractions of isolated guinea-pig ileum and rat aortic rings. Results were compared with those obtained from nifedipine. The new analogues and nifedipine inhibited the contractile response of guinea-pig ileum to electrical stimulation and the pIC50 value of the compounds did not differ significantly from each other. The compounds also antagonized the contractile responses of K⁺-depolarized guinea-pig ileum to cumulative concentrations of calcium. The inhibitory effect of mebudipine was significantly higher than that of nifedipine whereas the inhibitory effects of dibudipine and nifedipine were not different. All three compounds relaxed KCl (40 mm )–treated isolated aortic rings; the pIC50 values for relaxation were: mebudipine > nifedipine > dibudipine. It is concluded that these new dihydropyridine derivatives are potent relaxants of vascular and ileal smooth muscles and therefore have high potential for use as antihypertensive and anti-anginal agents.     

The Role of Angiotensin Receptor Blocker and Calcium Channel Blocker Combination Therapy in Treating Hypertension

Hypertension remains a significant health problem, affecting approximately 30% of the US population. Of these, only 36.8% have BP controlled to recommended levels of <140/90mmHg for uncomplicated hypertension and <130/80 mmHg for patients with diabetes mellitus or renal disease. For those with uncontrolled hypertension, the risk of diabetes, renal disease, stroke, and cardiovascular disease is increased. Therapeutic options for the treatment of hypertension include several major classes of drugs: diuretics, ß-adrenoceptor antagonists (ß-blockers), ACE inhibitors, angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]), renin inhibitors, calcium channel blockers, and central sympatholytics, alone or in combination. Guidelines recommend thiazide diuretics as preferred first-line monotherapy. However, only 50% of patients will respond adequately to this therapy and the rest will require two or more antihypertensive agents to achieve BP goals. Clinical evidence demonstrates that some drugs have advantages when used in combination rather than as monotherapy. Drugs that block the renin-angiotensin-aldosterone system not only provide BP control but may also provide vascular protection and are metabolically neutral. This is a concise review of the safety and efficacy of ARBs in combination with amlodipine for the treatment of hypertension, with focus on the telmisartan-amlodipine combination. A MEDLINE search of the English literature from 2006 to 2009 of amlodipine in combination with ARBs revealed six publications, which are included in this review.     

Disposition of bemitradine,a Renal Vasodilator and Diuretic,in Man

1. ¹⁴C-Bemitradine (50 mg) was rapidly and efficiently absorbed (β89%) in man following a single oral dose, as a solution in gelatine capsules. Peak ¹⁴Clevels of 895 ± 154 ng equiv./ml (mean ± S.E.M.) were reached within 2h, and declined with half-lives of 1·07 ± 0·25 and 13·0± 5·6h.

2. No bemitradine was detected in plasma, but peak concn. (124±29ng/ml) of its desethyl metabolite were reached at 1·05±0·28h, and declined with a half-life of 1·32±0·08h.

3. Desethylbemitradine was rapidly metabolized to its ether glucuronide, a phenol and a dihydrodiol which were also present as glucuronide conjugates. The glucuronides were the major compounds in plasma from 2h after drug administration.

4. Excretion in 5 days amounted to 88·8±2·3% and 10·4±2·1% dose in urine and faeces respectively. No bemitradine or desethylbemitradine were excreted unchanged. 8-(2-Hydroxyethyl)-7-(3,4-dihydroxycyclohexa-l,5-dienyl)-l,2,4-triazolo-l,5c-pyrimidine-5-amine (E; 17% dose); 8-(2-hydroxyethyl)-7-(4-hydroxyphenyl)-l,2,4-triazolo-1.5c-pyrimidine-5-amine (F; 4% dose), their glucuronides (A, 19% dose and B, 6% dose respectively), desethylbemitradine glucuronide (D, 25% dose) and an unidentified metabolite (C, 12% dose) were excreted in urine. Compound F was the major faecal metabolite.     

l-Carnitine for the Treatment of a Calcium Channel Blocker and Metformin Poisoning

Introduction

The object of the current communication is to discuss the theory and the evidence for the use of l-carnitine in calcium channel blocker and metformin poisonings.

Case Report

A 68-year-old male known for hypertension and type II diabetes was admitted to the critical care unit of a community hospital following an overdose of amlodipine and metformin. The patient was intubated, ventilated, and hemodynamically supported with vasopressors. Despite calcium, glucagon, high-dose insulin (HDI), and lipid emulsion for calcium channel blocker and bicarbonate for metabolic acidosis, the patient remained hemodynamically unstable. The patient was considered too unstable to initiate continuous renal replacement therapy; and without access to extracorporeal life support, the administration of l-carnitine was administered as a last resort. One hour after l-carnitine, the norepinephrine requirements started to decrease, the patient began to improve and was subsequently extubated successfully without apparent sequelae in less than 4 days.

Discussion

l-Carnitine combined with HDI may have helped with the calcium channel blocker (CCB) poisoning by decreasing insulin resistance, promoting intracellular glucose transport, facilitating the metabolism of free fatty acids, and increasing calcium channel sensitivity. It may have also stimulated oxidative utilization of glucose instead of converting pyruvate into lactate and contributed to decrease lactate production with metformin poisoning.     

选择性α1受体阻滞剂盐酸阿夫唑嗪的合成

由香兰醛经12步反应合成选择性α     

Pharmacological Profile of U-37883A, a Channel Blocker of Smooth Muscle-Type ATP-Sensitive K Channels

U-37883A (PNU-37883A, guanidine; 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl hydrochloride) was originally developed as a potential diuretic with specific binding in kidney and vascular smooth muscle rather than in brain or pancreatic beta cells. U-37883A inhibits ATP-sensitive K(+) channels (K(ATP) channels) in vascular smooth muscle at submicromolar concentrations whilst even at high concentrations (> or =10 microM) it has no inhibitory effect at pancreatic, cardiac or skeletal K(ATP) channels. Thus, it is generally thought that U-37883A is a selective inhibitor of vascular smooth muscle K(ATP) channels. Approximately one decade ago, K(ATP) channels were cloned and found to consist of at least two subunits: an inwardly-rectifying K(+) channel six family (K(ir)6.x; K(ir)6.1 and K(ir)6.2) which forms the ion conducting pore and a modulatory sulphonylurea receptor (SUR.x; SUR1, SUR2A, and SUR2B) that accounts for several pharmacological properties. It is generally believed that different combinations of K(ir)6.x and SUR.x determine the molecular properties of K(ATP) channels. Thus, K(ir)6.2/SUR1 channel represents the pancreatic beta-cell K(ATP) channel, K(ir)6.2/SUR2A channel is thought to represent the cardiac K(ATP) channel, whereas K(ir)6.1/SUR2B channel is likely to represent the vascular smooth muscle K(ATP) channel. Recent molecular studies have shown that U-37883A selectively suppresses the activity of recombinant K(ATP) channels which contain K(ir)6.1 subunits in the channel pore unit. It was thus thought that U-37883A was a selective pharmacological tool which could be used to investigate the activity of vascular smooth muscle K(ATP) channels. However, due to its multiple pharmacological actions on several ion channels and poor tissue selectivity, U-37883A should not be viewed as a selective blocker of smooth muscle K(ATP) channels.     

Percutaneous Absorption of Nicardipine and Ketorolac in Rhesus Monkeys

Vehicle effects on the percutaneous absorption of nicardipine base, nicardipine hydrochloride, ketorolac acid, and ketorolac tromethamine were determined using the rhesus monkey as an in vivo model for human skin penetration. Vehicles investigated included blends of propylene glycol, trimethylene glycol, ethanol, Azone, Tween 20, water, and long-chain fatty acids. Formulations were prepared such that the compound dose, application area, and percentage saturation of the compound in the vehicle were held constant. Variations in absorption of the compounds were therefore attributable to vehicle effects. Each formulation was applied to three monkeys for a period of 24 hr using 10 Hill Top Chambers. Plasma samples were taken at appropriate intervals for 36 to 48 hr. The results indicated that trimethylene glycol and Tween 20 did not enhance absorption of the test compounds despite claims by other investigators. Azone and ethanol provided moderate enhancement of both the rate and the extent of absorption, while long-chain fatty acids in combination with propylene glycol significantly enhanced penetration. In general, higher fluxes were observed with the more lipophilic compounds nicardipine base and ketorolac acid as compared to the hydrochloride and tromethamine salts.     

Influence of Certain Calcium-channel Blockers on Some Aspects of Lorazepam-dependence in Mice

The effect of acute and chronic treatments of the calcium-channel blockers, isradipine, diltiazem and flunarizine in protecting against lorazepam dependence has been demonstrated in mice. Dependence was induced by twice-daily administration of lorazepam (1 mg kg^?1) for 10 days, doubling the dose during the next 10 days. Withdrawal symptoms and changes in the noradrenaline, dopamine and 5-hydroxytryptamine content of different regions of the brain were observed after either 24-h withdrawal or flumazenil administration. Isradipine inhibited lorazepam withdrawal symptoms, the effect being accompanied in the 24-h withdrawal group by significant decreases in the noradrenaline and dopamine content of the thalamus and hypothalamus and in the noradrenaline content of the mid-brain. In the flumazenil-treated group isradipine produced significant decreases in mid-brain noradrenaline and dopamine levels and in the dopamine content of the thalamus and hypothalamus. Diltiazem did not, on the other hand, afford significant protection against lorazepam withdrawal symptoms and did not induce any significant change in the neurotransmitters studied. Flunarizine significantly inhibited lorazepam withdrawal symptoms, an effect accompanied by significant reduction in noradrenaline and dopamine levels in the thalamus and hypothalamus. Dopamine was also significantly reduced in the cerebral cortex. Similar effects were produced in the flumazenil-treated group, and the noradrenaline content was reduced in the medulla, pons and cerebellum. It was concluded that isradipine and flunarizine might be of value in ameliorating lorazepam withdrawal symptoms.     

Semi-Mechanistic Pharmacodynamic Modeling for Degarelix, a Novel Gonadotropin Releasing Hormone (GnRH) Blocker

An integrated semi-mechanistic pharmacodynamic (PD) model describing the relationship between luteinizing hormone (LH) and testosterone (T) after short-term administration of degarelix was developed. Data from three clinical studies involving, intravenous (IV) and subcutaneous (SC) dosing, in healthy male subjects were available. Degarelix pharmacokinetic (PK) data from all studies were modeled simultaneously. One intravenous study was used to develop the PD model and the two other studies (IV and SC dosing) were used to qualify the model. Degarelix PK follows a two-compartment model and exhibits flip-flop kinetics after subcutaneous dosing. Based on physiological mechanism, the gonadotropin releasing hormone (GnRH) time course was described using a pulsatile release model. A precursor-dependent pool model was used to describe the kinetics of LH in the pituitary and plasma compartment. In males, LH regulates T production in leydig cells. Degarelix inhibits the release of LH from the pool compartment to the plasma compartment leading to decreased T production. The plasma half-life of LH (2.6–3.3 hr) and T (2.7 hr) match well with the literature reports. The proposed PD model reasonably described the time course of LH and T including the LH rebound for short-term studies. The model predicted the time course of LH and T for the second IV and SC dosing studies very well. However, the long term simulations from the final model did not match with literature reports. A modification is suggested based on the physiological understanding of the system. The proposed novel modification to precursor models can be of general use for predicting long term responses.The views expressed in this article are those of the authors and do not necessarily reflect the official views of FDA.