Calcium Channel Blockers Research Papers (original) (raw)

Atrial fibrillation (AF) is the most common cardiac arrhythmia requiring medical therapy, and present treatment modalities are inadequate. Over the past few years, we have learned a great deal about the phenomenon of electrical remodeling, by which rapid atrial activation leads to changes in atrial electrical properties that promote AF initiation and maintenance. This knowledge opens up the possibility that electrical remodeling may itself be a novel therapeutic target in AF. The present paper reviews what is known about the basic mechanisms of atrial electrical remodeling and then discusses the experimental and clinical evidence that remodeling can be prevented by drug therapy. Despite great potential value, the development of pharmacological interventions to prevent atrial electrical remodeling is still in its infancy.

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- Biomedical Engineering, Electrophysiology, Antioxidants, Atrial Fibrillation

C YCLOSPORINE (Cs) is the main immunosuppressive drug used in organ transplantation. However, its use often produces arterial hypertension and nephrotoxicity. 1,2 Diltiazem (DTZ), a calcium channel blocker (CCB) of the benzothiapene class, minimizes these side effects. 3 Cs decreases the renal blood flow and, consequently, the glomerular filtration rate, and DTZ counteracts this effect protecting the renal function. 4 Moreover, DTZ has antihypertensive and anti-atherogenic properties. 1 Additionally, DTZ has an inhibitory effect on the Cs metabolism by hepatic cytochrome P450 enzymes increasing Cs blood levels, which allows a reduction in the Cs dose ranging from 20% to 50%. A lower incidence of graft rejection has been reported with the association of CCB and Cs in renal and cardiac transplantation. 3,5 There are, however, no known studies on that effect in liver transplantation (LTx).

- by S. Mies
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- Adolescent, Child, Liver Transplantation, Cyclosporine

The present study aimed to produce verapamil hydrochloride-loaded solid lipid microparticles (SLM) by the w/o/w emulsion solvent evaporation technique, using diethyl ether as solvent phase, glyceryl monostearate as biodegradable polymer and Span 60 as surfactant. SLM of spherical shape were prepared by simple dilution of the emulsion with water. To increase the lipid load the process was conducted at 50 degrees C, and in order to reach sub-micron size, a high-shear homogenizer was used. The encapsulation efficiency of prepared SLM reached 74.29 +/- 0.76%. Particle size (98.55 +/- 1.42 microm), surface morphology (spherical) and drug loading efficiency (18.57 +/- 1.25% w/w) were investigated. And optimization of drug polymer ratio (3:1), nature and concentration of emulsion stabilizer in the external aqueous (0.1%), phase viscosity of external aqueous phase (0.5%), volume of external aqueous phase and stirring rate (1000 rpm) were detected. Analysis of microsphere content after proce...

The dissolution rate of the model drugs carbamazepine and nifedipine was improved by adsorbing solutions of the drugs in hydrophilic nonvolatile or volatile solvents onto carriers with a large surface area. This was accomplished by dissolving the drug in methanol or the non-toxic hydrophilic liquids PEG 400 or 2-pyrrolidone, and adsorbing these solutions onto the surface of silica (Aerosil w) or crosslinked polyvinylpyrrolidone (Kollidon w CL-M). The solvent binding capacities decreased in the order of methanol, PEG 400, 2-pyrrolidone for Aerosil w 200, 300, 380 and for Kollidon w CL-M. Kollidon bound less liquid than Aerosil because of the smaller surface area. Differential scanning calorimetry measurements showed higher interactions between drugs and Kollidon compared to Aerosil, suggesting a low aggregation of precipitated drug particles. The drug release from the adsorbent systems was enhanced when compared to micronized drug and independent of the drug loading in the investigated range. The drugs were also dissolved in various liquid, paste-like or solid solubilisers (polyoxyl-40-hydrogenated castor oil (Cremophor w RH 40), macrogol-15-hydroxystearate (Solutol HS w), poloxamers (Lutrol w F68, Pluronic w F87NF and Pluronic w L44NF) and adsorbed onto Kollidon. These adsorbent systems also exhibited an increased dissolution rate when compared to pure drug.

- by Bernd Fussnegger
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- Adsorption, Differential scanning calorimetry, Silica, Methanol

Chronic treatment with several antihypertensive agents, including calcium channel blockers, may interfere with remodeling of large arteries and increased arterial stiffness. We hypothesize that even a short, sevenday administration of calcium channel blockers might alter an aortic remodeling in spontaneously hypertensive rat (SHR). Male SHR and normotensive WKY rats (n = 14 each) were treated by either vehicle, vasculoselective calcium channel blocker nifedipine (1 mg/kg/day) or cardiac/vascular calcium channel blockers diltiazem (5 mg/kg/day) or verapamil (4 mg/kg/day, n = 6 for each treatment) subcutaneously twice daily for seven days. Additional SHR rats were randomized for termination 24, 72 or 120 h (n = 5 each) after the withdrawal of nifedipine. Systolic blood pressure was measured by tail cuff and thoracic aorta was collected for histomorphometric and functional analysis including acetylcholine-induced endotheliumdependent relaxation. Seven-day administration of diltiazem and nifedipine, but not verapamil decreased blood pressure in SHR. All drugs significantly attenuated abnormal aortic wall thickness, cross-sectional area and media-to-lumen ratio, but only nifedipine improved impaired endothelium-dependent relaxation. Following the withdrawal of nifedipine, all measured parameters returned back to control SHR values within 72 h. Seven-day treatment with distinct calcium channel blockers attenuates hypertensive remodeling of aorta, which might be, in case of nifedipine, reactivated even by a very short withdrawal of the drug. Therefore, vasculoprotection by calcium channel blockers is not restricted to a prolonged blood pressure modulation, but occurs rapidly. These findings could be relevant for an intervention in augmented vascular stiffness and related cardiovascular risk.

- by Jan Kyselovic
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- Functional Analysis, Cardiovascular Risk, Hypertension, Blood Pressure

The aim of this study was to compare nifedipine and carvedilol in the treatment of de novo arterial hypertension after orthotopic liver transplantation (OLT). The study included 50 patients who developed arterial hypertension after OLT. Twenty-five patients received nifedipine (group A), and 25 received carvedilol (group B). Patients were defined as intolerant to nifedipine or carvedilol if severe adverse effects developed. These patients stopped the first drug and were switched to the other one. Patients were defined as full responders to monotherapy if there was normalization of blood pressure, and they were defined as partial responders by the need to add a second antihypertensive drug, ramipril. The 2 groups of patients were similar for baseline conditions. At the end of the study, patients intolerant to monotherapy were 48% of group A and 12.5% of group B (P Ͻ 0.01). Full responders were 20% of group A and 33.33% of group B (P Ͻ 0.01). Partial responders were 22% of group A and 54.1% of group B (P Ͻ 0.01). The addition of ramipril normalized blood pressure in 19% of partial responders to monotherapy (75% in partial responders to nifedipine and 30% in partial responders to carvedilol, P Ͻ 0.01). In responders to either monotherapy or combined therapy, there was a significant improvement of renal function. In responders to carvedilol, but not in responders to nifedipine, the daily dose of tacrolimus at 1 year should be reduced to 50% compared to the baseline dose to maintain the blood trough level in the therapeutic range.

- by Angelo Gatta and +1
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- Treatment Outcome, Arterial hypertension, Prospective studies, Hypertension

The present study was undertaken to elucidate the mode of action of methanol extract from aerial parts of L. caulescens (TC-MELc) as spasmolytic agent on in vitro rat ileum test, and investigate the possible antibacterial activity of... more

Cannabinoids modulate nociceptive processing in models of acute, inflammatory and neuropathic pain. We have investigated the location and function of cannabinoid receptors on cultured neonatal dorsal root ganglion (DRG) neurones and F-11 cells, a dorsal root ganglion×neuroblastoma hybridoma which displays several of the features of authentic DRG neurones. CB 1 receptor immunolabelling was observed on the cell bodies and as fine puncta on processes of both cultured DRG neurones and F-11 cells. Additionally, fluorescence-activated cell sorting (FACS) analysis provided evidence that both CB 1 and CB 2 receptors are expressed on populations of cells within the cultured DRG and F-11 cells. The cannabinoid receptor agonist (+)-WIN55212 (10 and 100 nM) inhibited the mean voltage-activated Ca 2+ current in DRG neurones by 21% and 30%, respectively. The isomer, (Ϫ)-WIN55212 (10 and 100 nM) produced significantly less inhibition of 6% and 10% respectively. The CB 1 selective receptor antagonist SR141716A (100 nM) enhanced the peak high voltage-activated Ca 2+ current by 24% and simultaneous application of SR141716A (100 nM) and (+)-WIN55212 (100 nM) resulted in a significant attenuation of the inhibition obtained with (+)-WIN55212 alone. These data give functional evidence for the hypothesis that the analgesic actions of cannabinoids may be mediated by presynaptic inhibition of transmitter release in sensory neurones.

- by Andrew Irving
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- Psychology, Fluorescence, Neuropharmacology, Immunohistochemistry
- by douglas douglas
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- Hypertension, African Americans, Aged, Randomized Controlled Trial

Trigeminal autonomic cephalalgias (TACs) are a group of primary headache syndromes characterised by two main clinical characteristics: pain and oculofacial autonomic phenomena. Three headache forms are grouped as TACs: cluster headache (CH), paroxysmal hemicrania (PH) and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) [1]. These are distinguished mainly on the basis of attack duration. It lasts from 15 to 180 min in CH, from 2 to 30 min in PH and from 5 to 240 s in SUNCT. The most effective drug preventative in PH is indomethacin even if in few cases other non-steroidal anti-inflammatory drugs have been reported to be effective . SUNCT is commonly described as drug resistant. Recent studies report that lamotrigin may be the drug of choice for SUNCT .

- by G. Broggi and +1
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- Lithium, Trigeminal Neuralgia, Drug Resistance, Headache

Aims Using a stable isotope technique which allows simultaneous and differential measuring of orally and intravenously administered drugs we compared the pharmacokinetics and pharmacodynamics of unlabelled modified release verapamil p.o. (steady state) and deuterated verapamil i.v. (single dose) following morning and evening administration. Methods Twelve female and 12 male healthy volunteers were studied in a randomized, crossover design. During the last day of each treatment period (day 6 and day 10) pharmacokinetics and pharmacodynamics (PR interval) of verapamil were assessed; 1 h before ingestion of a new R/S-verapamil 240 mg modified release formulation (08.00 h vs 20.00 h) a single dose of 10 mg d 7 -R/S-verapamil was administered intravenously. Serum levels of unlabelled and labelled R/S-verapamil were measured by gas chromatography/mass spectrometry. In selected samples of serum which were chosen at t min,po and t max,po the enantiomers were separated by chiral high-performance liquid chromatography in order to calculate R-to S-verapamil serum concentration ratios. Results We observed no significant differences in pharmacokinetics (AUC po , C max , t max , CL o , F and R/S enantiomer ratio) between morning and evening treatment with modified release verapamil and there was no influence of time of dosing on mean prolongation of PR interval. AUC iv , CL, V ss and d 7 -R/d 7 -S enantiomer ratio following verapamil i.v. did not show circadian variation. t 1/2 was slightly but statistically significantly increased after the morning infusion. PR-prolongation was significantly greater after verapamil i.v. in the morning than in the evening. The 90% confidence intervals of the differences between morning and evening administration in AUC po , C max and AUC iv were within the equivalence range of 0.8-1.25. Conclusions Time of dosing has no significant influence on pharmacokinetics and pharmacodynamics of this new modified release formulation of verapamil. Circadian variation in presystemic metabolism of verapamil was not observed.

- by Klaus Eckhardt
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- Electrocardiography, Sex Factors, Biological Availability, Cross-Over Studies
- by IQBAL HASSAN
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- Pediatrics, Prospective studies, Magnesium, Randomised Controlled Trial

The glucocorticoid-inducible protein annexin (ANXA) 1 is an anti-inflammatory mediator that down-regulates the host response. Endogenously, ANXA1 is released in large amounts from adherent polymorphonuclear neutrophils (PMN) and binds to their cell surface to inhibit their extravasation into inflamed tissues. The present study determined the effects of exogenous ANXA1 on several functions of human PMN in vitro. Addition of 0.1-1 µM human recombinant ANXA1 to the PMN provoked rapid and transient changes in intracellular Ca 2+ concentrations that were blocked by the Ca 2+ channel inhibitor SKF-96365. Although ANXA1 did not affect oxidant production and only minimally affected PMN chemotactic properties, the ANXA1promoted Ca 2+ influx was associated with two important functional effects: shedding of Lselectin and acceleration of PMN apoptosis. The latter effect was confirmed using three distinct technical procedures, namely, cell cycle, Hoechst staining, and ANXA5 binding assay. ANXA1induced PMN apoptosis was insensitive to inhibitors of L-selectin shedding, whereas it appeared to be associated with dephosphorylation of the proapoptotic intracellular mediator BAD. In conclusion, exogenous ANXA1 displayed selective actions on human PMN. We propose that the new proapoptotic effect reported here may be part of the spectrum of ANXA1-mediated events involved in the resolution of acute inflammation.

- by Ahmad Kamal
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- Physiology, Cell Cycle, Calcium, Apoptosis

ABSTRACT: Inhibitory and excitatory connecblockers (MgCl 2 and nifedipine) to the high-KCl metions of remarkably precise topographic order are dium reduced organotypicity drastically, indicating characteristic features of the mammalian auditory that a depolarization-induced increase of intracellular system, particularly within the superior olivary comcalcium is indispensable. Furthermore, the temporal plex (SOC). Little is known about the requirements course of the expression of the calcium-binding profor the correct development of these specific connectein parvalbumin in culture under high KCl mimics tions. Previous in vivo experiments have demonstrated that in vivo, demonstrating developmental processes a high expression of calcium-binding proteins in this during incubation. The need for calcium influx into system during development, pointing to the need for neurons of this auditory network in vitro (which is precise calcium regulation. Here, we have employed not seen in other slice culture systems) strengthens an organotypic slice culture from the above neuronal the hypothesis that an optimal calcium concentration network and analyzed the requirements for the mainis exceptionally important in auditory neurons. The tenance and development of this system in vitro. When effect of KCl in the slice cultures may substitute for slices from neonatal rats were incubated in standard input activity regulating intracellular calcium in audiculture medium for up to 7 days, we found no organotory neurons in vivo. ᭧ 1998 John Wiley & Sons, Inc. J typic features. Only if 25 mM KCl was added to the Neurobiol 34: 97-112, 1998

- by Eckhard Friauf
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- Cognitive Science, Calcium, Neurobiology, Calcium Channel

Desmostachya bipinnata, despite of its popular medicinal uses, has not been widely studied for its effect in diarrhea, indigestion, and asthma. The aim of the present investigation was to provide scientific rationale for these applications. The crude aqueous-methanolic extract of D. bipinnata (Db.Cr) was evaluated through in vivo and in vitro experiments. Db.Cr (100-500 mg/kg) protected mice against castor oil-induced diarrhea, similar to loperamide. When tested on gut preparations, Db.Cr produced an atropine-sensitive spasmogenic effect in rabbit jejunum up to 5 mg/mL, followed by a partial relaxation at 10 mg/mL. With atropine preincubation, a verapamil-like inhibitory effect was evident against spontaneous and high K + (80 mM)-induced contractions. The maximum stimulant effect was comparable with the acetylcholine-induced maximum contraction and was similarly reproducible in guinea pig ileum. Db.Cr inhibited carbachol (1 mM)-induced contraction in rabbit trachea but caused an atropine-sensitive accentuation of high K + -induced contraction at 0.003-0.3 mg/mL followed by inhibition at 1-5 mg/mL. On activity-directed fractionation, inhibitory effect was concentrated on organic and stimulant effect in aqueous fraction. This study, suggesting the presence of calcium antagonist activity, possibly underlying its medicinal effect in hyperactive gut and respiratory disorders, and cholinergic activity, possibly underlying its digestive effect, provides rationale for these therapeutic uses of D. bipinnata.

- by Hafiz Rahman
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- Biological Sciences, Phytotherapy, Mice, Jejunum

Pinaverium bromide is a specific calcium channel blocker used in the treatment of irritable bowel syndrome (JBS) for its spasmolytic activity. The aim of the present study was to evaluate the effect of ora!ly administered pieeverium bromide on jejunal motility and total and segmental colonic transit time in control subjects. Gastrointestinal studies were performed in 10 healthy volunteers (30 + 3 years), before and after a t~atment phase of 14 days (150 mgld). Jejunal motility was measured by prolonged manometry f 14 h) and colonic transit time by a multiple ingestion, single marker technique. No significant modification of phase III of the migrating motor complexes was demonstrated. On the contrary, a significant (p c 0.01) but weak decrease of the frequency of contraction was found. Unlike previous studies, no decrease of total or segmental colonic transit time was demonstrated.

- by Michel Bouchoucha
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- Jejunum, Parasympatholytics, Gastrointestinal motility, Colon

Among the more than 253,000 patients that underwent coronary artery bypass surgery (CABS); over half were over the age of 65. 1 Older individuals often present for surgery with multiple chronic diseases and multiple prescription and nonprescription medications. These factors, in addition to age related physiological changes, make this population at risk for medication related problems. 2 In addition, these problems may be compounded by symptoms experienced during the post-operative period. Common postoperative symptoms include chest incision symptoms (pain, discomfort), shortness of breath, loss of appetite, 3 fatigue, 3,4 and difficulty sleeping. 3,5,6 Psychological symptoms such as depression/sadness and anxiety/uneasiness have also been identified post-CABS. 7-9 Many of these symptoms are reported for weeks and months after surgery. 10-12 A patient's ability to discern between postoperative symptoms and new medication side effects may result in reluctance to adhere to the medication regimens. Medication adherence is critical for optimal recovery from surgery and secondary prevention of coronary artery disease. While much research has been done on medication regimens and symptoms in the postoperative CABS period, little data has been reported regarding the relationship between post-operative medications and post-operative symptoms following CABS. As more people age 65 and older choose to undergo revascularization procedures, examining this relationship has become more important. Therefore the purpose of this secondary analysis was to describe the frequently used postoperative medications and examine the relationship between postoperative symptoms and medication side effects in CABS patients. The specific aims of this study are: Aim 1: Describe frequently occurring medications used by CABS patients in the preoperative period and at three and six weeks and three months postoperatively. Aim 2: Describe medication use and selected symptoms/problems at three and

- by Lani Zimmerman
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- Nursing, Medicine, Cardiac Surgery, Risk factors

Abstract. Concerns regarding the safety of nifedipine emerged in 1995 with the report of an increased risk of myocardial infarction associated with adult patients receiving short-acting calcium channel blockers. There have been few case... more

- by Ronald Perkin
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- Evaluation, Adolescent, Case Report, Child

Pha1b is a potent toxin obtained from the spider Phoneutria nigriventer that blocks neuronal voltage-sensitive Ca 2þ channels. This study compared the antiallodynic effects of Pha1b, u-conotoxin MVIIA and morphine in mice and their side effects in rats. Mechanical allodynia was measured in mice receiving single intrathecal administration of Pha1b, u-conotoxin MVIIA or morphine before or after the incisional plantar procedure. The effect of the treatments on cardiovascular profile and global neurological were evaluated in rats. The expression of pro or anti-inflammatory cytokines of human polymorph mononuclear cells was also evaluated.

- by Carine Vieira
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- Pain, Polymorphism, Cytokines, Performance Assessment

+ binding proteins, including troponin C, calmodulin, and others to initiate the stimulus-response coupling processes of the cell.7 Dr. David J. Triggle received the degrees of B.Sc. and Ph.D. in chemistry from the Universities of Southampton and Hull, respectively, in the United Kingdom. His interests, initially in physical-organic chemistry, switched during a postdoctoral fellowship in Ottawa with Bernard Belleau studying the synthesis of muscarine and related compounds. Following further postdoctoral work in London Dr. Triggle returned to North America and since 1962 has been in Buffalo where his work has focused for some 25 years on the relationships between chemical structure and biological activity with particular reference for the past 10 years on drugs affecting Ca2+ regulation. His contributions in the whole area of ion transport systems have been significant and fundamental. Dr. David Langs received his Ph.D. in inorganic chemistry from the State University of New York at Buffalo in 2968. After postdoctoral research positions at Georgetown University and the UnizJersity of Sydney, he joined the Medical Foundation of Buffalo in 1973. His interests have included investigating the structure-activity relationships of steroids, prostaglandins, peptide hormones, membrane ionophores, and antibiotics. He has collaborated with Dr. Triggle in his analysis of calcium channel drugs since 1984. Dr. Langs is regarded as one of the world's leaders in the application of diffraction methods to solve crystal structures of ever increasing complexity. Dr. Janis is presently Principal Staff Scientist at the lnstitute for Preclinical Pharmacology, Miles lnc. His current work is on the development of Ca2+ channel antagonists, and on putatizw endogenous ligands for Ca2+ channels. Before joining Miles lnc. in 1980, he was Associate

- by David Triggle
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- Structure, Calcium, Biological activity, Structure activity Relationship
- by Fraser Moss
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- Multidisciplinary, Autonomic Nervous System, Mice, Calcium channels

the treatment of hypertension. The objective of this meta-analytical approach was to assess the efficacy of antihypertensive drugs most commonly used in France in reducing clinical SBP and DBP. Methods: The antihypertensive drugs selected were hydrochlorothiazide, indapamide sustained release (SR), furosemide and spironolactone for diuretics; amlodipine and lercanidipine for calcium channel antagonists; atenolol for ↑-adrenoceptor antagonists (↑-blockers); enalapril and ramipril for ACE inhibitors; and candesartan cilexetil, irbesartan, losartan, and valsartan for angiotensin II receptor antagonists. The trials selected were published between 1973 and 2004, evaluated monotherapy with trial drugs as fixed-dosage or with dosage increase, and assessed blood pressure reduction between 2 and 3 months. The analysis method used was based on the calculation of the sum weighted for the trial size. Results: A total of 72 trials (comprising 9094 patients) were selected and analyzed. No trial evaluating furosemide or spironolactone satisfied the inclusion criteria for this analysis. For SBP, the reduction was more marked with diuretics, calcium channel antagonists, and ACE inhibitors. Of all the drugs studied, indapamide SR gave the greatest SBP reduction (-22.2mm Hg). Evaluated therapeutic classes had a similar magnitude of effect on DBP, i.e. reduction between -11.4mm Hg with ↑-adrenoceptor antagonists and -10.3mm Hg with angiotensin II type 1 receptor antagonists. Conclusion: Indapamide SR 1.5mg appeared to be the most effective drug for a significant reduction in SBP within 2-3 months, which is an essential element in optimizing cardiovascular prevention among hypertensive patients. The clinical application of these results should take into consideration all the limitations discussed in this analysis.

- by Pascal Auquier
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- Treatment Outcome, France, Hypertension, Blood Pressure

Significant protective effects of the feed additives: water extract of artichoke, sesame seed, Roxazyme-G and L-(3 phenylalanine against the growth inhibitory effect of ochratoxin A (OTA) and associated pathomorphological changes were seen. Similarly, there was less OTA-induced decrease in serum total protein and increase of serum creatinine and urea in the chicks. Whereas OTA induced strong degenerative changes and an increase in weight of kidneys and liver as well as a decrease of the weight of lymphoid organs the additives variously gave protection against these changes. The protection of Roxazyme-G and sesame seed was better expressed in kidneys and liver, whereas the phenylalanine better protected the weight changes in gizzard, heart and the changes in differential WBC count. Notably, sesame seed gave strong protection against 5 ppm OTA-induced suppression of humoral immune response, for which artichoke also had some beneficial effect, whereas phenylalanine had hardly any effect.

- by Stoycho Stoev
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- Animal Feed, Vegetables, Serum Creatinine, Plant extracts

The objective of the study was to demonstrate that reduction in mean 24-hour diastolic blood pressure with 160 mg valsartan and 12.5 mg hydrochlorothiazide was not inferior to 10 mg amlodipine in hypertensive blacks. A total of 482 blacks with stage 1 and stage 2 hypertension (mean seated blood pressure 140 to 180/90 to 110 mm Hg) were enrolled in a double-blind, randomized, prospective study. After a placebo run-in period, patients were randomized to 160 mg valsartan or 5 mg amlodipine for 2 weeks, then force-titrated to 160 mg valsartan and 12.5 mg hydrochlorothiazide or 10 mg amlodipine for an additional 10 weeks. Blood pressure was assessed by 24-hour ambulatory blood pressure monitoring. Other assessments included quality of life, peripheral edema, and safety. Noninferiority of valsartan/hydrochlorothiazide to amlodipine was demonstrated by comparable reductions in mean 24-hour diastolic blood pressure with both treatments (Ϫ10.2Ϯ8.6 mm Hg versus Ϫ9.1Ϯ8.3 mm Hg, respectively; PϽ0.001 for noninferiority), as well as in mean 24-hour systolic blood pressure (Ϫ15.9Ϯ12.1 mm Hg versus Ϫ14.5Ϯ12.2 mm Hg; PϽ0.001 for noninferiority). The proportion of patients reporting adverse events and the incidence of most events were similar in both treatment groups, although more patients treated with amlodipine reported peripheral edema (5.8% versus 1.7%; Pϭ0.03) and joint swelling (2.9% versus 0%; Pϭ0.008) compared with valsartan/hydrochlorothiazide. We conclude that a starting dose of valsartan/hydrochlorothiazide (160/12.5 mg) is as effective as high-dose amlodipine (10 mg) in reducing blood pressure in blacks with stage 1 and stage 2 hypertension, and valsartan/hydrochlorothiazide is better tolerated. (Hypertension. 2005;46:508-513.)

- by John Flack
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- Treatment Outcome, Prospective studies, Hypertension, Blood Pressure

Hypertensive crises are divided into hypertensive urgencies and emergencies. Together they form a heterogeneous group of acute hypertensive disorders depending on the presence or type of target organs involved. Despite better treatment options for hypertension, hypertensive crisis and its associated complications remain relatively common. In the Netherlands the number of patients starting renal replacement therapy because of 'malignant hypertension' has increased in the past two decades. In 2003, the first Dutch guideline on hypertensive crisis was released to allow a standardised evidence-based approach for patients presenting with a hypertensive crisis. In this paper we give an overview of the current management of hypertensive crisis and discuss several important changes incorporated in the 2010 revision. These changes include a modification in terminology replacing 'malignant hypertension' with 'hypertensive crisis with retinopathy and reclassification of hyp...

- by Bert-jan Van Den Born
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- Internal Medicine, Hypertension, Netherlands, Nifedipine

Bilateral hypertensive retinopathy and choroidopathy with bullous retinal detachment was diagnosed in a 17-year-old, female spayed Domestic Short-haired cat. The underlying cause of the systemic hypertension could not be determined. The blood pressure was lowered successfully with the oral application of the L-type calcium channel blocker amlodipine besylate. The cat subsequently regained vision. The improvement in retinal function was documented using electroretinography.

- by Stacy Andrew
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- Cats, Hypertension, Retinal detachment, Differential Diagnosis

Anal fissure management has rapidly progressed in the last 15 years as our understanding of fissure pathophysiology has developed. All methods of treatment aim to reduce the anal sphincter spasm associated with chronic anal fissures. Surgical techniques have been used for over 100 years with success. Lateral internal sphincterotomy remains the surgical treatment of choice for many practitioners. Postoperative impairment of continence remains controversial. Recently, less invasive methods of treatment have been explored. Topical nitrates, calcium channel blockers and botulinum toxin are established treatments. These and other non-surgical treatments are described in this review. Various guidelines and treatment algorithms for anal fissure are also discussed.

- by Jon Lund
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- Algorithms, Chronic Disease, Clinical Sciences, Topical Drug Administration

Placebo-controlled trials have evaluated the efficacy of several medications in the treatment of social anxiety disorder but information regarding their relative efficacy is lacking. We compared the efficacy of medications systematically studied for the treatment of social anxiety disorder using meta-analytic techniques. The methodology included a database search of articles published between January 1980 and June 2001 and manual searches of bibliographies in published manuscripts. Trials were included if they reported outcome data on the Liebowitz Social Anxiety Scale (LSAS) or a categorical measure of responder status. Data were extracted independently by two authors. The Q statistic was used to assess homogeneity across trials. All analyses were conducted using intent-to-treat data. There was substantial heterogeneity across trials. The medications with largest effect sizes were phenelzine [effect size, 1.02; 95% Confidence Interval (CI), 0.52-1.52], clonazepam (effect size, .97; 95% CI, 0.49-1.45), gabapentin (effect size, .78; 95% CI, 0.29-1.27), brofaromine (effect size, .66; 95% CI, 0.38-0.94), and the selective serotonin reuptake inhibitors (SSRIs; effect size, .65; 95% CI, 0.50-0.81). There were no statistically significant differences between medications or medication groups. However, formal methods of interim monitoring adapted for meta-analyses suggested strongest evidence of efficacy for SSRIs and brofaromine. Several medications are efficacious for the treatment of social anxiety disorder. The stability of the SSRI effect size estimate in conjunction with other evidence for safety and tolerability and their ability to treat comorbid conditions supports the use of SSRIs as the first-line treatment. Direct comparisons of SSRIs vs. other promising medications deserve consideration. Depression and Anxiety 18:29-40,

- by Franklin Schneier
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- Psychology, Anxiety Disorders, Depression, Treatment Outcome

It is estimated that over 10% of the adult population in developed countries have some degree of chronic kidney disease (CKD). CKD is a progressive and irreversible deterioration of the renal excretory function that results in implementation of renal replacement therapy in the form of dialysis or renal transplant, which may also lead to death. CKD poses a growing problem to society as the incidence of the disease increases at an annual rate of 8%, and consumes up to 2% of the global health expenditure. CKD is caused by a variety of factors including diabetes, hypertension, infection, reduced blood supply to the kidneys, obstruction of the urinary tract and genetic alterations. The nephropathies associated with some of these conditions have been modeled in animals, this being crucial to understanding their pathophysiological mechanism and assessing prospective treatments at the preclinical level. This article reviews and updates the pathophysiological knowledge acquired primarily from experimental models and human studies of CKD. It also highlights the common mechanism(s) underlying the most relevant chronic nephropathies which lead to the appearance of a progressive, common renal phenotype regardless of aetiology. Based on this knowledge, a therapeutic horizon for the treatment of CKD is described. Present therapy primarily based upon renin-angiotensin inhibition, future diagnostics and therapeutic perspectives based upon anti-inflammatory, anti-fibrotic and hemodynamic approaches, new drugs targeting specific signaling pathways, and advances in gene and cell therapies, are all elaborated.

- by Francisco Hernandez V
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- Pharmacology, Genetics, Global Health, Chronic kidney disease

Fragestellung Eine interdisziplinäre Leitlinie zur Therapie des Fibromyalgiesyndroms (FMS) und chronischer Schmerzen in mehreren Körperregionen (engl. „chronic widespread pain“, CWP) wurde in Kooperation von 10 medizinischen bzw. psychologischen Fachgesellschaften und 2 Patientenselbsthilfeorganisationen erstellt. Methodik Eine Literatursuche über alle kontrollierten Studien (engl. „randomized controlled trial“, RCT) zur medikamentösen Therapie des FMS bzw. von CWP wurde unter Benutzung der Cochrane Collaboration Reviews (1993–12/2006), Medline (1980–12/2006), PsychInfo (1966–12/ 2006) und Scopus (1980–12/ 2006) durchgeführt. Für die Vergabe von Evidenzklassen wurde das System des Oxford Centre for Evidence-Based Medicine verwendet. Für die Vergabe von Empfehlungsgraden wurde die Empfehlungsgraduierung der nationalen Versorgungsleitlinien verwendet. Die Erstellung der Empfehlungen erfolgte in einem mehrstufigen nominalen Gruppenprozess. Ergebnisse Die zeitlich befristete Verwendung von Amitriptylin erhielt den Empfehlungsgrad A. Den Empfehlungsgrad B für die zeitlich befristete Verwendung erhielten Fluoxetin und Duloxetin. Schlussfolgerung Die Empfehlungen zur medikamentösen Therapie des FMS werden durch die kurze Studiendauer sowie fehlende Untersuchungen nach Therapieende und zur Kosteneffektivität eingeschränkt. Background An interdisciplinary guideline for the treatment of fibromyalgia syndrome (FMS) and chronic widespread pain (CWP) was developed in cooperation with ten German medical and psychological associations and two patients’ self-help organizations. Methods Using the Cochrane Collaboration Reviews (1993–12/2006), Medline (1980–2006), PsychInfo (1966–12/2006), and Scopus (1980–12/ 2006) a systematic literature search was performed, which included all randomised controlled trials (RCT) evaluating multicomponent therapy in FMS and CWP. Levels of evidence were assigned according to the classification system of the Oxford Centre for Evidence-Based Medicine. The strength of recommendation was graded according to the German program for disease management guidelines. Consensus was achieved using a multi-step nominal group procedure. Results The short-term use of amitriptyline is strongly recommended (grade A) and the short-term use of fluoxetine und duloxetine is recommended (grade B). Conclusions The recommendations regarding pharmacological treatment of FMS are limited by the short duration of the RCT, the lack of follow-ups and absence of cost-effectiveness studies.

- by B Moradi
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- Research Design, Pain, Evidence Based Medicine, Self Care

Little is known about associations of calcium channel blockers (CCBs) with outcomes in patients with heart failure and preserved ejection fraction (EF). Of the 10 570 hospitalized patients with heart failure and preserved EF, ≥65 years, EF ≥40%, in the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure (OPTIMIZE-HF; 2003-2004), linked to Medicare data (through December 31, 2008), 7514 had no prior history of CCB use. Of these, 815 (11%) patients received new discharge prescriptions for CCBs. Propensity scores for CCB initiation, calculated for each of the 7514 patients, were used to assemble a matched cohort of 1620 (810 pairs) patients (mean age, 80 years; mean EF, 56%; 65% women; 10% black) receiving and not receiving CCBs, balanced on 114 baseline characteristics. The primary composite end point of all-cause mortality or heart failure hospitalization occurred in 82% and 81% of patients receiving and not receiving CCBs (hazard ratio for ...

- by Meredith Kilgore
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- Treatment Outcome, Heart Failure, Hospitalization, Propensity Score

Cerebral vasospasm is a recognised but poorly understood complication for many patients who have aneurysmal subarachnoid haemorrhage and can lead to delayed ischaemic neurological deficit (stroke). Morbidity and mortality rates for vasospasm are high despite improvements in management. Since the middle of the 1970s, much has been written about the treatment of cerebral vasospasm. Hypervolaemia, hypertension, and haemodilution (triple-H) therapy in an intensive-care setting has been shown in some studies to improve outcome and is an accepted means of treatment, although a randomised controlled trial has never been undertaken. In this review, the rationale for this approach will be discussed, alongside new thoughts and future prospects for the management of this complex disorder.

- by Antonio Belli
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- Hypertension, INTENSIVE CARE, Subarachnoid hemorrhage, Randomised Controlled Trial

- by Michel Bouchoucha
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- Jejunum, Parasympatholytics, Gastrointestinal motility, Colon

Gastrointestinal motility and transport as well as concomitant food intake are factors that are known to influence pharmacokinetics derived after intake of extended release dosage forms. However, the mechanisms behind these influencing factors are mostly unknown. In this study the gastrointestinal transit and the in vivo drug release of magnetically labelled extended release tablets containing felodipine were monitored together with the drug absorption phase of pharmacokinetics under fasting and fed conditions in six healthy volunteers using Magnetic Marker Monitoring. It was found that the in vivo drug release profiles of the tablets compared well under fasting and fed conditions. However, the plasma concentration profiles were strongly influenced by concomitant food intake. This could be attributed to elongated residence of the tablets in proximal parts of the stomach, resulting in delayed drug absorption and the occurrence of late high plasma peak concentrations. The lag time until the first appearance of felodipine in plasma and the residence time of the tablets in the proximal stomach, were found to be directly correlated. The study shows that increased plasma peak drug concentrations after intake of extended release formulations together with food can be explained by poor mixing in the proximal part of the stomach and are not necessarily due to failure of the formulation to control drug release (dose dumping).

- by Erik Söderlind and +1
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- Algorithms, Biomedical Engineering, Controlled release, Solubility

traction. Nifedipine significantly reduced Ca 2+ wave frequency and tonic contraction, while the nifedipine-insensitive component was abolished by SKF-96365. Ca 2+ waves and tonic contraction were abolished by 2-aminoethoxydiphenylborate, but were unaffected by ryanodine or tetracaine. Conclusion: Phenylephrine-induced Ca 2+ waves underlie tonic contraction in resistance-sized mesenteric arteries and appear to be produced by repetitive cycles of regenerative Ca 2+ release from the sarcoplasmic reticulum. Decreased frequency of Ca 2+ waves in Marfan syndrome appears to be responsible for reduced tonic contraction.

- by Cornelis van Breemen
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- Calcium, Confocal Microscopy, Mice, Calcium Signaling
- by Curt Furberg and +1
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- Decision Making, Quality of life, Treatment, General Internal Medicine

tensive treatment in elderly patients in terms of cardiovascular morbidity and mortality rate reduction. 7-11 However, because the risk of side effects is a major concern when treating the elderly, the use of low-dose combination... more

- by Athanase Benetos
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- Quality of life, Treatment Outcome, Safety, Hypertension
- by Theophile Godfraind
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- Calcium, Multidisciplinary, Ion Channels, Smooth muscle

Antiarrhythmic drugs play a major role in the management of the most common types of arrhythmias. The margin between the beneficial and toxic effects of these drugs is often narrow. Thus, a precise knowledge of dosages, drug-target tissue interactions, pharmacodynamics and pharmacokinetics of antiarrhythmic drugs is needed to better predict how effective a particular drug will be in the treatment of a specific arrhythmia in a given patient. Despite the large amount of information that is available on the electrophysiological and pharmacological effects of antiarrhythmic drugs, we still do not know enough about their true mechanism of action in individual patients. The results of the Cardiac Arrhythmia Suppression Trial (CAST) firmly established that the use of class I drugs is potentially dangerous in a specific subset of patients. Additionally, several meta-analyses have reported that quinidine has severe proarrhythmic effects in patients with atrial fibrillation. The management of arrhythmias in elderly patients is difficult because of age-related factors that may influence the pharmacokinetics and pharmacodynamics of antiarrhythmic drugs.

- by Klaus Romero
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- Atrial Fibrillation, Heart, Cardiac Arrhythmias, Age Factors

To describe for pharmacists the basics of hypertension with a specific emphasis on the role of calcium channel blockers in the management of this condition. Data sources: Published literature on hypertension identified via a search of PubMed and pertinent government Web sites. Data synthesis: Hypertension affects more than 70 million Americans, and many patients are unaware of their condition. The pathophysiology, risk factors, and nonpharmacologic and pharmacologic management of hypertension are described in this article. Pharmacists can play a major role in educating patients on hypertension, counseling patients on the importance of lifestyle modifications and drug therapy, and encouraging adherence. Conclusion: Hypertension is a major risk factor for cardiovascular morbidity and mortality. By understanding hypertension and its appropriate management, pharmacists can effectively manage patients, reducing adverse events and improving longterm outcomes.

- by Luigi Cubeddu
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- Kinetics, Drug interactions, Kidney, Hypertension

Background: Eperisone hydrochloride, a centrally acting muscle relaxant, is a calcium antagonist that causes vasodilation and antispastic actions. Aceclofenac, an anti-inflammatory analgesic and antipyretic drug, has similar efficacy and improved gastrointestinal tolerance compared with other nonsteroidal antiinflammatory drugs, such as diclofenac. Although eperisone hydrochloride and aceclofenac are frequently coadministered, no published studies have reported on the pharmacokinetic interactions between these 2 drugs.

- by Yook-Hwan Noh and +1
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- Randomization, Pharmacokinetics, Drug interactions, Young Adult
- by Maria Jose Alvarado
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- Blood sampling, Steady state, Clinical Sciences, Tablets

Hypertension is the most common condition seen in primary care and leads to myocardial infarction, stroke, renal failure, and death if not detected early and treated appropriately. Patients want to be assured that blood pressure (BP) treatment will reduce their disease burden, while clinicians want guidance on hypertension management using the best scientific evidence. This report takes a rigorous, evidence-based approach to recommend treatment thresholds, goals, and medications in the management of hypertension in adults. Evidence was drawn from randomized controlled trials, which represent the gold standard for determining efficacy and effectiveness. Evidence quality and recommendations were graded based on their effect on important outcomes.

- by Eduardo Ortiz
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- Pharmacology, Health Sciences, Pharmacy, Epidemiology

sea, headache, and fatigue were observed infrequently. The results of this controlled, large-scale multicenter trial sug-gest that amlodipine significantly increased exercise capacity and was well tolerated when added to the antianginal... more

- by Stephen Glasser
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- Treatment, Adolescent, Electrocardiography, Hemodynamics

Although the new generation of atypical antipsychotic agents could some day eliminate concerns about tardive dyskinesia (TD), this disorder remains a significant clinical problem for both patients and physicians. Fortunately, many, if not most, cases of TD are mild. For patients with mild to moderate TD, therapeutic efforts are primarily directed at minimizing neuroleptic exposure or, when possible, changing to atypical agents. Most cases of TD do not seem to progress, suggesting that the risk of remaining on typical neurolep-Hcs is probably small. Patients with moderate to severe forms of TD present greater challenges. These patients frequently require medication to suppress their dyskinesias. A variety of suppressive agents have been tried with limited success. No treatment strategy has emerged that is clearly superior or even successful in most patients. Increasing doses of typical neuroleptics may be useful for short-term suppression; however, the long-term efficacy and risk of this strategy have not been studied carefully. Data on atypical neuroleptics are scant. Clozapine's short-term suppressive effects seem, at best, weak, but patients may improve with long-term treatment Medications with relatively few side effects that may have suppressive efficacy for some patients include calcium channel blockers, adrenergic antagonists, and vitamin E. Gammaamino-butyric acid agonists agents and dopamine depleters are frequently useful, but have troubling side effects of their own. A variety of other medications have been employed, but are not well studied. For patients with tardive dystonia, anticholinergic agents or botulinum toxin has been particularly effective. Efforts to understand the neurobiology of TD may shed light on this persistent clinical conundrum.

- by Jose Apud
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- Schizophrenia, Dopamine, Antioxidants, Dystonia
- by Bethany Mlinar
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- Electrophysiology, Biological Sciences, Neural Crest, Thyroid gland