Sheila A Doggrell

Rat models of hypertension, cardiac hypertrophy and failure

Time for primary review 24 days. Animals have been used by humans for centuries to understand their own biology. In cardiovascular research, animal models have allowed the study of cardiovascular disease in the early stages, as well as the investigation of the mechanisms of the pathogenesis of cardiovascular disease and the effects of drug intervention. The aim of these studies is to provide clear concepts for selected investigations in humans. An ideal animal model for any cardiovascular disease in humans should have five characteristics: (i) mimic the human disease, (ii) allow studies in chronic, stable disease, (iii) produce symptoms which are predictable and controllable, (iv) satisfy economical, technical and animal welfare considerations, and (v) allow measurement of relevant cardiac, biochemical and haemodynamic parameters. The use of rats as animal models is rational from the economic viewpoint and many techniques have been developed to measure relevant functional parameters. However, there is often insufficient consideration as to whether the other criteria, especially the mimicry of human disease, are satisfied with the choice of rat models of cardiovascular disease. Three examples illustrate the problems. Firstly, cardiovascular diseases such as hypertension and heart failure in humans are usually slowly developing with wide-ranging neurohumoral adaptations in contrast to the acute onset of symptoms in many surgical or drug-induced rat models of these important diseases. Secondly, cardiovascular disease is uncommon in young humans but markedly increases with age [1]yet most models of hypertension and heart failure only use young adult rats. Animal models of ageing have been recently reviewed [2]. Thirdly, the development of atherosclerosis is very unusual in most strains of rats, even in the presence of sustained high blood lipid levels, in contrast to humans where atherosclerosis is common and an important risk factor in hypertension and heart failure. Although this review … * Corresponding author. Tel.: +64 (9) 373 7599 ext. 6418; Fax: +64 (9) 373 7556.

Adherence to Medicines in the Older-Aged with Chronic Conditions: Does Intervention by an Allied Health Professional Help?

Adherence to medicines is a major determinant of their effectiveness. However, estimates of non-adherence in the older-aged (defined as those aged ≥65 years) with chronic conditions vary from 40% to 75%. The problems caused by non-adherence in the older-aged include residential care and hospital admissions, progression of the disease and increased costs to society. The reasons for non-adherence in the older-aged include items related to the medicine (e.g. cost, number of medicines, adverse effects) and those related to the person (e.g. cognition, vision, depression). It is also known that there are many ways adherence can be increased (e.g. use of blister packs, cues).Although it is assumed that interventions by allied health professionals (i.e. other than the prescriber/doctor), including a discussion of adherence, will improve adherence to medicines in the older-aged, the evidence for this has not been reviewed. There is some evidence that telephone counselling concerning adherence by a nurse or pharmacist improves short- and long-term adherence. However, face-to-face intervention counselling at the pharmacy or during a home visit by a pharmacist has shown variable results, with some studies showing improved adherence and some not. Broad-based education programmes during hospital stays have not been shown to improve medication adherence following discharge, whereas education programmes specifically for subjects with hypertension have been shown to improve adherence. In combination with an education programme, both counselling and a medicine review programme have been shown to improve short-term adherence in the older-aged.Thus, there are many unanswered questions about the most effective interventions for promoting adherence. More studies are needed to determine the most appropriate interventions by allied health professionals, and such studies need to consider the disease state, demographics and socioeconomic status of the older-aged subject, and the intensity and duration of intervention required.

Pegaptanib: the first antiangiogenic agent approved for neovascular macular degeneration.

Age-related macular degeneration is the leading cause of irreversible visual loss in the industrialised world. Angiogenesis underlies the neovascularisation, and vascular endothelial growth factor (VEGF) is an angiogenesis growth factor. In the VEGF Inhibition Study in Ocular Neovascularisation-1 (VISION-1) trial, pegaptanib (an aptamer inhibitor of VEGF) was tested in neovascular age-related macular degeneration. The 1186 patients received a sham injection or intravitreous injection of pegaptanib (0.3, 1.0 or 3.0 mg) every 6 weeks over a period of 48 weeks. The primary end point was the proportion of patients who lost < 15 letters of visual acuity between baseline and 54 weeks, and this occurred in 164/296 patients (55%) who received the sham injection. A higher percentage of patients maintained this visual acuity if they were treated with pegaptanib 0.3 mg (54/206 patients, 70%). There was no evidence that pegaptanib 1 or 3 mg was more effective than 0.3 mg. There was no excess of systemic adverse effects with pegaptanib, but ocular adverse effects occurred more commonly with pegaptanib than with sham injection; vitreous floaters (33 versus 8%), vitreous opacities (18 versus 10%) and anterior chamber inflammation (14 versus 6%). Although these results represent a new, beneficial and relatively safe approach to age-related macular degeneration, the progression was not halted or reversed, and further improvement to treatment for this condition should be sought.

Berberine--a novel approach to cholesterol lowering.

Although low-density lipoprotein (LDL)-cholesterol lowering with the statins reduces the mortality and morbidity associated with coronary artery disease, considerable mortality and morbidity remains. Berberine upregulates the LDL receptor (LDLR) by a mechanism distinct from that of the statins, which involves stabilising the LDLR mRNA. In hamsters fed a high-fat and high-cholesterol diet for 2 weeks, the oral administration of berberine 100 mg/kg for 10 days reduced total serum cholesterol from ∼ 4.8 to 2.7 mmol/l, and LDL-cholesterol from ∼ 2.5 to 1.4 mmol/l. In subjects with hypercholesterolaemia, berberine hydrochloride (0.5 g b.i.d. for 3 months) reduced LDL-cholesterol (from 3.2 to 2.4 mmol/l) without any effect on high-density lipoprotein-cholesterol. Berberine also caused a reduction in triglyceride levels from 2.3 to 1.5 mmol/l. As berberine and statins both upregulate LDLR, their lipid-lowering profiles are similar. Thus, this mechanism is unlikely to make berberine an attractive alternative to statins for lipid lowering in most circumstances. However, the other effects of berberine (antihypertensive, inotropic and class III antiarrhythmic properties) may make it a useful agent in the treatment of cardiovascular disease.

Sarpogrelate: cardiovascular and renal clinical potential

Sarpogrelate is a selective 5-hydroxytryptamine receptor subtype 2A (5-HT2A) antagonist. It is metabolised to racemic M-1 and both enantiomers of M-1 are also antagonists of 5-HT2A receptors. Sarpogrelate inhibits responses to 5-HT mediated by 5-HT2A receptors such as platelet aggregation, vasoconstriction and vascular smooth muscle proliferation. There is no information available on the pharmacokinetics of sarpogrelate. Sarpogrelate is efficacious in animal models of thrombosis, coronary artery spasm, atherosclerosis, restenosis, peripheral vascular disease, pulmonary hypertension, ischaemic heart disease, myocardial infarction, diabetes and kidney disease. Small clinical trials indicate that sarpogrelate may be beneficial in the treatment of coronary artery disease, angina, restenosis, heart valve prostheses surgery, diabetes mellitus, Raynaud’s phenomenon, systemic sclerosis and Buerger’s disease. Larger, randomised, double-blind, placebo-controlled clinical trials of sarpogrelate in intermittent claudication, coronary artery disease, restenosis and diabetes should be considered.

The role of 5-HT on the cardiovascular and renal systems and the clinical potential of 5-HT modulation

The main peripheral sources of 5-hydroxytryptamine (5-HT) are as a neurotransmitter and local hormone in the gastrointestinal tract, and stored in circulating platelets and pulmonary neuroepithelial bodies. 5-HT has been shown to have many possible physiological and pathophysiological roles on the cardiovascular and renal systems. Thus, 5-HT may contribute to valvular heart disease, coronary artery disease, pulmonary hypertension, pulmonary embolism, pre-eclampsia, peripheral vascular disease and diabetic nephropathy. Consequently, modulators of the 5-HT system have diverse clinical potential. For instance, selective 5-HT subtype 3 receptor (5-HT3) antagonists may have potential in the treatment of the pain associated with myocardial infarction. MCI-9042 (sarpogrelate) or other 5-HT2A antagonists may have clinical potential for the treatment of vasospastic angina, ischaemic heart disease, reperfusion injury and hindlimb ischaemia. Several modulators of 5-HT (5-HT transporter inhibitors, 5-HT1B and 2B antagonists) may have potential alone or in combination in the treatment of pulmonary hypertension. In hypertension, agonists at the 5-HT7 and antagonists at the 5-HT2B may reduce blood pressure, and in diabetes, sarpogrelate may protect against nephropathy.

BMS-354825: a novel drug with potential for the treatment of imatinib-resistant chronic myeloid leukaemia

The BCR-ABL tyrosine kinase inhibitor imatinib has greatly improved the outcome for patients with chronic myeloid leukaemia (CML). Unfortunately, mutations causing resistance to imatinib are leading to relapses in some patients. In addition to inhibiting the wild-type BCR-ABL, BMS-354825 inhibited 14 of 15 BCR-ABL mutants. BMS-354825 treatment of immunodeficient mice prevented the progression of the disease in mice treated with the most clinical common imatinib-resistant mutant Met351Thr. The safety and efficacy of BMS-354825 is presently being evaluated in a phase I/II clinical trial in CML patients with imatinib resistance. The frequency of clinical use of BMS-3548125 in CML patients will depend on its efficacy/safety profile in clinical trial.

Dronedarone: an amiodarone analogue.

Of the antiarrhythmic drugs in current use, amiodarone is one of the most effective and is associated with a comparatively low risk of drug-induced pro-arrhythmia, probably due to its multiple pharmacological actions on cardiac ion channels and receptors. However, amiodarone is associated with significant extra-cardiac side effects and this has driven development of amiodarone analogues. These analogues include short acting analogues (e.g., AT-2001) with similar acute effects to amiodarone, the thyroid receptor antagonist KB-130015 and dronedarone. Dronedarone, (SR-33589; Sanofi-Synthelabo), is a non-iodinated amiodarone derivative that inhibits Na+, K+ and Ca2+ currents. It is a potent inhibitor of the acetylcholine-activated K+ current from atrial and sinoatrial nodal tissue, and inhibits the rapid delayed rectifier more potently than slow and inward rectifier K+ currents and inhibits L-type calcium current. Dronedarone is an antagonist at α- and β-adrenoceptors and unlike amiodarone, has little effect at thyroid receptors. Dronedarone is more potent than amiodarone in inhibiting arrhythmias and death in animal models of ischaemia- and reperfusion-induced arrhythmias. In the Dronedarone Atrial Fibrillation Study After Electrical Cardioversion (DAFNE) clinical trial, dronedarone 800 mg/day appeared to be effective and safe for the prevention of atrial fibrillation relapses after cardioversion. The Antiarrhythmic Trial with Dronedarone in Moderate-to-Severe Congestive Heart Failure Evaluating Morbidity Decrease (ANDROMEDA) trial was stopped due to a potential increased risk of death in the dronedarone group. Trials of dronedarone in the maintenance of sinus rhythm in patients with atrial fibrillation and a safety and tolerability study in patients with an implantable cardioverter defibrillator are ongoing. Further experimental and clinical studies are required before we have a definitive answer to whether dronedarone has advantages over amiodarone and other amiodarone analogues.

Comparison of clinical trials with sildenafil, vardenafil and tadalafil in erectile dysfunction

Erectile dysfunction (ED) affects up to 50% of men, between 40 and 70years of age. In the first major trial of sildenafil in ED, at 24weeks, improved erections were reported by 77 and 84% of men taking sildenafil 50 and 100mg, respectively. Subsequently, sildenafil has been reported to be effective in men with ED associated with diabetes and prostate cancer, and in psychogenic ED. Sildenafil is safe in men with coronary artery disease, provided it is not used with the nitrates (a contraindication). The most commonly reported adverse effects with sildenafil are headache, flushing and dyspepsia. Vardena-fil is more potent and more selective than sildenafil at inhibiting phosphodiesterase-5. Vardenafil is similarly effective to sildenafil in the treatment of ED. The only advantage that vardenafil has over sildenafil is that it does not inhibit phosphodiesterase-6 to alter colour perception, a rare side effect which sometimes occurs with sildenafil. Tadalafil has a longer duration of action than sildenafil and vardenafil. Tadalafil is similarly effective as sildena-fil in the treatment of ED. In comparison studies, tadalafil is preferred to sildenafil (50/100mg) by men with ED, possibly because of its longer duration of action. Of the phosphodiesterase inhibitors, tadalafil may displace sild-enafil as the drug of choice among men with ED.

The spironolactone renaissance

Until recently, spironolactone was considered only as an antagonist at the aldosterone receptors of the epithelial cells of the kidney and was used clinically in the treatment of hyperaldosteronism and, occasionally, as a K+-sparing diuretic. The spironolactone renaissance started with the experimental finding that spironolactone reversed aldosterone-induced cardiac fibrosis by a cardiac action. Experimentally, spironolactone also has direct effects on blood vessels. Spironolactone reduces vascular fibrosis and injury, inhibits angiogenesis, reduces vascular tone and reduces portal hypertension. The rationale for the Randomized Aldactone Evaluation Study (RALES) of spironolactone in heart failure was that ‘aldosterone escape’ occurred through non-angiotensin II mechanisms. The RALES clinical trial was stopped early when it was shown that there was a 30% reduction in risk of death among the spironolactone patients. In RALES, spironolactone also reduced hospitalisation for worsening heart failure and improved the symptoms of heart failure. Other recent clinical trials have shown that spironolactone reduces cardiac and vascular collagen turnover, improves heart variability, reduces ventricular arrhythmias, improves endothelial dysfunction and dilates blood vessels in human heart failure and these effects probably all contribute to the increased survival in heart failure. Spironolactone may also be useful in the treatment of left ventricular hypertrophy, portal hypertension and cirrhosis. There have also been some recent small clinical trials of spironolactone as an anti-androgen showing potential in acne, hirsutism and precocious puberty.