Antihypertensive agents acting on the renin–angiotensin system and the risk of sepsis

AimsIn response to safety concerns from two large randomized controlled trials, we investigated whether the use of telmisartan, an angiotensin receptor blocker (ARB), ARBs as a class and angiotensin-converting enzyme inhibitors (ACEIs) increase the risk of sepsis, sepsis-associated mortality and renal failure in hypertensive patients.MethodsWe performed a nested case–control study from a retrospective cohort of adults with hypertension from the UK General Practice Research Database diagnosed between 1 January 2000 and 30 June 2009. All subjects hospitalized with sepsis during follow-up were matched for age, sex, practice and duration of follow-up with 10 control subjects. Exposure was defined as current use of antihypertensive drugs.ResultsFrom the cohort of 550 436 hypertensive patients, 1965 were hospitalized with sepsis during follow-up (rate 6.9 per 10 000 per year), of whom 824 died and 346 developed acute renal failure within 30 days. Compared with use of β-blockers, calcium-channel blockers or diuretics, use of ARBs, including telmisartan, was not associated with an elevated risk of sepsis (relative risk 1.09; 95% confidence interval 0.83–1.43); but use ACEIs was (relative risk 1.65; 95% confidence interval 1.42–1.93). Users of ARBs, β-blockers, calcium-channel blockers or diuretics, but not users of ACEIs, had lower rates of hospitalization for sepsis compared with untreated hypertensive patients. Findings were similar for sepsis-related 30 day mortality and renal failure.ConclusionsHypertensive patients treated with ARBs, including telmisartan, do not appear to be at increased risk of sepsis or sepsis-related 30 day mortality or renal failure. On the contrary, users of ACEIs may have an increased risk.     

Urgent problems in the search for and creation of β-adrenergic blocking agents

The results are presented of a search for hybrid -adrenergic blocking agents (combining -adrenergic blocking activity with -adrenergic blocking, vasodilating properties, and also the ability to inhibit the angiotensin-converting enzyme) and -adrenergic blocking agents with a prolonged effect among the derivatives of 5-phenoxymethyl-1,2,4-oxadiazole and 4-(2-hydroxy-3-alkylaminopropoxy)indole. One of the studied substances (proxodolol) was introduced into medical practice as a highly efficacious antihypertensive. antianginal, and antiglaucoma drug.     

Targeting the renin–angiotensin system for the reduction of cardiovascular outcomes in hypertension: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers

Agents that counteract the negative impact of the renin–angiotensin–-aldosterone system (RAAS) are effective antihypertensives and reduce the risk of developing Type 2 diabetes. Contrary to common perception, angiotensin-converting enzyme inhibitors do not share the apparent benefit of angiotensin II receptor blockers (ARBs) in reducing risk of cardiovascular-disease outcomes, particularly stroke, in randomised clinical trials. RAAS agents, especially ARBs, are well tolerated. Use of ARBs alone or in combination with other classes of antihypertensive agents to lower blood pressure and/or medications to control other conditions (e.g., insulin sensitivity) reduces risk of cardiovascular disease outcomes and Type 2 diabetes with excellent tolerability. Selected issues related to use of RAAS agents as antihypertensive therapies (e.g., Type 2 diabetes, global risk management, multiple drug therapy and coronary heart disease) are addressed.     

Postexposure management and treatment of anthrax in dogs—Executive councils of the American academy of veterinary pharmacology and therapeutics and the American college of veterinary clinical pharmacology

Dogs are generally at low risk of developing disease following exposure to anthrax. When disease does occur, it appears associated with oral exposure to the bacteria leading to massive swelling of the head, neck, and mediastinal regions. Death is due to toxemia and shock. For animals at high risk, such as search and rescue dogs with a known exposure, doxycycline at 5 mg/kg orally once daily for 45 to 60 days is suggested as a prophylactic treatment. Additional information on the diagnosis, prevention, and treatment of the disease in dogs is presented.     

Predominantβ-adrenoceptor blocking effect of xamoterol averaged over the day in patients with mild to moderate heart failure: insight into the mechanism of its long-term clinical efficacy

Summary Xamoterol acts as a ₁-adrenoceptor agonist at low sympathetic activity and as an antagonist at high activity. Although its long-term efficacy has been proven in patients with mild to moderate heart failure, it remains unclear which effect, agonism or antagonism, accounts for its long-term activity.To clarify the effect of xamoterol on cardiac sympathetic activity in daily life, 24-h R-R interval histograms were obtained during administration of xamoterol 100 mg b. d. for 1 week to 10 patients with mild to moderate heart failure. Eight normal subjects were also studied as controls. To examine the relation between the effect of xamoterol and sympathetic activity, plasma noradrenaline (NA) levels were measured under 5 graded conditions simulating daily living.Xamoterol administration significantly decreased the standard deviation of the R-R interval, both in patients with heart failure and in normal subjects. The mean R-R interval, however, was increased in patients with heart failure, relative to normal subjects.In both groups, the R-R interval histograms had two peaks, i. e. a short daytime peak and a long night-time peak. Xamoterol decreased the median of the night-time peak without changing the daytime peak in normal subjects. In contrast, it increased the median of the daytime peak without producing a significant change in the nighttime peak in patients with heart failure. Levels of plasma NA were significantly higher in patients than in normal subjects under all conditions.Thus, in normal subjects xamoterol predominantly increased the slower heart rate at night with only a minor effect on the higher heart rate in the daytime, whereas it predominantly attenuated the daytime tachycardia induced by sympathetic stimulation in patients with heart failure.It is concluded that xamoterol tends overall to act as a-adrenoceptor antagonist during the day, especially in the daytime in patients with mild to moderate heart failure. Its antagonist rather than its agonist effect may account for the long-term efficacy of xamoterol in patients with mild to moderate heart failure.     

Clinical pharmacology and efficacy of rotigotine (Neupro® patch) in the treatment of restless leg syndrome

Introduction: Restless legs syndrome/Willis Ekbom disease (RLS/WED) is a sensorimotor disorder characterized by unpleasant sensations in the legs accompanied by an urge to move them, that typically occurs and tend to worsen in the evening/night or during period of inactivity. Standard medications for RLS/WED are dopamine agonists and calcium channel α-2-δ ligands. The clinical spectrum of RLS/WED is very broad, ranging from individuals suffering from the disease during limited periods up to those severely affected, with daily symptoms. In such cases a long-acting drug like rotigotine should be considered.

Areas covered: The clinical pharmacology and efficacy of rotigotine was examined to evaluate the evidence supporting its use in RLS/WED.

Expert opinion: The rotigotine transdermal patch provides constant delivery of the drug, maintaining a stable plasma concentration over 24 hours by means of a single daily application. Several randomized, double-blind, placebo-controlled trials have demonstrated the efficacy of rotigotine in improving moderate-to-severe RLS/WED symptoms. Rotigotine is generally well tolerated. The most common adverse effects were application-site reactions, dose-dependent, more frequently reported in the first period of treatment. Incidence of augmentation in RLS/WED patients treated with oral dopamine agonists is higher when compared with the use of transdermal rotigotine.     

1974–2014: Reflections on the evolution of clinical pharmacology in the past 40 years and a message to our readers

Hypersensitivity reactions including anaphylaxis have been reported for nearly all classes of therapeutic reagents and these reactions can occur within minutes to hours of exposure. These reactions are unpredictable, not directly related to dose or the pharmacological action of the drug and have a relatively high mortality risk. This review will focus on the clinical presentation, immune mechanisms, diagnosis and prevention of the most serious form of immediate onset drug hypersensitivity reaction, anaphylaxis. The incidence of drug-induced anaphylaxis deaths appears to be increasing and our understanding of the multiple and complex reasons for the unpredictable nature of anaphylaxis to drugs is also expanding. This review highlights the importance of enhancing our understanding of the biology of the patient (i.e. immune response, genetics) as well as the pharmacology and chemistry of the drug when investigating, diagnosing and treating drug hypersensitivity. Misdiagnosis of drug hypersensitivity leads to substantial patient risk and cost. Although oral provocation is often considered the gold standard of diagnosis, it can pose a potential risk to the patient. There is an urgent need to improve and standardize diagnostic testing and desensitization protocols as other diagnostic tests currently available for assessment of immediate drug allergy are not highly predictive.     

Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system and proinflammatory cytokines in hypertension

Aims

To explore whether reactive oxygen species (ROS) scavenger (tempol) in the hypothalamic paraventricular nucleus (PVN) attenuates renin–angiotensin system (RAS) and proinflammatory cytokines (PICs), and decreases the blood pressure and sympathetic activity in angiotensin II (ANG II)-induced hypertension.

Methods and results

Male Sprague–Dawley rats were infused intravenously with ANG II (10 ng/kg per min) or normal saline (NS) for 4 weeks. These rats were treated with bilateral PVN infusion of oxygen free radical scavenger tempol (TEMP, 20 μg/h) or vehicle (artificial cerebrospinal fluid, aCSF) for 4 weeks. ANG II infusion resulted in increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA). These ANG II-infused rats also had higher levels of gp91^phox (a subunit of NAD(P)H oxidase), angiotensin-converting enzyme (ACE), and interleukin-1beta (IL-1β) in the PVN than the control animals. Treatment with PVN infusion of TEMP attenuated the overexpression of gp91^phox, ACE and IL-1β within the PVN, and decreased sympathetic activity and MAP in ANG II-infused rats.

Conclusion

These findings suggest that ANG II infusion induces elevated PICs and oxidative stress in the PVN, which contribute to the sympathoexcitation in hypertension. Inhibition of reactive oxygen species in hypothalamic paraventricular nucleus attenuates the renin–angiotensin system, proinflammatory cytokines and oxidative stress in ANG II-induced hypertension.     

The clinical efficacy and abuse potential of combination buprenorphine–naloxone in the treatment of opioid dependence

Background: Opioid dependence is a chronic relapsing condition for which long-term opioid substitution treatment (OST) is effective. However, safety and community acceptance of OST is compromised by diversion of prescribed medication. The development of a formulation combining buprenorphine and naloxone is designed to reduce the likelihood of intravenous misuse, and the therefore the value of the medication if diverted to the black market. Objective: To evaluate the evidence for 4:1 buprenorphine–naloxone as an efficacious OST, and as a deterrent to diversion and intravenous misuse. Methods: The literature on buprenorphine–naloxone in a 4:1 ratio is reviewed. Results/conclusion: The addition of naloxone does not appear to affect the efficacy of buprenorphine as a maintenance drug. While offering some deterrence of injection through precipitated withdrawal, there are many circumstances where injecting of buprenorphine–naloxone is reinforcing rather than aversive. The combination will reduce, but not eliminate, intravenous misuse; clinicians therefore need to monitor patients in OST, and be selective in providing patients with medication to be taken without observation.     

Adverse effects of neuromuscular blocking agents based on yellow card reporting in the U.K.: are there differences between males and females?

BACKGROUND: Adverse drug reactions (ADRs) are known to occur during anaesthesia; in the U.K. such ADRs may be reported through the Yellow Card Scheme (YCS). Our aim was to determine the demographics of ADRs to neuromuscular blocking drugs without formal causality assessment. METHODS: A retrospective analysis of ADRs to seven neuromuscular blocking drugs reported via the YCS during a greater than 30-year period was performed. Sex and age were analysed in order to identify at risk groups. RESULTS: Of 998 reports, 969 included gender. Non-allergic suspected reactions occurred with almost the same frequency as those with an allergic component. The majority occurred in females 676 (70%), and significant sex differences were measured between drugs. Males were more likely to have suffered an ADR to atracurium (p = 0.01) whilst females experienced more ADRs to suxamethonium (p = 0.01). ADRs proved fatal in 81 (9%) of the 950 reports for single drugs. Mortality following suxamethonium was significantly higher in males at 22% compared with 9% females (p < 0.001). More women than men were reported to have allergic reactions, 73% (362/499) compared with 27% (137/499) respectively. The female:male ratio for ADRs was reversed for subjects < 10 years compared with peak ADR reports during the decade from 31-40 years. CONCLUSIONS: Sex differences in mortality exist in this analysis. The unexpected high frequency of non-allergic ADRs suggests that morbidity and mortality from reactions to established drugs is twice that expected from allergic reactions alone. Standards and guidance for the reporting of ADRs warrant urgent development.     

Pharmacokinetics,pharmacodynamics, and clinical efficacy of albuterol RespiClick™ dry-powder inhaler in the treatment of asthma

Introduction: Incorrect use of inhaler devices by patients with asthma is common and can adversely affect clinical outcomes. Devices that are straightforward to use are less likely to result in dosing errors and can improve patients’ satisfaction with therapy and adherence. A novel dry-powder formulation of the rescue bronchodilator albuterol (salbutamol) administered using a multidose dry-powder inhaler (mDPI; RespiClick?) has recently been approved in the USA.

Areas covered: Studies on the albuterol mDPI were identified in searches of PubMed and www.clinicaltrials.gov. Pharmacokinetic, pharmacodynamic, efficacy, and safety data, and patients’ experiences with the albuterol mDPI are presented.

Expert opinion: The albuterol mDPI has an efficacy/tolerability profile consistent with other inhaled forms of albuterol, and is reliable, easy to use, and associated with a high level of patient satisfaction. This is the first albuterol dry-powder inhaler (DPI) to become available in the USA, with most other formulations being delivered using a pressurized metered-dose inhaler (pMDI). The availability of a breath-actuated device avoids the challenge of coordinating actuation and breathing when using pMDIs, and could simplify treatment for patients also using a DPI for controller medication. Additional features of RespiClick, such as an integrated dose counter and minimal pre-inhalation preparation, facilitate its use.     

Cardiovascular safety of oncologic agents: a double-edged sword even in the era of targeted therapies – Part 2

Introduction: Patients with cancer are subject to the cardiotoxic effects of cancer therapy. Improved cancer treatments lead to more cancer-survivors, who though are exposed to various forms of cardiovascular (CV) disease (CVD) as they age. Aging patients are at increased risk of developing both malignancy and CVD or they may have survived some form of CVD as a result of effective CV treatments. Furthermore, patients with CVD may develop cancer and require treatment (and vice versa), all contributing to increased morbidity and mortality. The prevalence of both malignancy and CVD will increase due to the trend toward a longer lifespan.

Areas covered: In part 2 of this review, the discussion of the CV effects of specific oncology drugs is completed with inclusion of additional immunological agents, current hormonal and other agents. Early detection and monitoring of cardiotoxicity, use of biomarkers and other imaging and diagnostic methods and prevention and treatment options are also discussed.

Expert opinion: As outlined in part 1 of this review, oncologists need to be aware of the CV adverse-effects of their treatments and make careful and expectant clinical decisions, especially in patients with preexisting CVD or CV risk factors. Similarly, cardiologists should consider a detailed previous history of treatment for malignant disease, including prior chemotherapy exposure, dose(s) received, and/or combined modality therapy with chest radiotherapy. Both specialists should collaborate in order to minimize the impact of these two ubiquitous diseases (cancer and CVD) and mitigate the adverse effects of treatment modalities.     

Valproic acid prevents the deregulation of lipid metabolism and renal renin–angiotensin system in l-NAME induced nitric oxide deficient hypertensive rats

The present study was aimed to investigate the antihyperlipidemic and renoprotective potential of valproic acid against N^ω-nitro-l arginine methyl ester hydrochloride (l-NAME) induced hypertension in male albino Wistar rats. In hypertensive rats, mean arterial pressure (MAP), kidney weight, levels of oxidative stress markers in tissues were increased. Dyslipidemia was also observed in hypertensive rats. Moreover, enzymatic and nonenzymatic antioxidant network also deregulated in tissues. Valproic acid (VPA) supplementation daily for four weeks brought back all the above parameters to near normal level and showed no toxicity which was established using serum hepatic marker enzyme activities and renal function markers. Moreover the up regulated expression of renin–angiotensin system (RAS) components were also attenuated by VPA treatment. All the above outcomes were confirmed by the histopathological examination. These results suggest that VPA has enough potential to attenuate hypertension, dyslipidemia and renal damage in nitric oxide deficiency induced hypertension.