Orthostatic hypotensive effect of antipsychotic drugs in Wistar rats by in vivo and in vitro studies of alpha1-adrenoceptor function.

RATIONALE: Many antipsychotics cause orthostatic hypotension possibly due to antagonist action on resistance vessel alpha1A-adrenoceptors (alpha1A-AR). OBJECTIVE: We have tested this possibility by determining in Wistar rats how the orthostatic hypotensive effect of several antipsychotic drugs compares with their affinity for adrenoceptors in mesenteric small arteries (MSA with mainly alpha1A-AR) and aorta (mainly alpha1D-AR). MATERIALS AND METHODS: Using a tilt setup, orthostatic hypotension was measured in anaesthetized rats for prazosin and the antipsychotics haloperidol, sertindole, risperidone, clozapine, ziprasidone, domperidone, olanzapine, and aripiprazole. For in vitro studies, segments of MSA and aorta were mounted on a wire myograph for isometric tension recording. Cumulative concentration-response curves were constructed to phenylephrine (PE) in the absence and presence of the drugs. Apparent affinity (pA2) was calculated by Schild analysis. RESULTS: Prazosin antagonized tilt-induced and PE responses in both studies (threshold 4 ng/ml, pA2 9.52 MSA, 10.1 aorta). The rank order of the potency of the antipsychotics in the tilt experiments correlated (r2 = 0.69, P = 0.01) with the pA2-values in MSA: Risperidone and sertindole had the highest potency in the tilt test (threshold 159 and 97 ng/ml) and the highest apparent affinity in MSA (pA2 8.92 and 8.78), in contrast with aripiprazole and domperidone, which had the lowest in each case (threshold 4.1 and 3.0 microg/ml, pA2 7.17 and 6.99). In aorta, the pA2 values did not correlate with the in vivo potencies; in particular, sertindole had no functional affinity in aorta. CONCLUSION: We conclude that the orthostatic hypotensive effect in rats of the antipsychotic drugs investigated is mediated through alpha1A-ARs.

An overview of the safety pharmacology society strategic plan.

Safety Pharmacology studies are conducted to characterize the confidence by which biologically active new chemical entities (NCE) may be anticipated as safe. Non-clinical safety pharmacology studies aim to detect and characterize potentially undesirable pharmacodynamic activities using an array of in silico, in vitro and in vivo animal models. While a broad spectrum of methodological innovation and advancement of the science occurs within the Safety Pharmacology Society, the society also focuses on partnerships with health authorities and technology providers and facilitates interaction with organizations of common interest such as pharmacology, physiology, neuroscience, cardiology and toxicology. Education remains a primary emphasis for the society through content derived from regional and annual meetings, webinars and publication of its works it seeks to inform the general scientific and regulatory community. In considering the future of safety pharmacology the society has developed a strategy to successfully navigate forward and not be mired in stagnation of the discipline. Strategy can be defined in numerous ways but generally involves establishing and setting goals, determining what actions are needed to achieve those goals, and mobilizing resources within the society to accomplish the actions. The discipline remains in rapid evolution and its coverage is certain to expand to provide better guidance for more systems in the next few years. This overview from the Safety Pharmacology Society will outline the strategic plan from 2016 to 2018 and beyond and provide insight into the future of the discipline which builds upon a previous strategic plan established in 2009.

The Benefits of Streamlined Hip Fracture Management in a Regional Hospital.

INTRODUCTION: Hip fracture is an increasingly common injury in the growing elderly population. The morbidity and mortality associated with this injury can be reduced by minimizing delays to surgical treatment. We describe the impact of a regional hospital service redesign project that utilized the principles of smart simplicity, a management strategy that lays emphasis on collaboration to achieve desired goals. METHODS: Prior to the redesign, patients with hip fractures were taking an average of 72 hours for surgical treatment. A hip fracture working group was created to examine closely the process of hip fracture care, and a single key performance indicator (KPI) of "surgery within 48 hours" was adopted. This allowed identification of processes that could be clarified and streamlined, with the agreement of relevant stakeholders, in the creation of a new hip fracture pathway. RESULTS: In the first 3 months of the pathway's implementation, 16 of 18 patients had surgery within 48 hours of presentation. In a 6-month follow-up audit after 2 years of implementation, 36 of 39 patients were treated within 48 hours. This was significantly different to the time to surgery seen in the 12 months prior to the redesign (P < .001, Student t test). The mean time to surgery was reduced from 72 hours to 36 hours, a saving in an annual acute bed stay cost of A$152 000. DISCUSSION: Decreased time to the operating room, the cost savings inherent to this, can be achieved with the introduction of the best standard of care. A redesign that mandates collaboration in achieving a single KPI has allowed a significant culture shift in the treatment of hip fractures in our institution in the months following its institution. CONCLUSION: Collaborative, multidisciplinary collaboration has facilitated a higher standard of care and demonstrated significant cost benefit.

Chronic treatment with antipsychotics in rats as a model for antipsychotic-induced weight gain in human.

Several clinical reports have demonstrated that most antipsychotics of the new generation, but not the typical antipsychotic haloperidol, induce weight gain in schizophrenic patients. Since weight gain induces serious health complications in humans, it is crucial to test upcoming antipsychotic compounds in an animal model of weight gain. With the aim of evaluating whether the rat can be used as a model for antipsychotic-induced weight gain, we have investigated the effect of chronic treatment (3 weeks) with one antipsychotic drug inducing weight gain in clinic (olanzapine) and one antipsychotic not inducing weight gain in clinic (haloperidol), on food and water intake and body weight gain in rats. We included both female and male rats in this study. To reduce spontaneous high food intake in rats, and to be able to evaluate the treatment effect on a potential increase of food intake or metabolic changes, we allowed animal to receive only low-palatability chow. In male rats, none of the two compounds induced weight gain, but in female rats, both compounds induced weight gain. Consequently, the effect observed in rats does not match the clinical situation, and Wistar rats in this set-up cannot be considered a relevant model for antipsychotic-induced weight gain in humans.

Species differences in expression of angiotensin II receptors and angiotensin-converting enzyme in human, canine and rat mitral valve leaflets.

In normal valvular collagen turnover in the rat, angiotensin (Ang) II and angiotensin-converting enzyme (ACE) seem to be involved. In common human and canine valvular diseases, changes in valvular collagen play a pathogenetic role and the valvular renin-angiotensin system is therefore of particular interest in these species. Healthy mitral valve leaflets and adjacent left ventricular myocardium were taken from five rats and five dogs immediately after euthanasia, and from five humans at autopsy. The valvular and myocardial Ang II receptors and ACE were detected and measured by quantitative autoradiography. In rat valves, high levels of Ang II receptors and ACE were found. In human and canine valves, insignificant levels were found. Significant myocardial levels of Ang II receptors and ACE were found only in the rat. The study demonstrated major species differences regarding the level of valvular and myocardial Ang II receptors and ACE in man, dog and rat. The lack of valvular Ang II receptors and ACE in man and dog, suggest that the renin-angiotensin system plays a minor, if any, role in the physiological valvular collagen formation in these two species. The findings in humans, however, need to be confirmed using fresh material.

Neuroendocrine changes in Dachshunds with mitral valve prolapse examined under different study conditions.

Neuroendocrine changes associated with canine mitral valve prolapse (MVP) were studied in 159 Dachshunds older than two years. In study 1, 102 dogs were sampled without controlling diet or fasting period. In good accordance with human findings, the MVP severity correlated positively with plasma renin activity and tended to correlate negatively with plasma aldosterone. These findings were not attributable to any coexistent mitral regurgitation (MR). In study 2, in which diet and fasting period were controlled, 57 Dachshunds younger than seven years were sampled twice through an i.v. cannula: once after approximately 15 minutes in lateral recumbency and again after 10 minutes of walking. In both study 2 settings, neither MVP nor MR correlated significantly with plasma levels of renin, aldosterone, angiotensin-converting enzyme, norepinephrine, epinephrine, or cortisol. We conclude that the increased renin release found in early canine mitral disease is not reproducible under all study conditions, and that it correlates with the severity of MVP and not of MR.

Auscultation in mild mitral regurgitation in dogs: observer variation, effects of physical maneuvers, and agreement with color Doppler echocardiography and phonocardiography.

Observer variation in diagnosing mild mitral regurgitation in dogs by cardiac auscultation was assessed by having 6 veterinarians with different levels of experience examine 57 Cavalier King Charles Spaniels. Comparisons with color Doppler echocardiography and phonocardiography were made, and the effects of 2 physical maneuvers on the auscultatory findings were evaluated. Using mildly diseased dogs, interobserver agreement in diagnosing the presence or absence of left-sided murmurs ranged from 63% to 88%. The agreement with phonocardiography (range, 53-91%) increased with the amount of observer experience. The 2 most experienced observers could discern soft ejection murmurs from regurgitant murmurs and were able to diagnose 89% of the dogs with regurgitant jets larger than 30% of the left atrial area. In general, less experienced observers diagnosed most jets larger than 50%. In many dogs with small jets, no murmur was found by auscultation and phonocardiography. The audibility of mild regurgitation was significantly reduced in dogs that were difficult to auscultate. Early systolic murmurs were typical of mild regurgitation, whereas holosystolic murmurs typified severe regurgitation. In a few dogs, late systolic murmurs alternated with holosystolic murmurs. Systolic clicks were found phonocardiographically in 18 dogs with mild to moderate regurgitation, but the audibility apparently was low. In many mildly affected dogs, physical maneuvers increased murmur intensity. Thus, some form of dynamic auscultation might facilitate the diagnosis of mild regurgitation. Auscultatory findings in mild regurgitation appear to depend on observer experience, circulatory status, and how difficult the dog is to auscultate.

Heart rate variability in young, clinically healthy Dachshunds: influence of sex, mitral valve prolapse status, sampling period and time of day.

OBJECTIVE: This study investigatest the influence of sampling period duration, time of day, age, sex, body weight and degree of mitral valve prolapse (MVP) on various measures of heart rate variability (HRV) in the dog. The correlations between the HRV parameters were also investigated. BACKGROUND: Holter recording is increasingly being used in dogs but method studies are sparse. Previous studies suggest that canine MVP is related to a high vagal tone. METHODS: Twenty-four hour ambulatory electrocardiographic recording (Holter recording) was performed on 24 Dachshunds (11 males and 13 females). All dogs were between 2 and 6 years of age and without heart murmurs. RESULTS: The majority of the HRV parameters depended on the duration of the sampling period and they generally exhibited circadian variation. Higher values in males than in females were found for several parameters, especially low frequency power (LF) during 24 hour recording (P = 0.0002). Although a number of HRV parameters correlated positively with MVP severity and negatively with age, the influence of these two factors was not clear and consistent in all sampling periods. The degree of MVP related to the number of episodes of supraventrucular tachycardia occuring during the day. Generally, a large inter-individual variation was found with regard to the HRV parameters and the correlations between the parameters were weaker than correlations reported in humans. Two manually measured ECG parameter related to vagal tone correlated strongly with 2 out of 3 vagal indexes derived from the HRV analysis. CONCLUSION: HRV parameters are influenced especially by sex and sampling period duration, but also by age and MVP status in young, clinically healthy Dachshunds.

Hypomagnesemia and mitral valve prolapse in Cavalier King Charles spaniels.

There is a high incidence of mitral valve prolapse (MVP), an abnormal displacement of one or both mitral valve leaflets during systole, in Cavalier King Charles Spaniels (CKCS). In humans, MVP is known to be associated with a low magnesium status. In this study, the plasma magnesium concentration was measured in 30 CKCS without heart failure. It was also investigated whether MVP-severity and degree of regurgitation correlated with plasma magnesium and a number of parameters of the renin-angiotensin system, and whether 4 weeks magnesium supplementation affected plasma magnesium or the high renin/low aldosterone profile associated with MVP. A high prevalence of hypomagnesemia was observed: plasma concentrations < 0.70 mmol/l were found in 15 dogs (50%) before and in 12 dogs (40%) after 4 weeks magnesium supplementation. The mean plasma level was 0.69 +/- 0.07 mmol/l before and 0.71 +/- 0.07 mmol/l after magnesium (P = 0.22). Plasma magnesium concentrations did not correlate with MVP-severity and degree of regurgitation. Plasma aldosterone levels correlated negatively with MVP-severity and positively with the degree of regurgitation, and serum angiotensin-converting enzyme activities correlated negatively with the degree of regurgitation. Magnesium supplementation had no effects on renin and aldosterone nor on the ratio between the two. In conclusion, many CKCS without heart failure have hypomagnesemia whether they are fed supplementary magnesium or not--a finding which may be associated with the high prevalence of MVP in this breed. Further studies, however, are needed to clarify the role of a low magnesium status in canine MVP.

Increased endothelin-receptor density in myxomatous canine mitral valve leaflets.

In dogs and humans, myxomatous mitral valve disease results in mitral valve prolapse and mitral regurgitation. Diseased leaflets display endothelial damage, which in turn might lead to subendothelial growth through release of paracrine mediators such as endothelin-1. The aim of the study was to investigate the presence and distribution of endothelin receptors and relate these to the presence and severity of myxomatous valve disease in the dog. Valves with clear macroscopic signs of disease were taken at postmortem from five old dogs. Control valves without macroscopic signs of disease were taken from five young dogs. Endothelin receptors in the leaflets were examined by using radiolabeled endothelin-1 detected by autoradiography. The endothelin-receptor density was graded semiquantitatively. To determine disease severity, adjacent sections stained with periodic acid-Schiff (PAS)/Alcian blue were examined histologically. The leaflet thickness was measured, and the mucopolysaccharide deposition, collagen degeneration, and fibrosis were graded semiquantitatively. Diseased areas displayed high endothelin-receptor densities; normal-looking areas showed low densities. The endothelin-receptor density within as well as on the leaflets correlated positively with all four measures of disease severity in the distal most affected third of the cusps, suggesting that endothelin plays a pathogenetic role in canine myxomatous mitral valve disease.

No expression of angiotensin II receptors and angiotensin-converting enzyme in myxomatous canine mitral valve leaflets. An autoradiographic study.

The renin-angiotensin system, including angiotensin (Ang) II and angiotensin-converting enzyme (ACE), plays an important role in cardiac fibrous tissue formation. Since changes in valvular collagen are a central part of myxomatous mitral valve disease in the dog, we speculated that Ang II and ACE might play a role in the pathogenesis of this disease. In 10 mitral valves, five with and five without clear myxomatous changes, the presence and distribution of Ang II receptors and ACE was examined autoradiographically, using 125I-Ang II and 125I-lisinopril, respectively. At postmortem examination, diseased valves were taken from old dogs, control valves from young adult dogs. No significant level of Ang II and lisinopril binding was found in normal as well as diseased valve leaflets. Equally low, insignificant levels of 125I-Ang II binding were found in the myocardium of dogs with and without valvular disease. No significant level of myocardial 125I-lisinopril binding was found. The lack of autoradiographic evidence of Ang II receptors and ACE in normal and diseased canine mitral valve leaflets suggests that the renin-angiotensin system does not play a major role in the pathogenesis of the valvular changes.