Preventable suicides involving medicines: A systematic case series of coroners' reports in England and Wales.

Background: In England and Wales coroners have a duty to write a report, called a Prevention of Future Deaths report or PFD, when they believe that actions should be taken to prevent future deaths. Coroners send PFDs to individuals and organisations who are required to respond within 56 days. Despite the increase in mental health concerns and growing use of medicines, deaths reported by coroners that have involved medicine-related suicides had not yet been explored. Therefore, this study aimed to systematically assess coroners' PFD reports involving suicides in which a medicine caused or contributed to the death to identify lessons for suicide prevention. Methods: Using the Preventable Deaths Tracker database (https://preventabledeathstracker.net/), 3037 coroners' PFD reports in England and Wales were screened for eligibility between July 2013 and December 2019. Reports were included if they involved suicide or intentional self-harm and prescribed or over-the-counter medication; illicit drugs were excluded. Following data extraction, descriptive statistics, document and content analysis were performed to assess coroners' concerns and the recipients of reports. Results: There were 734 suicide-related coroner reports, with 100 (14%) reporting a medicine. Opioids (40%) were the most common class involved, followed by antidepressants (30%). There was wide geographical variation in the writing of reports; coroners in Manchester wrote the most (18%). Coroners expressed 237 concerns; the most common were procedural inadequacies (14%, n = 32), inadequate documentation and communication (10%, n = 22), and inappropriate prescription access (9%, n = 21). 203 recipients received the PFDs, with most sent to NHS trusts (31%), clinical commissioning groups (10%), and general practices (10%), of which only 58% responded to the coroner. Conclusions: One in four coroner reports in England and Wales involved suicides, with one in seven suicide-related deaths involving a medicine. Concerns raised by coroners highlighted gaps in care that require action from the Government, health services, and prescribers to aid suicide prevention. Coroner reports should be routinely used and monitored to inform public health policy, disseminated nationally, and responses to coroners should be transparently enforced so that actions are taken to prevent future suicides.

Cloning and expression of an endothelin receptor subtype B from human prostate that mediates contraction.

Recent evidence suggests a role for endothelin (ET) in contraction of human prostate [J. Urol. 149:495-499 (1993)]. Although both ETA and ETB receptors have been shown to mediate contraction of smooth muscle, the molecular identity of the contractile ETB receptor is controversial. The aim of this study was to examine the receptor subtype that mediates ET-induced contraction in prostate from patients with benign prostatic hyperplasia. Saturation binding with 125I-ET-1 and 125I-ET-3 in prostate stromal cells (PSC) indicated the presence of receptors with subnanomolar affinity for these radioligands, with equivalent receptor densities. Inhibition of specific 125I-ET-1 or 125I-ET-3 binding in PSC revealed a rank order of potency of ET-1 - ET-3 = sarafotoxin S6c >> BQ-123. These data are consistent with a predominance of ETB receptors in PSC. The functional effects of ET stimulation of PSC were examined in a collagen gel contraction assay. ET-1 and ET-3 caused contraction of underlying collagen gel matrices with EC50 values of 0.4 +/- 0.04 and 0.7 +/- 0.2 nM, respectively. To determine the molecular nature of the contractile ETB receptor in PSC, reverse transcription-polymerase chain reactions were conducted with oligonucleotide primers to the 5' and 3' ends of the coding sequence of the full length human ETB receptor. DNA sequence analysis of the 1.3-kilobase DNA product showed 99% homology to other human ETB receptor cDNAs. The encoded protein has a deduced amino acid sequence identical to that of other human ETB receptors, with the exception of two conservative substitutions. Expression of the PSC ETB cDNA in COS-7 cells resulted in a binding profile similar to that observed in parent cells. Polymerase chain reaction analysis revealed the presence of prepro-ET-1 mRNA in PSC. Collectively, these data indicate that PSC from patients with benign prostatic hyperplasia express ETB receptors that mediate ET-induced contraction.

Salmeterol, a novel, long-acting beta 2-adrenoceptor agonist: characterization of pharmacological activity in vitro and in vivo.

1. Salmeterol, a novel, long-acting beta-adrenoceptor agonist, has been compared with isoprenaline and salbutamol for activity in vitro on a range of beta-adrenoceptor containing preparations from laboratory animals and man, and in vivo for bronchodilator activity in the conscious guinea-pig. 2. Salmeterol, like isoprenaline and salbutamol, relaxed preparations of both guinea-pig trachea (contracted by prostaglandin (PG)F2alpha or electrical stimulation) and human bronchus (contracted by PGF 2 alpha) in a concentration-related fashion. Salmeterol was of similar potency to isoprenaline and more potent than salbutamol on both airway preparations. 3. Relaxant responses of superfused guinea-pig trachea and human bronchus to isoprenaline and salbutamol declined rapidly when the agonists were washed from the tissues, with complete recovery within 10 min, whereas responses to salmeterol were more persistent. In electrically-stimulated guinea-pig trachea preparations, inhibition by salmeterol persisted for periods of up to 12h, despite continuous superfusion with agonist-free medium. However, these persistent responses were rapidly and fully reversed by the beta-adrenoceptor blocking drug, propranolol (0.1 microM). In further studies on guinea-pig trachea, propranolol caused concentration-related parallel, rightward shifts of salmeterol concentration-effect curves, yielding a pA2 of 9.0. The slope of the Schild plot was 1.02. 4. Another beta-adrenoceptor blocking drug, sotalol (10 microM), also fully and rapidly reversed established submaximal responses to salmeterol in superfused guinea-pig trachea. However, after administration of sotalol was stopped, the antagonism waned, and salmeterol responses were reasserted without the addition of further agonist. 5. In the beta 1-adrenoceptor containing preparation, rat left atria, isoprenaline exhibited potent, concentration-related, positive inotropic activity, whereas salbutamol and salmeterol were at least 2000-5000 fold less potent, and appeared to be partial agonists. At a concentration of 72 microM, salmeterol exhibited weak antagonism of isoprenaline-induced increases in atrial force of contraction. This antagonism was less marked than that caused by salbutamol (42 microM).6. On the guinea-pig isolated gastric fundus strip, a putative beta3-adrenoceptor containing preparation, salbutamol and salmeterol had only modest agonist activity, being 20-30 fold less potent than isoprenaline and the selective ,beta3-adrenoceptor agonist, BRL 35135.7. In conscious guinea-pigs, inhaled salmeterol and salbutamol were approximately equipotent in causing dose-related bronchodilatation. Whereas the duration of action of salbutamol at its threshold-effective dose was less than 90min, the responses to a similarly effective dose of salmeterol were well-maintained for at least 6 h.8. Salmeterol is therefore a potent and selective beta2-adrenoceptor agonist with a remarkably long duration of action in isolated superfused airways smooth muscle. It also causes persistent bronchodilatation in vivo, in the guinea-pig, when administered by the inhaled route.

Anti-ischemic activity of the novel benzazepine calcium antagonist SQ 31,486.

We tested the benzazepine, SQ 31,486 for its ability to selectively block the voltage-dependent calcium channel and to protect the ischemic myocardium. SQ 31,486 was found to be a selective calcium antagonist in vascular tissue with an IC50 value of 1.5 microM in KCl-contracted rabbit aorta. SQ 31,486 decreased contractile function and increased coronary flow in nonischemic isolated rat hearts in a concentration-dependent manner. SQ 31,486 also significantly reduced postischemic lactate dehydrogenase (LDH) release and end-diastolic pressure (EDP) compared to vehicle. Reperfusion double product [heart rate (HR) x left ventricular developed pressure (LVDP)] was also significantly improved by SQ 31,486. Diltiazem was a less potent anti-ischemic agent and was significantly more cardiodepressant relative to its anti-ischemic efficacy than was SQ 31,486. Thus, SQ 31,486 should have a larger therapeutic index. In a model of pacing-induced myocardial ischemia in anesthetized, open chest dogs, SQ 31,486 reduced pacing-induced ST-segment elevation approximately 50% at 10, 40, and 70 min after drug administration. This protective effect occurred despite a lack of effect of SQ 31,486 on ischemic regional blood flow and peripheral hemodynamic status.

Approaches to a long-acting, selective beta 2-adrenoceptor stimulant.

Selected beta 2-stimulants were sought that would stick more firmly than salbutamol at their sites of action on the beta 2-adrenoceptor protein in the cell membrane. Of the substance synthesized and tested it was concluded that salmeterol represented a new class of beta 2-stimulants that because of their exceptionally long duration of action have potential clinical advantages over current available beta 2-stimulants in the treatment of asthma.

Perinephritis hypertension in Macaca fascicularis (cynomolgus monkey): studies of the renin-angiotensin-aldosterone axis and renal hemodynamic function.

The purpose of the present study was to characterize the etiology of bilateral perinephritis hypertension in the non-human primate. Hypertension was induced in female cynomolgus (Macaca fascicularis) monkeys by wrapping both kidneys under sterile surgical procedures. Mean arterial pressure (MAP), plasma renin activity (PRA), plasma aldosterone concentration (ALDO), para-aminohippurate (PAH) clearance, glomerular filtration rate (GFR), urine volume, and sodium and potassium excretion were measured before and weekly after induction of the hypertension. MAP increased progressively from 108 +/- 1 to 135 +/- 4 mmHg during the first 6 weeks; thereafter, MAP remained at this elevated level, PRA was elevated two- to fivefold for up to 10 weeks after the hypertension and ALDO was elevated during 1 (139%), 4 (60%), 6 (196%), 8 (249%) and 10 (148%) weeks of the hypertension. PAH clearance and GFR were significantly reduced during week 1 of the hypertension, but returned to control values by week 2. Urine volume was increased significantly during the first week of the hypertension, while sodium and potassium excretion were not changed. Captopril (15 mumol/kg, intravenously) normalized the blood pressure regardless of the severity or duration of the disease. Additionally, captopril lowered ALDO and increased PRA. It is concluded that bilateral perinephritis hypertension in the monkey is dependent on increased activity of the renin-angiotensin-aldosterone axis.

AH23848: a thromboxane receptor-blocking drug that can clarify the pathophysiologic role of thromboxane A2.

Despite numerous suggestions in the literature that thromboxane A2 is involved in a variety of occlusive vascular diseases, no definitive evidence is available. Arguments have been presented to support the view that such evidence can only come from clinical studies with a highly specific thromboxane receptor-blocking drug. We have now identified such a drug, AH23848, in our laboratories. Preliminary experiments with AH23848, ([1 alpha (Z), 2 beta,5 alpha]-(+/-)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-2-(4-morpholin yl)-3-oxocyclopentyl]-4-heptenoic acid), show that it is a potent, specific thromboxane receptor-blocking drug that is orally active and has a long duration of action. It should be a valuable tool in elucidating any physiologic or pathologic role of thromboxane A2.

Neural and Pavlovian influences on immunity.

The traditional view that the nervous and immune systems are functionally independent (aside from general stress effects and autoimmune disorders of the nervous system) is being challenged by a new view that the nervous system regulates the activity of the immune system. If this is true, it should be possible to change the activity of the immune system by means of Pavlovian conditioning, just as it is possible to condition other physiological events influenced by the autonomic nervous system or neuroendocrine substances. Evidence for autonomic and neuroendocrine modulation of immune activity is briefly reviewed; and, the various studies reporting conditioned immune effects, the physiological mechanisms most likely involved, and their possible significance are discussed.

Pharmacological basis for the induction of gastric carcinoid tumours in the rat by loxtidine, an insurmountable histamine H2-receptor blocking drug.

The very late occurrence of gastric carcinoids in a life-span carcinogenicity study with loxtidine in the rat might have resulted from continuous achlorhydria induced by this long-acting unsurmountable histamine H2-antagonist. The nature of the anti-secretory activity of loxtidine was compared with that of ranitidine on histamine-induced acid secretion in the perfused stomach preparation of the rat and in the rat isolated gastric mucosa preparation. Ranitidine and loxtidine had qualitatively different inhibitory effects on acid secretion, ranitidine being a competitive antagonist of histamine even at high concentrations, whereas the effect of loxtidine on both preparations was unsurmountable at relatively low concentrations. These results support the hypothesis that the late formation of gastric carcinoids in rats receiving loxtidine is a consequence of persistent achlorhydria caused by unsurmountable blockade of parietal cell H2-receptors.

Histamine H2-antagonists--past, present and future.

In this selective review of histamine H2-antagonists, we emphasize the significance of burimamide, the first specific H2-antagonist, in physiology and pharmacology and describe how its discovery led to the development of cimetidine as a new treatment of acid-aggravated disease of the alimentary tract. Developments since cimetidine, include ranitidine, which is a more potent, selectively acting H2-antagonist. A new series of H2-blockers with prolonged activity is discussed, and exemplified, particularly AH 23844. Its prolonged action and its unusual, apparently insurmountable, blocking action is explained in fundamental physicochemical terms.

The alpha- and beta-adrenoceptor blocking potencies of labetalol and its individual stereoisomers in anaesthetized dogs and in isolated tissues.

1 The antagonist potencies of labetalol and each of its four stereoisomers have been compared at alpha 1-, beta 1- and beta 2-adrenoceptors in anaesthetized dogs and in isolated tissues. 2 The RR stereoisomer is a potent, non-selective antagonist at beta-adrenoceptors but has only weak alpha 1-adrenoceptor blocking activity. 3 The SR stereoisomer was the most potent antagonist at alpha 1-adrenoceptors, and it also had similar potency as an antagonist at beta-adrenoceptors. 4 The alpha- and beta-adrenoceptor blocking profile of the RS stereoisomer is intermediate between that of the RR and SR, but the SS stereoisomer is a relatively weak antagonist at both alpha- and beta-adrenoceptors. 5 It is concluded that, although most of the alpha 1-adrenoceptor blocking activity of labetalol is attributable to the SR stereoisomer and nearly all of its beta-adrenoceptor blocking activity resides in the RR stereoisomer, each of the stereoisomers contributes to the overall pharmacological profile of labetalol.

A review of the animal pharmacology of ranitidine--a new, selective histamine H2-antagonist.

The animal pharmacology and metabolism of ranitidine have been reviewed. Experiments using guinea-pig isolated right atrium and ileum preparations have shown that ranitidine is a selective, potent, and competitive histamine H2-receptor antagonist. In the conscious dog gastric acid secretion induced by histamine, pentagastrin, bethanechol and food was inhibited by ranitidine at doses 4 to 12 times lower than equi-effective doses of cimetidine. Ranitidine inhibited the formation of aspirin-induced gastric lesions, both in the presence and absence of gastric acid. Unlike cimetidine, ranitidine neither possessed anti-androgenic activity, nor did it inhibit the mixed function oxygenase metabolizing enzyme system in the liver. Ranitidine has been recommended for clinical trial in the treatment of peptic ulcer disease.

Informed consent 1980.

The right of a patient, in most cases, to have the final authority to consent to a treatment, operation, or diagnostic procedure is guaranteed by 200 years of legal precedent. The right of that same patient to be adequately informed so that the decision is entirely his or her own seems to be equally well protected. It is unlikely that the medical profession can find a mechanical solution to the problem. That intangible patient-physician relationship must be developed to the point where there is a true interchange of the same information a physician would use to consent to undergo such a procedure or agree to it for a loved one. Finally, the physicians must decide, on the basis of their experience, the literature, personal attorney input, and other sources, the best method of documenting that moment when truly informed consent has been obtained.