Short- and medium-term effects of light to moderate alcohol intake on glycaemic control in diabetes mellitus: a systematic review and meta-analysis of randomized trials.

BACKGROUND: People with diabetes are told that drinking alcohol may increase their risk of hypoglycaemia. AIMS: To report the effects of alcohol consumption on glycaemic control in people with diabetes mellitus. METHODS: Medline, EMBASE and the Cochrane Library databases were searched in 2015 to identify randomized trials that compared alcohol consumption with no alcohol use, reporting glycaemic control in people with diabetes. Data on blood glucose, HbA1c and numbers of hypoglycaemic episodes were pooled using random effects meta-analysis. RESULTS: Pooled data from nine short-term studies showed no difference in blood glucose concentrations between those who drank alcohol in doses of 16-80 g (median 20 g, 2.5 units) compared with those who did not drink alcohol at 0.5, 2, 4 and 24 h after alcohol consumption. Pooled data from five medium-term studies showed that there was no difference in blood glucose or HbA1c concentrations at the end of the study between those who drank 11-18 g alcohol/day (median 13 g/day, 1.5 units/day) for 4-104 weeks and those who did not. We found no evidence of a difference in number of hypoglycaemic episodes or in withdrawal rates between randomized groups. CONCLUSIONS: Studies to date have not provided evidence that drinking light to moderate amounts of alcohol, with or without a meal, affects any measure of glycaemic control in people with Type 2 diabetes. These results suggest that current advice that people with diabetes do not need to refrain from drinking moderate quantities of alcohol does not need to be changed; risks to those with Type 1 diabetes remain uncertain.

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.

Forbidden fruit.

Although citrus fruits prevent and cure scurvy, they may not always be as good for you as you thought.

Diagnostic test guidelines based on high-quality evidence had greater rates of adherence: a meta-epidemiological study.

OBJECTIVES: To determine the association between the quality of guidelines for diagnostic tests (both the quality and reporting and the quality of the evidence underpinning recommendations) and nonadherence. STUDY DESIGN AND SETTING: We conducted a meta-epidemiological study. We previously published a systematic review that quantified the percentage of test use that was nonadherent with guidelines. For the present study, we assessed these guidelines using the Appraisal of Guidelines for Research & Evaluation (AGREE) II tool. We then assessed the quality of evidence underpinning recommendations within these guidelines using Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Linear models were then constructed to determine the association between guideline nonadherence and (1) AGREE II score and (2) GRADE score. RESULTS: There was no significant association between AGREE II score and nonadherent testing (P = 0.09). There was a significant association between GRADE score and nonadherence: recommendations based on low-quality and very low-quality evidence had 38% (P < 0.01) and 24% (P = 0.02) more nonadherent testing, compared with recommendations based on high-quality evidence. CONCLUSION: Diagnostic test guideline recommendations based on high-quality evidence are adhered to more frequently.

Evidence-based guidelines for treating bipolar disorder: Revised third edition recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology guidelines specify the scope and targets of treatment for bipolar disorder. The third version is based explicitly on the available evidence and presented, like previous Clinical Practice Guidelines, as recommendations to aid clinical decision making for practitioners: it may also serve as a source of information for patients and carers, and assist audit. The recommendations are presented together with a more detailed review of the corresponding evidence. A consensus meeting, involving experts in bipolar disorder and its treatment, reviewed key areas and considered the strength of evidence and clinical implications. The guidelines were drawn up after extensive feedback from these participants. The best evidence from randomized controlled trials and, where available, observational studies employing quasi-experimental designs was used to evaluate treatment options. The strength of recommendations has been described using the GRADE approach. The guidelines cover the diagnosis of bipolar disorder, clinical management, and strategies for the use of medicines in short-term treatment of episodes, relapse prevention and stopping treatment. The use of medication is integrated with a coherent approach to psychoeducation and behaviour change.

Increases in Na/K pump numbers in isolated human lymphocytes exposed to lithium in vitro. Reversal by myo-inositol and by inhibitors of protein kinase C and the Na/H antiport.

Lithium (1-8 mM) caused a dose-dependent increase in the number of [3H]ouabain binding sites and in sodium/potassium (Na/K) pump activity in normal lymphocytes after incubation for 72 h. The increase in Na/K pump activity was due to an increase in the Vmax of the pump, with no change in the apparent affinity (Km) for potassium (rubidium). There was no change in the turnover number of the pump and the intracellular sodium concentration fell. The increase in [3H]ouabain binding sites was prevented by the addition of myo-inositol (10 mM), by inhibition of the protein kinase C with staurosporine (100 nM) and by inhibition of the Na/H antiport with dimethylamiloride (50 microM). These results suggest that the increase in Na/K pump activity caused by lithium is due to an increase in pump numbers and not due to increased activity of individual pumps or to an alteration in the affinity of the pumps for potassium. The increase in Na/K pump numbers and activity in lymphocytes exposed to lithium for 72 h may be related to altered Na/H antiport activity secondary to inhibition of phosphoinositol breakdown by lithium.

The effect of beta 2-adrenoceptor stimulation and blockade of L-type calcium channels on in vivo Na+/H+ antiporter activity in rat skeletal muscle.

We have studied the in vivo response of the Na+/H+ antiporter in skeletal muscle to beta 2-adrenoceptor stimulation with isoprenaline and the effect of blocking L-type calcium channels with nifedipine. Na+/H+ antiporter activity in skeletal muscle in vivo increased after beta 2-adrenoceptor stimulation with isoprenaline; nifedipine attenuated that effect. This suggests that opening of L-type calcium channels is necessary for full activation of the Na+/H+ antiporter in skeletal muscle. Bleeding also increased Na/H+ antiporter activity, which we believe could be explained by an increase in sympathetic nervous system activity as a result of hypotension. This may be one of the mechanisms by which animals under stress prepare their skeletal muscle for exercise as part of the 'fright and flight' reaction.

The effects of a low extracellular concentration of potassium on the activity and numbers of Na+/K+ pumps in an EB-virus transformed human lymphocyte cell line.

The BM1A EB-virus transformed human lymphocyte cell line contains approximately 950,000 Na+/K(+)-ATPase sites per cell. The turnover number of each site is approx. 2240 molecules of rubidium per min. When cells are exposed to a low extracellular concentration of potassium the intracellular concentration of sodium rises, and the cells respond in the short term by increasing the Vmax of 86Rb+ uptake. In the longer term the cells respond by increasing both the Vmax of 86Rb+ uptake and the Bmax of [3H]ouabain binding. The suggestion that increases in the intracellular concentration of sodium is responsible for these changes is supported by the finding that monensin, which increases intracellular sodium without affecting intracellular potassium, is capable of inducing both the short- and long-term changes associated with a low external concentration of potassium.

Evidence for an altered mode of action of the sodium-lithium countertransporter in vivo in patients with untreated essential hypertension.

OBJECTIVE: To study the activity of the sodium-lithium (Na(+)-Li+) countertransport system in vivo in the erythrocytes of patients with untreated essential hypertension. DESIGN: Lithium substitutes for sodium efflux in the sodium-sodium (Na(+)-Na+) countertransport system. In essential hypertension the efflux of lithium from cells in vitro has been used as a measure of the activity of the Na(+)-Na+ countertransporter and has been shown to be increased. We administered oral lithium and used its disposition in erythrocytes to measure Na(+)-Li+ countertransporter activity in vivo. PATIENTS: Ten men with essential hypertension who had never taken any antihypertensive treatment were matched with 10 male controls for age, weight, and plasma and erythrocyte sodium and potassium concentrations. METHODS: Repeated measurements were made of plasma and intra-erythrocytic lithium concentrations during the 48h after the oral administration of 16.2 mmol lithium carbonate. Data were analysed using standard pharmacokinetic techniques. RESULTS: The rate of lithium efflux from the erythrocytes was increased in all patients with hypertension and in none of the normotensive controls. Hill plots derived from in vivo activation curves for erythrocytic Na(+)-Li+ countertransport showed that the normotensive participants had a Hill slope of 1 (SD 0.1), whereas the hypertensives had a Hill slope of 3.2 (SD 1.0). CONCLUSIONS: The activity of the Na(+)-L+ countertransport system is increased in untreated essential hypertension in vivo; this confirms in vitro findings. A new finding is that there is a change in either the stoichiometry or the co-operativity of lithium efflux via the Na(+)-L+ countertransport system, suggesting that the rate of sodium efflux may be greater than that of influx in the cells of people with hypertension.

Evidence for increased in vivo sodium-potassium pump activity and potassium efflux in skeletal muscle of spontaneously hypertensive rats.

We have used 87Rb nuclear magnetic resonance spectroscopy (NMR) to study in vivo rubidium kinetics in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls, using rubidium as a marker for potassium. We gave 15 male, 13-week-old SHR, mean +/- s.d. blood pressure 180 +/- 10 mmHg, and 15 age-matched normotensive controls, mean blood pressure 120 +/- 9 mmHg, a daily dose of RbCl (2 mmol/kg intraperitoneally). We made repeated NMR measurements of skeletal muscle rubidium concentrations until steady state was reached. We then withdrew rubidium and made further measurements of rubidium concentrations, at intervals, for up to 1 week after the last injection. We also measured plasma and erythrocyte rubidium concentrations by flame atomic absorption spectroscopy at similar intervals after the withdrawal of rubidium. Rubidium concentrations rose at a faster rate in SHR skeletal muscle, but the steady-state muscle rubidium concentration was the same (45 mmol/l) in both SHR and WKY rats. There was also a threefold increase in the rate of rubidium efflux from both muscle and erythrocytes in SHR. These results are consistent with a marked increase in Na+,K(+)-ATPase activity and an increase in the rate of rubidium efflux in vivo in SHR. The increased rate of rubidium efflux in SHR could represent increased K+ efflux via calcium-activated K+ channels and/or result as part of cell volume regulation secondary to increased Na(+)-H+ antiporter activity.

Evidence for increased in vivo Na(+)-H+ antiporter activity and an altered skeletal muscle contractile response in the spontaneously hypertensive rat.

We have assessed the in vivo activity of the Na(+)-H+ antiporter skeletal muscle in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls using phosphorus (31P) nuclear magnetic resonance spectroscopy to measure changes in cytosolic acid concentrations during isometric contraction. During contraction there was a small rate of rise in skeletal muscle cytosolic acid concentration to a smaller maximum concentration in SHR. This difference in acid response was removed by amiloride and was not attributable to differences in cell buffering or the rate of production of lactic acid, suggesting that the difference in acid response in SHR skeletal muscle is due to increased in vivo Na(+)-H+ antiporter activity. Amiloride reduced resting muscle glycogen concentration and increased muscle lactate concentration in the SHR. This could be related to altered in vivo calcium metabolism. The maximum tension produced by skeletal muscle during contraction in SHR was less than in WKY rats, and relaxation between twitches was significantly greater, consistent with the finding of increased vascular smooth muscle relaxation in essential hypertension. Since increased Na(+)-H+ antiporter activity occurs in association with increased relaxation of both skeletal and vascular smooth muscle, these data are not consistent with a relationship between increased Na(+)-H+ antiporter activity and increased maximal muscle tension development. However, they show that increase Na(+)-H+ antiporter activity is associated with increased muscle relaxation.

Structural requirements for voltage-dependent block of muscle sodium channels by phenol derivatives.

We have studied the effects of four different phenol derivatives, with methyl and halogen substituents, on heterologously expressed human skeletal muscle sodium channels, in order to find structural determinants of blocking potency. All compounds blocked skeletal muscle sodium channels in a concentration-dependent manner. The methylated phenol 3-methylphenol and the halogenated phenol 4-chlorophenol blocked sodium currents on depolarization from -100 mV to 0 mV with IC(50) values of 2161 and 666 microM respectively. Methylation of the halogenated compound further increased potency, reducing the IC(50) to 268 microM in 2-methyl-4-chlorophenol and to 150 microM in 3,5-dimethyl-4-chlorophenol. Membrane depolarization before the test depolarization increased sodium channel blockade. When depolarizations were started from -70 mV or when a 2.5 s prepulse was introduced before the test pulse inducing slow inactivation, the IC(50) was reduced more than 3 fold in all compounds. The values of K(D) for the fast-inactivated state derived from drug-induced shifts in steady-state availability curves were 14 microM for 3,5-dimethyl-4-chlorophenol, 19 microM for 2-methyl-4-chlorophenol, 26 microM for 4-chlorophenol and 115 microM for 3-methylphenol. All compounds accelerated the current decay during depolarization and slowed recovery from fast inactivation. No relevant frequency-dependent block after depolarizing pulses applied at 10, 50 and 100 Hz was detected for any of the compounds. All the phenol derivatives that we examined are effective blockers of skeletal muscle sodium channels, especially in conditions that are associated with membrane depolarization. Blocking potency is increased by halogenation and by methylation with increasing numbers of methyl groups.

Voltage-dependent blockade of normal and mutant muscle sodium channels by benzylalcohol.

1. We studied the effects of benzylalcohol on heterologously expressed wild type (WT), paramyotonia congenita (R1448H) and hyperkalaemic periodic paralysis (M1360V) mutant alpha-subunits of human skeletal muscle sodium channels. 2. Benzylalcohol blocked rested channels at -150 mV membrane potential, with an ECR(50) of 5.3 mM in wild type, 5.1 mM in R1448H, and 6.2 mM in M1360V. When blockade was assessed at -100 mV, the ECR(50) was reduced in R1448H (2 mM) compared with both wild type (4.3 mM; P<0.01) and M1360V (4.3 mM). 3. Membrane depolarization before the test depolarization significantly promoted benzylalcohol-induced sodium channel blockade. The values of K(D) for the fast-inactivated state derived from benzylalcohol-induced shifts in steady-state availability curves were 0.66 mM in wild type and 0.58 mM in R1448H. In the presence of slow inactivation induced by 2.5 s depolarizing prepulses, the ECI(50) for benzylalcohol-induced current inhibition was 0.59 mM in wild type and 0.53 mM in R1448H. 4. Recovery from fast inactivation was prolonged in the presence of drug in all clones. 5. Benzylalcohol induced significant frequency-dependent block at stimulating frequencies of 10, 50, and 100 Hz in all clones. 6. Our results clearly show that benzylalcohol is an effective blocker of muscle sodium channels in conditions that are associated with membrane depolarization. Mutants that enter voltage-dependent inactivation at more hyperpolarized membrane potentials compared with wild type are more sensitive to inhibitory effects at the normal resting potential.

Potassium channels in nervous tissue.

There is a multiplicity of potassium channels in nervous tissue. These have been characterized on the basis of their electrophysiological actions but more information is required on their structures and on the functions of the different subtypes of channel in different parts of the nervous system. We currently also lack drugs which are specific in opening or closing individual subtypes of channel. However, when more is known about the structure and function of these channels and when more specific modulators of their activity are available, it is likely that the use of such compounds may be of great value in the treatment of a variety of conditions affecting the nervous system, including epilepsy, the damage due to cerebral anoxia, neurodegenerative disorders and demyelinating disorders.

Reversal of the effects of a low extracellular potassium concentration on the number and activity of Na+/K+ pumps in an Epstein-Barr virus-transformed human lymphocyte cell line.

A reduction in the extracellular concentration of potassium to 0.5 mM (low K) in Epstein-Barr (EB) virus-transformed lymphocytes caused changes in the number and activity of Na+/K+ pumps in the cell membrane, with increases in the Bmax and apparent Kd of ouabain binding, and concomitant increases in the Vmax and apparent Km of potassium (rubidium) influx. However, recovery from the effects of low K occurred more quickly than the original up-regulation. Furthermore, there were differences in the time-courses of the separate rates of recovery of the Bmax and Kd of ouabain binding after the cells were returned to normal K, the rate of recovery of the Kd being quicker than that of the Bmax, which was biphasic, with slow and fast rates of recovery. Inhibition of protein synthesis by emetine caused an increase in the rate of recovery of the Bmax of ouabain binding, but no effect on the Kd, suggesting that the slow phase of recovery of the Bmax is attributable to the synthesis and insertion of new protein, while the rapid phase of recovery is independent of protein synthesis and may represent internalization. The results suggested that during up-regulation of pump number in response to low K about 40% of the newly inserted Na+/K+ pumps are normal and the rest are abnormal. The half-time of removal of the abnormal pumps from the cell membrane during recovery from low K stress was 2.8 hr and the half-time of internalization of the normal pumps was 4.3 hr.

Confusion over similar drug names. Problems and solutions.

Confusion over similar drug names is one of the reasons for errors in the prescribing or administration of drugs. The risks of such errors could be reduced by some simple measures. National and international agencies: Licensing authorities should exercise more control over the naming of new proprietary formulations; Nonproprietary names should be internationalised; New proprietary names should be internationalised; Common prefixes in names should be avoided if possible. Pharmaceutical manufacturers: Manufacturers should play their part in ensuring that new names are carefully chosen and internationalised; Over-the-counter formulations should be given unique names; Generic formulations should be marketed under their nonproprietary names, not new proprietary names. Doctors: Should inform patients about the nature and risks of their therapy; Should issue printed prescriptions if possible, or use clearly-penned block capitals in handwritten prescriptions. In most cases they should use nonproprietary names when prescribing. Abbreviations of drug names should never be used. Pharmacists: Should discuss the nature and risks of patients' therapy with them and check that they recognise the medicines they are taking; Should ask patients to hand in their old medicines containers when they fill a new prescription; In hospital, clinical pharmacists can help to check doctors' prescriptions and to liaise between doctors and nurses, advising on correct therapy. Special cases: Special care should be taken with sulphonylureas: manufacturers should produce distinctive formulations and pharmacists should keep them in a separate section in the dispensary.

The effects of digoxin and dopamine on the oxygen consumption, lactate production and haemodynamic performance of an isolated, perfused, working guinea-pig heart.

We have adapted an established technique for perfusing the isolated, working rat heart to the guinea-pig heart and characterized its biochemical and haemodynamic performance. After 20 min of anoxia the heart recovers about 50% of its pre-anoxic performance ('post-anoxic cardiac failure') and after 90 min of continuous work total cardiac output falls to 50% of its initial, stable value ('spontaneous cardiac failure'). We have studied the effects of digoxin (10(-7) M and 2 x 10(-7) M) and dopamine (10(-5) M) on these two forms of cardiac failure and shown that digoxin improves the haemodynamic performance of the heart without altering its metabolism and therefore increases its efficiency. In contrast dopamine improves the haemodynamic performance of the heart at the expense of increased aerobic and anaerobic metabolism. The preparation is of value in studying the effects of cardioactive drugs on hearts subjected to constant pre-load and after-load.

Incomplete evidence: the inadequacy of databases in tracing published adverse drug reactions in clinical trials.

BACKGROUND: We would expect information on adverse drug reactions in randomised clinical trials to be easily retrievable from specific searches of electronic databases. However, complete retrieval of such information may not be straightforward, for two reasons. First, not all clinical drug trials provide data on the frequency of adverse effects. Secondly, not all electronic records of trials include terms in the abstract or indexing fields that enable us to select those with adverse effects data. We have determined how often automated search methods, using indexing terms and/or textwords in the title or abstract, would fail to retrieve trials with adverse effects data. METHODS: We used a sample set of 107 trials known to report frequencies of adverse drug effects, and measured the proportion that (i) were not assigned the appropriate adverse effects indexing terms in the electronic databases, and (ii) did not contain identifiable adverse effects textwords in the title or abstract. RESULTS: Of the 81 trials with records on both MEDLINE and EMBASE, 25 were not indexed for adverse effects in either database. Twenty-six trials were indexed in one database but not the other. Only 66 of the 107 trials reporting adverse effects data mentioned this in the abstract or title of the paper. Simultaneous use of textword and indexing terms retrieved only 82/107 (77%) papers. CONCLUSIONS: Specific search strategies based on adverse effects textwords and indexing terms will fail to identify nearly a quarter of trials that report on the rate of drug adverse effects.

The upregulation of Na+,K(+)-ATPase pump numbers in lymphocytes from the first-degree unaffected relatives of patients with manic depressive psychosis in response to in vitro lithium and sodium ethacrynate.

Patients with manic depressive disorder (DSM-III-R bipolar disorder) have an abnormality of the Na+,K(+)-ATPase pumps in their lymphocytes: the pump numbers do not upregulate to stimulation with lithium and ethacrynate. We have now investigated the in vitro adaptive responses of lymphocyte Na+,K(+)-ATPase pumps in the first-degree unaffected relatives of patients with a clear history of manic depressive disorder. The lymphocytes of the healthy relatives upregulated their Na+,K(+)-ATPase pumps normally, suggesting that the abnormal response that we have previously observed in patients with the disorder reflects a complex relation between the biochemical phenotype and the development of clinical symptoms.