Zuclopenthixol, melperone and haloperidol/levomepromazine in the elderly. Meta-analysis of two double-blind trials at 15 nursing homes in Norway.

A meta-analysis was carried out of the data from two double-blind, multi-centre studies with identical methodology which compared the effectiveness of treatment of elderly patients with zuclopenthixol and with other antipsychotic drugs. In one study, patients were treated for 4 weeks with either zuclopenthixol or melperone; in the other, with either zuclopenthixol or a combination of haloperidol and levomepromazine. The meta-analysis evaluated the results of 96 patients, 49 in the zuclopenthixol group and 47 in the comparison group. Doses, which were adjusted to individual patient's needs, were low as shown by the percentages of defined daily doses for each of the study drugs. The results indicated that all three treatment alternatives were effective in the treatment of elderly patients with symptoms of agitation and hostility/aggressiveness. There was a trend, however, for zuclopenthixol to have a more rapid onset of effect. Zuclopenthixol also has the advantage for both patients and nursing staff that dosage is once daily. Only few and mild side-effects were reported with the three drug regimens.     

Intramuscular aripiprazole for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder: a double-blind, placebo-controlled comparison with intramuscular haloperidol

Introduction This double-blind, placebo-controlled study investigated the efficacy and safety of intramuscular (IM) aripiprazole and IM haloperidol for the treatment of acute agitation in patients with schizophrenia or schizoaffective disorder.Materials and methods Four-hundred and forty-eight patients were randomized (2:2:1 ratio) to IM aripiprazole 9.75 mg, IM haloperidol 6.5 mg, or IM placebo. Patients could receive up to three injections over the first 24 h, with second and third injections administered ≥2 and ≥4 h, respectively, after the first if deemed clinically necessary. Primary efficacy measure was mean change in Positive and Negative Syndrome Scale Excited Component (PEC) score from baseline to 2 h.Results Mean improvement in PEC at 2 h was significantly greater for IM aripiprazole (−7.27) vs placebo (−4.78; p<0.001); IM aripiprazole was noninferior to IM haloperidol (−7.75) on PEC. All secondary efficacy measures showed significantly greater improvements at 2 h for IM aripiprazole and IM haloperidol over placebo. Mean number of injections/patient and percentage of patients requiring benzodiazepines were significantly lower for IM aripiprazole vs placebo (p<0.01). IM aripiprazole was well tolerated. Extrapyramidal symptom-related adverse events were similar for aripiprazole (1.7%) and placebo (2.3%) and lower than with haloperidol (12.6%).Conclusion These results show that IM aripiprazole is an effective treatment, comparable to IM haloperidol, and well-tolerated for acute agitation in patients with schizophrenia.Joint first authorship for authors Raisa Andrezina and Richard Josiassen.     

Atypical antipsychotics in the elderly: a review of therapeutic trends and clinical outcomes

Recent emerging data regarding the safety and tolerability of atypical antipsychotics in elderly patients with dementia have called into question common prescribing practices. Although the lifetime risk of developing significant psychopathology in dementia patients approaches nearly 100%, treatment options remain scant and controversial. Millions of people are suffering the consequences of these debilitating dementias. Yet the lack of regulatory approval or even recognition of the problem creates a dilemma for clinicians in practice who are trying to care for severely ill patients. There are data indicating that certain behavioral features can be treated successfully with atypical antipsychotics, offset by a high rate of adversity. This does not lead to the simple conclusion that they should never be used, since the alternatives are either fraught with the same shortcomings or actually lack evidence of benefit altogether. Further, it is not realistic to assume that nonpharmacological approaches, although preferred, will always carry the day. Since we do not have the evidence to define best practice for treating psychopathology, we are forced to make the most of the data we have and exercise best judgment about risk and benefit on a case-by-case basis.     

A double-blind, placebo-controlled investigation of the residual psychomotor and cognitive effects of zolpidem-MR in healthy elderly volunteers

AIM: To assess residual psychomotor and cognitive effects of a modified-release formulation of zolpidem (zolpidem-MR), developed to provide sustained hypnotic efficacy during the whole night, compared with placebo and flurazepam. METHODS: Twenty-four healthy elderly volunteers received four study treatments (zolpidem-MR 6.25 mg and 12.5 mg, placebo and flurazepam 30 mg) using a randomized, cross-over, double-blind design. Residual psychomotor and cognitive effects were assessed with a psychometric test battery. Quality of sleep and residual effects were evaluated subjectively with the Leeds Sleep Evaluation Questionnaire. RESULTS: Psychometric performance was significantly impaired with flurazepam but not with zolpidem-MR at either dose. Ease of falling asleep and sleep quality were significantly improved with both doses of zolpidem-MR and with flurazepam. Neither active drug modified perception of well-being on awakening. CONCLUSION: In elderly subjects, zolpidem-MR showed no residual functional impairment in psychometric or cognitive tests sensitive to flurazepam.     

Scabies outbreaks in nursing homes for the elderly: recognition, treatment options and control of reinfestation

The scabies mite is an ectoparasite able to infest humans. Its clinical presentation is typical, although in immunocompromised, mentally retarded and elderly patients the clinical presentation may be altered. Diagnosis may therefore be difficult in such patient groups, who often reside in nursing homes. Because delay in diagnosis may induce rapid spread of the scabies mite, immediate diagnosis and treatment are necessary. Normal scabies (scabies vulgaris) and crusted scabies (scabies crustosa, scabies norvegica), although sometimes difficult to diagnose, especially in the elderly, are fortunately quite easy to treat. However, the elderly patient may experience toxicity from local or systemic scabicidal treatment. Single cases of scabies vulgaris should be treated with permethrin cream because of its outstanding efficacy and favourable adverse events profile. Scabies outbreaks and cases of scabies crustosa can easily be managed using combination therapy consisting of topical application of permethrin and two oral doses of ivermectin 200 microg/kg (administered 1 week apart). In addition to treatment of the scabies infestation, preventative measures are necessary, particularly in nursing homes.     

Efficacy and safety of tapentadol prolonged release formulation in the treatment of elderly patients with moderate-to-severe chronic osteoarthritis knee pain: a pooled analysis of two double-blind,randomized, placebo-, and active-controlled trials

Objective: To compare efficacy and safety of tapentadol prolonged release (PR) vs oxycodone controlled release (CR) in younger patients (<65?years of age) and in elderly patients (≥65 and ≥75 years of age) in the treatment of moderate-to-severe chronic osteoarthritis (OA) knee pain.

Methods: Data from two double-blind, randomized, placebo-, and oxycodone CR-controlled phase 3 trials were pooled and stratified by age. Primary efficacy end-points were change from baseline in average pain intensity at week 12 (US end-point) and over the entire maintenance period (non-US end-point).

Results: A total of 1357 patients <65?years, 653 patients ≥65?years, and 176 patients ≥75?years of age were assessed. The comparison between tapentadol PR and oxycodone CR showed numerically better pain relief under tapentadol PR for both primary end-points in all three age groups. More favorable improvements were also observed for patient global impression of change, the Short Form-36 physical component score, and EuroQoL-5Dimensions health status index. In the elderly, incidences of dizziness and somnolence were comparable between active treatments, but incidences of nausea, vomiting, and constipation were considerably lower under tapentadol PR. Treatment completion rates were lowest under oxycodone CR;?>?50% of elderly oxycodone CR patients named side-effects as the main reason for discontinuation.

Conclusions: Tapentadol PR was effective in the treatment of moderate-to-severe chronic OA pain in elderly and younger patients. Compared to oxycodone CR, the overall and the gastrointestinal tolerability profile in particular were better in all tapentadol PR groups, regardless of age.     

老年急性心肌梗死患者的临床特点及护理

目的探讨老年人急性心肌梗死（AMI）患者临床特点及护理措施。方法将71例确诊为AMI的住院患者按年龄分为≥60岁组（老年组）和〈60岁组（对照组）,收集其性别结构、基础病变和临床特点等资料,进行对比分析。结果老年组与对照组相比,女性患者的比例及糖尿病、不典型症状者、心衰、心源性休克、心律失常发生率高（P〈0.05）,死亡率亦高（P〈0.05）,老年组前壁加下壁心梗、无Q波性心肌梗死多于对照组（P〈0.05）。结论针对老年人AMI患者的临床特点采取相应的护理措施,能减少并发症,降低病死率,提高其生存质量。     

A comparison of the effects of olanzapine, haloperidol and placebo on cognitive and psychomotor functions in healthy elderly volunteers.

The cognitive and psychomotor effects of olanzapine (3 mg) were compared with haloperidol (3 mg) and placebo in a double-blind, cross-over study. Fourteen healthy elderly volunteers (>65 years) were randomized to receive once daily medication for 4 days with a 16-day interval between treatment periods. Assessments of attention, memory and motor control were made prior to dosing on each day, at 2, 4, 6 and 8 h after dosing on days 1 and 4, and at 24 and 48 h following the last dose. On day 1, detectable impairment was observed at all time points in both groups. On day 4, haloperidol treated subjects showed increased impairment compared with day 1 and this was sustained throughout the 48 h of testing. Olanzapine treated subjects showed reduced day 4 deficit (compared with day 1), with no significant difference from placebo beyond 6 h post dose. These results suggest that both haloperidol and olanzapine have a measurable initial effect on cognitive and psychomotor function in elderly volunteers. However, acute effects associated with olanzapine decrease with repeated dosing and show substantial adaptation within 4 days. In contrast, effects seen with haloperidol are sustained and increase with repeated dosing over the same period.     

A double-blind comparison of the pharmacodynamic effects of single doses of lofepramine,amitryptyline and placebo in elderly subjects

Summary In a double-blind five-way cross-over study, six drug free healthy elderly subjects received single oral doses of lofepramine (70 mg, 105 mg and 140 mg), amitriptyline (50 mg) and matched placebo tablets.A dose related increase in plasma drug levels and pharmacological effects of lofepramine was observed. Lofepramine (140 mg) improved psychomotor performance (choice reaction time and letter cancellation), but no such change was seen with lower dose regimes or placebo. No significant differences between lofepramine and placebo were observed in other parameters measured.Amitriptyline, as expected, reduced salivary volume, produced drowsiness and impaired psychomotor performance. These changes correlated with plasma amitriptyline levels. The incidence of subjective side-effects with amitryptyline was also higher than that of lofepramine or placebo.In the dosage used, lofepramine exhibited no deleterious effect on the peripheral cholinergic system or psychomotor performance. This drug therefore is likely to be a relatively safe antidepressant for the elderly, but further investigations during long-term medication are required to verify these observations.     

Objective outcome criteria in trials of anti-parkinsonian therapy in the elderly: sensitivity, specificity and reliability of measures of brady- and hypo-kinesia.

1. We compare the sensitivity and specificity of chosen outcome criteria in a placebo-controlled, randomised cross-over study of the efficacy of maintenance therapy with the levodopa/carbidopa combination (Sinemet Plus) alone. Patients were characterised by having idiopathic Parkinsonism with no overt fluctuations in control in relation to individual doses of medication. 2. The effect of omission of a morning dose of maintenance therapy on simple timed tests of mobility and manual dexterity, and on distance/time parameters of gait was studied in fourteen patients (aged 64 to 88 years). Measurements made 2, 4 and 6 h after morning active and placebo treatments were standardised by taking the pre-treatment measurement on that day as baseline. 3. In a linear model, which allowed for the structure of the study, neither the total time taken by each patient to get up from a chair, walk an individually set distance, turn, return to and sit in the chair, nor the rate of progress at fastening the same set of buttons, was sensitive to the treatment effect. 4. Three of the gait parameters, free walking speed, mean stride length and mean double support time, were sensitive to the treatment effect. Correction for the speed of each walk, caused some reduction in the sensitivity of stride length to treatment effect, but that of double support time remained. Speed, and double support time or stride length, appeared to be complementary in defining the treatment effect. 5. The linear modelling revealed the complexity of the treatment effect. Although active treatment, by comparison with placebo, increased free walking speed (P = 0.019), the more levodopa found in the plasma following treatment, (P = 0.0005) and the greater the increment in the concentration of its peripheral metabolite, 3-O-methyldopa (P = 0.006), the less the beneficial effect. This model may reflect reduced uptake into the brain and/or an adverse effect of parent drug or a metabolite. 6. The specificity of free walking speed for the treatment effect was good, as was that of mean stride length, after it had been corrected for speed of each walk, and of mean double support time, after correction for speed and incorporation of the change in lying blood pressure accompanying treatment into the model. 7. The measurements of gait parameters were ranked according to reliability.(ABSTRACT TRUNCATED AT 400 WORDS)     

多沙唑嗪控释片治疗前列腺增生症的对照研究

目的评价多沙唑嗪控释片、特拉唑嗪片和坦索罗辛片等3种α1受体阻滞剂治疗良性前列腺增生症(BPH)的临床有效性和安全性。方法对入选的183例BPH患者进行了一个前瞻性的随机、双盲和平行对照试验,过程分3个阶段:第一阶段为2周的清洗期,第二阶段为2周的单盲安慰剂导入期,第三阶段为12周的双盲药物治疗期。多沙唑嗪控释片、特拉唑嗪片和坦索罗辛片的起始剂量分别为4 mg/d、1 mg/d和0.4 mg/d,如果治疗4周后最大尿流率(Qmax)增加<3 mL/s,国际前列腺症状评分(IPSS)下降<30%,则将3种药物分别加量为8 mg/d、8 mg/d和0.8 mg/d。主要评价指标为从基线到最后1次随访的IPSS和Qmax的变化值,以及治疗中常见不良事件的发生率。统计方法采用方差分析和χ2检验。结果多沙唑嗪控释片、特拉唑嗪片和坦索罗辛片均能显著减轻BPH的下尿路梗阻症状,增加Qmax(P<0.01),但是前两种药物对IPSS的降低显著优于坦索罗辛片(P<0.05)。多沙唑嗪控释片组没有因为与治疗相关的不良事件而退出试验的患者,并且在头晕、恶心、体位性低血压等主要不良事件的发生率与特拉唑嗪片组和坦索罗辛片组比较,差异有统计学意义(P<0.05)。结论α1受体阻滞剂均能有效缓解BPH的下尿路症状。多沙唑嗪控释片作用全面,有效性和安全性显著提高,是这类药物的首选。     

Neuroleptic-induced hypersensitivity of striatal dopamine receptors in the rat as a model of tardive dyskinesias. Effects of clozapine,haloperidol, loxapine and chlorpromazine

The present study has compared the abilities of clozapine, haloperidol, chlorpromazine and loxapine to induce dopamine (DA)-receptor hypersensitivity in rats, as measured by the apomorphine response after withdrawal of the antipsychotic drugs. Haloperidol, chlorpromazine and loxapine, but not clozapine, potentiated the apomorphine response during 1–2 weeks after withdrawal. Clozapine, given prior to apomorphine, reduced the responses of the haloperidol and loxapine groups to the control level. The effects of haloperidol and clozapine were quantified in rats with unilateral striatal lesions.Biochemical investigations showed that tolerance developed to the increase in striatal homovanillic acid (HVA) after chronic treatment with haloperidol, chlorpromazine and loxapine, whereas clozapine (20 mg/kg p.o.) failed to affect the HVA content, and no tolerance developed to the increase seen at 80 mg/kg. Cross-tolerance to the rise in HVA was seen with haloperidol, chlorpromazine and loxapine, but chronic pretreatment with clozapine failed to affect the rise in HVA induced by a single dose of the former compounds.On the basis of these results, it is predicted that tardive dyskinesias are unlikely to develop after this drug, and that clozapine may attenuate or abolish neuroleptic-induced tardive dyskinesias.Part of this work was presented at the IXth Congress of the C.I.N.P. in Paris, July 1974.     

Cardiovascular effects of two different xanthines in healthy subjects. Studies at rest,during exercise and in combination with a beta-agonist,terbutaline

Summary The haemodynamic response to two xanthines, enprofylline and theophylline, was studied in 6 healthy male volunteers at rest, during exercise and in combination with the beta₂-agonist, terbutaline. At rest the haemodynamic effects of both xanthines were small and were qualitatively different from each other. While theophylline exerted a pressor response, enprofylline seemed to have arterial dilating ability. During exercise both xanthines as compared to placebo were associated with a higher heart rate and in general with increased systolic blood pressure. In combination with terbutaline enprofylline and theophylline both increased systolic blood pressure more than placebo, i. e. they augmented the positive inotropic effect of terbutaline. The systolic blood pressure was higher after theophylline than enprofylline despite their equipotent bronchodilator activity. This may reflect different inotropic effects of the xanthines as well as a difference in their influence on the response to adenosine.     

Pharmacokinetics,pharmacodynamics and safety profile of the dual orexin receptor antagonist vornorexant/TS-142 in healthy Japanese participants following single/multiple dosing: Randomized,double-blind,placebo-controlled phase-1 studies

The pharmacokinetics, pharmacodynamics and safety profile of vornorexant were investigated in healthy Japanese participants in three double-blind studies: a single ascending dose of 1–30 mg (Study 101; n = 6) and multiple ascending doses of 10–30 mg (Study 102; n = 6). Study 202 consisted of two steps: an open-label, 20 mg repeated-dose in non-elderly individuals (Step 1; n = 12) and a double-blind, 20 mg repeated-dose in elderly individuals (Step 2; n = 8/3 for vornorexant/placebo). Vornorexant was rapidly absorbed and eliminated under fasting conditions, with a time to maximum plasma concentration of 0.500–3.00 h (range) and elimination half-life of 1.32–3.25 h. The area under the plasma concentration-time curve (AUC) of vornorexant increased proportionally with dose increments. Sleepiness-related pharmacodynamic outcome changes (Karolinska sleepiness scale, digit symbol substitution test and psychomotor vigilance task) were generally increased with dose increments at 1 and 4 h post-dose, whereas no consistent dose-related changes were detected the next morning. Food intake did not affect the maximum observed plasma concentration of vornorexant but increased the AUC_0–inf. Exposure in elderly individuals was generally comparable to that in non-elderly individuals. Altogether, vornorexant may have a favourable profile for insomnia treatment, including rapid onset of action and minimal next-day residual effects.     

In vitro and in vivo evaluation of the estrogenic, androgenic, and progestagenic potential of two cyclic siloxanes.

The purpose of these experiments was to determine the potential estrogenic, androgenic, and progestagenic activity of two cyclic siloxanes, octamethylcyclotetrasiloxane (D4) and decamethylcyclopentasiloxane (D5). Receptor-binding experiments and a luciferase reporter gene assay were used to determine if the materials were able to bind and activate either the estrogen receptors (ERs) or progesterone receptors (PRs)-alpha or beta. The rat uterotrophic assay (RUA) for estrogenic activity and the Hershberger assay for androgenic activity were utilized as the in vivo assays. For the ER-binding studies, D4 was shown to bind to ERalpha but not to ERbeta. D5 did not bind to either of the two receptors. D4 activated the reporter gene at 10 microM, while D5 was considered negative in the estrogen reporter gene assay. Neither material was a ligand for the PRs. Both the RUA and Hershberger assays were conducted using whole-body inhalation of the two materials for 16 h/day. D4 resulted in a small but significant increase in both wet and blotted uterine weight as well as increases in both luminal and glandular epithelial cell height in both Sprague Dawley and Fischer 344 rats. D5 was negative in both rat strains, indicating that D5 does not possess estrogenic activity. Neither material possessed any significant antiestrogenic activity. Both materials were negative in the Hershberger assay indicating that neither material possesses any significant androgenic activity. Our studies have shown that D4 exhibits a low affinity for ERalpha in vitro and a weakly estrogenic response in vivo.     

Analysis of the variation in the action of L-365,260 at CCKB/gastrin receptors in rat, guinea-pig and mouse isolated gastric tissue assays.

1. Since L-365,260 was first described as a selective antagonist at cholecystokinin (CCK)B/gastrin receptors, we have used it periodically as a reference compound in isolated tissue assays of guinea-pig gastric muscle and lumen-perfused stomachs from mouse and immature rat. L-365,260 behaved as a surmountable antagonist and produced parallel rightward shifts of pentagastrin concentration-effect curves' in each of the replicate experiments. The experiments were performed by several different experimenters in the same laboratories over a five year period. 2. In the isolated, lumen-perfused, immature rat stomach assay, L-365,260 behaved as a simple competitive antagonist (Schild plot slope = 1.00 +/- 0.10, pKB = 7.54 +/- 0.03 from a global analysis of the data) acting at a homogeneous population of receptors in five separate, highly-reproducible, experiments. In contrast, the replicate data sets obtained from the interaction in the isolated, lumen-perfused mouse stomach and guinea-pig gastric muscle assays, over the same period, were not consistent with the presence of a single receptor population. The guinea-pig gastric muscle data were relatively reproducible between experiments but some individual Schild plot slopes and the slope estimated from a global analysis of all the data were significantly less than unity (slope = 0.80 +/- 0.07, pA2 = 8.56 +/- 0.05 from the global analysis). The data obtained in the mouse stomach were significantly more variable than that obtained in the same assay, during the same period, from the interaction between histamine and the H2-receptor antagonist, famotidine. The individual Schild plot slopes ranged from being very flat (0.20) to being not significantly different from unity (1.23) and the pA2 values ranged from 7.68 to 8.70. 3. Overall, the data could be accounted for by assuming the variable expression of two receptor subtypes across the assays. The rat stomach appeared to express a single receptor characterized by a low affinity constant for L-365,260 (pKB approximately 7.5). The guinea-pig gastric muscle and mouse stomach data could be explained by the presence of this receptor and a second one characterized by a high affinity constant for L-365,260 (pKB approximately 8.6). The activity of the two proposed receptor subtypes was consistent between experiments in the guinea-pig and the high affinity receptor appeared to be predominant. In contrast, the mouse stomach data could only be simulated by assuming that the proportion and absolute number of each subtype varied significantly between the replicate experiments. 4. The L-365,260 affinity estimates at the inferred receptor subtypes were indistinguishable from those obtained in a corresponding analysis of the behaviour of L-365,260 in CCKB/gastrin receptor radioligand binding experiments in guinea-pig gastric gland and mouse and rat cerebral cortex preparations.     

Potential in vitro antioxidant and protective effects of Gymnema montanum H. on alloxan-induced oxidative damage in pancreatic β-cells, HIT-T15

The present study describes the antioxidant activities of ethanol extract from Gymnema montanum (GLEt) which is an endemic plant of India. Antioxidant activity of the GLEt was studied in vitro based on scavenging of hydroxyl radicals, superoxide anions, nitric oxide, hydrogen peroxide, peroxynitrite, reducing power and inhibition of lipid peroxidation estimated in terms of thiobarbituric acid reactive substances (TBARS). Further, we examined its protective effect against alloxan-induced oxidative stress in pancreatic β-cells, HIT-T15 by measuring the free radical generation, malonaldehyde formation and antioxidant levels such as CAT, GPx and GSH. Results showed that G. montanum leaves exhibited significant antioxidant activities measured by various in vitro model systems. The HIT-T15 cell line studies showed the tendency of GLEt to increase antioxidant levels meanwhile decrease the free radical formation and inhibit the lipid peroxidation. The antioxidant activity was found to be well correlated with the phenolic phytochemicals present in the extract. GC–MS analyses revealed the presence of few phenolic compounds in the extract. As this plant has already been demonstrated for a variety of medicinal properties from our laboratory, results of this study suggest that G. montanum is an interesting source for antioxidant compounds and useful for various therapeutic applications.     

17O, 14N and 15N n.m.r. studies of the CO2+ complexes of cyclo(Pro17O-Gly15N) and cyclo(Gly17O-Pro) in aqueous solution

The complexation of cyclo(Pro¹⁷O-Gly¹⁵N) and cyclo(Gly¹⁷O-Pro) with CO²⁺ ions has been studied by ¹⁷O, ¹⁴N and ¹⁵N n.m.r. spectroscopy in aqueous solution. ¹⁷O, ¹⁴ N and ¹⁵N transverse relaxation times and chemical shifts were measured as a function of temperature. The ¹⁷O n.m.r. studies unequivocally demonstrate that the cobaltous ion binds to the peptide oxygen of both compounds. The hyperfine coupling constant and the peptide residence times were found to be A =–0.165 MHz and – 0.145 MHz, μ= 16, and 92μsec for cyclo(Pro¹⁷O-Gly¹⁵N) and cyclo(Gly¹⁷O-Pro), respectively. The ¹⁴N and ¹⁵N studies of labeled cyclo(Pro¹⁷O-Gly¹⁵N) do not indicate binding at either the Gly¹⁵N or the Pro¹⁴N site.