A randomized,double-blind,placebo-controlled,crossover study on the effect of oral oestradiol on acute menopausal symptoms

Acute menopausal symptoms occur less frequently in Asian than in Caucasian women. Oestrogen replacement therapy has been shown to be effective in controlling acute symptoms in Caucasians, but the effect of oestrogens is not well documented in Asian women. A randomized, double-blind, placebo-controlled, crossover study of the effect of oral oestradiol on the incidence of acute menopausal symptoms was conducted in 83 Hong Kong Chinese women who had experienced a surgical menopause. Although there was a significant increase in the oestradiol concentration with treatment compared with placebo (P < 0.001), there were no significant differences in the reporting of symptoms between the treatment and placebo groups. There is no obvious explanation for this apparent lack of effect of oestrogen on acute menopausal symptoms in Chinese women. Whilst it may be related to the generally low incidence of symptoms or to a higher dietary intake of phytoestrogens in Chinese women, further studies are necessary to explain these findings.     

A randomized, double-blind, placebo-controlled crossover study of the effect of exogenous melatonin on delayed sleep phase syndrome

OBJECTIVE: The effects of exogenous melatonin on sleep, daytime sleepiness, fatigue, and alertness were investigated in 22 patients with delayed sleep phase syndrome whose nocturnal sleep was restricted to the interval from 24:00 to 08:00 hours. This study was a randomized, double-blind, placebo-controlled crossover trial. Subjects received either placebo or melatonin (5 mg) daily for 4 weeks, underwent a 1-week washout period, and then were given the other treatment for an additional 4 weeks. Patients could take the melatonin between 19:00 and 21:00 hours, which allowed them to select the time they felt to be most beneficial for the phase-setting effects of the medication. METHODS: Two consecutive overnight polysomnographic recordings were performed on three occasions: at baseline (before treatment), after 4 weeks of melatonin treatment, and after 4 weeks of placebo treatment. RESULTS: In the 20 patients who completed the study, sleep onset latency was significantly reduced while subjects were taking melatonin as compared with both placebo and baseline. There was no evidence that melatonin altered total sleep time (as compared with baseline total sleep time), but there was a significant decrease in total sleep time while patients were taking placebo. Melatonin did not result in altered scores on subjective measures of sleepiness, fatigue, and alertness, which were administered at different times of the day. After an imposed conventional sleep period (from 24:00 to 08:00), subjects taking melatonin reported being less sleepy and fatigued than they did while taking placebo. CONCLUSIONS: Melatonin ameliorated some symptoms of delayed sleep phase syndrome, as confirmed by both objective and subjective measures. No adverse effects of melatonin were noted during the 4-week treatment period.     

Novelty response of rats determines the effect of prefrontal alpha-2 adrenoceptor modulation on anxiety

In this study we provide evidence that animals of the same population, although identical in age and sex, have individual reactions to the prefrontal modulation of adrenoceptors. We have examined the dose-dependent action of α(2)-adrenoceptor agents on the anxiety of rats with different response to novelty in the elevated plus maze (EPM) apparatus. Rats were divided into high (HR) and low responder (LR) groups based on their locomotor activity in a novel open field environment. HR rats also showed increased locomotion and low anxiety in the EPM. Prefrontal injection of α(2)-receptor antagonist yohimbine, BRL44408 or imiloxan caused anxiety only in HR rats. The α(2A/D)-receptor agonist guanfacine increased anxiety levels of both groups. However, the effective dose was lower in HR rats. The present results propose different prefrontal adrenoceptor sensitivity of rats showing distinct baseline activity levels.     

Inhibitory effect of a leukotriene receptor antagonist (montelukast) on neurokinin A-induced bronchoconstriction

BACKGROUND: Tachykinins are potent contractors of human airways producing a dose-related bronchoconstriction when administered by means of inhalation to asthmatic subjects. OBJECTIVE: The aim of this study was to examine the effective role played by leukotrienes (LTs) in neurokinin A (NKA)-induced bronchoconstriction in asthmatic patients. METHODS: To address this question, we investigated the protective effect of a selective cysteinyl LT receptor antagonist, montelukast, against inhaled NKA and determined LTE(4) excretion in the urine. RESULTS: Inhaled NKA in the absence of any drug treatment produced a concentration-related bronchospasm with a geometric mean provocative concentration required to produce a 15% decrease in FEV(1) from the postsaline baseline value (PC(15)) value of 290.9 microg/mL (+SE, 407.1 microg/mL; -SE, 207.84 microg/mL). Montelukast pretreatment significantly increased (P <.01) the PC(15) NKA value (708.8 microg/mL; +SE, 890.47 microg/mL; -SE, 564.15 microg/mL) in comparison with placebo (394.4 microg/mL; +SE, 491.88 microg/mL; -SE, 248.16 microg/mL) and produced a shift of the NKA concentration-response curve to the right in all the subjects studied. When compared with placebo, montelukast did not have a significant protective effect against methacholine challenge; the geometric mean PC(15) values obtained were 0.87 and 0.96 mg/mL with placebo and montelukast, respectively. Although we have not observed any increase in urinary LTE(4) excretion after NKA inhalation, we have shown that pretreatment of asthmatic subjects with montelukast elicits a significant protection against NKA-induced bronchoconstriction. CONCLUSION: In asthmatic subjects NKA-induced bronchoconstriction is indirectly caused by the release of LTs, and this mechanism could explain some of the antiasthmatic and anti-inflammatory effects of LT antagonists.     

Effects of methoxamine, and alpha-1 adrenoceptor agonist, and prazosin, an alpha-1 antagonist, on the stages of the sleep-waking cycle in the cat

In these experiments the effects of alpha 1-adrenoceptor agonism and antagonism were studied on the stages of the sleep-waking cycle of the cat, in order to determine optimal levels of alpha 1-adrenergic transmission for these stages. Polygraphic 16-h recordings showed that prazosin, an alpha 1-adrenoceptor antagonist, at 1 mg/kg i.p., increased paradoxical sleep (PS) time from 15.3% to 26.4% (p less than 0.001) of total time, and the number of PS episodes from 30.4 to 43.6 (p less than 0.001). The effect was prompt, reaching a maximum during the first 4 h with a shortening of PS latency from 40.4 min to 11.0 min (p less than 0.001). Prazosin at doses of 0.5 and 3.0 though not at 10.0 mg/kg also slightly, but significantly, increased PS. Methoxamine, and alpha 1-adrenoceptor agonist, at doses of 0.5 and 3.0 mg/kg, increased aroused waking time (low voltage mixed frequency EEG) during the first 4 h from 23.5% to 33.3% (p less than 0.05) and to 50.3% (p less than 0.01), and decreased PS. Prazosin potentiated dose-dependently clonidine-induced drowsiness ( hypersynchronized 4-8 Hz EEG), whereas the decrease in deep slow wave sleep and PS were potentiated only at the largest dose of it. These results indicate that moderate inhibition of cerebral alpha 1-adrenergic transmission facilitates paradoxical sleep in the cat. Furthermore, they suggest that the level of cerebral alpha 1-adrenergic transmission is high during aroused waking and low during drowsy waking.     

Randomized, double-blind, crossover challenge study in 53 subjects reporting adverse reactions to melon (Cucumis melo)

BACKGROUND: Few studies have evaluated IgE-mediated hypersensitivity to melon with details of clinical reactions confirmed by double-blind, placebo-controlled, food challenges (DBPCFCs). OBJECTIVE: We sought to investigate clinical features (type and severity of reactions, age at onset, results of skin prick and in vitro tests, and incidence of other allergic diseases and associated food allergies) of acute allergic reactions to melon confirmed by DBPCFCs. METHODS: Fifty-three consecutive adult patients complaining of adverse reactions to melon were included in the study. Skin prick tests and detection of specific IgE were performed in all patients with melon, avocado, kiwi, banana, chestnut, latex, pollen, and other offending foods. Patients first underwent an open food challenge, unless they had a convincing history of severe anaphylaxis. Positive open food challenge reactions were subsequently evaluated by DBPCFCs. RESULTS: Actual clinical reactivity was confirmed in 19 (36%) of 53 patients. The most frequent symptom was oral allergy syndrome (n = 14), but two patients experienced life-threatening reactions, including respiratory symptoms and hypotension. The positive predictive value for a skin prick test was 42%, and that for specific IgE measurement was 44%. Forty-five reactions to 15 other foods were confirmed in 18 patients. The most common foods associated with melon allergy were avocado (n = 7), banana (n = 7), kiwi (n = 6), watermelon (n = 6), and peach (n = 5). Onset of melon-induced allergic symptoms occurred from 6 to 45 years (median, 20 years), preceded by seasonal rhinitis, asthma, or both in 88% (15/17). CONCLUSION: About one third of reported reactions to melon are confirmed by means of DBPCFC, which has been proven to be the most reliable procedure in the diagnosis of clinical fruit allergy. Isolated melon allergy is rare, with most patients either having allergic rhinitis, asthma, or both and associated food allergies.     

Effects of methoxamine,an alpha-1 adrenoceptor agonist,and prazosin,an alpha-1 antagonist,on the stages of the sleep—waking cycle in the cat

In these experiments the effects of α₁-adrenoceptor agonism and antagonism were studied on the stages of the sleep-waking cycle of the cat, in order to determine optimal levels of α₁-adrenergic transmission for these stages. Polygraphic 16-h recordings showed that prazosin, an α₁-adrenoceptor antagonist, at 1 mg/kg i.p., increased paradoxical sleep (PS) time from 15.3% to 26.4% (p<0.001) of total time, and the number of PS episodes from 30.4 to 43.6 (p<0.001). The effect was prompt, reaching a maximum during the first 4 h with a shortening of PS latency from 40.4 min to 11.0 min (p<0.001). Prazosin at doses of 0.5 and 3.0 though not at 10.0 mg/kg also slightly, but significantly, increased PS. Methoxamine, an α₁-adrenoceptor agonist, at doses of 0.5 and 3.0 mg/kg, increased aroused waking time (low voltage mixed frequency EEG) during the first 4 h from 23.5% to 33.3% (p<0.05) and to 50.3% (p<0.01), and decreased PS. Prazosin potentiated dose-dependently clonidine-induced drowsiness (hypersynchronized 4–8 Hz EEG), whereas the decrease in deep slow wave sleep and PS were potentiated only at the largest dose of it. These results indicate that moderate inhibition of cerebral α₁-adrenergic transmission facilitates paradoxical sleep in the cat. Furthermore, they suggest that the level of cerebral α₁-adrenergic transmission is high during aroused waking and low during drowsy waking.     

Examining the influence of biological and psychological factors on cognitive performance in chronic fatigue syndrome: A randomized,double-blind,placebo-controlled,crossover study

The pathophysiology of chronic fatigue syndrome (CFS) remains unclear; however, both biological and psychological factors have been implicated in establishing or maintaining this condition. People with CFS report significant and disabling cognitive difficulties such as impaired concentration that in some cases are exacerbated by exposure to chemical triggers. The aim of this study was to determine if neuropsychological deficits in CFS are triggered by exposure to chemicals, or perceptions about the properties of these substances. Participants were 36 people with a primary diagnosis of CFS, defined according to Centers for Disease Control (CDC) criteria. A randomized, double-blind, placebo-controlled, crossover design was used, with objective assessment of neuropsychological function and participant rating of substance type, before and after exposure to placebo or chemical trigger. Results showed decrements in neuropsychological tests scores on three out of four outcome measures when participants rated the substance they had been exposed to as “chemical. ” No change in performance was found based on actual substance type. These results suggest that cognitive attributions about exposure substances in people with CFS may be associated with worse performance on neuropsychological tasks. In addition, these findings suggest that psychological interventions aimed at modifying substance-related cognitions may reduce some symptoms of CFS.     

Inhibitory effect of midaglizole on alpha adrenoceptor agonist-induced contractions of canine tracheal smooth muscle

To determine why midaglizole is effective in some patients with severe asthma, we investigated the inhibitory effects of midaglizole, prazosin or yohimbine on the BHT 920-, phenylephrine-, or noradrenaline-induced contractions of canine tracheal smooth muscle. After pretreatment with atropine (10(-6) M) and propranolol (10(-6) M) and precontraction with serotonin (3 x 10(-7) M), the tracheal muscle showed contractile responses to the exogenous administration of both alpha 1 and alpha 2 adrenoceptor agonists. Every alpha antagonist inhibited these agonist-induced contractions. Inhibitory activity of midaglizole (10(-4) M) for the alpha agonists was BHT-920 greater than noradrenaline greater than or equal to phenylephrine, while that of prazosin (3 x 10(-6) M) was phenylephrine greater than noradrenaline greater than BHT-920. Moreover, yohimbine completely inhibited the contractions at the lower concentration of 3 x 10(-7) M than that of other two antagonists. Our findings demonstrate that midaglizole dose-dependently inhibits airway contractions induced by alpha adrenoceptor agonists.     

Inhibitory effect of buflomedil on prostate alpha1A adrenoceptor in the Wistar rat

The inhibitory effect of buflomedil on alpha1A-adrenoceptor (AR) in the prostate of Wistar rat was investigated in this study. Normotensive and spontaneous hypertensive rats were orally fed with buflomedil (150 mg/kg). The drug effects on blood pressure and heart rate were monitored by photoelectric volume oscillometric method. Prostate tissue strips from normotensive rats were contracted in vitro in organ bath by phenylephrine (10(-8) to 10(-2)M). The inhibitory effects of buflomedil (10(-9) to 10(-7)M) on the phenylephrine-induced contractions were measured. Radioligand binding displacement study by buflomedil was performed on rat prostate alpha1A-adrenoceptor (AR) and spleen alpha1B-AR. Furthermore the effects of buflomedil and WB-4101 on phenylephrine (10 microM) activated uptake of 2-[14C]-deoxy-d-glucose (2-DG) into C2C12 cells were evaluated. The results showed that buflomedil feeding did not alter the systolic blood pressure of either spontaneous hypertensive rats or normal rats. Dose-inhibition curves of phenylephrine-induced prostate contraction demonstrated a higher potency of buflomedil than tamsulosin. Buflomedil displaced [3H]prazosin binding in a concentration-dependent manner both in rat prostate alpha1A-AR and spleen alpha1B-AR. The ratio of affinity to alpha1A-AR and alpha1B-AR for buflomedil was 4.06/6.84, indicating selectivity on alpha1A-AR over alpha1B-AR. Activation of C2C12 cell alpha1A-AR by phenylephrine increased the glucose uptake to 116%. Both buflomedil and WB-4101 inhibited the uptake in a concentration-dependent manner. In conclusion, the findings showed that buflomedil has preferential alpha1A-AR antagonistic effect to inhibit prostate contraction without significantly affecting the blood pressure.     

The effect of the calcium-entry blocker nifedipine on cold-induced digital vasospasm. A double-blind crossover study versus placebo

The effects of the calcium-entry blocker nifedipine 20 mg, two 10 mg capsules, t.i.d. in patients with cold-induced digital vasospastic disease of idiopathic or traumatic origin was tested in 28 patients, using double-blind crossover technique on both symptoms and test results. The effect of treatment on digital blood pressure during local cooling was assessed using the Nielsen-Lassen method. Symptomatic improvement was reported by 5 patients during placebo treatment and 17 during nifedipine treatment (p less than 0.01). The symptomatic improvement was significant in the total group of patients and in the group of patients with idiopathic vasospastic disease. The digital blood pressure during local cooling improved significantly with nifedipine at 5, 10, 15 (p less than 0.001) and 20 degrees C (p less than 0.05) for the total study population and for the two subgroups except for the change at 20 degrees C in the IDIOP group. At a digital temperature of 10 degrees C, 2 patients reached normal digital blood pressure during placebo treatment compared to 16 during nifedipine treatment (p less than 0.001). The number of side-effects increased significantly (p less than 0.05) during nifedipine treatment. We consider the use of nifedipine in patients with cold-induced digital vasospastic disease to be of great value, especially in patients with digital vasospastic disease of idiopathic origin.     

Rapid onset of action of levodopa in restless legs syndrome: a double-blind, randomized, multicenter, crossover trial

OBJECTIVE: To investigate the efficacy and safety of levodopa plus benserazide in the treatment of restless legs syndrome (RLS), in terms of the frequency of periodic limb movements (PLMs), objective and subjective criteria of sleep, onset of action, and withdrawal effects. DESIGN: A randomized, double-blind, placebo-controlled, multicenter, crossover trial, with two 4-week treatment periods. SETTING: Outpatient units of three specialist centers in Germany. PATIENTS: Eligible patients had to fulfill the diagnostic criteria of the International RLS Study Group and have sleep disturbances and PLMs during sleep shown on polysomnography at screening. Thirty-five patients were recruited, of whom 32 (13 men, 19 women) completed the study. INTERVENTIONS: Patients received a single dose of standard-release levodopa/benserazide 100/25 mg or placebo at bedtime each night for 4 weeks, before crossing over to receive the alternative treatment for a further 4 weeks; the dose could be doubled if required. The average dosages were 159 +/- 31 mg of levodopa and 1.56 +/- 0.29 capsules of placebo. RESULTS: Levodopa/benserazide significantly reduced the number of PLMs per hour (p<0.0001), increased the time in bed without limb movements (p<0.0001), and improved subjective quality of sleep (p=0.0004). The onset of action was rapid after the first dose, and full efficacy was achieved within the first few days of therapy; these improvements disappeared immediately when treatment was discontinued. Levodopa/benserazide treatment was well tolerated and safe. CONCLUSIONS: Levodopa/benserazide is effective and safe in the treatment of RLS. Objective and subjective measures of sleep improved rapidly after the first dose. RLS symptoms recurred immediately after treatment was discontinued.     

Effect of azelastine on the seasonal increase in non-specific bronchial responsiveness to methacholine in pollen allergic patients. A randomized, double-blind placebo-controlled, crossover study

Azelastine, a phthalazinone derivative, is a new potent, long acting, orally active anti-allergic compound with particularly strong H1-histamine receptor antagonistic effects which has been proven to possess in vitro and in vivo a number of anti-inflammatory properties. The aim of the present study was to investigate whether azelastine would be able to prevent and/or reverse the seasonal increase in non-specific bronchial responsiveness to methacholine in pollen allergic patients. Twelve atopic patients (5 males, mean age 31 years), skin positive exclusively to grass and/or Parietaria pollen extract, with rhinitis and mild asthma occurring in the spring for at least two years previously, were studied. After a 2 week run-in period, oral azelastine, 4 mg twice daily, or placebo, was given for 2 weeks from the start of the pollen season, according to a randomized, double-blind design. After 2 weeks, the treatments were crossed over. During both the run-in and study periods, patients recorded rhinitis and asthma symptoms, additional antihistamine and bronchodilator drugs taken and peak expiratory flow measurements. A methacholine inhalation test was carried out on four occasions in each patient: before the run-in period, before the start of the treatment, and at the end of the two 2 week treatment periods. Azelastine significantly reduced rhinitis symptoms and the need for antihistamine drugs, whereas asthmatic symptoms, use of bronchodilator drugs, peak flow recordings and bronchial responsiveness to methacholine were unaffected by the treatment. Compliance level and adverse side-effects were not significantly different between active treatment and placebo. In the final subjective evaluation of the two treatments, eight out of 12 patients preferred azelastine.(ABSTRACT TRUNCATED AT 250 WORDS)     

The protective action of fluocortin butylester (FCB) in the nasal antigen provocation test: a controlled double-blind, crossover study

Fluocortin butylester (FCB), a locally active corticosteroid, was inhaled as a fine powder mixed with lactose using the rhinolator in a comparative double-blind, crossover study against placebo. Fifty patients of both sexes and aged from 16 to 46 years with an established seasonal allergic rhinitis, but free of symptoms, took part in this trial. The determination of the protective action after allergen provocation was performed after seven days treatment with 4 mg FCB or placebo. Measurements of the nasal resistance and the temperature were taken after provocation. The symptoms of nose and eyes were recorded. The protective effect of FCB against nasal provocation with grass pollen extracts was statistically proved.