Placebo Phase Research Articles

Long-term improvement of QT dispersion is unaffected by short-term changes in blood pressure during treatment of systemic hypertension with enalapril.

We report the reduction of QT and QTc dispersion in patients treated for 7 years with enalapril for systemic hypertension with left ventricular (LV) hypertrophy. We assess the correlation between QT dispersion and LV mass during this period and at the end of an 8-week period of suspension of enalapril treatment after 5 years. Twenty-four previously untreated patients with this condition took enalapril (20 mg twice daily) for 7 years, except during an 8-week period following 5-year follow-up. Cardiovascular parameters were determined by two-dimensional guided M-mode echocardiography, and QT interval was measured, in a pretreatment placebo phase, 8 weeks and 1, 3, 5, and 7 years after the start of the therapy, at the end of the 8-week suspension effected after 5 years, and 8 weeks after the end of the suspension. Therapy rapidly reduced blood pressure (BP) from 156/105 mmHg to normal values: 134/84 mmHg after 8 weeks' treatment, 130-84 mmHg at 7-year follow-up (P < 0.001 with respect to the placebo phase). LV mass index decreased progressively until at 5-year follow-up the reduction had reached 39% (P < 0.001), after which neither LV mass nor any other structural parameter underwent any further significant change. During this time, QT dispersion (DeltaQT) and the dispersion of "corrected" QT (DeltaQTc) decreased significantly: DeltaQT (from 61 +/- 21 to 37 +/- 13 ms) and DeltaQTc (from 67 +/- 27 to 41 +/- 16 ms). After suspension of treatment for 8 weeks following 5-year follow-up, DeltaQT was 40 +/- 14 ms and DeltaQTc was 44 +/- 17 ms; there were no significant changes either in DeltaQT and DeltaQTc or LV hypertrophy although BP had returned to pretreatment values (BP: 150 +/- 16; 101 +/- 10 mmHg). Long-term enalapril treatment of hypertensive patients with LV hypertrophy induces marked regression of LV mass and improvement of QT dispersion. These improvements occur on a longer timescale than improvement in BP, and are not affected by transient changes in BP values.

Candesartan and hydrochlorothiazide in isolated systolic hypertension

Aim: We investigated the efficacy and safety of daily candesartan 8/16 mg and hydrochlorothiazide 12.5 mg as monotherapy and in combination in older patients with systolic hypertension. Methods: The study used a double-blind randomized placebo-controlled crossover design. Treatment phases were of 6 weeks duration. For inclusion, patients were aged 55-84 years with sitting systolic blood pressure (SBP) 160-210 mmHg and diastolic blood pressure (DBP) <95 mmHg. Nineteen patients (11 male, eight female, median age 68 years) completed the study. Major findings: Compared with the placebo phase, clinic and ambulatory SBP was significantly reduced with both dose-adjusted candesartan and fixed-dose hydrochlorothiazide as monotherapy, the effect of candesartan being greater than that of hydrochlorothiazide. In combination, the effects of the two drugs were additive. Both drugs were well tolerated either as monotherapy or in combination. Conclusion: Both candesartan and a low dose of hydrochlorothiazide are effective and well-tolerated antihypertensive agents in isolated systolic hypertension with additive effects in combination. Candesartan was more effective than hydrochlorothiazide, although it is possible that dose adjustment only of candesartan could have enhanced its relative effectiveness.

Tranexamic acid: a review of its use in the management of menorrhagia.

Tranexamic acid (Transamin), Cyklokapron, Exacyl, Cyklo-f) is a synthetic lysine derivative that exerts its antifibrinolytic effect by reversibly blocking lysine binding sites on plasminogen and thus preventing fibrin degradation. In a number of small clinical studies in women with idiopathic menorrhagia, tranexamic acid 2-4.5 g/day for 4-7 days reduced menstrual blood loss by 34-59% over 2-3 cycles, significantly more so than placebo, mefenamic acid, flurbiprofen, etamsylate and oral luteal phase norethisterone at clinically relevant dosages. Intrauterine administration of levonorgestrel 20 microg/day, however, produced the greatest reduction (96% after 12 months) in blood loss; 44% of patients treated with levonorgestrel developed amenorrhoea. Tranexamic acid 1.5 g three times daily for 5 days also significantly reduced menstrual blood loss in women with intrauterine contraceptive device-associated menorrhagia compared with diclofenac sodium (150 mg in three divided doses on day 1 followed by 25 mg three times daily on days 2-5) or placebo. Tranexamic acid, mefenamic acid, etamsylate, flurbiprofen or diclofenac sodium had no effect on the duration of menses in the studies that reported such data. In a large noncomparative, nonblind, quality-of-life study, 81% of women were satisfied with tranexamic acid 3-6 g/day for 3-4 days/cycle for three cycles, and 94% judged their menstrual blood loss to be 'decreased' or 'strongly decreased' compared with untreated menstruations. The most commonly reported drug-related adverse events are gastrointestinal in nature. The total incidence of nausea, vomiting, diarrhoea and dyspepsia in a double-blind study was 12% in patients who received tranexamic acid 1g four times daily for 4 days for two cycles (not significantly different to the incidence in placebo recipients). In conclusion, the oral antifibrinolytic drug tranexamic acid is an effective and well tolerated treatment for idiopathic menorrhagia. In clinical trials, tranexamic acid was more effective at reducing menstrual blood loss than mefenamic acid, flurbiprofen, etamsylate and oral luteal phase norethisterone. Although it was not as effective as intrauterine administration of levonorgestrel, the high incidence of amenorrhoea and adverse events such as intermenstrual bleeding resulting from such treatment may be unacceptable to some patients. Comparative studies of tranexamic acid with epsilon - aminocaproic acid, danazol and combined oral contraceptives, as well as long-term tolerability studies, would help to further define the place of the drug in the treatment of menorrhagia. Nevertheless, tranexamic acid may be considered as a first-line treatment for the initial management of idiopathic menorrhagia, especially for patients in whom hormonal treatment is either not recommended or not wanted.

Role of chromium supplementation in Indians with type 2 diabetes mellitus

Type 2 diabetes mellitus is a complex metabolic disorder with adverse cardiovascular risk. The role of micronutrients has not yet been well clarified in this condition, especially in India. The objectives of this study were to: (1) evaluate chromium status in Indian subjects with type 2 diabetes mellitus, (2) assess the effect of chromium picolinate (200 μg trivalent chromium twice daily) administration on glycaemic control and lipid profile in these subjects and (3) comment on the possible mechanism of any beneficial effect noted above. Fifty subjects were studied in a double blind, placebo-controlled, crossover fashion, with each treatment arm (chromium/placebo) lasting 12 weeks and 4 weeks’ wash-off period in between. 50 healthy age- and sex-matched volunteers served as controls. Serum chromium level appeared to be higher in the general population in our country compared to western countries (36.5–59.5 nmol/L as compared to 2.3–40.3 nmol/L) However, the local diabetics were found to have a lower serum chromium level than the healthy controls (32.3 nmol/L against 44.7 nmol/L; p < 0.0001) and a mean increase of 3.5 nmol/L was noted after 12 weeks of chromium supplementation that was, expectedly, not seen in the placebo phase ( p < 0.0001). Significant improvement in glycaemic control was noted in the chromium-treated group (ΔFasting serum glucose = 0.44 mmol/L, p < 0.001; ΔPost-prandial serum glucose = 1.97 mmol/L, p < 0.001; Δglycated hemoglobin = 0.01; p = 0.04, in comparison to placebo) This was accompanied by a significant greater fall in fasting serum insulin in the chromium-treated group, p < 0.05. The change in lipid parameters (total serum cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides) did not show significant difference between the chromium and placebo groups. Clinically significant hematological, renal or hepatic toxicity were excluded by routine hemogram, serum urea, creatinine, alanine amino transferase (ALT) and alkaline phosphatase estimations. In conclusion, chromium supplementation seems to improve glycaemic control in type 2 diabetic patients, which appears to be due to an increase in insulin action rather than stimulation of insulin secretion.

Preliminary experience with an ampakine (CX516) as a single agent for the treatment of schizophrenia: a case series

We used l-(quinoxalin-6-ylcarbonyl)piperidine (CX516) (a modulator of the α-amino-3-hydroxy-5-methyl-4-isoxasole propionic acid (AMPA) receptor) as a sole agent in a double blind placebo-controlled design in a small series of patients with schizophrenia who were partially refractory to treatment with traditional neuroleptics. The study entailed weekly increments in doses of CX516, from 300 mg tid for week 1 up to 900 mg tid on week 4. Patients were followed with clinical ratings, neuropsychological testing, and were monitored for adverse events. Four patients received 2 to 4 weeks of CX516, two received placebo and two withdrew during the placebo phase. Adverse events associated with drug administration were transient and included leukopenia in one patient and elevation in liver enzymes in another. No clear improvement in psychosis or in cognition was observed over the course of the study. CX516 at the doses tested did not appear to yield dramatic effects as a sole agent, but inference from this study is limited.

Reliability, Validity, and Responsiveness of the Six-minute Walk Test in Patients with Heart Failure.

Abstract Background Our purpose was to evaluate the reliability, validity, and responsiveness of the 6-minute walk test (6MWT) in patients with heart failure (HF) enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Methods A total of 768 patients was enrolled in a multicenter randomized clinical trial evaluating the effect of candesartan, enalapril, and metoprolol on left ventricular ejection fraction (LVEF), 6MWT distance, neurohormones, and quality of life. The 6MWT was performed once at screening and twice at baseline, 18 weeks, and 43 weeks by a standardized method. Results Test-retest reliability at baseline (intraclass correlation coefficient [ICC] = 0.90), 18 weeks (ICC = 0.88), and 43 weeks (ICC = 0.91) was very good. Baseline 6MWT distance was weakly inversely correlated to the quality-of-life cumulative score ( r = –0.26, P =.0001) and moderately inversely correlated to the New York Heart Association functional classification (NYHA-FC) ( r = –0.43, P =.001). In the RESOLVD study, the 6MWT was not responsive to change when effect sizes and standardized response means were used. Disease-specific quality of life was responsive to change in patients treated with candesartan and enalapril and NYHA-FC was responsive to change in the candesartan and enalapril combination and for enalapril alone with small effect sizes. The 6MWT, NYHA-FC, and quality of life were not responsive to change during the metoprolol or placebo phase. Conclusions The 6MWT is highly reproducible in patients with symptoms of HF. It is somewhat correlated to NYHA-FC and quality of life. Overall, quality of life was most responsive to change, whereas 6MWT and NYHA-FC were comparable but less responsive to change in the RESOLVD study. (Am Heart J 2001;142:698-703.)

Montelukast in the Treatment of Children with Moderate-To-Severe Atopic Dermatitis: A Pilot Study

Purpose to the Study. The role of leukotrienes in the pathogenesis of atopic dermatitis (AD) is uncertain. This double-blind, placebo-controlled crossover study addressed the efficacy of the leukotriene receptor antagonist montelukast in moderate to severe AD.Study Population. Fifteen patients (ages 6–16) with moderate to severe AD despite conventional therapy consisting of at least a class II steroid, soap substitutes, and emollients.Methods. Disease severity was evaluated by grading 8 areas of the body (head/neck, front of the trunk, the back, genitalia, and 4 limbs) on a scale of 0 to 3. A score of at least 40 was required to be enrolled in the study. The extent of disease was calculated by estimating the percentage of the body surface involvement. Patients were examined by the same physician on a biweekly basis and completed questionnaires to assess the impact of AD on daily life, as well as the effect of disease on relationships with family members and social life. There was a 2-week run-in period during which standardized topical treatment was initiated. Patients were randomized to receive either 5 mg montelukast or placebo daily for 4 weeks. There was a 2-week washout period before crossover for the second phase.Results. Eleven patients completed the study with 6 in group A (placebo first) and 5 in group B (drug first). Despite randomization, the baseline median disease severity score between groups was significantly different, group A 52 and group B 78 (P = .018). Group B had a significant decrease in the disease severity (P = .05) during the drug phase. There was also an increase in disease severity during the placebo phase, however, severity scores did not return to baseline. Group A had improvement during both the placebo and drug phase (P = .075 and .029, respectively). Patient index scores and extent of disease did not change significantly for either group.Conclusion. This pilot study shows that leukotrienes may be important mediators in AD and leukotriene receptor antagonists (LRAs) may be suitable adjuvant therapy in those patients with severe disease.Reviewers’ Comments. Although leukotrienes are important chemical mediators in asthma and allergic rhinitis, their role in the pathogenesis of AD is not as clear. This study suggests that they may have a role in AD and that LRAs may provide some clinical benefit. In practice, some patients do seem to improve although the responses have not been overwhelming, which is consistent with the results of this study. It may be worth a try in patients with severe disease and, in addition, patients who are started on an LRA for their asthma may experience some improvement in their AD.

Angiotensin converting enzyme inhibition and angiotensin II AT 1-receptor blockade reduce the levels of asymmetrical NG, NG-dimethylarginine in human essential hypertension

Background Asymmetrical N G, N G-dimethylarginine (ADMA) is associated with impaired endothelium-dependent vasodilation in humans. Methods Twenty young, male, mildly hypertensive subjects were included in a randomized, double-blind, fourfold cross-over study with placebo, enalapril (20 mg/day), eprosartan (600 mg/day), or a combination of both drugs (10 and 300 mg/day, respectively) each over 1 week, followed by a 2-week wash-out phase. After each treatment phase, ADMA concentration was measured. Results ADMA concentration was 1.69 ± 0.59 μmol/L in the placebo phase, and was significantly lower in the enalapril, eprosartan, and combination phases (1.41 ± 0.29, 1.42 ± 0.43, and 1.38 ± 0.30 μmol/L, respectively; all P < 0.05 v placebo). Changes in ADMA levels were independent of the drugs’ action on blood pressure (BP). Conclusions Levels of ADMA were reduced with enalapril and eprosartan therapy. Our results suggest a specific action of these drugs on ADMA levels that is independent of BP.

Clinical use of tricyclic anticonvulsants in painful neuropathies and bipolar disorders

1.1.1. Clinical trials of carbamazepine (CBZ) Trigeminal neuralgia (TN; commonly called tic douloureux) was the first condition in which the efficacy of antiepileptic drugs (AEDs) for neuropathic pain was evaluated. In 1853, Armand Trousseau, a French neurologist, hypothesized that the paroxysmal episodes of pain in this condition were due to an ‘‘epileptic discharge’’ within the trigeminal pathways and, therefore, that drugs for treating seizures might help in this condition. Following the first report of CBZ’s usefulness in this condition [1], its efficacy was evaluated in three double-blind, placebo-controlled, single-center, crossover-design clinical trials that enrolled a total of 151 patients [2–4]. The median daily dose of CBZ was approximately 600mg. Overall, the three trials showed a significant improvement in pain severity during the CBZ phase (56–75%) compared with the placebo phase (0– 26%). These results led the Food and Drug Administration to approve the labeling of CBZ for the treatment of TN. It is estimated that 70–90% of patients with newly diagnosed TN will have a good response to CBZ. Treatment is usually initiated at 200mg b.i.d., with a substantial improvement in symptoms noticed within a day or two. Once autoinduction takes place, the dose often needs to be increased and titrated according to clinical response. The usual effective dose ranges between 400 and 1000mg/day. Although the initial response to CBZ is usually good, long-term, open-label studies have documented a dropout rate of up to 40% at 1 year due to side effects or the development of tolerance.

Oral Corticosteroids Increase Esophageal Acid Contact Times in Patients With Stable Asthma

The prevalence of gastroesophageal reflux disease (GERD) is higher in people with asthma than in control populations. Predisposing factors for GERD development may include asthma medications such as prednisone. The objective of this study was to determine whether prednisone alters GERD parameters in people with asthma. Prospective, single-blinded, placebo-controlled, crossover study. University medical center clinic. Twenty adults with stable, moderate persistent asthma with minimal esophageal reflux symptoms (less than three times a week) who were not receiving antireflux therapy. Prednisone, 60 mg/d, for 7 days. Asthma, esophageal reflux symptoms, and spirometry were measured during baseline, placebo, and prednisone phases, each 7 days in duration. Dual-probe esophageal pH monitoring, esophageal and respiratory manometrics (20 subjects), and basal and stimulated gastric acid secretion (4 subjects) were measured after placebo and prednisone phases. There were significant increases in esophageal acid contact times at the distal and proximal pH probes during the prednisone phase. Total percentage of time that pH was < 4.0 at the distal probe was 2.5 +/- 0.4% for placebo compared with 5.9 +/- 0.9% for prednisone (p < 0.002). Total percentage of time that pH was < 4.0 at the proximal probe was 0.3 +/- 0.1% for placebo and 0.8 +/- 0.2% for prednisone (p < 0.0007). There were no significant changes in subject weight, spirometry, asthma or esophageal reflux symptoms, manometrics, or basal or stimulated gastric acid secretion. Prednisone, 60 mg/d for 7 days, increased esophageal acid contact times in this small population of people with stable asthma; however, the mechanism for this finding is unclear.

Comparative bioethics in bipolar and epilepsy research

Rationale: AEDs are increasingly evaluated for efficacy in bipolar disorders utilizing double-blind, placebo-controlled, randomized clinical trials (RCTs) as required by the FDA. However, the risk to patients is under-estimated in trial design. Bipolar depression has a significant risk for suicide; bipolar episodes can lead to kindling with increased long-term morbidity; rapid regression may occur during the placebo phase or during dose ranging trials with resultant active suicide status. The associated risks mandate that the ethics of FDA-required protocols are addressed.Method: Comparative analysis and literature review of bipolar and epilepsy research designs.Results: In psychiatry, all INDs require RCTs for approval. In epilepsy, AEDs are initially approved as add-on agents only. Once AEDs have demonstrated add-on efficacy, cross-over studies comparing active AEDs, sub-optimal dosing paradigms, new-onset, and pre-surgical inpatient placebo trials are utilized to prove efficacy of the new AED in monotherapy. Ethical considerations to avoid seizures and to minimize risks to subjects have led to newer clinical trial designs.Conclusions: The FDA initially requires add-on studies with new AEDs due to the risk of seizures during the placebo phase. The author argues that bipolar research warrants similar add-on studies to prove efficacy because the risk of suicide and increased long-term morbidity in the bipolar population is as significant as the risk of seizures in the epilepsy population. Although the number of patients needed to prove statistical efficacy would increase, the safety of such research would also markedly increase. The author further concludes that with the risk of suicide during bipolar research, ethical considerations require increased frequency of patient contact with a significant other co-signing the informed consent for research and serving as a contact for the coordinator.

Establishment of a diazepam preference in human volunteers following a differential-conditioning history of placebo versus diazepam choice.

This study examined whether preference for a drug (diazepam or placebo) could be switched using conditioning procedures. During the first 4 sessions of Phase 1, 6 participants received 5 mg of diazepam or placebo under double-blind conditions. During the remaining 5 sessions of Phase 1, participants selected the drug they wished to receive. The first 4 sessions of Phase 2 were a replication of Phase 1, except that following ingestion of the drug, participants completed a computer task for which they could earn money. Payment for the computer task was lowest following ingestion of the drug they preferred in Phase I and highest following the drug they had avoided. Preference was reassessed during the last 5 sessions of Phase 2. Five of the participants preferred placebo in Phase 1 but diazepam in Phase 2. Subjective responses to the drugs also changed across the 2 phases.

Adverse events during a placebo phase for inpatients with chronic schizophrenia

Background: This report builds on a previous analysis examining the long-term effects of a placebo period on a group of inpatients with chronic schizophrenia. In the present analysis, outcome was evaluated through the use of the Psychiatric Adverse Events Rating Scale. Methods: This retrospective analysis examined adverse events for 55 patients with chronic schizophrenia who were placed in a double-blind placebo study on the inpatient units of the National Institute of Mental Health Neuropsychiatric Research Hospital. The number and severity of adverse events experienced by these patients during baseline, placebo, and discharge periods were analyzed. Results: The frequency and severity of adverse events for this group of patients were modest. Most patients did not experience a statistically significant increase in adverse events during their placebo phase; however, a subgroup of patients who were hospitalized for less than 2 months after antipsychotic medications were restored did experience a statistical elevation in adverse events, and that frequency remained statistically elevated at discharge. Conclusions: The results confirm the findings from our previous analysis. Regardless of whether outcome is measured by a behavioral rating scale or by an adverse event scale, given a sufficiently lengthy recovery period, patients with chronic schizophrenia who go through a placebo phase return to baseline.

Reliability, validity, and responsiveness of the six-minute walk test in patients with heart failure

Background Our purpose was to evaluate the reliability, validity, and responsiveness of the 6-minute walk test (6MWT) in patients with heart failure (HF) enrolled in the Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Methods A total of 768 patients was enrolled in a multicenter randomized clinical trial evaluating the effect of candesartan, enalapril, and metoprolol on left ventricular ejection fraction (LVEF), 6MWT distance, neurohormones, and quality of life. The 6MWT was performed once at screening and twice at baseline, 18 weeks, and 43 weeks by a standardized method. Results Test-retest reliability at baseline (intraclass correlation coefficient [ICC] = 0.90), 18 weeks (ICC = 0.88), and 43 weeks (ICC = 0.91) was very good. Baseline 6MWT distance was weakly inversely correlated to the quality-of-life cumulative score (r = –0.26, P =.0001) and moderately inversely correlated to the New York Heart Association functional classification (NYHA-FC) (r = –0.43, P =.001). In the RESOLVD study, the 6MWT was not responsive to change when effect sizes and standardized response means were used. Disease-specific quality of life was responsive to change in patients treated with candesartan and enalapril and NYHA-FC was responsive to change in the candesartan and enalapril combination and for enalapril alone with small effect sizes. The 6MWT, NYHA-FC, and quality of life were not responsive to change during the metoprolol or placebo phase. Conclusions The 6MWT is highly reproducible in patients with symptoms of HF. It is somewhat correlated to NYHA-FC and quality of life. Overall, quality of life was most responsive to change, whereas 6MWT and NYHA-FC were comparable but less responsive to change in the RESOLVD study. (Am Heart J 2001;142:698-703.)

Nebivolol (Nebilet®) - ein sicherer Betablocker der dritten Generation - auch für Patienten mit obstruktiven Lungenerkrankungen?

Twenty-four patients with bronchial hyperreactivity due to asthma (8 patients), COPD (13) and of unknown origin (3) entered and completed a randomized double-blind intraindividual cross-over study. Thirteen patients first received the highly selective vasodilatating beta 1-blocker Nebivolol (5 mg) and 11 patients first placebo with a wash-out period of at least 2 days. Before the controlled oral intake of the tablets, the patients were challenged with increasing inhalative doses of carbachol between 8 and 9 a.m. according to the recommendation of the German Society of Pneumology. At 10, 11 and 12 a.m. and 1 and 2 p.m. control measurements of airway patency (Raw, FEV1) were performed in the body box. At the same time intervals, oxygen saturation and pulse rate (pulsoximetry) including systolic and diastolic blood pressure were monitored. From 2-3 p.m. the carbachol provocation was repeated as in the morning to assess the changes in hyperreactivity due to Nebivolol. During the Nebivolol phase, blood pressure values and pulse rates were significantly reduced compared to the placebo phase. At the same time intervals, no significant changes of the measured body box variables to assess airway obstruction were observed during therapy with Nebivolol compared to placebo. Comparing the measured variables (maximal deviation from base-line values of Raw and FEV1) during carbachol provocation in the afternoon under Nebivolol and placebo with the values in the morning before any medication (base-line values), there were also no significant detectable differences indicating an increase of bronchial hyperreactivity under Nebivolol treatment. It seems that Nebivolol in these hyperreactive patients is as safe as placebo despite its significant effect on blood pressure and pulse rate.

Oral contraceptives alter sleep and raise body temperature in young women.

Female reproductive steroids, oestrogen and progesterone, not only affect reproductive function, but also thermoregulation and sleep. Chronic administration of synthetic steroids, as occurs in women taking oral contraceptives, may affect these regulatory systems differently from endogenous oestrogen and progesterone. We therefore investigated body temperature and sleep in ten young women taking oral contraceptives, in the active and placebo phases of the contraceptive pack, and compared them to a group of nine women with ovulatory cycles, in the mid-follicular and mid-luteal phases. Body temperature was raised throughout 24 h in the women taking oral contraceptives in the active phase, and in the naturally cycling women in the luteal phase, compared to the follicular phase. The women taking oral contraceptives in the placebo phase, however, continued to have raised body temperatures, similar to those in the active phase, indicating a prolonged action of synthetic reproductive steroids on body temperature. Sleep also was influenced by the endogenous and synthetic reproductive steroids, but independently of body temperature. The women taking oral contraceptives had more stage-2 non-rapid eye movement sleep in the active phase, both compared to their placebo phase and the naturally cycling women. The naturally cycling women, however, had more slow wave sleep in the luteal phase compared to the contraceptive group of women. Exogenous reproductive steroids therefore influence body temperature and sleep differently from endogenous progesterone and oestrogen.

Raloxifene-mediated increase in matrix metalloproteinase-1 production by activated monocytes.

Matrix metalloproteinases (MMPs), proteolytic enzymes produced by monocytes, may contribute to atherosclerotic arterial wall remodeling and to plaque rupture. Because estrogen influences the synthesis of MMPs, we examined the effect of raloxifene, a selective estrogen receptor modulator, on monocyte MMP production. Human primary blood monocytes treated with raloxifene (10 micromol/L) in the presence of lipopolysaccharide (LPS) or tumor necrosis factor-alpha and granulocyte-macrophage colony-stimulating factor induced a 2- to 3-fold increase in MMP-1 production by monocytes. The enhancement of MMP-1 production by raloxifene in LPS-activated monocytes occurred through a cyclooxygenase-2- and prostaglandin E(2)-independent mechanism. Additionally, compared with monocytes acquired during the placebo phase, peripheral blood monocytes from 5 of 6 healthy postmenopausal women treated with raloxifene (60 mg daily for 1 month) in a clinical trial produced significantly higher levels of MMP-1 when the monocytes were activated with LPS. Furthermore, serum obtained during the raloxifene phase from 4 of these subjects, when added to control monocytes, significantly enhanced LPS-induced MMP-1 production compared with that from serum obtained during the placebo phase. In summary, raloxifene increases the production of MMP-1 in activated monocytes; this effect may be favorable in atherosclerotic arterial wall remodeling but unfavorable for plaque stability.

Ketamine for procedural pain relief in newborn infants

AIMTo assess the suitability of ketamine for relief of pain caused by tracheal suction during ventilator treatment in newborn infants.STUDY DESIGNIn a randomised, double blind, cross over trial, 16 newborn...

Efficacy of amitriptyline as a pharmacological adjunct to behavioral modification in the management of aggressive behaviors in dogs

The efficacy of amitriptyline as a pharmacological adjunct to behavioral modification in the clinical management of aggressive behaviors in dogs was evaluated in two phases. Twelve dogs presenting for aggressive behaviors were treated sequentially with amitriptyline (2 mg/kg body weight, per os [PO] bid) and a placebo for 4 weeks in a prospective, randomized, double-blind, placebo-controlled trial. Standardized protocols for behavior modification were implemented throughout the trial. Owners maintained behavioral records and reported on the number of aggressive incidents as well as the dog's overall improvement at the end of each 4-week period. In the second phase, 27 cases of dogs presenting for aggressive behaviors and treated with amitriptyline were reviewed, and clients were contacted to record each dog's response to treatment. Reports were compared to those for dogs receiving behavior modification alone (i.e., placebo phase of prospective study). No significant difference was observed in the patients' responses to adjunctive amitriptyline versus behavior modification alone.

The effect of sodium supplementation on glucose tolerance and insulin concentrations in patients with hypertension and diabetes mellitus

Severe short-term sodium restriction or extreme sodium loading may alter glucose tolerance and insulin resistance in patients with hypertension, but it is unclear whether variations in sodium intake within the clinically observed range affect glucose tolerance. To examine this issue, 21 patients with primary hypertension with average sodium excretion of 116 ± 55 mEq/day were randomized to consecutive 4-week periods of placebo therapy and sodium chloride supplementation 2 g four times a day in a single-blind crossover study design. A 75-g oral glucose tolerance test (GTT) with simultaneous insulin levels was performed at the end of each intervention period. For the group as a whole, urinary sodium excretion increased on sodium chloride to 267 ± 118 mEq/day versus control (placebo) phase of 135 ± 53 mEq/day, P < .001. Total glycemic response in the oral GTT (area under the glucose curve) was 8.0% lower during sodium supplementation, P < .001. Secondary analysis revealed that the effect of sodium was noteworthy in 1) type 2 diabetic subjects ( n = 8), 2) sodium-sensitive subjects ( n = 10), and 3) nondiabetic subjects receiving antihypertensive drug treatment ( n = 6). The total insulinemic response to oral GTT was also lowered by sodium loading among diabetic subjects. Thus, an abundant sodium intake may improve glucose tolerance and insulin resistance, especially in diabetic, salt-sensitive, and or medicated essential hypertensive subjects.