(1S)-(Z)-2-benzyloxy-N-(3-methyl-1-butylidene)-1-phenylethylamine N-oxide.

The preparation and crystal structure of the title compound, C(20)H(25)NO(2), are described. The N atom substituent of the nitrone function adopts a conformation which minimizes the 1,3-allylic strain.

Gender and the placebo analgesic effect in acute pain.

OBJECTIVE: Our objective was to examine the placebo arms from a series of clinical trials in which the post-third molar extraction dental pain model was used to elucidate the time course of the placebo effect and the proportion of the population that are responders, as well as to evaluate whether the placebo analgesic response of female subjects may differ from that of male subjects. METHODS: We performed a meta-analysis of 596 subjects included in the placebo treatment arm of 16 double-blind, post-third molar extraction dental pain (moderate to severe) studies submitted to the Food and Drug Administration electronically. The inclusion and exclusion criteria were practically identical in all studies. Pain relief and pain intensity measurements used the same metrics in all studies. The measurements were recorded just before drug administration and at least at postdose hours 0.5, 1, 1.5, 2, 3, 4, 5, and 6. RESULTS: There were 325 female subjects and 271 male subjects. They were all otherwise healthy, with a mean age of 21.6 years for female subjects and 22.3 years for male subjects. The postoperative baseline pain was greater in female subjects than in male subjects, and this difference was statistically significant. Both pain intensity and pain relief scores demonstrate the well-established placebo effect in 10% of the pooled subjects, as well as in all the individual studies. Over time, however, the mean pain intensity and pain relief scores for the female and male treatment groups were not noticeably different at any time point after medication. Further analysis of the data showed no gender difference in duration of action of the placebo. CONCLUSIONS: The results demonstrated no gender difference in response to placebo. These results were obtained from the post-third molar extraction situation, in which the least possible confounding factors were present. To fully establish the generality of this phenomenon, studies should be carried out in other pain models.

Paramagnetic NMR investigations of high-spin nickel(II) complexes. Controlled synthesis, structural, electronic, and magnetic properties of dinuclear vs. mononuclear species.

New dissymmetric tertiary amines (N(3)SR) with varying N/S donor sets have been synthesized to provide mono- and dinuclear complexes. Acetate ions are used to complete the octahedral coordination sphere around nickel(II) atom(s). The facile conversion of mononuclear to dinuclear systems can be controlled to produce either mono- or dinuclear complexes from the same ligand. The dinuclear complex a(BPh(4))(2) ([Ni(2)(N(3)SSN(3))(OAc)(2)](BPh(4))(2)) has been characterized in the solid state by X-ray diffraction techniques as solvate: a(BPh(4))(2).(1/2)[5(CH(3)OH).(CH(3)CN).(CH(3)CH(2)OH)]. The two Ni atoms are six-coordinated and bridged by a disulfide group and two bidentate acetates. Magnetic susceptibility reveals a weak ferromagnetic exchange interaction between the two Ni atoms with J = 2.5(7) cm(-1). UV-vis studies suggest that the six-coordinated structure persists in solution. The (1)H NMR spectrum of a(BPh(4))(2) exhibits sharp significantly hyperfine shifted ligand signals. A complete assignment of resonances is accomplished by a combination of methods: 2D-COSY experiments, selective chemical substitution, and analysis of proton relaxation data. Proton isotropic hyperfine shifts are shown to originate mainly from contact interactions and to intrinsically contain a small J-magnetic coupling and/or zero-field splitting contribution. A temperature dependence study of longitudinal relaxation times indicates that a very unusual paramagnetic Curie dipolar mechanism is the dominant relaxation pathway in these weakly ferromagnetically spin-coupled dinickel(II) centers. The mononuclear nickel(II) analogue exhibits extremely broader (1)H NMR signals and only partial analysis could be performed. These data are consistent with a shortening of electronic relaxation times in homodinuclear compounds with respect to the corresponding mononuclear species.

A search for sex differences in response to analgesia.

BACKGROUND: It is generally accepted that males and females respond differently to painful conditions. With few exceptions, according to the published literature, females demonstrate a lower pain threshold and a lower tolerance of painful stimuli. There is some support in the literature that females experience greater analgesic efficacy than do males after the administration of narcotic analgesics. We compared the analgesic response of females and males to ibuprofen in a post-third-molar extraction dental pain model. METHODS: We performed a meta-analysis of 314 subjects included in the ibuprofen treatment arm of 7 double-blind, post-third-molar extraction dental pain (moderate to severe) studies, which were submitted to the agency electronically. The inclusion and exclusion criteria were practically identical in all studies. Pain relief and pain intensity measurements used the same metrics in all studies and were recorded just before and at least at 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, 5.0, and 6. 0 hours after drug administration. RESULTS: The study included 195 female subjects and 119 male subjects (mean age, 21 years). Other than requiring dental extractions, the subjects were all healthy. Postoperative baseline pain was greater in females than in males to a statistically significant degree (P =.006). Both pain intensity and pain relief scores demonstrated the well-established analgesic effect of ibuprofen in the pooled data set as well as in all the individual studies. Moreover, the mean pain intensity and pain relief scores over time for the female and male treatment groups were not noticeably different at any time point after drug administration, with no imputation for missing values. Analysis of the data using the "baseline observation carried-forward" technique for remedicated subjects (the technique recommended by the Food and Drug Administration for efficacy analysis of acute analgesic medications) produced the same results, which were confirmed by analysis of variance and t tests at each time point of the study. CONCLUSIONS: Our results demonstrated no sex effect on the analgesic response to ibuprofen. These results were obtained under the post-third-molar extraction setting, in which the least possible confounding factors are present. To fully establish the generality of this phenomenon, studies should be carried out in other pain models and using analgesic medications with different mechanisms of action. Arch Intern Med. 2000;160:3424-3428.

Baseline pain and response to analgesic medications in the postsurgery dental pain model.

In designing clinical trials for the treatment of acute pain, enrollment of patients with moderate to severe pain is recommended even when the desired indication is treatment of mild pain. To test this approach, the authors explored the results of two studies that had the same standard placebo-controlled, parallel-group design and that compared the study medication to a single dose of ibuprofen 400 mg. One study had 25 subjects, the other 50 in its ibuprofen arm. Subjects indicating moderate or severe pain (on a scale ranging from 0 = none, 1 = mild, 2 = moderate, 3 = severe) following a surgical extraction of two or more third molars were enrolled. There was a difference between the ibuprofen groups in these two studies in average baseline pain intensity (PI) (2.88 +/- 0.33 vs. 2.26 +/- 0.44). In the higher baseline group, PI decreased faster, achieving lower levels of PI that were maintained for the rest of the study period. The results of pain relief measurements paralleled those of PI. The authors conclude that including patients with a higher degree of baseline pain in the postoperative dental pain model has the potential to increase discrimination of analgesic properties of new drugs.

Understanding and treating arm movement impairment after chronic brain injury: progress with the ARM guide.

Significant potential exists for enhancing physical rehabilitation following neurologic injury through the use of robotic and mechatronic devices (or "rehabilitators"). We review the development of a rehabilitator (the "ARM Guide") to diagnose and treat arm movement impairment following stroke and other brain injuries. As a diagnostic tool, the ARM Guide provides a basis for evaluation of several key motor impairments, including abnormal tone, incoordination, and weakness. As a therapeutic tool, the device provides a means to implement and evaluate active assist therapy for the arm. Initial results with three stroke subjects demonstrate that such therapy can produce quantifiable benefits in the chronic hemiparetic arm. Directions for future research regarding the efficacy and practicality of rehabilitators are discussed.

Additive deleterious effect of smoking on gastroduodenal pathology and clinical course in Helicobacter pylori-positive dyspeptic patients.

BACKGROUND: Cigarette smoking has long been regarded as an important factor in the pathogenesis of peptic ulcer disease. OBJECTIVE: To investigate whether cigarette smoking has an additive effect on the clinical presentation and course of disease in Helicobacter pylori-positive dyspeptic patients. PATIENTS AND METHODS: The study group comprised 596 consecutive H. pylori-positive dyspeptic patients (334 males and 262 females, mean age 50.6, range 12-81 years). Following upper gastrointestinal endoscopy, patients were subdivided by diagnosis as follows: Non-ulcer patient group (n = 312: gastritis 193, duodenitis 119), gastric ulcer (n = 19), and duodenal ulcer (n = 265). H. pylori infection was confirmed by histology and/or rapid urease test. In addition, 244 patients had a positive 14C-urea breath test prior to antimicrobial treatment. The patients' medical history and smoking habits were obtained using a detailed questionnaire completed by the patients and their referring physicians. RESULTS: There were 337 non-smoking patients, 148 current smokers and 111 past smokers. Gastric and duodenal ulcers were significantly less prevalent in non-smokers than in current or past smokers (gastric 1.8%, 4.1%, 6.3%; duodenal 39.8%, 50%, 51.4%, respectively) (P < 0.05). The incidence of gastrointestinal bleeding was significantly lower in non-smokers than in current or past smokers (7.1%, 8.1% and 20.7%, respectively) (P < 0.05). Bacterial density, as assessed by the UBT value in 244 patients, was higher in non-smokers (mean 352.3 +/- 273 units) than in past smokers (mean 320.8 +/- 199) or current-smokers (mean 229.9 +/- 162) (P < 0.05). Logistic regression analysis revealed that male gender, current smoking, and immigration from developing countries were all significant independent risks for developing duodenal ulcer, while only past smoking was associated with a higher rate of upper gastrointestinal bleeding in the past. CONCLUSIONS: In H. pylori-positive dyspeptic patients, current smoking as well as male gender and immigration from developing countries are associated with an increased risk for duodenal ulcer. This effect does not seem to be related to the bacterial density or increased urease activity of H. pylori organisms.

The acute effects of sublingual 17beta-estradiol on the cardiovascular system.

The beneficial effects of estrogen in postmenopausal women have been well documented. Cardioprotection by estrogen, which is probably the result of several metabolic alterations, appears after 2 or more years of constant use. However, acute administration of estrogen (intravenous or intracoronary) was found to improve cardiac hemodynamics and function through various non-genomic mechanisms. This article reviews data on the consequences of sublingual administration of estrogen, a non-invasive and simple dosing route which is associated with rapid absorption and prompt cardiovascular reactions. It appears that sublingual estradiol at 1 or 2 mg may improve ischemia and exercise performance in women with coronary artery disease, and augment the aortic and brachial blood flow as a result of vasodilation, whereas larger doses (4 mg) may lead to a decrease in myocardial contractility and aortic blood flow, and a slight drop in blood pressure. More data are needed to evaluate the actual clinical significance of sublingual estradiol in healthy women, in situations when endothelial dysfunction is anticipated (diabetes, hypertension) and in women with diagnosed coronary artery disease.

The effects of sublingual estradiol on left ventricular function at rest and exercise in postmenopausal women: an echocardiographic assessment.

OBJECTIVE: To evaluate the acute hemodynamic effects of 4 mg estradiol given sublingually. DESIGN: Rest and exercise echocardiographies were performed prior to estradiol administration. Then, another set of tests was done post-dose: rest examination at 1 h post-dose, isometric exercise at 65 min post-dose, and dynamic exercise at 100 min post-dose. RESULTS: The administration of 4 mg sublingual estradiol to 24 postmenopausal women (aged 48-58 years) was followed 60 min post-dose by a surge in mean estradiol serum levels (1759 +/- 704 pg/ml). At rest a slight drop in systolic and diastolic blood pressure was measured after estrogen ingestion: 132 +/- 24 mm Hg versus 127 +/- 21 mm Hg, p < 0.05; 83 +/- 11 mm Hg versus 78 +/- 10 mm Hg, p < 0.02. There were no changes in resting heart rate, double product, or vascular resistance. The left heart cavities became smaller: the left atrium diameter decreased from 33.7 +/- 4 mm to 32.3 +/- 4 mm, p < 0.01; the end-systolic diameter decreased from 24.9 +/- 3 mm to 23.6 +/- 4 mm, p < 0.01; the end-diastolic diameter decreased from 44.5 +/- 4 mm to 42.7 +/- 4 mm, p < 0.01. The peak aortic blood flow velocity fell from 120 +/- 19 cm/s to 116 +/- 22 cm/s (p < 0.05), and the flow velocity integral fell from 26.3 +/- 4 cm to 24.9 +/- 5 cm (p < 0.01); the cardiac output underwent a small change, with borderline significance: 7 +/- 2 L/min versus 6.7 +/- 2 L/min, p = 0.06. Only minor changes in the hemodynamic and echocardiographic parameters were recorded after estrogen for both isometric and dynamic exercises. Analyses were also made for two subgroups: 13 normotensive women were compared with 11 hypertensive women. The post-estrogen decreases in resting blood pressure and in peak blood velocity were observed only in the hypertensive subjects, whereas the changes in heart dimensions and in flow velocity integral were the same in both subgroups. CONCLUSIONS: Sublingual estradiol was associated with acute hemodynamic alterations mainly at rest but also after exercise.

Hormone replacement and simvastatin in the therapy of hypercholesterolemic postmenopausal women.

OBJECTIVES: To prospectively investigate the effect of cholesterol lowering diet, hormone replacement therapy and simvastatin on plasma lipid levels using a 3-month stepwise protocol. METHODS: Participants were postmenopausal women under the age of 60 with hypercholesterolemia (plasma total cholesterol > 240 mg/dl). The study started with 3 months of Step-One diet (phase I) followed by 3 months of diet and hormone replacement therapy (0.625 mg conjugated estrogens daily combined with 5 mg medroxyprogesterone acetate at days 13-25 of each cycle) (phase II). In women whose total cholesterol remained above 240 mg/dl or LDL-cholesterol above 160 mg/dl by the end of phase II, simvastatin at 10 mg daily was added (phase III). Plasma cholesterol levels as well as safety measurements were closely monitored. RESULTS: Sixteen (21%) of 75 patients who entered the study had satisfactory cholesterol levels by the end of 6 months. Another 25 patients (33%) dropped out of the study for various reasons by that time. In the 34 patients who started simvastatin, plasma total cholesterol levels did not significantly change during phase I and II, however, LDL-cholesterol significantly decreased (204 +/- 31 to 187 +/- 26 mg/dl, p = 0.04) and HDL increased (53 +/- 12 to 62 +/- 16 mg/dl, p = 0.04). A dramatic decrease occurred in both total and LDL-cholesterol levels after one month of phase III (281 +/- 26 to 213 +/- 30 mg/dl 187 +/- 26 to 122 +/- 30 mg/dl respectively, p < 0.0001), with no further changes during the rest of the study period. No significant changes occurred in HDL-cholesterol and triglyceride plasma levels at this phase. Adverse effects were few and minor throughout the study. CONCLUSIONS: Some of the hypercholesterolemic postmenopausal women will benefit from hormone replacement therapy as a single cholesterol lowering treatment in addition to diet (21% in our series). Nevertheless, combination therapy of estrogens and low dose simvastatin proved to be extremely effective in lowering cholesterol levels with no significant side effects. Such therapeutic regimen may also have a synergistic anti-atherogenic effect.

Exercise echocardiography in postmenopausal hormone users with mild systemic hypertension.

Rest and exercise echocardiography (at dynamic and isometric exercise) were performed in 30 postmenopausal women (aged 54 +/- 4 years) with borderline to mild hypertension. They were then divided into 2 groups: 17 women who started oral hormone replacement therapy (0.625 mg/day conjugated estrogens or 2 mg/day estradiol) and a control group of 13 nonusers. After 6 to 9 months, a second echocardiography was performed in 26 women (4 withdrew). There were only a few changes in values obtained in the 12 controls at the end of follow-up compared with baseline. Primarily, these changes included a slight decrease in systolic blood pressure at rest and on exercise. Several significant morphologic and hemodynamic alterations appeared in 14 hormone users. Left ventricular cavity dimensions and mass became smaller: mean end-diastolic diameter decreased from 45.9 +/- 3 mm at baseline to 44.4 +/- 3 mm at study termination (p = 0.007). The corresponding values for end-systolic diameter were 25.8 +/- 4 mm and 23.9 +/- 4 mm (p = 0.006); for left atrium diameter, it was 34.5 +/- 4 mm and 32.5 +/- 4 mm (p = 0.001); for left ventricular wall width, it was 19.9 +/- 2 mm and 19.3 +/- 2 mm (p = 0.02); for left ventricular mass, it was 197 +/- 28 g and 179 +/- 32 g (p = 0.006). The resting aortic blood flow velocity and acceleration increased: 119 +/- 18 cm/s before therapy versus 129 +/- 23 cm/s while on hormone substitution (p = 0.04), and 13.6 +/- 3 m/s2 versus 16.5 +/- 4 m/s2 (p = 0.008), respectively. Mean rest to peak exercise systolic blood pressure difference became smaller after hormones: 39 +/- 19 mm Hg versus 28 +/- 13 mm Hg (p = 0.03) during dynamic exercise, and 43 +/- 22 mm Hg versus 25 +/- 13 mm Hg (p = 0.004) during isometric exercise. The above data probably indicate that with hormone replacement therapy, there is an improvement in cardiac function both at rest and during exercise.

Prediction of renal impairment in elderly patients with congestive heart failure treated with captopril.

This study assessed the usefulness of the oral captopril test in the prediction of renal impairment among elderly patients with congestive heart failure (CHF). Forty-seven patients aged > or = 65 years with CHF (EF < 40%) participated in a prospective nonrandomized series. Blood samples for plasma renin activity (PRA) were drawn before and 60 minutes after 50 mg of oral captopril. Twenty-four hours later, captopril was administered (up to 75 mg/day over a 4 day period), and renal laboratory and clinical assessment were performed at baseline and for a 9 day period. In 7 of 47 patients (14.9%), deterioration of renal function was observed. During the captopril test, the PRA increased significantly after 1 hour in almost all patients and the mean blood pressure decreased from 99.2 +/- 14.6 mmHg to 92.2 +/- 13.7 mmHg (p < 0.001). All patients whose baseline PRA level was < 1.9 ng/ml/hr and whose stimulated PRA was < 3.2 ng/ml/hr maintained a stable renal function throughout the study period. Significant statistical correlation (p < 0.05) was found between the initial PRA, the changes in PRA or mean blood pressure during the captopril test, and the change in plasma creatinine and creatinine clearance in the entire group, and was even more evident in a subgroup of patients with an ejection fraction > or = 30%. All these correlations were not statistically significant in the patients with an ejection fraction < 30%. It is thus concluded that measurement of pretreatment PRA levels might be a useful laboratory tool for predicting the renal safety of captopril use in patients with CHF whose EF > or = 30%.

Intensive home-care surveillance prevents hospitalization and improves morbidity rates among elderly patients with severe congestive heart failure.

The purpose of this study was to examine the impact of intensive home-care surveillance on morbidity rates of elderly patients with severe congestive heart failure. Forty-two patients aged 78 +/- 8 years who had severe congestive heart failure (New York Heart Association functional classes III through IV, mean ejection fraction 27% +/- 6%), were examined at least once a week at home by internists from the district hospital and by a trained paramedical team. The year before entry to the home-care program was compared to the first year of home surveillance. The mean total hospitalization (hosp) rate was reduced from 3.2 +/- 1.5 hosp/yr to 1.2 +/- 1.6 hosp/yr and duration from 26 +/- 14 days/yr to 6 +/- 7 days/yr (p < 0.001 for both). Cardiovascular admissions decreased from 2.9 +/- 1.5 hosp/yr to 0.8 +/- 1.1 hosp/yr and duration from 23 +/- 13 days/yr to 4 +/- 4 days/yr (p < 0.001). The vital status (ability to perform daily activities, expressed in a 1 to 4 scale) was improved from 1.4 +/- 0.9 to 2.3 +/- 0.7 (p < 0.001). In conclusion, an intensive home-care program was associated with a marked decrease in the need for hospitalization and improved the functional status of elderly patients with severe congestive heart failure. Such a service might also have a cost-effective advantage and a major impact on health expenditure.

Anaerobic bacteremia: a retrospective four-year analysis in general medicine and cancer patients.

Anaerobic bacteremia was studied in 32 medical patients (mean age 72 years) in a four-year retrospective analysis. Malignancy was the most common underlying disease and probable portal of entry. The gastrointestinal tract was affected most often, followed by the respiratory and urinary tracts. Bacteremia occurred either following invasive (non surgical) procedures or spontaneously. The clinical course ranged from asymptomatic bacteremia, to mild febrile illness, to sepsis and septic shock (two, 12, 16 and two patients, respectively). The case fatality rate was 25%. The causative organisms were Clostridium and Bacteroides species. All organisms isolated were susceptible to chloramphenicol. Early diagnosis and prompt treatment may reduce mortality in cases of anaerobic sepsis.

Long-term effects of hormone replacement therapy on Doppler-derived parameters of aortic flow in postmenopausal women.

Eighteen postmenopausal women were examined by Doppler echocardiography before initiation of HRT (T1), then after ten weeks (T2) and one year (T3). This study group was compared with another in which HRT was not used. Flow velocity integral, which correlates with SV, and MA, an indicator of cardiac contractility, were calculated. In the study group, PFV was 107 +/- 18 cm/s at T1 and increased significantly at T2 and T3. Ejection time, which was prolonged at T2 compared to T1, returned to its basal value at T3. Flow velocity integral increased at T2, but this change was only partially sustained at T3. Mean acceleration maintained its increase throughout T2 to T3. None of the Doppler parameters showed a significant change in the controls from T1 to T3. Our results suggest that the peripheral hemodynamic effects of HRT, such as vasodilatation, are transient, whereas the central effects (increased inotropism) are long-lasting.

Long-term weight control study. IV (weeks 156 to 190). The second double-blind phase.

To assess continued efficacy of anorexiants after 3 years of use, 52 participants (43% of those starting) entered a second double-blind trial to compare 60 mg sustained-release fenfluramine plus 15 mg phentermine resin versus placebo added to behavior modification, caloric restriction, and exercise. Although participants in both the active medication and placebo groups gained weight, participants receiving fenfluramine plus phentermine (n = 27) gained significantly (p less than 0.01) less (4.4 +/- 0.5 kg or 5.3% +/- 0.5% of initial weight) than participants receiving placebo (n = 24) (6.9 +/- 0.8 kg or 8.5% +/- 1.1% of initial weight). At week 190, both groups were still below their initial weight (fenfluramine plus phentermine group, 5.0 +/- 1.4 kg; placebo group, 2.1 +/- 1.2 kg; p less than 0.01). Overall, 12 participants (23.5% of those still in the study) were greater than or equal to 10% below initial weight. One participant dropped out during this phase because of personal reasons and loss of medication efficacy. During the 30 weeks, participants receiving fenfluramine plus phentermine had 26 moderate or severe complaints versus eight participants receiving placebo. Fenfluramine plus phentermine provided better appetite control and only slightly more bother. Analysis of participant response in this phase by treatment assignment in the first double-blind phase (weeks 6 to 34) indicated that initial receipt of medication did not have negative learning effects. Eleven participants receiving active medication between weeks 6 and 34 and receiving placebo between weeks 160 to 190 gained 5.1 +/- 1.0 kg. In contrast, 13 participants originally taking placebo gained 8.3 +/- 9 kg in this second double-blind phase.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term weight control study. V (weeks 190 to 210). Follow-up of participants after cessation of medication.

Participants who completed up to week 190 in the long-term weight control study were monitored after cessation of medication between weeks 190 and 210. Caloric restriction, behavior modification sessions, exercise reinforcement, and physician visits continued. We assessed whether or not participants had reset their weight control mechanisms and compared the effect of stopping medication under open-label conditions (weeks 190 to 210) with the results of stopping anorexiants under double-blind conditions (weeks 160 to 190). At week 210, participants were, on average, 1.4 +/- 1.0 kg (mean +/- SEM, 1.5% +/- 1.1%) below their weights at baseline (week 0). Of the 48 participants who remained in the study, 13 were still 5% or more and seven were 10% or more below their initial weights. On average, participants gained 2.7 +/- 0.5 kg (3.2%) in the period from weeks 190 to 210. Those who had been taking medication in the period from weeks 160 to 190 gained weight at a somewhat faster rate than those who had been taking placebo. However, participants who had transferred from fenfluramine plus phentermine to no medication in this phase gained at a slower rate than participants who had changed from fenfluramine plus phentermine to placebo under double-blind conditions at week 160 (0.195 kg per week versus 0.277 kg per week). The findings indicate that participants had difficulty maintaining weight loss without anorexiant medications. Despite long periods of time at weights much lower than baseline, permanent resetting of weight control mechanisms could not be shown for most participants.