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.

Protein intake and kidney function in humans: its effect on 'normal aging'.

The effect of dietary protein on kidney function expressed by creatinine clearance was studied in healthy subjects following a "normal" unrestricted protein diet and compared with a group of vegetarians maintained on a long-term low-protein diet. Both groups had similar kidney function and displayed the same rate of progressive deterioration in renal function with age. These results suggest that, in contrast with the important therapeutic effect of low-protein intake on the progressive deterioration of kidney function in diseased kidneys, such a diet does not significantly affect kidney function with "normal aging" in healthy subjects.

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.

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.

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.

Renal toxicity of enalapril in very elderly patients with progressive, severe congestive heart failure.

We evaluated the safety of enalapril administration in 20 very old (76 +/- 7 years) patients with rapidly progressive congestive heart failure (deteriorating from New York Heart Association class 2 to class 4 on admission). They were all given increasing doses of enalapril regardless of concomitant diuretic therapy and state of hydration. Renal function deteriorated in four patients (group A) and remained unchanged in 16 (group B). The mean pretreatment serum creatinine level in group A was significantly higher than that in group B (2.4 vs 1.3 mg/dl, p less than 0.001). No patient with a serum creatinine level less than 1.9 mg/dl on admission had further impairment of renal function. Groups A and B did not differ by age, concomitant diseases (including hypertension and diabetes mellitus), or medications (including diuretics) or by in-hospital serum electrolyte concentrations and blood pressure. Renal damage was noted during the initial four days of the study and was reversible following discontinuation of enalapril. Our data suggest that enalapril can be safely administered to very old patients with rapidly progressive congestive heart failure provided that the initial serum creatinine level is below 1.9 mg/dl. In patients with a higher serum creatinine level, careful monitoring and prompt discontinuation of enalapril administration can prevent irreversible renal damage.

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.

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.

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.

Red blood cell sorbitol lowering effects and tolerance of single doses of AL 1576 (HOE 843) in diabetic patients.

The safety and biochemical effects of AL 1576 (HOE 483), a recently developed aldose reductase inhibitor, were evaluated. In a double-blind, placebo-controlled, clinical trial, AL 1576 (HOE 483) was administered to diabetic patients for the first time. Four single, orally administered dose levels were tested, (2, 5, 10, and 20 mg). No clinically important adverse effects were seen in any of the patients. AL 1576 (HOE 483) suppressed red blood cell (RBC) sorbitol concentrations in a dose-related fashion. Also found were statistically significant inverse correlations between the plasma drug concentration and both RBC sorbitol concentrations as well as RBC sorbitol/serum glucose ratios. In single doses up to 20 mg, AL 1576 (HOE 483) is well tolerated and decreases RBC sorbitol, a biochemical marker of pharmacologic activity, in diabetic patients.

Nephrotic syndrome complicating adenocarcinoma of the lung with resolution after resection.

Nephrotic syndrome is an uncommon complication of lung cancer. We present a case in which adenocarcinoma was complicated by the nephrotic syndrome, which resolved after resection of the cancer.

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.

Lupus anticoagulant, thrombosis and thrombocytopenia in systemic lupus erythematosus.

Thirty-six patients were studied for the presence of the lupus anticoagulant and its possible clinical and laboratory associations. Seven patients were found to have the anticoagulant. These patients had a significantly increased incidence of both thromboembolic complications (5/7 vs. 2/29) and thrombocytopenia (4/7 vs. 4/29). None of them had a bleeding tendency. Except for these associations, patients with the anticoagulant did not differ from those without the anticoagulant by any demographic, clinical, or laboratory parameter. The present study confirms observations that SLE patients with the lupus anticoagulant have an increased risk of thrombosis.

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.

[Sedural toxicity].

Phenazopyridine (Sedural) is widely used in the treatment of dysuria. It is considered a benign drug and most physicians are unaware of its potential toxicity. A 24-year-old woman who developed methemoglobinemia, acute renal failure and hemolytic anemia following a single 1 g dose of the drug is presented.