Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial.

BACKGROUND: In animals, insulin-like growth factor-1 (IGF-1) increases clearance of beta-amyloid, a pathologic hallmark of Alzheimer disease (AD), from the CNS. Serum IGF-1 level decreases with age, and shows a further decrease in AD. We examined whether the growth hormone secretagogue MK-677 (ibutamoren mesylate), a potent inducer of IGF-1 secretion, slows the rate of progression of symptoms in patients with AD. METHODS: A double-blind, multicenter study was conducted in which 563 patients with mild to moderate AD were randomized to receive MK-677 25 mg or placebo daily for 12 months. Efficacy measures were mean change from baseline at month 12 on the Clinician's Interview Based Impression of Change with caregiver input (CIBIC-plus), the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and the Clinical Dementia Rating-sum of boxes (CDR-sob). RESULTS: A total of 416 patients completed treatment and assessments at 12 months. Administration of MK-677 25 mg resulted in a 60.1% increase in serum IGF-1 levels at 6 weeks and a 72.9% increase at 12 months. In mixed-effects models that included treatment, time (month), randomization strata (baseline MMSE score < or =20 vs >20), and interaction of treatment-by-time, there were no significant differences between the treatment groups on the CIBIC-plus or the mean change from baseline scores on the ADAS-Cog, ADCS-ADL, or CDR-sob scores over 12 months. CONCLUSION: Despite evidence of target engagement as indicated by an increase in serum insulin-like growth factor-1, the human growth hormone secretagogue MK-677 25 mg was ineffective at slowing the rate of progression of Alzheimer disease.

Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study.

BACKGROUND: Inflammatory mechanisms have been implicated in the pathogenesis of Alzheimer's disease (AD) and may be mediated via the cyclo-oxygenase-2 enzyme. This study sought to evaluate the effect of rofecoxib, a nonsteroidal anti-inflammatory drug that selectively inhibits cyclo-oxygenase-2, in slowing the progression of dementia in patients with established AD. METHODS: A double-blinded, multicenter trial was conducted in which 692 patients with mild or moderate AD aged 50 years or older were randomly assigned to receive 25 mg rofecoxib or placebo daily for 12 months. The key efficacy measures were mean change from baseline at month 12 on the cognitive subscale of the AD Assessment Scale (ADAS-cog) and score on the Clinician's Interview Based Impression of Change with caregiver input (CIBIC+). RESULTS: Four hundred eighty-one patients (70%) completed assessments and remained on treatment at 12 months. No significant differences between treatments were found on the mean change from baseline error score for the ADAS-cog (rofecoxib = 4.84; placebo = 5.44; difference = -0.60) or mean score on the CIBIC+ (rofecoxib = 4.90; placebo = 4.87; difference = 0.03) over 12 months. This result persisted after adjusting for severity of dementia at baseline, presence of the APOE-epsilon4 allele, and donepezil use. Secondary analyses did not reveal any significant differences on any other measures. CONCLUSION: The failure of selective cyclo-oxygenase-2 inhibition to slow the progression of AD may indicate either that the disease process is too advanced to modify in patients with established dementia or that cyclo-oxygenase-2 does not play a significant role in the pathogenesis of the disorder.

Pharmacokinetic profile and tolerability of indinavir-ritonavir combinations in healthy volunteers.

This was a randomized, double-blind, placebo-controlled parallel study in human immunodeficiency virus type 1 (HIV-1)-uninfected healthy subjects to investigate the pharmacokinetic interaction between indinavir (IDV) and ritonavir (RTV). Subjects were allocated to treatment groups of IDV given with RTV in the following milligram doses twice daily: 800 mg of IDV-100 mg of RTV (800-100 mg), 800-200, 800-400, and 400-400 mg, placebo of IDV with RTV doses of 100, 200, and 400 mg, and placebo of both IDV and RTV. Doses of both drugs were administered for 14 days with a low-fat meal and one dose on day 15 with a high-fat meal. Blood was obtained for drug concentration measurements on days 14 and 15. Seventy-three volunteers enrolled in the study: 29 men and 44 women. Fifty-three volunteers completed the study. When compared to standard historical data for 800 mg of IDV every 8 h (q8h), the IDV area under the concentration-time curve for 24 h (AUC(24)) of IDV-RTV regimens 400-400, 800-100, and 800-200 mg were at least 1.4, 2.3, and 3.3 times higher, respectively, regardless of meal. The concentrations at the end of the dosing interval were 10 to 25 times higher than that observed in the standard regimen of 800 mg of IDV q8h for IDV-RTV 800-100 and 800-200 mg regimens, respectively. RTV at 200 mg maximally enhanced the IDV profile. Improved tolerability was associated with IDV-RTV 800-100 mg versus IDV-RTV 800-200, 800-400, and 400-400 mg q12h. The advantages of IDV-RTV twice daily over 800 mg of IDV q8h include no food restrictions and twice-daily dosing. Also, the regimens achieve levels of IDV that may be helpful in suppressing strains of HIV-1 that have reduced susceptibility to IDV or other protease inhibitors.

Indinavir did not increase the short-term risk of adverse cardiovascular events relative to nucleoside reverse transcriptase inhibitor therapy in four phase III clinical trials.

A retrospective person-time analysis of the randomized and non-randomized extension phases of four phase III trials was performed to assess the incidence of adverse cardiovascular events in 2680 HIV-infected patients receiving indinavir or nucleoside reverse transcriptase inhibitor therapy, or both. The observed rate of cardiovascular events was not increased in patients receiving indinavir-based regimens compared with therapy without a protease inhibitor. Extrapolation of these findings is limited by the brief length of therapy and the small number of cases.

Randomized, double-blind trial comparing indinavir alone, zidovudine alone and indinavir plus zidovudine in antiretroviral therapy-naive HIV-infected individuals with CD4 cell counts between 50 and 250/mm3.

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (p<0. 0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70% and 61%, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated.

Factors influencing the emergence of resistance to indinavir: role of virologic, immunologic, and pharmacologic variables.

A major problem with the use of human immunodeficiency virus type 1 (HIV-1) protease inhibitors as monotherapy has been an unacceptably high rate of emergence of resistance. To examine possible influences on the time to emergence of resistance, 24-week data were examined from five studies in which indinavir had been administered as monotherapy or as a component of combination therapy. Monotherapy data indicated a correlation between the level of HIV-1 RNA achieved and the risk of emergence of resistance: the lower the level, the lower the risk. When combination and monotherapy regimens were compared, the group receiving indinavir + lamivudine + zidovudine had a significantly lower risk of resistance, even after adjusting for the minimum HIV-1 RNA level achieved. The findings indicate that if at all possible, HIV-1-infected patients should receive combination chemotherapy to minimize the emergence of resistance to the protease inhibitor portion of the regimen. The goal of therapy should be to decrease the HIV-1 RNA load to a less-than-detectable level.

Safety testing of a new electronic toothbrush.

While there have been major advances in understanding the causes and treatments of the inflammatory periodontal diseases in the past decade, there is still high reliance on the patient to prevent progression of disease through daily oral hygiene, primarily toothbrushing and flossing. A new electronic toothbrush, which produces mild fluid cavitation as well as rapid fluid streaming, has been developed and has shown promise in the ease and efficacy with which it removes plaque. In order to determine the safety of frequent and prolonged use of this device, the gingival tissues of 6 mongrel dogs were exposed to excessively long daily exposures to this toothbrush for up to 2 months. Each quadrant of each dog's mouth was randomly assigned a different treatment: no brushing, manual brush 1.0 minute, electronic brush 1.0 minute, or electronic brush 7.5 minutes. The dogs were examined weekly by a periodontist who was blinded to the treatments. Plaque scores and bleeding on probing scores were calculated, and possible gingival irritation was monitored carefully. At the end of the trial gingival biopsies taken from all the test areas. These were processed for conventional histopathologic evaluation and examined by an oral pathologist who was also blinded as to the treatments. The results showed that brushing a single posterior segment of teeth for 7.5 minutes daily for 2 months with the electronic brush did not result in any clinically or histologically evident damage to the gingiva. Rather, the areas so treated showed excellent health as determined by both clinical and histologic criteria.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of patient position on the incidence of vasovagal response to venous cannulation.

BACKGROUND: This study was undertaken to determine the effect of patient position on the incidence of vasovagal responses to venous cannulation in ambulatory surgery patients. METHODS: Three hundred surgical outpatients, aged 18 to 40 years, were randomly assigned by week to the sitting or recumbent position. Blood pressure and heart rate were recorded during and for 6 minutes following venous cannulation. An observer recorded signs and symptoms suggestive of a vasovagal response. RESULTS: A vasovagal reaction occurred in 12.6% of sitting patients and 2.1% of recumbent patients. Two sitting patients, 1.3%, experienced frank syncope. Symptomatic patients were more likely (39.1%) than asymptomatic patients (8.3%) to have a history of fainting. In symptomatic patients who were sitting, mean arterial pressure fell from 90.4 mm Hg (SD, 10.6) at baseline to 64.4 mm Hg (SD, 14.3) during cannulation. Similarly, heart rate fell from 76.6 beats per minute (SD, 15.6) at baseline to 59.0 beats per minute (SD, 11.7) after cannulation. CONCLUSIONS: The vasovagal response during venous cannulation occurs more frequently in the sitting patient who has a history of fainting and is associated with a significant decline in blood pressure and heart rate.

Infusion of autologous platelet rich plasma does not reduce blood loss and product use after coronary artery bypass. A prospective, randomized, blinded study.

Prior nonblinded studies have suggested dramatic hemostatic effects and decreased plasma after cardiopulmonary bypass. Platelet rich plasma (8 to 10 ml/kg total body weight) was obtained (Haemonetics Plasma Saver; Haemonetics Corp., Natick, Mass.) from 51 patients undergoing primary coronary artery bypass grafting before heparinization. After double-blinded randomization, the platelet rich plasma was reinfused immediately in the control group or after heparin reversal in the treatment group. Homologous blood product usage, blood loss, and the surgeon's intraoperative subjective assessment of coagulation were evaluated. Additionally, thromboelastography, prothrombin time, partial thromboplastin time, activated clotting time, fibrinogen, platelet counts, and hematocrit values were evaluated before the operation, after heparin reversal, after infusion of platelet rich plasma or control solution, and 2 hours after infusion. The surgeon's subjective assessment of coagulation was not different between control and treatment groups (p = 0.78). According to specific predetermined transfusion guidelines, no statistically significant differences were found in the use of whole blood (p = 0.07), packed red blood cells (p = 0.62), platelets (p = 0.11), total units of blood products (p = 0.45), or in the percentage of patients receiving transfusions (control group 70%, treatment group 71%, p = 0.97). Cumulative amount of blood shed through the chest tube was not significantly different between the groups at any interval but tended toward significance at 4, 6, and 12 hours (p = 0.09, 0.07, and 0.09). The prothrombin time immediately after reinfusion of platelet rich plasma was significantly lower in the treatment group (p = 0.03), but all other laboratory studies were similar at each time interval. Infusion of platelet rich plasma after cardiopulmonary bypass in patients having uncomplicated primary coronary artery bypass grafting has minimal effects on the surgeon's assessment of coagulation, total transfusion requirements, mediastinal drainage, and laboratory studies of coagulation.

Three-dimensional transesophageal echocardiography for depiction of regional left-ventricular performance: initial results and future directions.

To assess the potential of a prototype transesophageal echocardiography probe for evaluating left-ventricular wall motion in three dimensions, we acquired images under anesthesia in 15 patients who had akinesia or dyskinesia and 8 patients who had normal function demonstrated on preoperative ventriculography. Short-axis, oblique transgastric scans were obtained in 16 of the patients and four-chamber, long-axis oblique scans were obtained in 12 patients, with five patients (22%) yielding good-quality scans of both types. Off-line, we outlined the endocardial borders manually and used the outlines to make computer-generated three-dimensional models of the endocardial surfaces, color-tiled according to regional ejection fraction. Compared with contrast ventriculograms, the regional ejection fraction histograms derived from these models showed 86% concordance for detecting dyssynergy. However, the concordance between the ventriculograms and the color-tiled models in localizing the dyssynergy was only 67% overall. Uncertainty in rotational alignment between the reconstructions and the ventriculograms appeared to contribute to misreading the location of dyssynergy. In addition, the apical region appeared to have been missed in 8 (50%) of the short-axis scans, whereas it was visualized in all long-axis scans. We conclude that three-dimensional analysis of the location, extent, and degree of left-ventricular dyssynergy is feasible from transesophageal echocardiograms and could have wide application in the study of regional ventricular function. However, improvements are necessary to enable the transducer to scan the cardiac apex more reliably from the short-axis viewpoint and to have a means for spatially orienting the images with respect to an external frame of reference.

Vaso-vagal reactions in an ambulatory surgery center.

This prospective study was undertaken to determine the incidence and factors predisposing to vaso-vagal reactions during venous cannulation in an ambulatory surgery population. In 141 ambulatory surgery patients, signs and symptoms of a reaction together with mean arterial pressure and heart rate were recorded at 1-min intervals during and for 6 min after venous cannulation. Overall, 10.6% of patients were symptomatic (95% confidence interval [CI] 6%-17%). The incidence was 16.6% (95% CI 8.4%-24.9%) in patients < or = 40 yr and 33.3% (95% CI 6.7%-60.0%) with a prior fainting history. Young age, duration or number of attempts at venous cannulation, and fainting history were independently associated with increased risk of a reaction (P < 0.03-0.004 by multiple repression analysis). Minimum mean arterial pressure was less in symptomatic patients than in those who were asymptomatic (58 mm Hg +/- 11.3 SD versus 82 mm Hg +/- 14.3 SD, P < 0.0001). We conclude that reactions occur commonly, particularly in the young or in patients with a history of fainting. Reactions are typically associated with significant hypotension that may require treatment.

Methodology for three-dimensional reconstruction of the left ventricle from transesophageal echocardiograms.

A technique is presented for three-dimensional (3-D) reconstruction of the left-ventricular endocardial surface from multiplanar transesophageal echocardiograms, using both commercial software and investigator written Fortran programs for Intel 80286 and 80386 microcomputers. The approach provides quantitative global and regional cardiac performance measures and allows viewing the endocardial surface, at end-diastole and end-systole, from chosen perspectives. Anatomical landmarks are incorporated to aid in orientation. For regional calculation, the surface is divided into equal angular elements with each conceptually connected to the left-ventricular end-diastole centroid, forming a pyramidal volume element. This angular division automatically normalizes for heart size. The fractional change of these elements over the cardiac cycle provides a regional ejection fraction measure which is color-coded on the reconstructed endocardial surface. Composite perspective views, regional ejection fraction histograms and calculations of global end-diastolic, end-systolic, and stroke volumes, are all performed by the method.

Comparison of desflurane with propofol in outpatients undergoing peripheral orthopedic surgery.

This study was undertaken to compare desflurane with propofol anesthesia in outpatients undergoing peripheral orthopedic surgery. Data were combined from two institutions participating in a multicenter study. Ninety-one patients, ASA physical status I or II, were each randomly assigned to one of four groups. After administration of fentanyl (2 micrograms/kg) and d-tubocurarine (3 mg), intravenous propofol was administered to induce anesthesia in groups I and II and desflurane in groups III and IV. Maintenance was provided by desflurane/N2O in groups I and III, propofol/N2O in group II, and desflurane/O2 in group IV. Emergence and recovery variables, psychometric test results, and side effects were recorded by observers unaware of the experimental treatment. Patients in group II experienced less nausea than other groups (P = 0.002) despite this group having required more intraoperative fentanyl supplementation than groups III and IV (P = 0.01). Time to emergence, discharge, and psychometric test results were similar in all groups. Desflurane appears to be comparable with propofol as an outpatient anesthetic, facilitating rapid recovery and discharge home.

Electroencephalography during surgery with cardiopulmonary bypass and hypothermia.

After more than 30 yr of use, electroencephalographic (EEG) monitoring during cardiopulmonary bypass has not gained wide clinical acceptance. To assess its utility to predict central nervous system injury, two-channel recordings were made from 78 patients undergoing cardiopulmonary bypass and anesthetized with fentanyl/diazepam/enflurane. The perfusion regimen included the use of high pump flow, a bubble oxygenator, and no arterial tubing filter. Target values were 28-32 degrees C for the minimum rectal temperature, 60-80 mmHg for mean arterial pressure, and 20-25% for hematocrit. Eight descriptors of the Fourier power spectra of the EEG were calculated off-line, and outcome comparisons were made with the results from neuropsychological tests. Among 58 patients yielding complete data of acceptable quality, a statistically significant reduction in total power was observed from prebypass to postbypass, accompanied by an increase in the fractional power in the theta and beta frequency bands and in the spectral edge frequency. The shifts in total and theta power were weakly associated with short-term but not with long-term changes in neuropsychological scores. Nearly 40% of the patients' EEGs were corrupted with electrical noise at some time during bypass. In 15 patients selected for having high-quality recordings and no neuropsychological deficit, an extensive statistical analysis failed to reveal any consistent variation in the EEG descriptors with hypothermia. Under the conditions studied, it appears that for other than gross signal dropout, the strong background variability in the EEG makes it have little value for detecting harbingers of brain injury.

Self-administration of midazolam for postoperative anxiety: a double blinded study.

Anxiety is almost inevitably present in patients facing surgery. The optimal management of postoperative pain requires the acknowledgement of perioperative anxiety and the inclusion of pharmacological and/or non-pharmacological means of alleviating the fear and worry inherent in the surgical experience. In a double-blind randomized design, 39 patients undergoing total abdominal hysterectomies were given postoperative access to a standard patient-controlled analgesia (PCA) morphine pump for pain and a PCA pump dispensing either low-dose midazolam or saline for anxiety. Measures of anxiety and pain were completed pre-operatively and for 2 days postoperatively. Utilization of morphine and 'anxiolytic agent' were recorded. Analysis of covariance was applied to the data to control for the imbalance of cancer patients between the 2 groups. While both groups of patients chose to utilize their 'anxiety pump' throughout the study, those patients receiving midazolam had significantly lower postoperative Spielberger State Anxiety scores and visual analogue scale anxiety scores. Patient-controlled midazolam in doses used in this study were safe and effective in managing anxiety but did not influence pain scores or the amount of PCA morphine patients used. Pre-operative levels of depression were significantly associated with postoperative pain levels independent of treatment group or cancer diagnosis.

Postoperative epidural morphine is safe on surgical wards.

The use of epidural morphine for postoperative analgesia outside of intensive care units remains controversial. In this report our anesthesiology-based acute pain service documents experience with 1,106 consecutive postoperative patients treated with epidural morphine on regular surgical wards. This experience involved 4,343 total patient days of care and 11,089 individual epidural morphine injections. On a 0-10 verbal analog scale, patient-reported median pain scores at rest and with coughing or ambulation were 1 (inter-quartile range 3) and 4 (interquartile range 4), respectively. The incidence of side effects requiring medication were as follows: pruritus 24%, nausea 29%, and respiratory depression 0.2%. There were no deaths, neurologic injuries, or infections associated with the technique. Migration of epidural catheters into the subarachnoid space and into epidural veins each occurred twice. Overall, 1,051 of the 1,106 patients (95%) experienced none of the following problems: catheter obstruction, premature dislodgement, painful injections, catheter migration, infection, or respiratory depression. We conclude that postoperative pain can be safely and effectively treated with epidural morphine on surgical wards.

Left ventricular ejection fraction: single-plane and multiplanar transesophageal echocardiography versus equilibrium gated-pool scintigraphy.

The relative accuracy and precision of estimating left ventricular ejection fraction (EF) in dogs were assessed by two-dimensional transesophageal echocardiography (2D-TEE) and by three-dimensional transesophageal echocardiographic (3D-TEE) imaging and reconstruction. This assessment was accomplished by comparing each echocardiographic method to a gated equilibrium blood pool radionuclide (RN) standard. By using both correlation and regression analysis, 2D-TEE performed reasonably well in estimating RNEF (correlation coefficient [r] = 0.80, slope = 1.01, intercept = 6.37, standard error of the estimate [SEE], 8.98), but not as well as 3D-TEE (r = 0.86, slope = 0.83, intercept = 3.38, SEE, 5.74). Using Altman and Bland's methods of comparison analysis, it was found that 2D-TEE overestimated RNEF by 7% (standard deviation [SD], 8.8). This degree of overestimation was not consistent across the range of measurement. In contrast, 3D-TEE slightly underestimated RNEF by less than 3% and showed less variability (SD, 6.0). The accuracy of the 3D-TEE determinations was not dependent on the magnitude of EF. Additionally, a significantly higher proportion of the 2D-TEE measurements (0.30) compared with the 3D-TEE measurements (0.10) differed from RN values by more than 10% (P = 0.009, McNemar's test). At the clinically important low end of the EF range (RNEF less than or equal to 35%), 2D-TEE may be expected (with 95% confidence) to be within -15% to +28% EF of reference values, whereas 3D-TEE can be expected to be within -8% to +5% EF relative to RN.(ABSTRACT TRUNCATED AT 250 WORDS)

Preoperative aspirin therapy and reoperation for bleeding after coronary artery bypass surgery.

We performed a case-control study to estimate the relative risk of reoperation for bleeding in coronary artery bypass graft patients who had taken aspirin within the 7 days preceding surgery. Comparison of 90 cases of reoperation with 180 matched control subjects gave an estimated odds ratio for reoperation of 1.82 (95% confidence interval, 1.23 to 3.32). Although their preoperative coagulation values were similar, cases used significantly more whole blood (cases, 9.5 +/- 5.2 units; control subjects, 3.0 +/- 2.0 units; median +/- interquartile range), packed red blood cells (cases, 2.1 +/- 4.0 units; control subjects, 0.9 +/- 2.0 units), and platelets (cases, 12.2 +/- 12.0 units; control subjects, 2.9 +/- 4.0 units) than control subjects. Cases had intensive care unit stays of 4.7 +/- 5.7 days (mean +/- SD) vs 2.1 +/- 1.9 days for control subjects and postoperative hospitalizations of 10.9 +/- 8.2 days vs 7.0 +/- 3.2 days for control subjects. We conclude that aspirin exposure within 7 days before coronary bypass surgery is associated with an increased rate of reoperation for bleeding and that reoperation is associated with large increases in transfusion requirements and intensive care unit and hospital stays.