Analgesic Efficacy of an Acetaminophen/Ibuprofen Fixed-dose Combination in Moderate to Severe Postoperative Dental Pain: A Randomized, Double-blind, Parallel-group, Placebo-controlled Trial.

PURPOSE: Acute pain is a significant burden to the individual and to society. There is a clear need for a pain medication that provides improved analgesia over common analgesics, without compromising tolerability. The goal of this study was to determine the efficacy of a new fixed-dose combination of acetaminophen 975 mg and ibuprofen 292.5 mg (FDC 975/292.5) relative to acetaminophen or ibuprofen monotherapy, or placebo. METHODS: This prospective, multicenter, randomized, double-blind, placebo-controlled, Phase III trial included 408 adult volunteers aged 18 to 60 years experiencing moderate to severe pain after surgical removal of at least 2 impacted third molars. Subjects were randomized in a 3:3:3:2 ratio to the following interventions: FDC 975/292.5, acetaminophen 975 mg, ibuprofen 292.5 mg, and placebo. Self-reported pain intensity scores were recorded over a 48-hour double-blind treatment period using a 100-mm visual analog scale. In addition, time to perceptible and meaningful pain relief was assessed by using the two-stopwatch method; use of rescue medication (oxycodone) was recorded; and patients rated their pain relief on a 5-point categorical scale. All adverse events during the 30-day study period were assessed. FINDINGS: The majority of participants were female (67.4%) and white (90.0%), with a mean age of 24.8 years. Demographic and baseline characteristics were balanced across treatment groups, with a mean baseline pain score of 56.4 mm. The primary end point was the time-adjusted sum of pain intensity differences over 48 hours, which was found to be significantly greater for FDC 975/292.5 than for both monotherapies and placebo (all, P < 0.001). The robustness of the procedures used in the calculation of the primary end point was confirmed in a series of sensitivity analyses. Statistical superiority of the combination was evident in all secondary end points (time to meaningful pain relief, maximum pain score, response rate, participants using supplementary analgesia, time to rescue, oxycodone consumption, and categorical pain relief score) with the exception of time to perceptible pain relief versus monotherapies and the time to peak response versus ibuprofen. The percentage of patients reporting adverse events was 37.3% in the FDC 975/292.5 group, with no significant differences between treatment groups. Nausea was the most common adverse event across all groups. IMPLICATIONS: Overall, the fixed-dose combination of acetaminophen and ibuprofen provided greater and more rapid analgesia than comparable doses of either agent alone or placebo in adults after removal of impacted third molars. ClinicalTrials.gov identifier: NCT01420653.

Effects of a 5-HT(3) antagonist, ondansetron, on fasting and postprandial small bowel water content assessed by magnetic resonance imaging.

BACKGROUND: 5-HT(3) antagonists have been shown to be effective in relieving the symptoms of irritable bowel syndrome with diarrhoea (IBS-D). Using a recently validated magnetic resonance imaging (MRI) method, we have demonstrated reduced fasting small bowel water content (SBWC) in IBS-D associated with accelerated small bowel transit. We hypothesized that slowing of transit with ondansetron would lead to an increase in SBWC by inhibiting fasting motility. AIM: To assess the effects of ondansetron compared with placebo in healthy volunteers on SBWC and motility in two different groups of subjects, one studied using MRI and another using manometry. METHODS: Healthy volunteers were given either a placebo or ondansetron on the day prior to and on the study day. Sixteen volunteers underwent baseline fasting and postprandial MRI scans for 270 min. In a second study, a separate group of n = 18 volunteers were intubated and overnight migrating motor complex (MMC) recorded. Baseline MRI scans were carried out after the tube was removed. RESULTS: Fasting SBWC was markedly increased by ondansetron (P < 0.0007). Ondansetron reduced the overall antroduodenal Motility Index (P < 0.04). The subjects who were intubated had significantly lower fasting SBWC (P < 0.0002) compared with the group of subjects who were not intubated. CONCLUSIONS: The 5-HT(3) receptor antagonism increased fasting small bowel water. This was associated with reduced fasting antroduodenal Motility Index which may explain the clinical benefit of such drugs.

Chronic deep brain stimulation for the treatment of tremor in multiple sclerosis: review and case reports.

BACKGROUND: Deep brain stimulation (DBS) offers a non-ablative alternative to thalamotomy for the surgical treatment of medically refractory tremor in multiple sclerosis. However, relatively few outcomes have been reported. OBJECTIVE: To provide a systematic review of the published cases of DBS use in multiple sclerosis and to present four additional patients. METHODS: Quantitative and qualitative review of the published reports and description of a case series from one centre. RESULTS: In the majority of reported cases (n=75), the surgical target for DBS implantation was the ventrointeromedial nucleus of the thalamus. Tremor reduction and improvement in daily functioning were achieved in most patients, with 87.7% experiencing at least some sustained improvement in tremor control postsurgery. Effects on daily functioning were less consistently assessed across studies; in papers reporting relevant data, 76.0% of patients experienced improvement in daily functioning. Adverse effects were similar to those reported for DBS in other patient populations. CONCLUSIONS: Few of the studies reviewed used highly standardised quantitative outcome measures, and follow up periods were generally one year or less. Nonetheless, the data suggest that chronic DBS often produces improved tremor control in multiple sclerosis. Complete cessation of tremor is not necessarily achieved, there are cases in which tremor control decreases over time, and frequent reprogramming appears to be necessary.

Blind smell: brain activation induced by an undetected air-borne chemical.

EEG and behavioural evidence suggests that air-borne chemicals can affect the nervous system without being consciously detected. EEG and behaviour, however, do not specify which brain structures are involved in chemical sensing that occurs below a threshold of conscious detection. Here we used functional MRI to localize brain activation induced by high and low concentrations of the air-borne compound oestra-1,3,5(10),16-tetraen-3yl acetate. Following presentations of both concentrations, eight of eight subjects reported verbally that they could not detect any odour (P = 0.004). Forced choice detection performed during the presentations revealed above-chance detection of the high concentration, but no better than chance detection of the low concentration compound. Both concentrations induced significant brain activation, primarily in the anterior medial thalamus and inferior frontal gyrus. Activation in the inferior frontal gyrus during the high concentration condition was significantly greater in the right than in the left hemisphere (P = 0.03). A trend towards greater thalamic activation was observed for the high concentration than the low concentration compound (P = 0.08). These findings localize human brain activation that was induced by an undetectable air-borne chemical (the low concentration compound).

PEG-rHuMGDF promotes multilineage hematopoietic recovery in myelosuppressed mice.

PEG-rHuMGDF administered to normal mice is a lineage-specific growth factor for megakaryocytes and platelets as judged by morphologic examination of hematologic cells in marrow and peripheral blood smears. The purpose of this study was to document that PEG-rHuMGDF in myelosuppressed mice promotes multilineage hematopoietic recovery. High-dose 5-fluorouracil (5-FU) in mice results in profound myelosuppression and 0-30% survival. Mice receiving a single dose of PEG-rHuMGDF (1000 microg/kg) 1 day after 5-FU (225 mg/kg) demonstrate an increased survival (76% vs 27% in control mice at 14 days). Compared to surviving controls, PEG-rHuMGDF-treated mice not only show the expected higher platelet counts, but also increased marrow colony-forming unit granulocyte-macrophage, increased multilineage marrow cellularity, and increased neutrophil, monocyte, and lymphocyte counts in peripheral blood. PEG-rHuMGDF- and vehicle-treated mice both develop hepatic abscesses after 5-FU treatment, but the abscesses in the PEG-rHuMGDF-treated mice contain more neutrophils, suggesting that myeloid reconstitution contributes to their survival. Furthermore, survival in 5-FU-treated mice is significantly improved by granulocyte colony-stimulating factor and antibiotics, suggesting that infection rather than thrombocytopenia is the predominant cause of death. PEG-rHuMGDF after 5-FU promotes survival accompanied by accelerated lymphohematopoietic repopulation, suggesting that PEG-rHuMGDF, a lineage-specific thrombopoietic factor in normal mice, promotes multilineage hematopoietic recovery in myelosuppressed mice.

Acute impairment of coronary blood flow by dynamic cardiomyoplasty.

The aim of this study was to quantify the effects of three different configurations of cardiomyoplasty on coronary blood flow in an acute dog model. Thirteen dogs had both latissimus dorsi muscles harvested and transposed to the chest. Coronary blood flow was measured using Doppler cuff probes on the left anterior descending and circumflex coronary arteries during each of three cardiomyoplasty configurations: left posterior, right anterior, and double. Multiple beat measures were made of systolic and diastolic flow during a control protocol and a subsequent protocol with the muscle(s) paced. Significant flow reductions during pacing were observed in the left anterior descending coronary artery during left posterior (17%, p = 0.003), right anterior (29%, p < 0.0001), and double (35%, p = 0.0001) myoplasty. Similar reductions occurred in the circumflex artery (14%, p = 0.0009; 20%, p = 0.001; 27%, p = 0.0053). The net flow over an entire pacing cycle also was reduced significantly: left anterior descending artery (11%, p = 0.0035; 23%, p = 0.0001; 23%, p = 0.0047) and circumflex artery (10%, p = 0.0025; 17%, p = 0.0018; 21%, p = 0.0091). Thus, in the acute setting cardiomyoplasty depresses coronary blood flow. A chronic setting will be needed to determine the ultimate significance of these results.

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs: VII. Verapamil and thiopental.

To assess the role of basal anesthesia in the negative inotropic properties of verapamil, the effect of thiopental (30 mg/kg followed by 3.5 mg.kg-1.min-1) on verapamil pharmacokinetics (200 micrograms/kg iv; n = 6) and its pharmacodynamics (3 and 6 micrograms.kg-1.min-1; n = 11) in chronically instrumented dogs was studied. In the presence of thiopental, verapamil pharmacokinetics remained essentially unchanged. In contrast, anesthesia altered verapamil hemodynamic properties. In the conscious animal verapamil infusions increased heart rate (14 +/- 3 and 27 +/- 4 beats/min, respectively), cardiac output (0.22 +/- 0.07 and 0.24 +/- 0.08, l/min, respectively) and PR interval (14 +/- 2 and 25 +/- 6 ms, respectively) and slightly decreased dP/dt (-315 +/- 114 and -419 +/- 106 mmHg/s, respectively). Systemic vascular resistance (SVR) decreased at the low dose (-2.7 +/- 0.7 mmHg.1.min-1), and stroke volume decreased at the high dose (-4.4 +/- 0.6 ml). Yet the presence of thiopental resulted in an accentuation of verapamil-induced tachycardia (27 +/- 7 and 31 +/- 6 beats/min, respectively), and a decrease in stroke volume (-5.3 +/- 2.0 and -6.3 +/- 2.1 ml, respectively). At 3 micrograms.kg-1.min-1 verapamil did not increase PR interval, cardiac output, or vasodilation. Finally, at 6 micrograms.kg-1.min-1 verapamil did not decrease dP/dt and increased renal blood flow (21.8 +/- 6.4 ml/min). These data provide evidence that the negative inotropic properties of verapamil are more pronounced in the presence of thiopental. However, the role of basal anesthesia appears to be limited.

Efficacy of vaccination with Skinner vaccine towards the prevention of herpes simplex virus induced cervical carcinoma in an experimental mouse model.

The incidence of cervical carcinoma, which had been induced by vaginal application of inactivated herpes simplex virus type 2 (HSV-2) with 20% croton oil, was significantly reduced in mice prevaccinated with the Skinner herpes vaccine. There was evidence of an immunological response in both vaccinated and unvaccinated mice.

N-2-mercaptopropionylglycine improves recovery of myocardial function after reversible regional ischemia.

Myocardial reperfusion after reversible regional ischemia is known to result in delayed recovery of contractile function, but the mechanism responsible for this phenomenon remains unclear. We examined the ability of N-2-mercaptopropionylglycine, a synthetic thiol compound with oxygen free radical scavenging properties, to attenuate postischemic dysfunction in open chest dogs undergoing a 15 minute occlusion of the left anterior descending coronary artery followed by 4 hours of reperfusion. Treated animals received an infusion of N-2-mercaptopropionylglycine (50 mg/kg per h) for 4 hours starting 15 minutes before coronary occlusion. Collateral flow, as determined with radioactive microspheres after 10 minutes of ischemia, was 0.07 +/- 0.01 ml/min per g (mean +/- SE) in both control (n = 20) and treated (n = 13) groups. The occluded vascular bed, as determined by postmortem perfusion, averaged 26.1 +/- 1.2% of the weight of the left ventricle in control and 29.6 +/- 1.3% in treated animals. Systolic wall thickening (an index of regional function) was assessed with an epicardial pulsed Doppler probe. The two groups exhibited comparable systolic thickening under baseline conditions and similar degrees of dyskinesia during ischemia. Nevertheless, recovery of function (expressed as percent of baseline) was considerably greater in the treated dogs at 1 hour (44.6 versus 12.8%, p = 0.05), 2 hours (64.0 versus 31.6%, p less than 0.02), 3 hours (77.1 versus 36.7%, p less than 0.01) and 4 hours of reperfusion (75.0 versus 40.0%, p less than 0.05). Thus, N-2-mercaptopropionylglycine produced a significant and sustained improvement in recovery of contractile function after a brief episode of regional myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of and interaction between calcium blocking drugs and anesthetics in chronically instrumented dogs. II. Verapamil, enflurane, and isoflurane.

The effects of enflurane and isoflurane on the cardiovascular system and cellular calcium kinetics are somewhat different. Consequently, the interaction with the calcium channel blocking drug, verapamil, may also differ. In order to compare the anesthetics, the authors studied the effects of two infusion doses of verapamil (which produced plasma levels of 90 and 180 ng X ml-1) on cardiovascular dynamics and regional blood flow in awake dogs. On two other days, in the same dogs, the effects of approximately 1.1 and 2 MAC enflurane and isoflurane were first studied and then the same verapamil dose regimens while the same anesthetic concentrations were maintained. Verapamil produced only increases in heart rate and the P-R interval in the awake animal. The high dose of both anesthetics markedly decreased mean aortic pressure and left ventricular rate of tension development (dP/dt), and increased heart rate. However, only enflurane also decreased myocardial segment length shortening and increased left atrial pressure. Neither anesthetic alone affected coronary or renal blood flow, while both increased carotid blood flow at the low dose. Verapamil infusion during 1.2 MAC enflurane was more depressant than during 1.2 MAC isoflurane, but the combination of verapamil with 2 MAC concentration of both anesthetics was equally depressant. Both doses of both anesthetics increased plasma verapamil levels compared with the same verapamil dosing regimen awake. When these results are compared with those previously reported for halothane, the effects of verapamil during all three anesthetics are more similar than different.(ABSTRACT TRUNCATED AT 250 WORDS)

Spontaneous genetic hypertension in the rat and its relationship to reduced ac cochlear potentials: implications for preservation of human hearing.

We present controlled laboratory studies of the spontaneously hypertensive rat which indicate that hypertension is an important pathophysiological risk factor in age-related hearing loss. Our results are in concert with previous retrospective clinical studies that pointed to this possibility in man. Hypertension as a risk factor for hearing loss is within the bounds of known measures of diagnosis, treatment, and even prevention, with monitoring early in life. Because hypertension is such a major public health problem in the United States, in view of our results it is possible that its treatment and early diagnosis will benefit a significant number of people who would otherwise lose their hearing with advancing age. We compared the round window ac cochlear potential-sensitivity and -intensity functions in 10 female spontaneously hypertensive rats and 10 female normotensive Wistar-Kyoto control rats. The animals were all 12 months old and weighed between 170 and 250 g. The normotensives had higher maximum cochlear potential-intensity values compared with the hypertensives: 1,000 Hz (P less than 0.005), 5,000 Hz (P less than 0.005), and 10,000 Hz (P less than 0.01). One-microvolt isopotential cochlear potentials for the low frequencies of the normotensives showed greater sensitivity than those of the hypertensives: 100 Hz (P less than 0.05), 200 Hz (P less than 0.10), 290 Hz (P less than 0.05), and 2,000 Hz (P less than 0.10). Blood pressure of the hypertensive group was significantly greater than that of the normotensive rats (P less than 0.001). The hearts and aortas of the hypertensive group were hypertrophied. Autonomic imbalance, platelet aggregation, decreased arterioles, and natriuretic hormone were discussed as possible etiologies for the measured sensory hearing loss.