Side effects during continuous epidural infusion of morphine and fentanyl

Respiratory effects, nausea, somnolence, and pruritus were compared during a 48-hr period of continuous epidural morphine (n = 34) and fentanyl (n = 32) infusion in 66 patients following elective total replacement of the hip or knee joint. Respiratory effects were assessed by PaCO2. Side effects were assessed by visual analogue scale and considered to be present when the score was above 30. Assessment was made at preoperative visits then 3, 6, 12, 24, 36, and 48 hr after the epidural injection. The bolus dose and subsequent infusion rate were 3,900 +/- 1,300 micrograms and 427 +/- 213 micrograms.hr-1 for morphine, and 85 +/- 46 micrograms and 56 +/- 27 micrograms.hr-1 for fentanyl. Pain relief was similar in both groups. In the morphine group, PaCO2 elevation and nausea occurred over a period of more than 12 hr (P less than 0.05). In the fentanyl group, there was no PaCO2 change, and nausea was confined to the first few hours. Nausea was more severe (P less than 0.01 at six hours and more frequent (24 hr cumulative incidence, 53 vs 28%, P less than 0.05) in the morphine group. Somnolence was prominent within several hours in two-thirds of patients in both groups. Somnolence continued to decline thereafter in the morphine group, but it was demonstrable in approximately half of the patients throughout the second day in the fentanyl group. The incidence was higher in the fentanyl group at the 48th hr (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Gemcitabine and ISIS-2503 for patients with locally advanced or metastatic pancreatic adenocarcinoma: a North Central Cancer Treatment Group phase II trial.

PURPOSE: Gemcitabine remains the standard therapy for metastatic pancreatic adenocarcinoma (ACA), but has limited activity. ISIS-2503 is an antisense compound directed against H-ras with preclinical activity against pancreatic ACA in tumor models. The combination of ISIS-2503 and gemcitabine has been evaluated in a prior phase I study. METHODS: Patients with metastatic or locally advanced pancreatic ACA not amenable to surgery or local radiation received gemcitabine 1,000 mg/m(2) intravenously over 30 minutes on days 1 and 8 and ISIS-2503 6 mg/kg/d as a continuous intravenous infusion over 14 days of an every-3-weeks cycle. Responses were monitored by radiologic imaging every 6 weeks. RESULTS: Forty-eight eligible patients were enrolled, 43 with metastatic disease. Median follow-up was 12.6 months (range, 2.2 to 16.8 months) for living patients. A median of four cycles of treatment was given (range, 1 to 18 cycles). All patients were assessable for response and toxicity. The 6-month survival percentage was 57.5% (95% CI, 44.9% to 73.5%) and the median survival was 6.6 months. The response rate was 10.4% (one complete response, four partial responses). Clinically significant toxicity was limited except for one fatal pulmonary embolism. CONCLUSION: This study shows a promising response rate to the combination of gemcitabine and ISIS-2503 in patients with pancreatic ACA. The observed 6-month survival rate in these patients met our protocol-defined criteria for success. This regimen is tolerable, but is of unclear benefit. Additional studies evaluating the role of gemcitabine and ISIS-2503 in the treatment of pancreatic ACA should be considered.     

The neuropeptide-Y Y5 receptor antagonist L-152,804 decreases alcohol self-administration in inbred alcohol-preferring (iP) rats.

Neuropeptide-Y (NPY) is the most abundant and widely distributed peptide in the mammalian central nervous system and increases feeding behavior through actions at the Y5 receptor subtype. Recent pharmacological evidence indicates that NPY activity at this receptor subtype can modulate ethanol reinforcement. The purpose of this study was to determine if NPY Y5 receptor antagonism reduces ethanol self-administration and reinforcement in a rodent genetic animal model of alcoholism. Selectively inbred alcohol-preferring (iP) rats were trained to voluntarily consume ethanol (10% vol/vol) versus H2O in a 24-h two-bottle choice test. An additional group of iP rats was trained in operant ethanol self-administration to lever press on a fixed-ratio 1 schedule for ethanol (10% vol/vol) reinforcement. Following establishment of baseline intake or ethanol-reinforced responding, iP rats were injected with L-152,804 (0-20 mg/kg) prior to two-bottle or operant ethanol self-administration sessions. In the two-bottle choice test, L-152,804 (3 and 10 mg/kg, ip) significantly reduced ethanol intake (g/kg) at 4- and 6-h postinjection and had no effect on food intake. In the operant procedure, L-152,804 (10 and 20 mg/kg, ip) significantly reduced both the dosage of self-administered ethanol (g/kg/1-h) and the total number of ethanol-reinforced responses. No effect was observed on latency to the first response or the number of inactive lever presses. These results indicate that blockade of NPY Y5 receptor activity decreases both voluntary ethanol drinking and ethanol reinforcement in a rodent genetic animal model of alcoholism. For this reason, NPY Y5 receptor antagonists may be useful in medical management of alcohol abuse and alcoholism in the human population.     

Perianesthetic risks and outcomes of pheochromocytoma and paraganglioma resection

Pheochromocytomas and paragangliomas are often surgically curable. However, resection of these tumors can be life threatening. We undertook this study to determine the frequency of, and risk factors for, perioperative complications in patients undergoing resection of pheochromocytoma or paraganglioma. We retrospectively reviewed the medical records of patients during 1983-1996 who underwent surgical resection of catecholamine-secreting pheochromocytoma or paraganglioma. Preoperative risk factors, adverse intraoperative events, and complications occurring in the 30 days after operation were recorded. Blood pressures were collected from manual records. The ranked sum test and Fisher's exact test were used for analyses. Adverse perioperative events or complications occurred in 45 of 143 patients (31.5%; exact 95% confidence interval, 24.0% to 39.8%). Of these 45 patients, 41 experienced one or more adverse intraoperative events. The most common adverse event was sustained hypertension (36 patients). There were no perioperative deaths, myocardial infarctions, or cerebrovascular events. Preoperative factors univariately associated with adverse perioperative events included larger tumor size (P: = 0.007), prolonged duration of anesthesia (P: = 0.015), and increased levels of preoperative urinary catecholamines and catecholamine metabolites: vanillylmandelic acid (P: = 0.019), metanephrines (P: = 0.004), norepinephrine (P: = 0. 014), and epinephrine (P: = 0.004). Despite premedication of most patients with phenoxybenzamine and a beta-adrenergic blocker, varying degrees of intraoperative hemodynamic lability occurred. Implications: Few patients who had pheochromocytoma or paraganglioma resection experienced significant perioperative morbidity and none died in the largest retrospective study on this topic to date. This study confirms the very good perioperative outcomes demonstrated in smaller studies on this high-risk population, and identifies several risk factors for adverse outcomes.     

Multisensory auditory-somatosensory interactions in early cortical processing revealed by high-density electrical mapping

We investigated the time-course and scalp topography of multisensory interactions between simultaneous auditory and somatosensory stimulation in humans. Event-related potentials (ERPs) were recorded from 64 scalp electrodes while subjects were presented with auditory-alone stimulation (1000-Hz tones), somatosensory-alone stimulation (median nerve electrical pulses), and simultaneous auditory-somatosensory (AS) combined stimulation. Interaction effects were assessed by comparing the responses to combined stimulation with the algebraic sum of responses to the constituent auditory and somatosensory stimuli when they were presented alone. Spatiotemporal analysis of ERPs and scalp current density (SCD) topographies revealed AS interaction over the central/postcentral scalp which onset at approximately 50 ms post-stimulus presentation. Both the topography and timing of these interactions are consistent with multisensory integration early in the cortical processing hierarchy, in brain regions traditionally held to be unisensory.     

Temperature-dependent pharmacokinetics and pharmacodynamics of vecuronium

BACKGROUND: The authors evaluated the influence of temperature on the pharmacokinetics and pharmacodynamics of vecuronium because mild core hypothermia doubles its duration of action. METHODS: Anesthesia was induced with alfentanil and propofol and maintained with nitrous oxide and isoflurane in 12 healthy volunteers. Train-of-four stimuli were applied to the ulnar nerve, and the mechanical response of the adductor pollicis was measured. Volunteers were actively cooled or warmed until their distal esophageal temperatures were in one of four ranges: < 35.0 degrees C, 35.0-35.9 degrees C, 36.0-36.9 degrees C, and > or = 37.0 degrees C. With temperature stabilized, vecuronium was infused at 5 microg x kg(-1) x min(-1) until the first response of each train-of-four had decreased by 70%. Arterial blood (for vecuronium analysis) was sampled at intervals until the first response recovered to at least 90% of its prevecuronium level. Vecuronium, 20 microg x kg(-1) x min(-1), was then infused for 10 min, and arterial blood was sampled at intervals for up to 7 h. Population-based nonlinear mixed-effects modeling was used to examine the effect of physical characteristics and core temperature on vecuronium pharmacokinetics and pharmacodynamics. RESULTS: Decreasing core temperature over 38.0-34.0 degrees C decreases the plasma clearance of vecuronium (11.3% per degrees C), decreases the rate constant for drug equilibration between plasma and effect site (0.023 min(-1) per degrees C), and increases the slope of the concentration-response relationship (0.43 per degrees C). CONCLUSIONS: Our results show that reduced clearance and rate of effect site equilibration explain the increased duration of action of vecuronium with reducing core temperature. Tissue sensitivity to vecuronium is not influenced by core temperature.     

PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib.

PURPOSE: Gastrointestinal stromal tumors (GISTs) commonly harbor oncogenic mutations of the KIT tyrosine kinase, which is a target for the kinase inhibitor imatinib. A subset of GISTs, however, contains mutations in the homologous kinase platelet derived growth factor receptor alpha (PDGFRA), and the most common of these mutations is resistant to imatinib in vitro. Little is known of the other types of PDGFRA mutations that occur in GISTs. MATERIALS AND METHODS: We determined the KIT and PDGFRA mutation status of 1,105 unique GISTs using a combination of denaturing high-performance liquid chromatography and direct sequencing. RESULTS: 66 in exon 18, 11 in exon 12, and three in exon 14. Transient expression of representative PDGFRA isoforms in CHO cells revealed imatinib sensitivity of exon 12 mutations (SPDHE566-571R and insertion ER561-562) and an exon 14 substitution (N659K). However, most isoforms with a substitution involving codon D842 in exon 18 (D842V, RD841-842KI, DI842-843IM) were resistant to the drug, with the exception of D842Y. Interestingly, other mutations in exon 18 (D846Y, N848K, Y849K and HDSN845-848P) were all imatinib sensitive. Proliferation studies with BA/F3 cell lines stably expressing selected PDGFRA mutant isoforms supported these findings. CONCLUSION: Including our cases, there are 289 reported PDGFRA-mutant GISTs, of which 181 (62.6%) had the imatinib-resistant substitution D842V. However, our findings suggest that more than one third of GISTs with PDGFRA mutations may respond to imatinib and that mutation screening may be helpful in the management of these tumors.     

Entwicklungsneurologie – vernetzte Medizin und neue Perspektiven

Developmental neurology is one of the major areas of neuropediatrics and is among other things (legally) responsible for monitoring the motor, cognitive and psychosocial development of all infants using standardized monitoring investigations. The special focus is on infants born at risk and/or due to premature birth before 32 weeks of gestation or a birth weight less than 1500?g. Early diagnosis of deviations from normal, age-related development is a prerequisite for early interventions, which may positively influence development and the long-term biopsychosocial prognosis of the patients. This article illustrates the available methods in developmental neurology with a focus on recent developments. Particular attention is paid to the predictive value of general movements (GM). The current development of markerless automated detection of spontaneous movements using conventional depth imaging cameras is demonstrated. Differences in spontaneous movements in infants at the age of 12 weeks are illustrated and discussed exemplified by three patients (healthy versus genetic syndrome versus cerebral palsy).