Canadian recommendations for the management of breakthrough cancer pain.

Breakthrough cancer pain (btcp) represents an important element in the spectrum of cancer pain management. Because most btcp episodes peak in intensity within a few minutes, speed of medication onset is crucial for proper control. In Canada, several current provincial guidelines for the management of cancer pain include a brief discussion about the treatment of btcp; however, there are no uniform national recommendations for the management of btcp. That lack, accompanied by unequal access to pain medication across the country, contributes to both regional and provincial variability in the management of btcp. Currently, immediate-release oral opioids are the treatment of choice for btcp. This approach might not always offer optimal speed for onset of action and duration to match the rapid nature of an episode of btcp. Novel transmucosal fentanyl formulations might be more appropriate for some types of btcp, but limited access to such drugs hinders their use. In addition, the recognition of btcp and its proper assessment, which are crucial steps toward appropriate treatment selection, remain challenging for many health care professionals. To facilitate appropriate management of btcp, a group of prominent Canadian specialists in palliative care, oncology, and anesthesiology convened to develop a set of recommendations and suggestions to assist Canadian health care providers in the treatment of btcp and the alleviation of the suffering and discomfort experienced by adult cancer patients.

Spatial distribution and temporal onset of NF-kB activation and inducible nitric oxide synthase within pancreatic islets in the pre-diabetic stage of genetic, diabetic-prone BB rats: attenuation by drug intervention decreases inflammatory cell infiltration and incidence of diabetes.

OBJECTIVE AND DESIGN: To document in vivo immunolocalization and activation of nuclear factor-kappaB (NF-kappaB) and inducible nitric oxide synthase (iNOS) expression in prediabetic stages of diabetes mellitus. MATERIAL OR SUBJECTS: Genetic, diabetic-prone or diabetic-resistant BB rats (total = 189). TREATMENT: Various doses of an oral dithiocarbamate derivative, NOX-700, or cyclosporine (2.5 mg/kg) starting at 30 or 60 days of age. METHODS: Immunohistochemistry, electrophoretic mobility shift assays, plasma glucose. RESULTS: NF-kappaB and iNOS was increased in pancreas of hyperglycemic, diabetic-prone rats but not normoglycemic, diabetic-resistant rats. Immunostaining for NF-kappaB and iNOS was largely confined to islets and occurred in diabetic-prone rats prior to overt hyperglycemia. NOX-700 decreased cell infiltration, delayed the onset of disease and decreased the incidence of hyperglycemia to levels achieved by immunosuppressant therapy. NOX-700 also decreased the intensity of immunoreactive NF-kappaB and iNOS within pancreatic islets. CONCLUSIONS: These studies support a role of NF-kB and iNOS in diabetogenesis in vivo.

Generic substitution: issues for problematic drugs.

The methodology and criteria for bioequivalence testing have been firmly established by the Food and Drug Administration (FDA). For certain drugs with a narrow therapeutic index (e.g., digoxin, levothyroxine, warfarin), generic substitution may not be advisable or even allowable, depending on the substitution laws of individual states. Digoxin and levothyroxine tablets are examples of drugs for which no New Drug Applications (NDAs) currently exist. However, commercially available generic products for both of these drugs have not been determined by the FDA to be therapeutically equivalent to the innovator products. Generic versions of warfarin have been approved by the FDA as being therapeutically equivalent to the innovator products, as have generic versions of the rescue inhaler albuterol. Yet, misinformation and myths persist regarding the adequacy and proven reliability of the FDA's determination of bioequivalence for these products.

Effect of barium sulfate on wound healing in the gastrointestinal tract of the rat.

PURPOSE: To study the effect of barium sulfate on wound healing in the gastrointestinal tract of the rat. MATERIALS AND METHODS: Sixty rats weighing approximately 320 g were divided into four groups: Fifteen control rats had gastric, small-bowel, and colonic incisions; 15 rats had gastric incision; 15 rats had small-bowel incision; and 15 rats had colonic incision. Barium sulfate was placed into the incision before closure in all rats except those in the control group, and the effects were documented clinically and histopathologically for 3 months. Autopsy was performed in five rats from each group at 1, 4, and 12 weeks. The incisions in the rats receiving barium sulfate were compared with those in the control rats. RESULTS: There was no difference in the clinical course (weight gain, activity, and viability) between the control and experimental groups. Early and late autopsy findings and histopathologic grading of healing and inflammatory response were similar for both the control and experimental groups. CONCLUSION: Under the conditions of this study, the effect of barium sulfate on visceral transmural wound healing in the gastrointestinal tract of the rat was minimal.

A generic drug primer: regulatory aspects and scientific concepts.

The regulatory aspects of generic drug substitution and the scientific concepts that serve as the basis for generic drug approval are discussed, with emphasis on the source of therapeutic equivalence information compiled by the Food and Drug Administration in Approved Drug Products with Therapeutic Equivalence Evaluations. The Food and Drug Administration's determination of bioequivalence for immediate-release and extended-release dosage forms is summarized, with a discussion of the underlying assumptions and current issues regarding bioequivalence testing. Medical practitioners must comply with the regulations stated in each state's Pharmacy Practice Act when allowing generic substitution and should ensure that the substituted product is therapeutically equivalent to the prescribed product.

Clinical effects of low-level exposures to chemical warfare agents in mice and chickens.

Concerns that chemical warfare (CW) agents themselves or in combination with other chemicals may cause long-term damage to nerve and muscle are reviewed and discussed. Experiments on mice and hens underway with agent GA and pyridostigmine bromide (PB) and their effects (either separately or together) are presented.

Monitoring the pesticide-exposed worker.

Cholinesterase inhibitors-the organophosphates and the carbamates-are the most acutely toxic and widely used insecticides. They also comprise the only group of pesticides for which state laws exit requiring worker monitoring. This chapter focuses on cholinesterase monitoring, with attention to available assays and testing kits.

Heart rate variability following cardiac surgery fails to predict short-term cardiovascular instability.

The heart rate variability of 40 patients has been examined by spectral analysis following cardiac surgery. The heart rate variability was measured upon patient arrival in ICU in both a resting supine position, and following passive straight-leg raising. After 12 hours in ICU, the patients were classified as having been cardiovascularly stable or unstable according to a specially devised inventory. Their heart rate variability data was then examined to seek any predictor of instability. Passive straight-leg raising induced a decrease in spectral power across all of the component frequency bands. The LF/HF ratio rose with passive straight-leg raising, but failed to reach significance. None of these changes were sustained. There was no significant difference in heart rate variability patterns between the stable and unstable groups, and so no predictor was identified. Initial clinical assessment was also studied, and it too provided no reliable prediction of short-term cardiovascular instability.

Variability of R-R, P wave-to-R wave, and R wave-to-T wave intervals.

We analyzed the effect of changing posture from supine to standing on the variability of R-R, P-R, and R-T intervals in 10 healthy volunteers using power spectral analysis. An electrocardiogram and respiratory trace were recorded before and after posture change. Variability in the P-R and R-T intervals was much less than in the R-R interval and demonstrated a lower-frequency (LF)-to-high-frequency (HF) ratio. Changing from a supine to a standing position showed no change in indexes of vagal influence on the P-R and R-T variability, in contrast to the well-documented decrease in the indexes of vagal influence on the R-R variability (HF power decreased from 2.33 to 0.41 ms2, P = 0.003; amplitude of the respiration-to-heart rate impulse response decreased from 31.6 to 14.4 ms.ml-1.s-1, P = 0.03; and LF/HF increased from 1.96 to 5.22, P = 0.005). We concluded from this study that the effects of standing were an observed reduction in vagal influence on the heart rate variability of the R-R interval and maintenance of lung volume-related vagal modulation of the P-R and R-T intervals.

Bioequivalence: individual and population compartmental modeling compared to the noncompartmental approach.

PURPOSE: The purpose of this study were to evaluate the use of individual compartmental and population compartmental methods for bioequivalence determination, and to determine their utility as adjuncts to the current methods used for bioequivalence assessment. METHODS: Data from three bioequivalence studies of chlorthalidone were analyzed with PCNONLIN using individual compartmental modeling and NONMEM for population analyses. These results were compared with results obtained from the traditional noncompartmental or SHAM (slopes, heights, areas, and moments) approach for bioequivalence assessment and the 90% confidence interval procedure. RESULTS: Individual compartmental modeling and population compartmental modeling techniques performed well on this routine set of bioequivalence data which displayed simple pharmacokinetic properties. A direct assessment of the analysis methods was made by comparing the final estimates and 90% confidence intervals for the test to reference ratios (T/R) of AUC and CMAX. The final estimates and 90% confidence intervals for AUC T/R and CMAX T/R were similar and suggest consistency of results, independent of the method used. CONCLUSIONS: These results demonstrate the utility of modeling techniques as adjuncts to the traditional noncompartmental approach for bioequivalence determination.

Factors in standardizing automated cholinesterase assays.

A scientific panel assembled by the U.S. Environmental Protection Agency (EPA) determined that variability in cholinesterase (ChE) activities in the agency's pesticide/animal study database likely was due to a lack of accepted guidelines for ChE methodology. A series of trials was held in which participating laboratories measured ChE activity in blood and brain samples from untreated and pesticide-treated rats using a colorimetric assay method. The degree of inhibition of ChE activity in plasma and brain samples compared to controls was consistent among most of the laboratories. The ChE activity in erythrocyte samples differed more between laboratories due to a high blank, low erythrocyte AChE activity and hemoglobin absorption at the wavelength of the assay. Strategies are suggested for minimizing the variability of ChE activity in hemoglobin-rich samples.

Heart rate variability in patients recovering from general anaesthesia.

We studied heart rate variability (HRV) using spectral analysis techniques in 58 adult patients recovering from general anaesthesia. The aim was to discover how HRV was affected by a variety of common preoperative, intraoperative and postoperative factors. ECG, respiration, level of consciousness, nausea, pain and arterial pressure were recorded during the first hour of recovery from general anaesthesia. HRV was found to decrease with increased weight, age, complexity of operation, use of reversal agents for neuromuscular block and preoperative beta-block. These effects were not mediated by changes in respiration. HRV was unaffected by administration of morphine. The level of nausea or pain had no effect on HRV except that pain decreased the relative ratio of high frequency to low frequency power within the power spectrum. In the group of patients that did not receive reversal agents, there was an abrupt increase in HRV when patients became responsive to verbal command.

Immunocytes and abnormal gastrointestinal motor activity during ileitis in dogs.

Infiltration of specific immunocytes and stimulation of abnormal gastrointestinal motor activity during ileal inflammation induced by mucosal exposure to ethanol and acetic acid were investigated in 17 dogs. Ileal inflammation significantly increased the frequency of giant migrating contractions (GMCs) and decreased the frequency of migrating motor complexes (MMCs). The frequency of retrograde giant contractions (RGCs) increased only on the day of ethanol and acetic acid treatment. Diarrhea, urgency of defecation, and apparent abdominal discomfort were related to the increased frequency of GMCs. Ileal inflammation also prolonged the duration of postprandial MMC disruption. Histological and immunohistochemical findings indicated transmural inflammation with marked increase in polymorphonuclear cells in the lamina propria and muscularis externa layers. Myeloperoxidase activity increased severalfold in both layers. Cells containing interleukin-2 receptor (IL-2R) increased in the lamina propria. Other immunocytes, such as B and T lymphocytes, dendritic cells, and human leukocyte antigen DR-1 (HLADR)-positive cells, did not exhibit a significant increase in the inflamed ileum compared with the normal proximal jejunum. We conclude that stimulation of GMCs may be the major motility marker of intestinal inflammation.

Heart rate variability and preoperative anxiety.

Power spectral analysis of heart rate variability has been used to gain some understanding of the activity of the autonomic nervous system. In this study various indices of heart rate variability were related to the degree of preoperative anxiety experienced by 32 patients presenting for day case surgery. It was found that there was no correlation between anxiety and mean heart rate, or between anxiety and the spectral power in the mid frequency band (0.05-0.15 Hz). However, there was an increase in the relative power of the higher frequency band (0.15-0.5 Hz) with increasing anxiety levels (Spearman correlation r = 0.4034). This suggests that preoperative anxiety may often be associated with a relative vagal predominance in the sympathovagal balance.