Pharmacokinetics of eltanolone in male and female patients following intravenous bolus injection

BACKGROUND: The pharmacokinetics of the steroid anesthetic eltanolone have been studied in male volunteers. However, steroids may exhibit gender-related differences in pharmacokinetics and surgery may alter drug disposition. METHODS: Male (n = 12) and female (n = 9) ASA 1-2 patients (age 26-45 yrs) undergoing discectomy with microsurgical technique were included. Anesthesia was induced with eltanolone 0.75 mg/kg and maintained with nitrous oxide, fentanyl and atracurium. Venous blood was sampled for up to 12 h and analyzed for eltanolone and its major metabolites. RESULTS: Induction was smooth and anesthesia uneventful, except that five cases developed a mild transient erythema. Loss of verbal contact occurred within 20-60 s. Pharmacokinetics in one person deviated significantly from the rest of the subjects. No difference between groups with respect to the primary outcome variable noncompartmental clearance (Cl, 1/min) 1.7 vs 1.6, was found. However, the volume of distribution at steady state (Vss, 1/kg) was larger in women (3.1) compared to men (1.3). The pharmacokinetics followed a three-compartment model. The half-lives (min) of the alpha, beta and gamma phases (men vs women, medians) were 1.5 vs 2.2, 42 vs 40 and 222 vs 360, respectively. Area under the curve (AUC, min microgram/l) was 39,810 vs 34,905. Context-sensitive modelling indicated that it may take 10 min more for women than men to recover from an eltanolone infusion of 2 h duration. CONCLUSION: The gender-related differences in the pharmacokinetics of eltanolone were small, and of little clinical significance for induction of anesthesia with eltanolone.     

Focus on mobilisation after lower abdominal surgery. A double-blind randomised comparison of epidural bupivacaine with morphine vs. lidocaine with morphine for postoperative analgesia

BACKGROUND: Epidural infusion of morphine, usually with bupivacaine, for postoperative pain relief has proved to be safe and effective. Lidocaine with its short duration of action and low toxicity may be an alternative to bupivacaine. The clinical importance of the choice of local anaesthetic drug on mobilisation after lower abdominal surgery has not been studied previously. METHODS: A total of 52 patients was randomised to epidural infusion of morphine (1.6-4.4 micrograms.kg-1.h-1) with either lidocaine (0.44-0.98 mg.kg-1.h-1) or bupivacaine (0.10-0.28 mg.kg-1.h-1) in a double-blind fashion. The time to mobilisation, degree of pain relief, blood pressure, respiration and motor function were recorded at regular intervals postoperatively for 40 h. Serum concentrations of lidocaine, its main metabolite monoethylglycinexylidide (MEGX) and bupivacaine were measured at 3, 15 and 40 h. RESULTS: There were no significant differences in the clinical characteristics between the two patient groups. There were no significant differences in the time from the end of surgery to the time the patients were able to stand without support (bupivacaine: median 24 h (interquartile range (IQR): 22-31), lidocaine: median 28 h (IQR 23-40), P = 0.15) or were able to walk without support (bupivacaine: median 46 h (IQR 28-62), lidocaine: median 48 h (IQR 35-54), P = 0.78). No significant differences between the groups were recorded with respect to pain relief, blood pressure, respiration, sedation score and motor function. The plasma concentration of lidocaine and bupivacaine increased significantly during the treatment period (P < 0.01 for both drugs), but not the concentration of MEGX. The highest venous lidocaine concentration was 17.5 mumol/l and the highest bupivacaine concentration was 18.8 mumol/l. There was a significant correlation between the concentration of both lidocaine and bupivacaine and the concentration of alpha 1-acid glycoprotein (AAG) (lidocaine: r = 0.77, P < 0.001, bupivacaine: r = 0.60, P < 0.001), suggesting that the free fraction of the drugs did not increase. No patients showed serious signs of toxicity. The epidural infusion rates remained stable in both groups during the study period. CONCLUSION: There were no clinically or statistically significant differences in the postoperative course after lower abdominal surgery in patients who received an epidural infusion of morphine combined with bupivacaine as compared to patients who received morphine with lidocaine. Further clinical studies to establish the place of lidocaine in postoperative epidural analgesia should be performed.     

Higher levels of antibodies against the psoriasis-associated antigen pso p27 in cerebrospinal fluid from patients with low back pain and sciatica

STUDY DESIGN: A prospective study comparing the presence of antibodies against the psoriasis-associated antigen pso p27 in pain-free control subjects and patients with low back pain and/or sciatica. OBJECTIVES: To analyze the amount of local inflammation present in human lumbar disc disorders, using anti-pso p27 antibodies in the cerebrospinal fluid as a marker and to analyze whether pain intensity correlates with this marker of inflammation. SUMMARY OF BACKGROUND DATA: Pso p27 is a major antigen in psoriasis that is also present, mostly locally, in other inflammatory disorders, such as sarcoidosis, inflammatory bowel disease, and ankylosing spondylitis, inflammation is also thought to play a major role in the generation of lumbar and radicular pain in degenerative disc disorders. METHODS: Anti-pso p27 antibodies in cerebrospinal fluid were quantified using an indirect enzyme-linked immunosorbent assay with pso p27 obtained from patients with psoriasis for use as an antigen. Fifteen patients with spinal stenosis, 11 patients without myelographic disc herniation, 17 patients with disc herniation, and 24 pain-free patient control subjects were studied. RESULTS: Significantly higher levels of anti-pso p27 antibodies were found in patients with myelographic signs of disc herniation than in with patients with no signs of herniation, patients with spinal stenosis, and control subjects. Patients with no known signs of disc herniation and patients with myelographic signs of spinal stenosis (< 10 mm in diameter) caused by degenerative changes, had higher levels of anti-pso p27 antibodies than did control subjects. However, these differences reached only borderline statistical significance. CONCLUSIONS: The results support those in previous reports, that inflammation probably plays an important role in degenerative disk disorders, particularly in disk herniations. That there was no correlation between pain intensity and anti-pso p27 activity indicates that the antigen is probably not essential in pain generation per se. The results may indicate that pso p27 is expressed secondary to, not as an initiator of, inflammation.     

Responding to out-of-hours demand: the extent and nature of urgent need.

BACKGROUND: Little research has been undertaken concerning GPs' perceptions about urgent or 'appropriate' out-of-hours demand. OBJECTIVE: We aimed to measure GPs' perceptions about patients' need for urgent out-of-hours general medical help according to indicators of physical, psychological/emotional and social need, and the medical necessity of a home visit. METHODS: Twenty-five practices participated in an audit and research study whereby GPs completed an audit form for all contacts during November/December 1995 and February/March 1996. Each contact was assessed according to the indicators of urgent need and GPs commented on reasons for making such assessments. RESULTS: Audit forms were completed on 1862 patients, and GPs considered that 66.6% (1027) of contacts had either a physically, psychologically/emotionally or socially urgent need for help and were uncertain about a further 10.7% (165). Over half (53.0%) were considered to have an urgent physical need, almost one-third (31.0%) to have an urgent psychological/emotional need and 10.1% (119) to have an urgent social need for help. Over half (55.2%) of visits were considered to be medically necessary, the majority of which (89.9%) were assessed as having an urgent physical need for help. CONCLUSIONS: The findings raise questions about the strategic direction of newer forms of service delivery (GP Co-operatives) and suggest the need for further research to inform the strategic reduction in home visiting, particularly in inner-city areas where many residents have little access to transport out-of-hours to enable them to attend a primary care centre. GP co-operatives are, however, well placed to improve interagency working and cross-referral to other health and social service personnel, and respond more 'appropriately' to some psychological/emotional and social problems.     

Decreased glutamate metabolism in cultured astrocytes in the presence of thiopental.

The effect of thiopental on glutamate metabolism was studied by 13C magnetic resonance spectroscopy. Cerebral cortical astrocytes were incubated with 0.5 mM [U-13C]glutamate for 2 hr in the presence of 0.5 or 1 mM thiopental. Labeled glutamate, glutamine, aspartate, and glutathione were observed in cell extracts, and glutamine, aspartate, and lactate in the medium. Not only present in the medium was uniformly labeled glutamate, but also glutamate derived from the tricarboxylic acid (TCA) cycle, and thus glutamate release could be detected. The amounts of [U-13C]glutamate and unlabeled glucose taken up by astrocytes were unchanged in the presence of 0.5 mM thiopental and decreased to about 50% and 80%, respectively when the concentration was increased to 1 mM. The amounts of most metabolites synthesized from [U-13C]glutamate were unchanged in the presence of 0.5 mM thiopental, but decreased [U-13C]glutamine, [U-13C]aspartate, and [U-13C]lactate were observed in the 1 mM group. Surprisingly, the amounts of [1,2,3-13C]glutamate, [2,3-13C]aspartate, and [3,4-13C]aspartate (2nd turn via the TCA cycle) were unchanged. However, this was not the case for [1,2-13C]lactate and [2,3-13C]lactate. Such variations indicate cellular compartmentation, possibly caused by a heterogeneous glutamate concentration within the cells affecting TCA cycle turnover rates differently.     

The anticonvulsant BW534U87 depresses epileptiform activity in rat hippocampal slices by an adenosine-dependent mechanism and through inhibition of voltage-gated Na+ channels

1. The cellular and molecular actions of BW534U87 were studied using intracellular and extracellular recordings from the CA1 region of rat hippocampal slices and whole-cell voltage-clamp recordings of recombinant human brain type IIA Na+ channels expressed in Chinese hamster ovary (CHO) cells. 2. Normal excitatory and inhibitory postsynaptic potentials evoked in hippocampal slices were unaffected by BW534U87 or the adenosine deaminase inhibitor EHNA. However, epileptiform activity was depressed by BW534U87 (50 micronM) and this inhibition was reversed by the adenosine receptor antagonist 8-phenyl theophylline (8-PT, 30 micronM). EHNA (10 micronM) mimicked the effects of BW534U87. Furthermore, BW534U87 enhanced the inhibitory effects of exogenous adenosine on evoked synaptic potentials. BW534U87 (50 micronM) also voltage- and use-dependently inhibited action potentials elicited by current injection, independent of the adenosine system, since it was not affected by 8-PT. 3. In CHO cells expressing the recombinant human brain Na+ channel, BW534U87 produced a concentration- and voltage-dependent inhibition of Na+ currents with a half-maximal inhibitory concentration of 10 micronM at a Vh of -60 mV. Use-dependent inhibition was evident at high-frequencies (20x20 ms pulse train at 10 Hz). 4 In conclusion, BW534U87 blocks hippocampal epileptiform activity by a dual mechanism. The first action is similar to that produced by EHNA and is dependent on endogenous adenosine probably by inhibition of adenosine deaminase. Secondly, BW534U87 directly inhibits voltage-gated Na+ channels in a voltage- and frequency-dependent manner. Both actions of BW534U87 are activity-dependent and may synergistically contribute to its overall anticonvulsant effects in animal models of epilepsy.     

The comparative validity of eleven alcoholism typologies

OBJECTIVE: This study directly compared the clinical validity of 11 empirically defined alcoholism typologies to determine whether some typologies are clinically more valid than others. METHOD: A sample of 360 hospitalized alcoholic men were extensively evaluated at entry into the study and again 1 year later. Twenty-three measures of clinical validity were employed; 15 were postdictive and 8 were predictive. Postdictive retrospective measures obtained at entry into the study included family history, age of onset and lifetime course characteristics associated with alcoholism severity, general psychopathology and psychosocial functioning. Predictive outcome measures drawn from information obtained during the 1-year follow-up included: abstinence, alcoholism severity and clinician ratings of outcome. The measures were subjected to various statistical analyses, including factor analysis. RESULTS: We found that all of the alcoholism typologies met at least 7 of the 23 a priori measures of clinical validity. The correlations between these conceptually and methodologically disparate typologies were often striking. Exploratory factor analysis, which explained 35% of the variance, suggested three possible underlying dimensions to account for the overlap among typologies: (1) age and its correlates, including age-of-alcoholism onset; (2) "pure" alcoholism versus psychiatrically heterogeneous alcoholism that encompassed antisocial personality disorder; and (3) current severity of psychiatric distress, impairment and dysfunction. CONCLUSIONS: No single method of subtyping alcoholics clearly emerged as superior. All demonstrated some degree of predictive and postdictive clinical validity. Most methods of subtyping correlated positively with each other at moderate, but typically significant, levels.     

Minimally invasive cardiac surgery for removal of the greater saphenous vein

Objective

To determine if saphenous vein required for coronary bypass could be quickly, easily and safely removed with a minimally invasive technique.

Design

A consecutive series.

Setting

A university centre.

Material and Methods

In cadavers, a standard mediastinoscope was used to remove segments of the greater saphenous vein. Thigh segments, superior leg segments and ankle segments were removed. Fifteen minutes were allowed for removal of a segment.

Results

Segments of vein 15 to 17 cm long could be removed. One segment could not be removed within 15 minutes. Thigh segments were easy to remove, calf segments were the most difficult. There were no avulsed side branches. All incisions were less than 5 cm long.

Conclusions

Saphenous vein can be harvested quickly and safely by a minimally invasive method. Lower extremity complications may be reduced and long-term patency improved with this in-situ technique of vein removal.     

Factors influencing the emigration of physicians from Canada to the United States.

OBJECTIVE: To determine whether location of postgraduate medical training and other factors are associated with the emigration of physicians from Canada to the United States. DESIGN: Case-control study, physicians were surveyed with the use of a questionnaire mailed in May 1994 (with a reminder sent in September 1994), responses to which were accepted until Dec. 31, 1994. PARTICIPANTS: Physicians randomly selected from the CMA database, 4000 with addresses in Canada and 4000 with current addresses in the United States and previous addresses in Canada. OUTCOME MEASURES: Sex, age, location of undergraduate and postgraduate medical training, qualifications, practice location, opinions concerning residence decisions, current satisfaction and plans. RESULTS: The overall response rate was 49.6% (50.0% among physicians in the United States and 49.2% among those in Canada). Age and sex distributions were similar among the 8000 questionnaire recipients and the nearly 4000 respondents. Physicians living in the United States were more likely to be older (mean 53.2 v. 49.6 years of age), male (87% v. 75%) and specialists (79% v. 52%) than those practising in Canada. Postgraduate training in the United States was associated with subsequent emigration (odds ratio 9.2, 95% confidence interval 7.8 to 10.7). However, in rating the importance of nine factors in the decision to emigrate or remain in Canada, there was no significant difference between the two groups in the rating assigned to location of postgraduate training. Professional factors rated most important by most physicians in both groups were professional/clinical autonomy, availability of medical facilities and job availability. Remuneration was considered an equally important factor by those in Canada and in the United States. Six of seven personal/family factors were rated as more important to their choice of practice location by respondents in Canada than by those in the United States. Current satisfaction was significantly higher among respondents in the United States. Most physicians in each group planned to continue practising at their current location. Of Canadian respondents, 22% indicated that they were more likely to move to the United States than they were a year beforehand, whereas 4% of US respondents indicated that they were more likely to return to Canada. CONCLUSIONS: Factors affecting the decision to move to the United States or remain in Canada can be categorized as "push" factors (e.g., government involvement) and "pull" factors (e.g., better geographic climate in the US). Factors can also be categorized by whether they are amenable to change (e.g., availability of medical facilities) or cannot be managed (e.g., proximity of relatives). An understanding of the reasons why physicians immigrate to the United States or remain in Canada is essential to planning physician resources nationally.     

Evaluation of a new fletcher applicator using cesium-137

The improved Fletcher Applicator¹ is a recent modification of the afterloading Fletcher system. Its aluminum construction reduces the weight by 50 % and is more comfortable for the patient. Removable caps contain medially placed tungsten screens that shield tissues anteriorly and posteriorly. When the caps are removed, the colpostats can be used as Delclos mini-ovoids. A method for evaluating the dosimetry of brachytherapy applicators in a water phantom was devised so this applicator could be studied and compared with other gynecologic applicators. The results show that the transmission ratios—the fraction of radiation transmitted through the tungsten shields—differ from those of the preloaded Fletcher colpostat, but are similar to the transmission ratios of the Fletcher-Suit applicator. There is a 10 % to 25 % reduction in the radiation dose to the region of the bladder trigone and anterior rectum with the shield containing cap in place. This percent reduction in dose is in agreement with other Fletcher applicators. Misalignment of the source basket within the colpostat, and motion of the source in the carrier cause variations in the dose rate at specific distances from the colpostat.