FLUMAZENIL IN ALCOHOL WITHDRAWAL: A DOUBLE-BLIND PLACEBO-CONTROLLED STUDY

The purpose of the present study was to study -aminobutyricacid (GABA)-A receptor function in alcohol-dependent subjectsduring withdrawal, using the benzodiazepine antagonist flumazenil.In particular, we wanted to examine the hypotheses that an endogenousinverse agonist ligand at the GABA-A benzodiazepine receptor(GBzR) is active during withdrawal (in which case flumazenilshould be anxiolytic), or whether chronic alcohol intake resultsin a shift in sensitivity of the receptor in the inverse agonistdirection (in which case flumazenil should be anxiogenic). Resultsfrom 15 alcohol-dependent subjects in a double-blind placebo-controlledcross-over study showed that flumazenil was neither anxiolyticnor anxiogenic, although withdrawal scores were reduced duringthe course of the study. The fact that flumazenil was not anxiogenic,as it is in panic disorder, suggests that the GBzR is functioningdifferently in these two clinically similar conditions.     

Immunomodulation by Metals

A symposium entitled Immunomodulation by Metals was held atthe 32nd Annual Meeting of the Society of Toxicology (SOT) inNew Orleans, Louisiana. The symposium was cosponsored by theImmunotoxicology and Metals Specialty Sections of SOT and wasdesigned to describe the types of adverse immunological reactionswhich occur in response to environmental and/or occupationalexposure to metals. Epidemiological evidence and underlyingmechanisms responsible for the observed alterations were alsodiscussed. The following is a summary of each of the individualpresentations.     

Immunotoxicological Profile of Morphine Sulfate in B6C3F1 Female Mice

This study was undertaken to investigate a number of immuneparameters which may be compromised with exposure to morphinesulfate. Mice were implanted subcutaneously with 8-, 25-, or75-mg morphine sulfate pellets. Placebo pellets of identicalmakeup to the 75-mg morphine pellet (without morphine of course)were used as a control. Twenty-four hours after implantationof a 75-mg morphine pellet, blood levels reached a peak of 1610ng/ml. Corticosterone increased in parallel with morphine andreached a peak level of 966 ng/ml 24 hr after implantation.The dose response of morphine to increase corticosterone, however,was fiat. The weight of the lymphoid organs, spleen and thymus,and the liver were significantly reduced in the morphine-treatedgroups. Morphine treatment was associated with an increase inserum albumin, SGPT, BUN, and alkaline phosphatase indicativeof hepatic damage. In contrast to increased serum proteins,the C3 component of complement was reduced in a dose-dependentmanner. Leukocyte number in the peripheral blood was significantlyreduced, while erythro-cyte number and hematocrit were bothincreased. The number of B cells and T cells was decreased inmorphine-treated animals. However, the percentage of T cellsrelative to B cells was increased. The primary IgM antibodyresponse to the T-depen-dent antigen, sheep red blood cells,was decreased. Natural killer cell activity was reduced in responseto morphine, as was the phagocytic capacity of Kupffer cells.Host-resistance models of Listeria monocytogenes or Streptococcuspneumoniae showed an increased resistance following administrationof morphine. This increased host resistance, however, was notdue to an increase in antimicrobial action of sera obtainedfrom mice treated with morphine. The majority of morphine'seffects on the immune system exhibited a flat dose response,suggesting that these effects may be mediated secondarily throughcorticosterone.     

Dietary Changes Favorably Affect Bone Remodeling in Older Adults

OBJECTIVE: To determine whether dietary counseling to increase milk intake could produce useful changes in the calcium economy and what, if any, other nutrition-related changes might be produced. DESIGN: Randomized, open trial. SUBJECTS/SETTING: Two hundred four healthy men and women, aged 55 to 85 years, who habitually consumed fewer than 1.5 servings of dairy foods per day. Six academic health centers in the United States. INTERVENTION: Subjects were instructed to consume 3 servings per day of nonfat milk or 1% milk as a part of their daily diets, or to maintain their usual diets, for a 12-week intervention period, which followed 4 weeks of baseline observations. MAIN OUTCOME MEASURES: Energy and nutrient intake assessed from milk intake logs and 3-day food records; serum calciotrophic hormone levels at baseline and at 8 and 12 weeks; urinary excretion of calcium and N-telopeptide at 12 weeks. STATISTICAL ANALYSES: Repeated-measures analysis of variance. RESULTS: In the milk-supplemented group, calcium intake increased by 729 +/- 45 mg/day (mean +/- standard error), serum parathyroid hormone level decreased by approximately 9%, and urinary excretion of N-telopeptide, a bone resorption marker, decreased by 13%. Urine calcium excretion increased in milk-supplemented subjects by 21 +/- 7.6 mg/day (mean +/- standard error), less than half the amount predicted to be absorbed from the increment in calcium intake. All of these changes were significantly different from baseline values in the milk group and from the corresponding changes in the control group. Bone-specific alkaline phosphatase level (a bone formation marker) fell by approximately 9% in both groups. Serum level of insulin-like growth factor-1 (IGF-1) rose by 10% in the milk group (P < .001), and the level of insulin-like growth factor binding protein-4 (IGFBP-4) fell slightly (1.9%) in the milk group and rose significantly (7.9%) in the control group (P < .05). APPLICATIONS/CONCLUSIONS: The changes observed in the calcium economy through consumption of food sources of calcium are similar in kind and extent to those reported previously for calcium supplement tablets. The increase in IGF-1 level and the decrease in IBFBP-4 level are new observations that are beneficial for bone health. Important improvements in skeletal metabolism can feasibly occur in older adults by consumption of food sources of calcium. Dietitians can be confident that food works, and that desired calcium intakes can be achieved using food sources.     

Coping with rheumatoid arthritis. How can specialist nurses influence it and promote better outcomes?

• ? Psychological stressors are said to be an important influence on the outcome of chronic illnesses such as rheumatoid arthritis (Engel, 1977).
• ? Helping patients to cope with stressors is identified as a central concept in the delivery of nursing care (Khan et al., 1994). It is thus reasonable to suggest that rheumatology nurses may be key players in the process of coping with rheumatoid arthritis.
• ? But in order for rheumatology nurses to be effective players in this process, they need to discourage coping behaviour(s) linked to poor outcomes, and/or promote an overall behaviour pattern linked to a better outcome. Literature showing the link between different coping behaviours and outcome is examined, and cognitive restructuring is emphasized as one method nurses could use.
• ? Having identified coping behaviour which is optimal in terms of future outcome, further study of different forms of coping-based educational intervention is suggested, to reveal how such patterns of behaviour can be taught by nurses in the most effective way

     

A study of the provision of health checks and health-promotion clinics in 18 general practices

Summary

• ? The objective of this study was to describe the variation in provision of health checks and health-promotion clinics operating under the regulations of the 1990 Contract for general practice in the UK.
• ? Eighteen group practices in three Family Health Service Authority (FHSA) areas of England (two in the South West Thames region and one in the Yorkshire region) were selected for the study. The nurses, largely responsible for the implementation of the health checks at these practices, were interviewed using semi-structured interview schedules. They were asked about age-groups targeted, means of recruiting patients for clinics, duration of clinic appointments, and procedures carried out in clinics.
• ? All practices offered health checks, and 55% had started doing so before introduction of the 1990 Contract. Recruitment for health checks took place in a number of ways: self-referral (83% of practices); opportunistically in those with coronary heart disease risk factors (78%); opportunistically during attendance for cervical smears (62%); screening in at least one patient group (78%). Blood pressure, height, weight, urinalysis and life-style advice were included by all practices. Stress management and quit smoking strategies were offered only by a minority of practices. Duration of first health-check appointment ranged between 15 and 30 minutes.
• ? The basic content of health checks, and life-style advice given appeared consistent between the widely varying practices. However, the resources available for intervention and follow up showed more variation.

     

Rapid Administration of High-Dose Human Antibody Fab Fragments to Dogs: Pharmacokinetics and Toxicity

Rapid Administration of High-Dose Human Antibody Fab Fragmentsto Dogs: Pharmacokinetics and Toxicity. Keyler, D. E., Salerno,D. M., Murakami, M. M., Ruth, G., and Pentel, P. R. (1991).Fundam. Appl Toxicol 17, 83-91. The treatment of drug overdosewith drug-specific antibody fragments may require very highantibody doses. To address the feasibility of this therapy,we studied the pharmacokinetics and toxicity of high-dose humannonspecific Fab fragments in beagles. Three dogs received 5.3g/kg Fab iv over 1 hr. Because nephrotoxicity was observed,three subsequent dogs received 3.2 g/kg. The fraction of theFab dose excreted in urine (10 ± 6%%) was lower thanreported values for either high or low doses of Fab in otherspecies. The terminal serum elimination half-life (42 hr forthe higher and 48 hr for the lower dose) was also longer thanreported values for other species, due to lower renal and nonrenalFab clearance. Fab administration was tolerated without adversehemodynamic effects. One of three dogs at each dose developedtransient oliguria. All dogs developed a transient but markedincrease in the serum creatinine concentration. At 2 weeks creatinineclearance had returned to normal. Urinary protein and albuminexcretion at 2 weeks were within the normal range for dogs butwere increased over their baseline values. The histology ofall organs was normal at 3 weeks by light microscopy, and renalhistology by electron microscopy was also normal. The mechanismof Fab nephrotoxicity, not observed previously with high-doseFab in rats or lower doses of Fab in other species includingdogs, is not clear. These data suggest that further study ofthe potential toxicity of high-dose Fab, and its reversibility,is needed to assess the feasibility of treating drug overdosewith this antibody fragment The long terminal half-life of high-doseFab in the dog and its low renal clearance contrast with valuesobserved with lower doses of Fab in other species but wouldnot be expected to preclude the use of high-dose Fab for drugoverdose.     

The Translocation of Inhaled Silicon Dioxide: An Empirically Derived Compartmental Model

The Translocation of Inhaled Silicon Dioxide: An EmpiricallyDerived Compartmental Model. VACEK, P. M., HEMENWAY, D. R.,ABSHER, M. P., AND GOODWIN, G. D. (1991). Fundam. Appl Toxicol.17, 614–626. The movement of inhaled silicon dioxide particleswas studied by measuring the amounts in alveolar fluid and cells,lung tissue, and lymphoid tissue during the 6 months followingshort-term aerosol exposure of Fischer 344 rats. A variety offirst-order compartmental models were fit to data from nineexposure experiments to identify the most feasible biologicpathways for the transfer of material among these sites andout of the body. A multivariate least-squares approach was usedto simultaneously fit the data from several compartments. Theresults indicate that transfer between alveolar cells and lungtissue occurs in both directions, suggesting that silica canreenter the alveolar space from the lung tissue. This featurehas not been included in previously published models. The resultsalso indicate that transfer from lung tissue to the mediastinallymph nodes and thymus is indirect; there are one or more unidentifiedextrapulmonary compartments that receive silica from the lung.Rates of transfer among compartments were dependent on mineraltype (quartz or cristobalite), heat treatment, and exposuredose. There was no evidence for direct clearance from the alveolarspace via the tracheobronchial tract.