Publications

To elucidate the underlying mechanisms involved in AIDS therapy-induced peripheral neuropathy, we have developed a model of nucleoside analog reverse transcriptase inhibitor-induced painful peripheral neuropathy in the rat, using 2',3'-dideoxycytidine (ddC), 2',3'-dideoxyinosine (ddI) and 2',3'-didehydro-3'-deoxythymidine (d4T), AIDS chemotherapeutic drugs that are also components of AIDS highly active anti-retroviral therapy. Administration of ddC, ddI and d4T produced dose-dependent mechanical hypersensitivity and allodynia. Peripheral administration of inhibitors of protein kinase A, protein kinase C, protein kinase G, p42/p44-mitogen-activated protein kinase (ERK1/2) and nitric oxide synthase, which have demonstrated anti-hyperalgesic effects in other models of metabolic and toxic painful peripheral neuropathies, had no effect on ddC-, ddI- and d4T-induced hypersensitivity. Since suramin, an anti-parasitic and anti-cancer drug, which shares with the anti-retroviral nucleoside analogs, mitochondrial toxicity, altered regulation of intracellular calcium, and a sensory neuropathy in humans, also produced mechanical hypersensitivity that was not sensitive to the above second messenger inhibitors we evaluated the role of intracellular calcium. Intradermal or spinal injection of intracellular calcium modulators (TMB-8 and Quin-2), which had no effect on nociception in control rats, significantly attenuated and together eliminated ddC and suramin-induced mechanical hypersensitivity. In electrophysiology experiments in ddC-treated rats, C-fibers demonstrated alterations in pattern of firing as indicated by changes in the distribution of interspike intervals to sustained suprathreshold stimuli without change in mechanical activation thresholds or in number of action potentials in response to threshold and suprathreshold stimulation. This study provides evidence for a novel, calcium-dependent, mechanism for neuropathic pain in a model of AIDS therapy-induced painful peripheral neuropathy.

Noxious stimuli inhibit inflammation by activating neuroendocrine stress axes, an effect that is potently attenuated by ongoing activity in subdiaphragmatic vagal afferents. Because this vagal afferent activity is carried in the coeliac and coeliac accessory branches of the subdiaphragmatic vagus, we tested the hypothesis that the activity arises from vagal afferents that innervate a proximal segment of the gastrointestinal tract. Surgical removal of the duodenum, but not the stomach, produces a marked (six orders of magnitude) leftward shift in the dose-response curve for intraplantar capsaicin-induced inhibition of synovial plasma extravasation induced by the potent inflammatory mediator bradykinin, in the knee joint; this is similar in magnitude to the inhibition produced by subdiaphragmatic or by coeliac plus coeliac accessory branch vagotomy. Fasting, to unload mechanically sensitive polymodal afferents in the proximal gastrointestinal tract, produces a similar leftward shift in the dose-response curve for the inhibitory effect of capsaicin, an effect that is reversed by balloon distension in the duodenum in fasted rats, while balloon distension postvagotomy had no effect. These results suggest that activation of mechanically sensitive vagal afferents in the duodenum contributes vagal afferent activity that modulates neuroendocrine control of the inflammatory response.

Ferredoxin, Fd, is often deficient in metronidazole-resistant strains of Trichomonas vaginalis and is thought to be necessary for drug activation. To directly test whether Fd is essential for metronidazole susceptibility, gene replacement technology has been developed for T. vaginalis. The selectable marker gene neomycin phosphotransferase (NEO) flanked by approximately 2.6 and approximately 2.0 kBp of the Fd 5' and 3' flanking regions (pKO-FD-NEO) was introduced into cells on linear DNA and selected for NEO gene expression. Stable transformants were shown to contain the NEO gene in the Fd locus and to have completely lost the Fd gene. Northern and immunoblot analyses confirm the loss of Fd mRNA and protein in pKO-FD-NEO cells. Analyses of the activity of hydrogenosomal proteins in Fd KO cells show a fourfold increase in hydrogenase activity and a 95% decrease in pyruvate/ferredoxin oxidoreductase (PFO) activity. In contrast, PFO and hydrogenase mRNA levels are unchanged. Surprisingly, Fd KO cells are not resistant to metronidazole under aerobic or anaerobic conditions. These cells are capable of producing molecular hydrogen, albeit at 50% the level of the parental strain, demonstrating that the Fd gene product eliminated in KO cells is neither necessary for hydrogen production nor metronidazole activation. Together these data indicate the presence of unidentified Fds or flavodoxins capable of drug activation or an unidentified mechanism that does not require either PFO or Fd for metronidazole activation.

OBJECTIVE

Two potential barriers to use of oral contraceptives (OCPs) are out-of-pocket expenditures and the inconvenience of monthly pharmacy visits. This study used nationally representative data to examine the out-of-pocket costs of OCPs and whether women obtain more than 1 pack per purchase.

METHODS

We used data from the 1996 Medical Expenditure Panel Survey. Dependent variables were out-of-pocket expenditures per pack and the number of packs obtained per purchase. Chi2 tests were used to examine the bivariate relationships between the dependent variables and covariates. Regression analyses were used to examine the predictors of OCP expenditures and the number of packs obtained per purchase.

RESULTS

Women paid an average of 14 dollars per pack of OCPs, and 73% obtained only 1 pack per purchase. On average, privately insured women paid 60% of the total expenditures for OCPs. Women who had no prescription drug coverage, who were uninsured, or who were privately insured but not in managed care plans had higher out-of-pocket expenditures. Women who were without prescription drug coverage or who were in managed care plans were more likely to obtain only 1 pack per purchase.

CONCLUSION

Out-of-pocket costs and dispensing restrictions may be barriers to consistent use of OCPs. Women's health care providers should consider options to overcome these barriers, such as the use of mail order prescription services.

OBJECTIVE

Buprenorphine and buprenorphine/naloxone combinations are effective pharmacotherapies for opioid dependence, but doses are considerably greater than analgesic doses. Because dose-related buprenorphine opioid agonist effects may plateau at higher doses, we evaluated the pharmacokinetics and pharmacodynamics of expected therapeutic doses.

DESIGN

The first experiment examined a range of sublingual buprenorphine solution doses with an ascending dose design (n = 12). The second experiment examined a range of doses of sublingual buprenorphine/naloxone tablets along with one dose of buprenorphine alone tablets with a balanced crossover design (n = 8).

PARTICIPANTS

Twenty nondependent, opioid-experienced volunteers.

METHODS

Subjects in the solution experiment received sublingual buprenorphine solution in single ascending doses of 4, 8, 16 and 32 mg. Subjects in the tablet experiment received sublingual tablets combining buprenorphine 4, 8 and 16 mg with naloxone at a 4 : 1 ratio or buprenorphine 16 mg alone, given as single doses. Plasma buprenorphine, norbuprenorphine and naloxone concentrations and pharmacodynamic effects were measured for 48-72 hours after administration.

RESULTS

Buprenorphine concentrations increased with dose, but not proportionally. Dose-adjusted areas under the concentration-time curve for buprenorphine 32 mg solution, buprenorphine 1 6 mg tablet and buprenorphine/naloxone 16/4 mg tablet were only 54 +/- 16%, 70 +/- 25% and 72 +/- 17%, respectively, of that of the 4 mg dose of sublingual solution or tablet. No differences were found between dose strengths for most subjective and physiological effects. Pupil constriction at 48 hours after administration of solution did, however, increase with dose. Subjects reported greater intoxication with the 32 mg solution dose, even though acceptability of the 4 mg dose was greatest. Naloxone did not change the bioavailability or effects of the buprenorphine 16 mg tablet.

CONCLUSION

Less than dose-proportional increases in plasma buprenorphine concentrations may contribute to the observed plateau for most pharmacodynamic effects as the dose is increased.

BACKGROUND

Agitation affects up to 70% of older people with dementia. Valproic acid has been used for the past 10 years to control agitation in dementia, but no systematic review of the effectiveness of this drug has been published to date. The current study examines three randomized, placebo-controlled trials of the effect of valproic acid on older people with dementia who were agitated.

OBJECTIVES

To determine whether evidence supports the use of valproic acid in the treatment of agitation of people with dementia.

SEARCH STRATEGY

Trials were identified from a last updated search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group on 10 July 2003 using the terms ("agitat*" or "distur*" or "behavi*" or "aggress*") and "valproic" or "valproate" or "divalpro*." This Register contains articles from all major health care databases and many ongoing trials databases and is regularly updated. The reviewers contacted the authors of publications and drug companies manufacturing valproic acid for additional information.

SELECTION CRITERIA

Randomized, placebo-controlled trials with concealed allocation where agitation and dementia of participants were assessed

DATA COLLECTION AND ANALYSIS

1. Two reviewers extracted data from published trials. 2. Odds ratios of average differences were calculated. 3. Only "intention to treat" analyses were included. 4. Analysis compared participants treated with valproic acid with controls.

MAIN RESULTS

Meta-analysis of the pooled results of the included trials could not be performed because of the following problems. In Porsteinsson 2001, although the physicians having direct responsibility for patient care were blinded, a non-blinded physician, who had no direct contact with these physicians, adjusted divalproex sodium dosage on the basis of reports from blinded raters. Therefore, because the physician who controlled therapy knew which patients were receiving divalproex, the trial did not satisfy the criterion of concealed allocation. In Tariot 2001, 54% of the treated patients dropped out compared with 29% of control patients. Of all treated patients, 22% dropped out because of adverse effects, and the study had to be discontinued prematurely. The third trial (Sival 2002) had a cross-over design. No results from the first phase of the study were available, and although the statistical section stated, "the t-test for independent samples is used to analyze the two-period cross-over trial", because the samples were not independent - they are the same patients in the treatment and placebo groups - a question must be raised about the correctness of the analyses. The type of valproate used in the trials varied - one used short-acting sodium valproate, one long-acting divalproex sodium, and the third early-onset acting divalproex sodium. Average doses differed (480mg/d - 1000mg/d), as did duration of therapy (3 wks - 6 wks), and ways of evaluating patients and their response to therapy. A limited meta-analysis, pooling the results concerning adverse effects (Porsteinsson 2001, Tariot 2001) revealed the following: Sedation occurred more frequently in patients treated with valproic acid than in controls Urinary tract infection was more common among patients treated with valproic acid than controls Because of differences in identifying adverse effects it was not possible to pool other observations concerning adverse effects between the two studies that were examined.

REVIEWERS' CONCLUSIONS

The trials reviewed should be regarded as preliminary. Individual reports suggest that low dose sodium valproate is ineffective in treating agitation among demented patients, and that high dose divalproex sodium is associated with an unacceptable rate of adverse effects. More research on the use of valproate preparations for agitation of people with dementia is needed. On the basis of current evidence, valproate preparations cannot be recommended for the treatment of agitation in dementia.

BACKGROUND

Nursing homes provide care for the elderly who require medical, nursing or rehabilitation services. Legislation for the public health model of mental health care for nursing home residents in the USA was enacted in 1987.

OBJECTIVE

To determine whether the USA act regulating psychiatric care for nursing homes may be applied in Israel.

METHODS

Publications analyzing the outcome of the USA regulations demonstrate improved care as reflected by decrease in restraints and better use of psychotropic compounds. The shortcomings as well as benefits of the USA legislation are tested as to their relevance to the specific economic, environmental and medical issues in Israel.

CONCLUSIONS

The adoption of USA legal acts regulating nursing home residents' psychiatric care may not be feasible in Israel. However, quality of care in nursing homes can be significantly improved if such regulations were "tailored" to Israel's unique structure of nursing homes.

The idiopathic interstitial pneumonias are a heterogeneous group of poorly understood diseases with often devastating consequences for those afflicted. Subclassification of the idiopathic interstitial pneumonia based on clinical-radiological-pathological criteria has highlighted important pathogenic, therapeutic and prognostic implications. The most critical distinction is the presence of usual interstitial pneumonia, the histopathological pattern seen in idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis has a worse response to therapy and prognosis. New insight into the pathophysiology of usual interstitial pneumonia suggests a distinctly fibroproliferative process, and antifibrotic therapies show promise. While the clinical and radiographic diagnosis of idiopathic interstitial pneumonias can be made confidently in some cases, many patients require surgical lung biopsy to determine their underlying histopathology. A structured, clinical-radiological-pathological approach to the diagnosis of the idiopathic interstitial pneumonias, with particular attention to the identification of idiopathic pulmonary fibrosis, insures proper therapy, enhances prognostication, and allows for further investigation of therapies aimed at distinct pathophysiology.