Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis.

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.

Perceptions of immunization information systems for collecting pandemic H1N1 immunization data within Canada's public health community: a qualitative study.

BACKGROUND: Immunization information systems (IISs) are electronic registries used to monitor individual vaccination status and assess vaccine coverage. IISs are currently not widely used across Canada, where health jurisdictions employ a range of approaches to capture influenza immunization information. Conducted in advance of the 2009 H1N1 vaccination campaign, the objectives of this study were to understand the perceived value of individual-level data and IISs for influenza control, identify ideal system functions, and explore barriers to implementation. METHODS: In July and August 2009, semi-structured interviews were conducted with key informants engaged in vaccine delivery and/or pandemic planning at regional, provincial/territorial and federal levels across Canada. Key informants were recruited using a combination of convenience and snowball sampling methodologies. Qualitative analysis was used to extract themes from interview content. RESULTS: Patient management, assessment of vaccine coverage, and evaluation of safety and effectiveness were identified as public health priorities that would be achieved in a more timely manner, and with greater accuracy, through the use of an IIS. Features described as ideal included system flexibility, rapid data entry, and universality. Financial and human resource constraints as well as coordination between immunization providers were expressed as barriers to implementation. CONCLUSIONS: IISs were perceived as valuable by key informants for strengthening management capacity and improving evaluation of both seasonal and pandemic influenza vaccination campaigns. However, certain implementation restrictions may need to be overcome for these benefits to be achieved.

Palliative care nursing: ensuring competent care at the end of life.

Major advances in enabling function and symptom management have occurred in the past decade. Older adults who would have been bed-bound at the end of life now can be offered interventions to help them live well until they die. People who once would have suffered from pain can expect to be kept comfortable with aggressive symptom management. Palliative care nursing is the art and science of quality end-of-life care. Appropriate interventions for competent palliative care often are not initiated for dying older adults and their families. Nursing professionals are beginning to assume leadership roles to ensure that comprehensive, holistic end-of-life care is available to all patients and families experiencing life-threatening progressive illnesses.

A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis.

Mycobacterium tuberculosis, which causes tuberculosis, is the greatest single infectious cause of mortality worldwide, killing roughly two million people annually. Estimates indicate that one-third of the world population is infected with latent M. tuberculosis. The synergy between tuberculosis and the AIDS epidemic, and the surge of multidrug-resistant clinical isolates of M. tuberculosis have reaffirmed tuberculosis as a primary public health threat. However, new antitubercular drugs with new mechanisms of action have not been developed in over thirty years. Here we report a series of compounds containing a nitroimidazopyran nucleus that possess antitubercular activity. After activation by a mechanism dependent on M. tuberculosis F420 cofactor, nitroimidazopyrans inhibited the synthesis of protein and cell wall lipid. In contrast to current antitubercular drugs, nitroimidazopyrans exhibited bactericidal activity against both replicating and static M. tuberculosis. Lead compound PA-824 showed potent bactericidal activity against multidrugresistant M. tuberculosis and promising oral activity in animal infection models. We conclude that nitroimidazopyrans offer the practical qualities of a small molecule with the potential for the treatment of tuberculosis.

Management of protease inhibitor-associated diarrhea.

Diarrhea is a common and often inadequately treated complication in patients with human immunodeficiency virus infection. Diarrhea has a significant impact on quality of life (QOL) and can contribute to malnutrition, weight loss, immunosuppression, and mortality. In addition, diarrhea may have a significant impact on compliance with antiretroviral therapy; however, this impact has not been adequately assessed. Medications, including protease inhibitors (PIs), are recognized as a common cause of diarrhea. Treatment of PI-associated diarrhea is largely nonspecific; most of the available literature is published only in abstract form and is based primarily on retrospective and survey data. Agents for which some efficacy has been shown for treatment of PI-associated diarrhea include oat bran, psyllium, loperamide, calcium carbonate, SP-303, and pancrelipase. Practitioners and patients need to work together to determine which treatment modality is appropriate based on efficacy, cost, and lifestyle. Management of diarrhea is crucial to improving QOL, controlling weight loss, and enhancing overall efficacy of antiretroviral therapy.

Time-lapsed confocal microscopy reveals temporal and spatial expression of the lysine epsilon-aminotransferase gene in Streptomyces clavuligerus.

To investigate the temporal and spatial expression patterns of the gene (lat ) encoding lysine epsilon-aminotransferase (LAT) for cephamycin C biosynthesis, a mutant form of green fluorescent protein (mut1GFP) was integrated into the Streptomyces clavuligerus chromosome (strain LH369), resulting in a translational fusion with lat. LAT activity and fluorescence profiles of the recombinant protein paralleled the native LAT enzyme activity profile in wild-type S. clavuligerus, which peaked during exponential growth phase and decreased slowly towards stationary phase. These results indicate that the LAT-Mut1GFP fusion protein retains both LAT and GFP functionality in S. clavuligerus LH369. LH369 produced wild-type levels of cephamycin C in minimal medium culture conditions supplemented with lysine. Time-lapsed confocal microscopy of the S. clavuligerus LH369 strain revealed the temporal and spatial characteristics of lat gene expression and demonstrated that physiological development of S. clavuligerus colonies leading to cephamycin C biosynthesis is limited to the substrate mycelia.

[The mechanism of the action of opiate receptor antagonists in acute shock-induced blood loss]. / K mekhanizmu deistviia antagonistov opiatnykh retseptorov pri ostroi shokogennoi krovopotere.

Experiments on 81 rabbits showed that intravenous infusion of naloxone and nalorphine in different periods of hemorrhagic shock promoted the death of animals. It is concluded that in hypoxia only the antagonistic activity of the drugs is manifested as total inactivation of the endogenous opioid system depriving it of its protective functions. Nalorphine infused after blood reinfusion exhibits agonistic activity and additional activation of the endogenous opioid system promotes the use of the biological reserves by the organism, which saves some of the animals from death or essentially prolongs the survival of the others. Infusion of naloxone after blood transfusion has no effect on the outcome.

Spectral analysis of a thalamus-to-cortex seizure pathway.

Physiological evidence has shown that the anterior thalamus (AN) and its associated efferents/afferents constitute an important propagation pathway for one animal model of generalized tonic-clonic epileptic seizures. In this study we extend and confirm the support for AN's role by examining neuroelectric signal indicators during seizure episodes. We show that the electroencephalogram (EEG) recorded from AN is highly coherent with the EEG derived from the cortex (CTX). By removing the effects of another thalamic nucleus, posterior thalamus (PT)-unaffiliated with the tract linking AN to cortex-partial coherence analysis leaves the CTX/AN coherence undiminished. The most robust band of strong CTX-AN coherence is centered around the spike-wave pacing frequency of 1-3 Hz. Partial-multiple coherence analysis techniques are used to remove the possible signal contribution from hippocampus in addition to PT. The CTX-AN coherence still remains undiminished in the low-frequency bands. Conclusive evidence from coherence studies and other spectral measures reaffirm the special role of the AN in the propagation of seizure activity from subcortex to cortex.

Death of a newborn: healing the pain through Carper's patterns of knowing in nursing.

This article will explain how a nurse's holistic integration of empirical, esthetic, ethical and personal knowledge, as described by Carper's (1978) patterns of knowing in nursing", guided her teaching and nursing practice and helped a couple heal the pain of their newborn's death.

Nurses' willingness to care for AIDS patients and spirituality, social support, and death anxiety.

OBJECTIVE: Use Rogers' (1992) framework of the science of unitary human beings to examine relationships among spirituality, perceived social support, death anxiety, and nurses' willingness to care for AIDS patients. DESIGN: Descriptive, correlational. POPULATION, SAMPLE, SETTING: Population, female RNs in the New York City Metropolitan area who care for patients with AIDS. Convenience sample of 220 RNs who worked in eight hospitals either on AIDS-dedicated units (n = 88), or medical-surgical scatterbed units (n = 132) with a daily AIDS patient census of between 5% to 50%. Data were collected in 1992. MEASURES: Spiritual Orientation Inventory, the Personal Resource Questionnaire-85, the Templer Death Anxiety Scale, and the Willingness to Care for AIDS Patients Instrument. METHODS: Pearson product-moment correlations and hierarchical multiple regression analyses to test hypotheses. FINDINGS: Willingness to care for AIDS patients was positively correlated with spirituality and perceived social support, and negatively correlated with death anxiety. Death anxiety moderated the relationship between spirituality and willingness to care. In total, 17% of the variance in nurses' willingness to care for AIDS patients was explained. Additional regression analyses indicated that group membership as either an AIDS-dedicated nurse or medical-surgical nurse did not moderate or change hypothesized relationships. CONCLUSION: Because group membership explained 22% of the variance in willingness to care, the data indicate that group culture or professional identity should be further examined as predictors of nurses' willingness to care for AIDS patients. CLINICAL IMPLICATIONS: Social support at work from administrators and colleagues, as well as the support from patients themselves is important to nurses and should be fostered.

The vitamin D receptor interacts with general transcription factor IIB.

The vitamin D receptor (VDR) heterodimerizes with retinoid X receptors (RXR) on many vitamin D-responsive promoter elements, suggesting that this complex is the active factor in vitamin D-mediated transcription. However, the mechanism of transcriptional regulation following VDR-RXR binding to DNA is not well characterized. Using a yeast two-hybrid protein interaction assay, we demonstrate that VDR forms specific protein: protein contacts with the basal transcription factor TFIIB. Deletion analysis indicated that the carboxyl-terminal ligand binding domain of VDR interacted with a 43-residue amino-terminal domain in TFIIB. The interaction with TFIIB showed selectivity for the ligand binding domain of VDR as similar regions of RXR alpha or of retinoic acid receptor alpha did not couple with TFIIB. Binding assays with purified proteins showed a direct interaction between VDR and TFIIB in vitro. These data suggest a mechanism for VDR-dependent transcription in which protein contacts between VDR and TFIIB may impart regulatory information to the transcription preinitiation complex.

[Stimulating and hypobiotic therapy in cardiogenic shock]. / Stimuliruiushchaia i gipobioticheskaia terapiia pri kardiogennom shoke.

Comparative evaluation of the efficacy of stimulating and hypobiotic agents in 122 dogs with experimentally induced cardiogenic shock and 56 patients with acute myocardial infarction complicated by cardiogenic shock allowed a relationship to be established of the efficiency of therapeutic measures to the phase and rate of progression of the pathological process. In rapid progression of clinical symptoms of cardiogenic shock it is predominantly preparations of hypobiotic action that are to be prescribed whereas in slow progression of these it is advisable to use agents of stimulating action.

[The reinfusion of blood and the administration of dalargin in experimental hemorrhagic shock]. / Reinfuziia krovi i vnutrivennoe vvedenie dalargina pri éksperimental'nom gemorragicheskom shoke.

In acute experiment on 95 adult rabbits it was determined that during the subdivided blood exfusion from femoral artery in the volume of (16 + 1) ml/kg the reversible hemorrhagic shock occurs and the animals survive without the hemorrhage compensation. The increase of hemorrhage volume up to (23 + 3) ml/kg leads to lethal hemorrhagic shock. The heparinized blood reinfusion in the early period promotes the survival of the whole of animals, in the late period it promotes trustworthy their life span increase. Under the influence of dalargin intravenous infusion in the dose of 0.1 mg/kg after the blood reinfusion in the late period of shock all the animals survived. Intravenous infusion of dalargin is expedient for the increase of the transfusion therapy effectiveness in the late period of hemorrhagic shock.

Unraveling the tapestry of life. Can we mend our earth?

PIP: The industrial revolution has reached its most significant turning point. For the 1st time in its history the limiting factor in its growth has not been our ability to utilize resources, but rather a lack of the resources themselves. At the same time the largest problem to ever face our species, the loss of biodiversity, is threatening our own survival. Clearly we can not support our current numbers under the current consumptive system. All our food is provided by wild species that have been genetically manipulated to serve our ends. Of the 80,000 known edible plant species only about 200 are cultivated regularly and only 3 (corn, wheat, rice) function as staples. Many of our industrial resources come from natural sources. 40% of our pharmaceuticals come from wild sources. It is impossible to isolate ourselves from the Earth ecosystem. Soil microorganisms are but one example of our dependence upon nature. The rainforests also serve as our planets lungs, without them we will choke to death. Yet we continue to destroy them at an alarming rate. They account for only 7% of our land area, and they have already shrunk some 40%. In purely economic terms the wholesale destruction of the rainforests is bad business: in rubber and fruit, 2.5 acres of rainforest is worth $9000 annually compared to cow pasture ($2500) and logging ($1000). Of course with fruit and rubber the rainforest remains sustainable while cow pasture and logging mean the destruction of the rainforest.^ieng

Ovine fetal breathing and swallowing activity in response to plasma glucose changes.

Fetal swallowing activity generally occurs simultaneously with fetal breathing movements (FBM) in sheep. The present study investigated the FBM and swallowing responses to altered fetal plasma glucose. Fetal lambs were chronically prepared with laryngeal, esophageal and diaphragm electromyogram (EMG) wires, an esophageal flow probe and vascular catheters. Beginning at 138 +/- 1 day, FBM and swallowing were monitored during control periods and in response to intravenous glucose infusions (14 mg/kg/min for 120 min) to fetuses of fed and fasted ewes. Glucose infusions to fetuses of fed ewes resulted in significant increases in fetal plasma glucose (21.2 +/- 0.7 to 40.5 +/- 1.9 mg/dl) and time breathing (46.2 +/- 6.3 to 60.0 +/- 9.5 min/2 h). In response to maternal fasting, fetal glucose levels (13.4 +/- 1.0 mg/dl) and time breathing (23.0 +/- 7.2 min/2 h) decreased significantly. Glucose infusion to fetuses of fasted ewes resulted in significant increases in time breathing (50.3 +/- 13.4 min/2 h) and diaphragmatic EMG activity (1,295 +/- 654 to 3,012 +/- 1,182 spikes/2 h). There was no change from basal levels of fetal EMG swallows (83.2 +/- 4.3 swallows/2 h) or esophageal flow (40.8 +/- 7.9 ml/2 h) in response to maternal fasting or fetal glucose infusions.

[The mechanism of action of opiate antagonists in experimental traumatic shock]. / K mekhanizmu deistviia antagonistov opiatov pri éksperimental'nom travmaticheskom shoke.

Acute experiments on 86 adult rabbits have shown that in the early period of Cannon's traumatic shock nalophine and naloxone relieve torpidity, restore motor activity and responses to standard stimuli. This prolongs the animal life (nalorphine) and increases the survivability (naloxone). However in some rabbits a premature relief of torpidity (0.5 mg/kg of nalorphine) precipitates the animal death. It is concluded that in the late period the drugs exert no effect on the shock outcome and that inactivation of opioid suppression system can either trigger the mechanism of shock withdrawal or promote a reduction of its severity.

Magnesium sulfate suppresses electroencephalographic manifestations of CNS oxygen toxicity.

We studied the effects of parenteral magnesium sulfate (MgSO4) administration on electroencephalographic seizures induced by hyperbaric oxygen (HBO) in awake rats. Sixteen rats chronically implanted with electrocorticographic electrodes were preinjected i.p. with either vehicle or 3 mmol/kg MgSO4 (the latter resulted in serum levels of 3.5-5.5 mmol/liter) and then exposed to 6 ATA O2 in a pressure chamber. The time to develop an electric ichtal seizure was measured and compared to that in the same animal receiving the alternate treatment 3 days later. Mean and median times after the magnesium treatment were almost double those of vehicle administration. A central anticonvulsive action of magnesium, which should be investigated over the entire HBO range, is indicated.