Asthma -- a need for a rethink?

Asthma is a major medical problem but, despite decades of research, the mechanisms that underlie this condition remain elusive. Although the eosinophil has been regarded as a cell that is central to the pathogenesis of asthma, the failure to abrogate asthma symptoms by novel treatments that are designed to suppress the recruitment of eosinophils to the airways challenges this dogma. Our approach to understanding bronchial asthma needs to be broadened to include alterations in the function of afferent nerves that supply airways. Changes in the activity of these nerves offer a possible mechanism by which asthmatic subjects are uniquely responsive to a wide range of physiological and chemical stimuli. Here, we review the current status of asthma research.     

Using a Serial Marker to Predict a Repeated Measures Outcome in a Cohort Design—Results of a Simulation Study

Abstract

Consider the cohort design and suppose that the outcome of primary interest is a continuous random variable observed repeatedly over time. Suppose that there is a second variable of clinical relevance which is also observed repeatedly. We are interested in assessing whether the “serial marker” is in some sense predictive of the primary outcome. We would also like to predict the trend for the primary outcome assuming that the clinical marker follows a profile of specific clinical interest. In series of earlier papers, we have addressed these issues by applying a bivariate repeated measures model. One regression model was prescribed to relate the primary outcome to important explanatory variables, while a second regression model was prescribed for the serial marker. In this paper, we perform a series of simulation studies to investigate the empirical properties of this approach. Bivariate repeated measures data were generated at random, and basic study parameters including the sample size, the number of time points, the degree of serial correlation within the clinical marker, and type of association between the serial marker and the primary outcome were varied. The ability of the methodology to capture the underlying relationship between the two set of repeated measures was assessed. The ability to predicting the primary outcome corresponding to a known marker profile of specific interest was examined.     

Acute hepatitis in a patient using a Chinese herbal tea ‐ a case report.

A case is presented of reversible acute hepatitis in a patient using a Chinese herbal tea. Upon identification of the tea mixture Aristolochia species, including A. debilis, which contains the highly toxic aristolochic acid, could be identified. We conclude that the acute hepatitis as described in this patient is most likely to be caused by (one of) the active ingredients of the Chinese herbal tea. Furthermore, this case illustrates that socalled natural products can cause unexpected severe adverse reactions.     

Oral bioavailability of phenobarbital: a comparison of a solution in myvacet 9‐08, a suspension, and a tablet

Purpose: A threeway crossover study with seven healthy male volunteers was conducted to determine the relative bioavailability of phenobarbital after single dose administration of 100 mg of phenobarbital as oral solution in Myvacet 908, and as a suspension, compared with a 100 mg phenobarbital tablet. Materials and methods: At 4week intervals each subject received the solution in Myvacet 908, the suspension and the tablet in randomized order. Blood samples were collected for 48 h after each dose for analysis of phenobarbital. From the individual serum concentrationversustime curves C _maxand T _max were determined and AUC₀₄₈ was calculated. Results: All three oral dosage forms of phenobarbital are bioequivalent. No significant diffences in T _maxwere observed. Conclusion: The oral solution in Myvacet 908, and the suspension of phenobarbital proved to be bioequivalent to a tablet.     

Good clinical practice: a nuisance,a help or a necessity for clinical pharmacology?

This article reviews the impact of good clinical practice (GCP) on clinical pharmacology with particular reference to the new European Union Clinical Trial Directive. The Directive will be applied to both commercial and noncommercial studies on medicinal products for human use. The Directive requires that GCP should be used in all clinical trials except noninterventional studies. GCP is likely to follow the International Conference on Harmonization GCP guidelines in many aspects. GCP will enforce tighter guidelines on ethical aspects of a clinical study. Higher standards will be required in terms of comprehensive documentation for the clinical protocol, record keeping, training, and facilities including computers. Quality assurance and inspections will ensure that these standards are achieved. The additional requirements of GCP are discussed and any advantage to the study subject. The impact of the new Directive within the Research Governance Framework of the UK Department of Health is reviewed.     

Bongkrekic Acid—a Review of a Lesser-Known Mitochondrial Toxin

Introduction

Bongkrekic acid (BA) has a unique mechanism of toxicity among the mitochondrial toxins: it inhibits adenine nucleotide translocase (ANT) rather than the electron transport chain. Bongkrekic acid is produced by the bacterium Burkholderia gladioli pathovar cocovenenans (B. cocovenenans) which has been implicated in outbreaks of food-borne illness involving coconut- and corn-based products in Indonesia and China. Our objective was to summarize what is known about the epidemiology, exposure sources, toxicokinetics, pathophysiology, clinical presentation, and diagnosis and treatment of human BA poisoning.

Methods

We searched MEDLINE (1946 to present), EMBASE (1947 to present), SCOPUS, The Indonesia Publication Index (http://id.portalgaruda.org/), ToxNet, book chapters, Google searches, Pro-MED alerts, and references from previously published journal articles. We identified a total of 109 references which were reviewed. Of those, 29 (26 %) had relevant information and were included. Bongkrekic acid is a heat-stable, highly unsaturated tricarboxylic fatty acid with a molecular weight of 486 kDa. Outbreaks have been reported from Indonesia, China, and more recently in Mozambique. Very little is known about the toxicokinetics of BA. Bongkrekic acid produces its toxic effects by inhibiting mitochondrial (ANT). ANT can also alter cellular apoptosis. Signs and symptoms in humans are similar to the clinical findings from other mitochondrial poisons, but they vary in severity and time course. Management of patients is symptomatic and supportive.

Conclusions

Bongkrekic acid is a mitochondrial ANT toxin and is reported primarily in outbreaks of food-borne poisoning involving coconut and corn. It should be considered in outbreaks of food-borne illness when signs and symptoms manifest involving the liver, brain, and kidneys and when coconut- or corn-based foods are implicated.

     

Could a structural damage mimic a Parkinson plus syndrome?

Corticobasal syndrome (CBS) is a progressive disease that includes a heterogeneous neuropathological spectrum. In the majority of cases, corticobasal degeneration (CBD) is the underlying disease. Clinical heterogeneity is reflected in the clinical presentation of the syndrome and consequently misdiagnosis is common. Our case is of interest because the symptoms, the poor response to L-dopa and the I123 Ioflupane CIT SPECT (DAT-SCAN) results were typical for CBD. However, the magnetic resonance imaging appearance suggested the possibility of a disease of vascular etiology. A 63-year-old woman presented in our outpatient clinic with symptoms of progressive clumsiness in the right arm when performing movements demanding fine motor skills, and mild speech difficulties. The brain magnetic resonance imaging (MRI) report described ischemic lesions in the left subcortical parietal areas, in the centrum semiovale, in periventricular white matter, cingulated gyrus bilaterally and moderate ventricle dilatation. A comprehensive neuropsychological study suggested mixed cortical and subcortical involvement. A DAT-SCAN examination showed a diminished dopamine transporter uptake in the left lenticular nucleus, suggesting parkinsonisn. For this patient, CBS-CBD was the most probable diagnosis, whereas vascular CBS was not excluded. This case report illustrates the low diagnostic sensitivity in predicting CBD and the overlap with other related neurodegenerative diseases. Finally, it demonstrates that in CBS, different underlying pathologies can be found at the same individual.     

How does a little acronym become a big transmitter?

After an overview of the early, chequered history of the discovery of GABA and its gradual acceptance as inhibitory synaptic transmitter in the brain, the article lists and discusses some of the more unexpected later developments in studies of GABA, especially its role as excitatory transmitter in the immature brain.     

Bimatoprost – a review

Bimatoprost is a synthetic prostamide analog that is efficacious in the treatment of open-angle glaucoma, ocular hypertension and other forms of glaucoma. It reduces intraocular pressure (IOP) by increasing uveoscleral and trabecular outflow. When used as a 0.03% topical preparation once daily, it demonstrates sustained lowering of IOP of 7 – 8 mmHg over a 24-h period. The drug has been found to be more effective than timolol. In some studies it has shown greater ability to lower IOP when compared with other prostaglandin analogs; whereas in others all three clinically used prostaglandin analogs were found to be equally effective. It shows good IOP reduction when used in combination with other glaucoma medications. A common side effect includes mild conjunctival hyperemia, which is generally reversible. Other side effects include periorbital pigmentation, discomfort, ocular surface hyperemia and skin changes. Pharmacoeconomic data indicate that bimatoprost is cost effective in the treatment of open-angle glaucoma.     

Constituents of Burasaïa madagascarensis: a new clerodane-type diterpene

From an ethanol extract of the stems of Burasa?a madagascarensis Thouars (Menispermaceae) were isolated N-acetylnornuciferine and two clerodane-type diterpenes, one of them, epicordatine, being new. The structures were established by the interpretation of the spectral data. All the described compounds exhibited weak antimalarial activity.     

Atypical antipsychotics and polydipsia: a cause or a treatment?

Primary polydipsia (PP) is a frequent complication that affects many chronic schizophrenic inpatients. Due to possible lethal consequences, for example, hyponatremia, coma and death, it's fundamental for the physician achieving early diagnosis and treating this condition. The first step is identifying polydipsia by clinical, biochemical and pharmacological means. Nowadays, the pathophysiology of PP remains unclear, and this limits the possibility of detecting an appropriate drug treatment. Typical antipsychotics have been associated to a worsening of polydipsic behavior, while more recently atypical antipsychotics have been reported as being useful. However results are still mixed and controversial. It appears that risperidone and olanzapine are not clearly effective; clozapine may improve symptoms, although it is difficult to manage from a therapeutic point of view; quetiapine has been poorly studied so far, nonetheless it has given interesting results. Through a case study analysis, this report presents a brief, yet selective, overview of the current state of psychopharmacology in the treatment of PP with atypical antipsychotics in schizophrenia.     

Donepezil in a chronic drug user—a potential treatment?

The objective of the current study was to explore the potential cognitive benefits of an anticholinesterase inhibitor, donepezil, in a former chronic drug user. A neuropsychological test battery composed of the vocabulary and matrix reasoning subtests of the Wechsler adult intelligence scale-III, measures of everyday executive functioning (behavioural assessment of the dysexecutive syndrome [BADS]), and verbal learning and memory tasks (California verbal learning test-II; Rivermead behavioural memory test) was completed at baseline, at 3 months after introducing donepezil, and at 3 months after donepezil was discontinued. After donepezil treatment, substantial improvements were found on tasks of nonverbal fluid reasoning (i.e. matrix reasoning) and other executive functioning tests (i.e. BADS). At entry into the study, poor academic performance and subjective problems with memory and concentration were reported, particularly after amphetamine use (i.e. MDMA and crystal methamphetamine); after donepezil treatment, dramatic increases in memory, concentration and academic achievement were observed. The finding of improvements in tests of executive functioning and in academic performance in this case study, together with the minimal adverse side effects of donepezil, warrants the investigation of controlled studies of cholinergic enhancement in chronic amphetamine and other drug users.