Interatrial Block in the Modern Era

Interatrial block (IAB; P-wave duration ≥ 110 ms), which represents a delay in the conduction between the atria, is a pandemic conduction abnormality that is frequently underappreciated in clinical practice. Despite its comprehensive documentation in the medical literature, it has still not received adequate attention and also not adequately described and discussed in most cardiology textbooks. IAB can be of varying degrees and classified based on the degree of P-duration and its morphology. It can transform into a higher degree block and can also manifest transiently. IAB may be a preceding or causative risk factor for various atrial arrhythmias (esp. atrial fibrillation) and also be associated with various other clinical abnormalities ranging from left atrial dilation and thromboembolism including embolic stroke and mesenteric ischemia. IAB certainly deserves more attention and prospective studies are needed to formulate a standard consensus regarding appropriate management strategies.     

Formulation studies and in vivo evaluation of a flurbiprofen-hydroxypropyl beta-cyclodextrin system

The purpose of this study was 1) to investigate in vivo advantages of a flurbiprofen (FPN)-hydroxypropyl beta-cyclodextrin (HPbetaCD) solid dispersion (SD) in rats, 2) to study factors affecting the drug release from SD formulations, and 3) to evaluate the pharmacokinetic profile of the drug when administered as SD, in humans. The solubility of FPN in water and dissolution media was evaluated as a function of HPbetaCD concentration. The SD was prepared by coevaporation from dilute aqueous NH3 and evaluated in rats. The release of the drug from tablet formulations and capsules of SD was studied in simulated gastric fluid and phosphate buffer, pH 7.2. The bioavailability of drug when administered as SD was evaluated in humans. HPbetaCD enhanced the solubility of the drug, and SD improved bioavailability and reduced ulcerogenicity of the drug in rats. The type of excipient used affected drug release from tablets. Presence of microcrystalline cellulose, a hydrophilic polymeric excipient, resulted in uptake of water and stabilization of the resulting gels-like structure of HPbetaCD-containing tablets. This adversely affected drug release. The release from capsules filled with SD was comparable to that obtained from plain SD powder. The drug-HPbetaCD association constant in water was much lower than the values reported in literature. The bioavailability (which could suffer in case of higher association constant) was enhanced on administration of SD-filled capsules to humans.     

Solid dispersion of hydroxypropyl beta-cyclodextrin and ketorolac: enhancement of in-vitro dissolution rates, improvement in anti-inflammatory activity and reduction in ulcerogenicity in rats

Ketorolac, is a non-steroidal anti-inflammatory drug, with strong analgesic activity. It is practically insoluble in water and has been implicated in causing gastrointestinal ulceration. This study describes the formulation of solid dispersions of ketorolac using hydroxypropyl beta-cyclodextrin (HPbeta-CyD) and beta-cyclodextin (beta-CyD) as carriers, to improve the aqueous solubility of the drug, thus enhancing its bioavailability. Also, reduction in ulcerogenicity was anticipated. Differential scanning calorimetry and X-ray diffraction studies indicated loss of crystalline nature of the drug, in the dispersions prepared with HPbeta-CyD. NMR studies revealed a strong interaction between drug and HPbeta-CyD. Solid dispersions of drug with beta-CyD retained the crystalline nature of the drug. All the solid dispersions showed a remarkable improvement in the rate and extent of dissolution of ketorolac. The kneaded dispersion with HPbeta-CyD prepared using a 1:1 alcohol-water mixture showed promise in reducing the ulcer-inducing effect of ketorolac in rats. Oral administration of this dispersion was found to inhibit carrageenan-induced paw oedema in rats to a significantly greater extent compared with ketorolac or its trometamol salt. Though beta-CyD as a carrier for ketorolac gave faster release of the poorly soluble drug, HPbeta-CyD proved to be superior to beta-CyD, as a carrier in the kneaded dispersion prepared using 1:1 alcohol-water mixture. These results suggest that solid dispersions of ketorolac with HPbeta-CyD aid in faster dissolution and better bioavailability of the drug. The higher solubility of the drug in the presence of HPbeta-CyD also reduces local gastrointestinal side-effects of the drug.     

Sequencing of the pncA gene in members of the Mycobacterium tuberculosis complex has important diagnostic applications: Identification of a species-specific pncA mutation in "Mycobacterium canettii" and the reliable and rapid predictor of pyrazinamide resistance

Testing for susceptibility to pyrazinamide (PZA) and analysis of the pncA gene sequences of 423 Mycobacterium tuberculosis complex isolates have revealed a unique silent nucleotide substitution that enables the rapid identification of "M. canettii" (proposed name). Moreover, the lack of a defined mutation within the pncA gene strongly suggests that an alternative mechanism is responsible for PZA resistance. Our results indicate that DNA sequencing of the pncA gene has the potential to shorten the turnaround time and increase the accuracy of PZA susceptibility testing of the M. tuberculosis complex.     

Insights Into the Dehydration Behavior of Thiamine Hydrochloride (vitamin B1) Hydrates: Part II

Thiamine hydrochloride (THCl) can exist as an anhydrate (AH) and as a hemihydrate (HH). AH sorbs water as a function of environmental water vapor pressure to form a nonstoichiometric hydrate (NSH). NSH dehydration is initiated at ～40°C to yield AH, an isomorphic desolvate (ID) of NSH (Chakravaty et al., 2009, J Pharm Sci). Upon heating, dehydration of HH occurs only at elevated temperatures (>120°C) and is accompanied by chemical decomposition. When heated at reduced temperature (60–90°C) and pressure (20–760 mTorr), HH was incompletely dehydrated with partial loss of long‐range lattice order. Complete dehydration of HH to AH was achieved through a solvent‐mediated transformation in ethanol. The crystal structures of NSH and HH exhibit pronounced differences in the hydrogen bonding of water. The dehydration mechanism of NSH and HH can be explained by the “continuous and unified” dehydration model.¹⁰. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1882–1895, 2010     

Design, optimization and evaluation of domperidone coevaporates.

Coevaporates of domperidone were prepared using different polymers by solvent evaporation technique. Ethyl cellulose and hydroxypropyl methylcellulose phthalate were used in preparation of coevaporates. The coevaporates were characterized by X-ray diffraction studies, IR spectrophotometry and differential scanning calorimetry. The dissolution behavior of coevaporates was studied using buffer solution of pH 1.2 for the first 2 h and that of pH 6.8 thereafter up to 12 h. A two-factor, three-level design was used to quantitate the effect of polymers on dissolution profile of domperidone. The drug release rate was found to be dependent on the concentration of polymers in the coevaporates. Dissolution of drug in a pH 6.8 buffer improved with increasing concentration of hydroxypropyl methylcellulose phthalate in coevaporates. Bioavailability studies in human volunteers confirmed that domperidone coevaporates sustained drug release.     

Phase transformation in thiamine hydrochloride tablets: Influence on tablet microstructure, physical properties, and performance

The objective of this article was to monitor phase transformation in thiamine hydrochloride, from a nonstoichiometric hydrate (NSH) to a hemihydrate (HH), in stored tablets, prepared both by direct compression and wet granulation, and to relate the storage-induced phase transformation with changes in tablet microstructure, physical properties, and performance. Raman spectroscopy revealed complete NSH → HH transformation in tablets, within 30 h of storage at 40°C/75% relative humidity. When the tablets were prepared by wet granulation of NSH alone, there was a marked increase in both tablet volume and hardness on storage. However, when microcrystalline cellulose (MCC) was included in granulation, the resulting stored tablets also exhibited a pronounced increase in disintegration time. In contrast, tablets prepared by dry processing via compression of a NSH-MCC physical mixture did not exhibit any changes in properties, despite the in situ solid form conversion. Scanning electron microscopy revealed growth of needle-like HH crystals in all stored tablets and mercury porosimetry revealed considerable changes in the pore size distribution during storage. Longer storage led to crystal growth (Ostwald ripening), causing further gradual but less dramatic changes in properties. The phase transformation and the complex interparticulate associations in the tablet influenced the changes in tablet microstructure, compact physical properties, and product behavior.     

Canon CP-TX1 camera – As a screening tool for amblyogenic risk factors

Purpose:To evaluate the Canon CP-TX1 camera as a screening tool for ARFs in a pediatric population and estimate the prevalence of ARFs.Methods:In a pediatric outpatient space, largely in the immunization clinic, after obtaining parental consent, we encouraged children to be photographed from a distance of 5 feet in a dim room by using a CP-TX1 camera with the red-eye reduction feature off. Based on the captured red reflex, children were labeled as normal (symmetrical red reflexes in the two eyes, with no visible crescents); all others were considered as abnormal or positive for ARFs. All photographed children were assessed by an optometrist/refractionist for VA by age-appropriate methods. Data were entered into a 2 × 2 contingency table on statpages.org, and diagnostic indices were calculated with 95%CI.Results:With a sample of 262 children, we obtained a sensitivity of 0.82, a specificity of 0.98, a positive predictive value of 0.92, a negative predictive value of 0.94, a positive likelihood ratio of 41.06, a negative likelihood ratio of 0.17, and a prevalence of 0.24 for ARFsConclusion:CP-TX1 performed well as a screening tool to identify ARFs in children. Placing such a camera in an immunization clinic offers a chance to identify children with ARFs at a time when amblyopia is eminently reversible.     

Pseudo-Outbreak of Pre-Extensively Drug-Resistant (Pre-XDR) Tuberculosis in Kinshasa: Collateral Damage Caused by False Detection of Fluoroquinolone Resistance by GenoType MTBDRsl

Fluoroquinolones are the core drugs for the management of multidrug-resistant tuberculosis (MDR-TB). Molecular drug susceptibility testing methods provide considerable advantages for scaling up programmatic management and surveillance of drug-resistant TB. We describe here the misidentification of fluoroquinolone resistance by the GenoType MTBDRsl (MTBDRsl) (Hain Lifescience GmbH, Nehren, Germany) line probe assay (LPA) encountered during a feasibility and validation study for the introduction of this rapid drug susceptibility test in Kinshasa, Democratic Republic of Congo. The double gyrA mutation 80Ala and 90Gly represented 57% of all fluoroquinolone mutations identified from MDR-TB patient sputum samples, as confirmed by DNA sequencing. This double mutation was previously found to be associated with susceptibility to fluoroquinolones, yet it leads to absent hybridization of a wild-type band in the MTBDRsl and is thus falsely scored as resistance. Our findings suggest that MTBDRsl results must be interpreted with caution when the interpretation is based solely on the absence of a wild-type band without confirmation by visualization of a mutant band. Performance of the MTBDRsl LPA might be improved by replacing the gyrA wild-type probes by additional probes specific for well-documented gyrA mutations that confer clinically relevant resistance.