Effect of Counterion on the Solid State Photodegradation Behavior of Prazosin Salts

The effect of counterion was evaluated on the photodegradation behavior of six prazosin salts, viz., prazosin hydrochloride anhydrous, prazosin hydrochloride polyhydrate, prazosin tosylate anhydrous, prazosin tosylate monohydrate, prazosin oxalate dihydrate, and prazosin camsylate anhydrous. The salts were subjected to UV–Visible irradiation in a photostability test chamber for 10 days. The samples were analyzed for chemical changes by a specific stability-indicating high-performance liquid chromatography method. pH of the microenvironment was determined in 10% w/v aqueous slurry of the salts. The observed order of photostability was: prazosin hydrochloride anhydrous > prazosin camsylate anhydrous ∼ prazosin-free base > prazosin hydrochloride polyhydrate > prazosin tosylate anhydrous > prazosin oxalate dihydrate ∼ prazosin tosylate monohydrate. Multivariate analysis of the photodegradation behavior suggested predominant contribution of the state of hydration and also intrinsic photosensitivity of the counterion. Overall, hydrated salts showed higher photodegradation compared to their anhydrous counterparts. Within the anhydrous salts, aromatic and carbonyl counterion-containing salts showed higher susceptibility to light. The pH of microenvironment furthermore contributed to photodegradation of prazosin salts, especially for drug counterions with inherent higher pH. The study reveals importance of selection of a suitable drug salt form for photosensitive drugs during preformulation stage of drug development.     

Development and Clinical Evaluation of Clotrimazole–β-Cyclodextrin Eyedrops for the Treatment of Fungal Keratitis

Fungal keratitis is a serious corneal disease that may result in loss of vision. There are limited treatment options available in Iraqi eye hospitals which might be the main reason behind the poor prognosis of many cases. The purpose of this study was to prepare and pharmaceutically evaluate clotrimazole–β-cyclodextrin (CTZ–β-CD) eyedrops then clinically assess its therapeutic efficacy on fungal keratitis compared with extemporaneous amphotericin B eyedrops (0.5% w/v). A CTZ–β-CD ophthalmic solution was prepared and evaluated by various physicochemical, microbiological, and biological tests. The prepared formula was stable in 0.05 M phosphate buffer pH 7.0 at 40 ± 2°C and 75 ± 5% RH for a period of 6 months. Light has no significant effect on the formula’s stability. The CTZ–β-CD eyedrops efficiently complied with the isotonicity, sterility, and antimicrobiological preservative effectiveness tests. Results of the clinical study revealed that 20 (80%) patients showed a favorable response to the CTZ–β-CD eyedrops, while 16 patients (64%) exhibited a favorable response to amphotericin B (P > 0.05). The mean course of treatment was significantly (P < 0.05) less in the CTZ treatment group than in the amphotericin group (21.5 ± 5.2 vs. 28.3 ± 6.4 days, respectively). The CTZ formulation was significantly (P < 0.05) more effective in the management of severe cases and also against Candida sp. than amphotericin B. There was no significant difference (P < 0.05) between both therapies against filamentous fungi. The CTZ–β-CD formulation can be used alternatively to other ophthalmic antimycotic treatment options in developing countries where stability, cost, or efficacy is a limiting factor.Key words: clotrimazole, β-cyclodextrin, eyedrops, fungal keratitis, Iraq     

Simple Chromatographic Method for Simultaneous Analyses of Phosphatidylcholine, Lysophosphatidylcholine, and Free Fatty Acids

This study describes a simple chromatographic method for the simultaneous analyses of phosphatidylcholine (PC) and its hydrolytic degradation products: lysophosphatidylcholine (LPC) and free fatty acids (FFA). Quantitative determination of PC, LPC, and FFA is essential in order to assure safety and to accurately assess the shelf life of phospholipid-containing products. A single-run normal-phase high-performance liquid chromatography (HPLC) with evaporative light scattering detector has been developed. The method utilizes an Allsphere silica analytical column and a gradient elution with mobile phases consisting of chloroform: chloroform–methanol (70:30%, v/v) and chloroform–methanol–water–ammonia (45:45:9.5:0.5%, v/v/v/v). The method adequately resolves PC, LPC, and FFA within a run time of 25 min. The quantitative analysis of PC and LPC has been achieved with external standard method. The free fatty acids were analyzed as a group using linoleic acid as representative standard. Linear calibration curves were obtained for PC (1.64–16.3 μg, r² = 0.9991) and LPC (0.6–5.0 μg, r² = 0.9966), while a logarithmic calibration curve was obtained for linoleic acid (1.1–5.8 μg, r² = 0.9967). The detection and quantification limits of LPC and FFA were 0.04 and 0.1 μg, respectively. As a means of validating the applicability of the assay to pharmaceutical products, PC liposome was subjected to alkaline hydrolytic degradation. Quantitative HPLC analysis showed that 97% of the total mass balance for PC could be accounted for in liposome formulation. The overall results show that the HPLC method could be a useful tool for chromatographic analysis, stability studies, and formulation characterization of phospholipid-based pharmaceuticals.KEY WORDS: evaporative light scattering detection, free fatty acid, lysophosphatidylcholine, phosphatidylcholine     

Miconazole Nitrate Oral Disintegrating Tablets: In Vivo Performance and Stability Study

The interest in and need for formulating miconazole nitrate (MN), a broad-spectrum antifungal, as an oral disintegrating tablet for treatment of some forms of candidiasis have increased. Formulation of MN in this dosage form will be more advantageous, producing dual effect: local in the buccal cavity and systemic with rapid absorption. Four formulations were prepared utilizing the foam granulation technique. The prepared tablets were characterized by measuring the weight uniformity, thickness, tensile strength, friability, and drug content. In addition, tablet disintegration time, in vitro dissolution, and in vivo disintegration time were also evaluated. Stability testing for the prepared tablets under stress and accelerated conditions in two different packs were investigated. Each pack was incubated at two different elevated temperature and relative humidity (RH), namely 40 ± 2°C/75 ± 5% RH and 50 ± 2°C/75 ± 5% RH. The purpose of the study is to monitor any degradation reactions which will help to predict the shelf life of the product under the defined storage conditions. Finally, in vivo study was performed on the most stable formula to determine its pharmacokinetic parameters. The results revealed that all the prepared tablets showed acceptable tablet characteristics and were stable under the tested conditions. The most stable formula was that containing magnesium stearate as lubricant, hydrophobic Aerosil R972 as glidant, low urea content, mannitol/microcrystalline cellulose ratio 2:1, and 9% Plasdone XL100 as superdisintegrant. The in vivo results revealed that the tested formula showed rapid absorption compared to the physical blend (t_max were 1 and 4 h, respectively), while the extent of absorption was almost the same.KEY WORDS: accelerated stability testing, bioavailability, foam granulation technique, miconazole nitrate, oral disintegrating tablet     

Temperature sensitivity of the low-moisture-content limit to negative seed longevity--moisture content relationships in hermetic storage

• Background and Aims The negative logarithmic relationship between orthodox seed longevity and moisture content in hermetic storage is subject to a low-moisture-content limit (m_c), but is m_c affected by temperature?• Methods Red clover (Trifolium pratense) and alfalfa (Medicago sativa) seeds were stored hermetically at 12 moisture contents (2–15 %) and five temperatures (–20, 30, 40, 50 and 65 °C) for up to 14·5 years, and loss in viability was estimated.• Key Results Viability did not change during 14·5 years hermetic storage at −20 °C with moisture contents from 2·2 to 14·9 % for red clover, or 2·0 to 12·0 % for alfalfa. Negative logarithmic relationships between longevity and moisture contents >m_c were detected at 30–65 °C, with discontinuities at low moisture contents; m_c varied between 4·0 and 5·4 % (red clover) or 4·2 and 5·5 % (alfalfa), depending upon storage temperature. Within the ranges investigated, a reduction in moisture content below m_c at any one temperature had no effect on longevity. Estimates of m_c were greater the cooler the temperature, the relationship (P < 0·01) being curvilinear. Above m_c, the estimates of C_H and C_Q (i.e. the temperature term of the seed viability equation) did not differ (P > 0·10) between species, whereas those of K_E and C_W did (P < 0·001).• Conclusions The low-moisture-content limit to negative logarithmic relationships between seed longevity and moisture content in hermetic storage increased the cooler the storage temperature, by approx. 1·5 % over 35 °C (4·0–4·2 % at 65 °C to 5·4–5·5 % at 30–40 °C) in these species. Further reduction in moisture content was not damaging. The variation in m_c implies greater sensitivity of longevity to temperature above, compared with below, m_c. This was confirmed (P < 0·005).     

Moderate- and high-intensity exhaustive exercise in the heat induce a similar increase in monocyte Hsp72

This study examined the relationship between exhaustive exercise in the heat at moderate and high intensities on the intracellular heat shock protein 72 (iHsp72) response. Twelve male subjects cycled to exhaustion at 60 and 75 % of maximal oxygen uptake in hot conditions (40 °C, 50 % RH). iHsp72 concentration was measured in monocytes before, at exhaustion and 24 h after exercise. Rectal temperature, heart rate and oxygen uptake were recorded during exercise. Volitional exhaustion occurred at 58.9 ± 12.1 and 27.3 ± 9.5 min (P < 0.001) and a rectal temperature of 39.8 ± 0.4 and 39.2 ± 0.6 °C (P = 0.002), respectively, for 60 and 75 %. The area under the curve above a rectal temperature of 38.5 °C was greater at 60 % (17.5 ± 6.6 °C min) than 75 % (3.4 ± 4.8 °C min; P < 0.001), whereas the rate of increase in rectal temperature was greater at 75 % (5.1 ± 1.7 vs. 2.2 ± 1.4 °C h⁻¹; P < 0.001). iHsp72 concentration increased similarly at exhaustion relative to pre-exercise (P = 0.044) and then increased further at 24 h (P < 0.001). Multiple regression analysis revealed no predictor variables associated with iHsp72 expression; however, a correlation was observed between exercise intensities for the increase in iHsp expression at exhaustion and 24 h (P < 0.05). These results suggest that iHsp72 expression increased in relation to the level of hyperthermia attained and sustained at 60 % and the higher metabolic rate and greater rate of increase in core temperature at 75 %, with the further increase in iHsp72 concentration 24 h after exercise reinforcing its role as a chaperone and cytoprotective agent.     

Product Development Studies on Surface-Adsorbed Nanoemulsion of Olmesartan Medoxomil as a Capsular Dosage Form

The present study aimed at development of capsular dosage form of surface-adsorbed nanoemulsion (NE) of olmesartan medoxomil (OLM) so as to overcome the limitations associated with handling of liquid NEs without affecting their pharmaceutical efficacy. Selection of oil, surfactant, and cosurfactant for construction of pseudoternary phase diagrams was made on the basis of solubility of drug in these excipients. Rationally selected NE formulations were evaluated for percentage transmittance, viscosity, refractive index, globule size, zeta potential, and polydispersity index (PDI). Formulation (F3) comprising of Capmul MCM® (10% v/v), Tween 80® (11.25% v/v), polyethylene glycol 400 (3.75% v/v), and double-distilled water (75% v/v) displayed highest percentage cumulative drug release (%CDR; 96.69 ± 1.841), least globule size (17.51 ± 5.87 nm), low PDI (0.203 ± 0.032), high zeta potential (−58.93 ± 0.98 mV), and hence was selected as the optimized formulation. F3 was adsorbed over colloidal silicon dioxide (2 ml/400 mg) to produce free-flowing solid surface-adsorbed NE that presented a ready-to-fill capsule composition. Conversion of NE to surface-adsorbed NE and its reconstitution to NE did not affect the in vitro release profile of OLM as the similarity factor with respect to NE was found to be 66% and 73% respectively. The %CDR after 12 h for optimized NE, surface-adsorbed NE, and reconstituted NE was found to be 96.69 ± 0.54, 96.07 ± 1.76, and 94.78 ± 1.57, respectively (p > 0.05). The present study established capsulated surface-adsorbed NE as a viable delivery system with the potential to overcome the handling limitations of NE.KEY WORDS: bioavailability, nanoemulsion, olmesartan medoxomil, oral     

Freeze-Dried Targeted Mannosylated Selenium-Loaded Nanoliposomes: Development and Evaluation

The aim of this investigation was to develop and evaluate freeze-dried mannosylated liposomes for the targeted delivery of selenium. Dipalmitoylphosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol were dissolved in a chloroform and methanol mixture and allowed to form a thin film within a rotatory evaporator. This thin film was hydrated with a sodium selenite (5.8 μM) solution to form multilamellar vesicles and homogenized under high pressure to yield unilamellar nanoliposomes. Se-loaded nanoliposomes were mannosylated by 0.1% w/v mannosamine (Man-Lip-Se) prior to being lyophilized. Mannosamine concentration was optimized with cellular uptake studies in M receptor expressing cells. Non-lyophilized and lyophilized Man-Lip-Se were characterized for size, zeta potential, and entrapment efficiency. The influence of liposomal composition on the characteristics of Man-Lip-Se were evaluated using acidic and basic medium for 24 h. Thermal analysis and powder X-ray diffraction were used to determine the interaction of components within the Man-Lip-Se. The size, zeta potential and entrapment efficiency of the optimum Man-Lip-Se were observed to be 158 ± 28.9 nm, 33.21 ± 0.89 mV, and 77.27 ± 2.34%, respectively. An in vitro Se release of 70–75% up to 24 h in PBS pH 6.8 and <8% Se release in acidic media (0.1 N HCl) in 1 h was observed. The Man-Lip-Se were found to withstand gastric-like environments and showed sustained release. Stable freeze-dried Man-Lip-Se were successfully formulated with a size of <200 nm, ∼75% entrapment, and achieved controlled release of Se with stability under acidic media, which may be of importance in the targeted delivery of Se to the immune system.

Electronic supplementary material

The online version of this article (doi:10.1208/s12249-013-9988-3) contains supplementary material, which is available to authorized users.Key words: mannosylation, nanoliposome, selenium, thermal properties     

Selective inhibition of MBNL1�CCCUG interaction by small molecules toward potential therapeutic agents for myotonic dystrophy type 2 (DM2)

Myotonic dystrophy type 2 (DM2) is an incurable neuromuscular disease caused by expanded CCUG repeats that may exhibit toxicity by sequestering the splicing regulator MBNL1. A series of triaminotriazine- and triaminopyrimidine-based small molecules (ligands 1–3) were designed, synthesized and tested as inhibitors of the MBNL1–CCUG interaction. Despite the structural similarities of the triaminotriazine and triaminopyrimidine units, the triaminopyrimidine-based ligands bind with low micromolar affinity to CCUG repeats (K_d ∼ 0.1–3.6 µM) whereas the triaminotriazine ligands do not bind CCUG repeats. Importantly, these simple and small triaminopyrimidine ligands exhibit both strong inhibition (K_i ∼ 2 µM) of the MBNL1–CCUG interaction and high selectivity for CCUG repeats over other RNA targets. These experiments suggest these compounds are potential lead agents for the treatment of DM2.     

Extracellular Hsp72 concentration relates to a minimum endogenous criteria during acute exercise-heat exposure

Extracellular heat shock protein 72 (eHsp72) concentration increases during exercise-heat stress when conditions elicit physiological strain. Differences in severity of environmental and exercise stimuli have elicited varied response to stress. The present study aimed to quantify the extent of increased eHsp72 with increased exogenous heat stress, and determine related endogenous markers of strain in an exercise-heat model. Ten males cycled for 90 min at 50 % in three conditions (TEMP, 20 °C/63 % RH; HOT, 30.2 °C/51%RH; VHOT, 40.0 °C/37%RH). Plasma was analysed for eHsp72 pre, immediately post and 24-h post each trial utilising a commercially available ELISA. Increased eHsp72 concentration was observed post VHOT trial (+172.4 %) (p < 0.05), but not TEMP (−1.9 %) or HOT (+25.7 %) conditions. eHsp72 returned to baseline values within 24 h in all conditions. Changes were observed in rectal temperature (T_rec), rate of T_rec increase, area under the curve for T_rec of 38.5 and 39.0 °C, duration T_rec ≥ 38.5 and ≥39.0 °C, and change in muscle temperature, between VHOT, and TEMP and HOT, but not between TEMP and HOT. Each condition also elicited significantly increasing physiological strain, described by sweat rate, heart rate, physiological strain index, rating of perceived exertion and thermal sensation. Stepwise multiple regression reported rate of T_rec increase and change in T_rec to be predictors of increased eHsp72 concentration. Data suggests eHsp72 concentration increases once systemic temperature and sympathetic activity exceeds a minimum endogenous criteria elicited during VHOT conditions and is likely to be modulated by large, rapid changes in core temperature.     

Development and Characterization of Lyophilized Diazepam-Loaded Polymeric Micelles

Polymeric micelles were studied as delivery carriers of diazepam, a practically insoluble drug in water, for rectal administration. The diazepam-loaded polymeric micelles were developed by using poloxamer 407 (P407), poloxamer 188, and d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS). Among the used polymers, TPGS resulted in polymeric micelles with good characteristics for encapsulation of diazepam which had the small particle size of 8–12 nm and narrow size distribution (PI 0.053–0.275). Additionally, 7.5% w/v of TPGS could entirely entrap the desired concentration of diazepam (5 mg/mL). To improve the physical stability upon lyophilization, an addition of P407 of 1% w/v prevented aggregation, increased physical stability, and maintained chemical stability of the lyophilized powders of diazepam-loaded polymeric micelles for 3 months storage at 4°C. The rate and amount of diazepam release from TPGS polymeric micelles mainly depended on the concentration of TPGS. The release data were fitted to Higuchi''s model suggesting that the drug release mechanism was controlled by Fickian diffusion. In conclusion, 10% w/v TPGS and 1% w/v P407 were the optimum formulation of lyophilized diazepam-loaded polymeric micelles.Key words: diazepam, lyophilization, poloxamer 407, polymeric micelles, d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS)     

Controlled Release of Ropinirole Hydrochloride from a Multiple Barrier Layer Tablet Dosage Form: Effect of Polymer Type on Pharmacokinetics and IVIVC

The purpose of the present study was to control in vitro burst effect of the highly water-soluble drug, ropinirole hydrochloride to reduce in vivo dose dumping and to establish in vitro–in vivo correlation. The pharmacokinetics of two entirely different tablet formulation technologies is also explored in this study. For pharmacokinetics study, FDA recommends at least 10% difference in drug release for formulations to be studied but here a different approach was adopted. The formulations F8A and F9A having similar dissolution profiles among themselves and with Requip® XL™ (f₂ value 72, 77, 71 respectively) were evaluated. The C_max of formulation F8A comprising hypromellose 100,000 cP was 1005.16 pg/ml as compared to 973.70 pg/ml of formulation F9A comprising hypromellose 4000 cP irrespective of T_max of 5 and 5.75 h, respectively. The difference in release and extent of absorption in vivo was due to synergistic effect of complex RH release mechanism; however, AUC_0–t and AUC_0–∞ values were comparable. The level A correlation using the Wagner–Nelson method supported the findings where R² was 0.7597 and 0.9675 respectively for formulation F8A and F9A. Thus, in vivo studies are required for proving the therapeutic equivalency of different formulation technologies even though f₂ ≥ 50. The technology was demonstrated effectively at industrial manufacturing scale of 200,000 tablets.KEY WORDS: controlled release polymer, in vitro–in vivo correlation (IVIVC), multiple barrier layer tablets, pharmacokinetics, ropinirole hydrochloride (RH)     

Enhanced Topical Delivery of Finasteride Using Glyceryl Monooleate-Based Liquid Crystalline Nanoparticles Stabilized by Cremophor Surfactants

The aim of this study was to investigate the capability of two surfactants, Cremophor RH 40 (RH) and Cremophor EL (EL), to prepare liquid crystalline nanoparticles (LCN) and to study its influence on the topical delivery of finasteride (FNS). FNS-loaded LCN was formulated with the two surfactants and characterized for size distribution, morphology, entrapment efficiency, in vitro drug release, and skin permeation/retention. Influence of FNS-loaded LCN on the conformational changes on porcine skin was also studied using attenuated total reflectance Fourier-transform infrared spectroscopy. Transmission electron microscopical image confirmed the formation of LCN. The average particle size of formulations was in the range of 165.1–208.6 and 153.7–243.0 nm, respectively. The formulations prepared with higher surfactant concentrations showed faster release and significantly increased skin permeation. Specifically, LCN prepared with RH 2.5% presented higher permeation flux (0.100 ± 0.005 μgcm⁻²h⁻¹) compared with lower concentration (0.029 ± 0.007 μgcm⁻²h⁻¹). Typical spectral bands of lipid matrix of porcine skin were shifted to higher wavenumber, indicating increased degree of disorder of the lipid acyl chains which might cause fluidity increase of stratum corneum. Taken together, Cremophor surfactants exhibited a promising potential to stabilize the LCN and significantly augmented the skin permeation of FNS.KEY WORDS: Cremophor, finasteride, liquid crystalline nanoparticles, skin permeation–retention     

Relative Bioavailability of Chlorothiazide from Mucoadhesive Compacts in Pigs

The relative bioavailability of chlorothiazide from mucoadhesive polymeric compacts is compared to commercial oral suspension in pigs. A single-dose randomized study was conducted in 12 healthy pigs that are 9–10 weeks old. After overnight fasting, pigs were divided into two groups of six animals. To the first group, a reference product containing 50 mg of chlorothiazide suspension, and in the second group, test product (mucoadhesive compacts) chlorothiazide (50 mg) was administered with 75 mL of water via gastric tubes. Blood samples were collected between 0 to 24 h using catheters inserted into the jugular vein. Plasma was separated by protein precipitation, and chlorothiazide concentrations were determined using a high-performance liquid chromatography method. The mean T_max and the C_max of chlorothiazide following the administration of oral suspension and mucoadhesive compacts were 0.58 ± 0.20 h and 682.97 ± 415.69 ng/mL and 2.17 ± 0.98 h and 99.42 ± 124.08 ng/mL, respectively. The K_el and T_1/2 of chlorothiazide were found to be 1.06 ± 0.28 h⁻¹ and 0.70 ± 0.21 h from suspension and 0.95 ± 1.11 h⁻¹ and 2.05 ± 1.90 h from the compacts, respectively. The T_max of mucoadhesive compacts were significantly longer (p < 0.05; 2.17 h) than the reference products (0.58 h), whereas the C_max of compacts were significantly lower (99 ng/mL) than the reference product (683 ng/mL; p < 0.05). The area under the curve (AUC) of compacts accounts only 50.15% (404.32 ± 449.93 ng h/mL) of the reference product’s AUC (806.27 ± 395.97 ng h/mL). The relative bioavailability of the compacts was lower than that of the suspension, and this may be due to the narrow window of absorption for chlorothiazide.Key words: bioavailability, chlorothiazide, mucoadhesive compacts, pigs     

Thermoreversible Nasal In situ Gel of Venlafaxine Hydrochloride: Formulation, Characterization, and Pharmacodynamic Evaluation

In order to improve the bioavailability of the antidepressant drug, venlafaxine hydrochloride, in situ mucoadhesive thermoreversible gel, was formulated using Lutrol F127 (18%) as a thermo gelling polymer. Mucoadhesion was modulated by trying carbopol 934, PVP K30, HPMC K4M, sodium alginate, tamarind seed gum, and carrageenan as mucoadhesive polymers. Results revealed that as the concentration of mucoadhesive polymer increased the mucoadhesive strength increased but gelation temperature decreased. Formulation was optimized on the basis of clarity, pH, gelation temperature, mucoadhesive strength, gel strength, viscosity, drug content, diffusion through sheep nasal mucosa, histopathological evaluation of mucosa, and pharmacodynamic study in rats. Final formulation T5 containing 18% Lutrol F127 and 0.3% PVP K30 was considered as an optimized formulation. T5 released 97.86 ± 0.073% drug in 150 min with a flux of 0.1545 mg cm⁻² min⁻¹ and gelation temperature 31.17 ± 0.30°C. Histopathological evaluation of nasal mucosa revealed that T5 formulation was safe for nasal administration as it caused no damage to nasal epithelium. From the results of pharmacodynamic study, mainly forced swim test (FST), it was concluded that venlafaxine hydrochloride was more effective as an antidepressant by nasal route as in situ gel nasal drops in comparison to oral administration of equivalent dose.Key words: lutrol F127, mucoadhesive, nasal in situ gel, thermoreversible, venlafaxine HCl     

Low efficacy of cardioversion of persistent atrial fibrillation with the implantable cardioverter-defibrillator

Aims

Atrial fibrillation (AF) and heart failure are conditions that often coexist. Consequently, many patients with an implantable cardioverter-defibrillator (ICD) present with AF. We evaluated the effectiveness of internal cardioversion of AF in patients with an ICD.

Methods

Retrospectively, we included 27 consecutive ICD patients with persistent AF who underwent internal cardioversion using the ICD. When ICD cardioversion failed, external cardioversion was performed.

Results

Patients were predominantly male (89 %) with a mean (SD) age of 65 ± 9 years and left ventricular ejection fraction of 36 ± 17 %. Only nine (33 %) patients had successful internal cardioversion after one, two or three shocks. The remaining 18 patients underwent external cardioversion after they failed internal cardioversion, which resulted in sinus rhythm in all. A smaller left atrial volume (99 ± 36 ml vs. 146 ± 44 ml; p = 0.019), a longer right atrial cycle length (227 (186–255) vs. 169 (152–183) ms, p = 0.030), a shorter total AF history (2 (0–17) months vs. 40 (5–75) months, p = 0.025) and dual-coil ICD shock (75 % vs. 26 %, p = 0.093) were associated with successful ICD cardioversion.

Conclusion

Internal cardioversion of AF in ICD patients has a low success rate but may be attempted in those with small atria, a long right atrial fibrillatory cycle length and a short total AF history, especially when a dual-coil ICD is present. Otherwise, it seems reasonable to prefer external over internal cardioversion when it comes to termination of persistent AF.     

The influence of residential distance on time to treatment in ST-elevation myocardial infarction patients

AimsTo evaluate the relation between residential distance and total ischaemic time in patients with acute ST-elevation myocardial infarction (STEMI).MethodsSTEMI patients were transported to the Isala Hospital Zwolle with the intention to perform primary percutaneous coronary intervention PCI (pPCI) from 2004 until 2010 (n = 4149). Of these, 1424 patients (34 %) were referred via a non-PCI ‘spoke'' centre (‘spoke’ patients) and 2725 patients (66 %) were referred via field triage in the ambulance (ambulance patients).ResultsA longer residential distance increased median total ischaemic time in ‘spoke’ patients (0–30 km: 228 min, >30-60 km: 235 min, >60-90 km: 264 min, p < 0.001), however not in ambulance patients (0–30 km: 179 min, >30-60 km: 175 min, >60-90 km: 186 min, p = 0.225). After multivariable linear regression analysis, in ‘spoke’ patients residential distance of >30-60 km compared with 0–30 km was not independently associated with ischaemic time; however, a residential distance of >60-90 km (exp (B) = 1.11, 95 % CI 1.01-1.12) compared with 0–30 km was independently related with ischaemic time. In ambulance patients, residential distance of >30-60 and >60-90 km compared with 0–30 km was not independently associated with ischaemic time.ConclusionA longer distance from the patient’s residence to a PCI centre was associated with a small but significant increase in time to treatment in ‘spoke’ patients, however not in ambulance patients. Therefore, referral via field triage in the ambulance did not lead to a significant increase in time to treatment, especially at long distances (up to 90 km).     

Survival of Desulfotomaculum spores from estuarine sediments after serial autoclaving and high-temperature exposure

Bacterial spores are widespread in marine sediments, including those of thermophilic, sulphate-reducing bacteria, which have a high minimum growth temperature making it unlikely that they grow in situ. These Desulfotomaculum spp. are thought to be from hot environments and are distributed by ocean currents. Their cells and spores upper temperature limit for survival is unknown, as is whether they can survive repeated high-temperature exposure that might occur in hydrothermal systems. This was investigated by incubating estuarine sediments significantly above (40–80 °C) maximum in situ temperatures (∼23 °C), and with and without prior triple autoclaving. Sulphate reduction occurred at 40–60 °C and at 60 °C was unaffected by autoclaving. Desulfotomaculum sp. C1A60 was isolated and was most closely related to the thermophilic D. kuznetsovii^T (∼96% 16S rRNA gene sequence identity). Cultures of Desulfotomaculum sp. C1A60, D. kuznetsovii^Tand D. geothermicum B2T survived triple autoclaving while other related Desulfotomaculum spp. did not, although they did survive pasteurisation. Desulfotomaculum sp. C1A60 and D. kuznetsovii cultures also survived more extreme autoclaving (C1A60, 130 °C for 15 min; D. kuznetsovii, 135 °C for 15 min, maximum of 154 °C reached) and high-temperature conditions in an oil bath (C1A60, 130° for 30 min, D. kuznetsovii 140 °C for 15 min). Desulfotomaculum sp. C1A60 with either spores or predominantly vegetative cells demonstrated that surviving triple autoclaving was due to spores. Spores also had very high culturability compared with vegetative cells (∼30 × higher). Combined extreme temperature survival and high culturability of some thermophilic Desulfotomaculum spp. make them very effective colonisers of hot environments, which is consistent with their presence in subsurface geothermal waters and petroleum reservoirs.     

Positively Charged Polymeric Nanoparticle Reservoirs of Terbinafine Hydrochloride: Preclinical Implications for Controlled Drug Delivery in the Aqueous Humor of Rabbits

Frequent instillation of terbinafine hydrochloride (T HCl) eye drops (0.25%, w/v) is necessary to maintain effective aqueous humor concentrations for treatment of fungal keratitis. The current approach aimed at developing potential positively charged controlled-release polymeric nanoparticles (NPs) of T HCl. The estimation of the drug pharmacokinetics in the aqueous humor following ocular instillation of the best-achieved NPs in rabbits was another goal. Eighteen drug-loaded (0.50%, w/v) formulae were fabricated by the nanopreciptation method using Eudragit® RS100 and chitosan (0.25%, 0.5%, and 1%, w/v). Soybean lecithin (1%, w/v) and Pluronic® F68 (0.5%, 1%, and 1.5%, w/v) were incorporated in the alcoholic and aqueous phases, respectively. The NPs were evaluated for particle size, zeta potential, entrapment efficiency percentage (EE%), morphological examination, drug release in simulated tear fluid (pH 7.4), Fourier-transform IR (FT-IR), X-ray diffraction (XRD), physical stability (2 months, 4°C and 25°C), and drug pharmacokinetics in the rabbit aqueous humor relative to an oily drug solution. Spherical, discrete NPs were successfully developed with mean particle size and zeta potential ranging from 73.29 to 320.15 nm and +20.51 to +40.32 mV, respectively. Higher EE% were achieved with Eudragit® RS100-based NPs. The duration of drug release was extended to more than 8 h. FT-IR and XRD revealed compatibility between inactive formulation ingredients and T HCl and permanence of the latter’s crystallinity, respectively. The NPs were physically stable, for at least 2 months, when refrigerated. F5-NP suspension significantly (P < 0.05) increased drug mean residence time and improved its ocular bioavailability; 1.657-fold.Key words: aqueous humor, chitosan, Eudragit® RS100, nanoparticles, terbinafine hydrochloride     

Photodegradation and Stabilization of Betamethasone-17 Valerate in Aqueous/Organic Solvents and Topical Formulations

The effects of solvent [acetonitrile, methanol, and acetonitrile/water mixture (20:80, v/v)], buffer concentration (phosphate buffer, pH 7.5), ionic strength and commonly employed adjuvants on the photodegradation of betamethasone-17 valerate in cream and gel formulations have been studied on exposure to UV light (300–400 nm). A validated high-performance liquid chromatography method has been used to determine the parent compound and its photodegraded products. The photodegradation data in the studied solvents showed greater decomposition of the drug in solvents with a lower dielectric constant. A comparatively higher rate of photodegradation was observed in the cream formulation compared to that for the gel formulation. The kinetic treatment of the photodegradation data revealed that the degradation of the drug follows first-order kinetics and the apparent first-order rate constants for the photodegradation reactions, in the media studied, range from 1.62 to 11.30 × 10⁻³ min⁻¹. The values of the rate constants decrease with increasing phosphate concentration and ionic strength which could be due to the deactivation of the excited state and radical quenching. The second-order rate constant (k′) for the phosphate ion-inhibited reactions at pH 7.5 has been found to be 5.22 × 10⁻² M⁻¹ s⁻¹. An effective photostabilization of the drug has been achieved in cream and gel formulations with titanium dioxide (33.5–42.5%), vanillin (21.6–28.7%), and butyl hydroxytoluene (18.2–21.6%).Key words: betamethasone-17 valerate, creams and gels, kinetics, photodegradation, photostabilization