Quality of medicines stored together in multi-compartment compliance aids

Background and Objective: Dispensing medicines into compliance aids is a common practice in pharmacy contrary to manufacturers’ advice and studies have shown the appearance of light-sensitive tablets is compromised by such storage; we previously found evidence of reduced bioavailability at elevated temperature and humidity. Our objective was to examine the physicochemical stability of two generic atenolol tablets in different compliance aids and with aspirin co-storage at room temperature and at 40 °C/75% relative humidity. Methods: The physicochemical stability of atenolol tablets was evaluated after 28 days of storage and compared with controls by examining visual appearance, weight, disintegration, dissolution, friability and hardness to accepted standards and using a previously validated HPLC method for chemical assay. Results and Discussion: The response to storage was brand-dependent and not straightforward. With one make of atenolol (Alpharma), storage in compliance aids even at room temperature impacted on physical stability, reducing tablet hardness, with storage in Dosett® exerting a greater impact than storage in Medidos® (t-test P < 0·001). Co-storage at elevated temperature and humidity also impacted on the appearance of non-coated aspirin tablets (Angette™). The chemical stability of atenolol was not affected and we did not find evidence of changes to bioavailability with either make. Certainly data for one atenolol make (CP Pharmaceuticals) co-stored with aspirin (Angette™ and Nu-Seals) in both compliance aids at room temperature provided evidence of short-term stability. But medicines are dispensed into compliance aids in multi-factorial ways so our study highlights not only the lack of evidence but also a realization that evidence to support real practice may not be accomplished through research. Conclusion: Reassuring practitioners of the continued stability of medicines in compliance aids under the countless condition in which they are dispensed in practice may requires a different approach involving medical device regulators and more definitive professional guidance.

Pilot study of the short-term physico-chemical stability of atenolol tablets stored in a multi-compartment compliance aid

Study objectives: There is a possibility that lower air, moisture and light protection could impact on physico-chemical stability of medicines inside multi-compartment compliance aids (MCCAs), although this has not yet been proved. The objectives of the study were to examine the physico-chemical stability of atenolol tablets stored in a compliance aid at room temperature, and at elevated temperature and humidity to simulate practice conditions. Methods: Atenolol 100 mg tablets in 28-chamber, plastic compliance aids with transparent lids were stored for four weeks at room temperature and at 40°C with 75% relative humidity. Tablets were also stored at room temperature in original packaging and Petri dishes. Physical tests were conducted to standards as laid down in the British Pharmacopoeia 2005, and dissolution to those of the United States Pharmacopoeia volume 24. Chemical stability was assessed by a validated high-performance liquid chromatography (HPLC) method. Results: Tablets at room temperature in original packaging, in compliance aids and Petri dishes remained the same in appearance and passed physico-chemical tests. Tablets exposed to 40°C with 75% relative humidity in compliance aids passed tests for uniformity of weight, friability and chemical stability but became pale and moist, softer (82 newtons ± 4; p< 0.0001) than tablets in the original packaging (118 newtons ± 6), more friable (0.14% loss of mass) compared with other tablets (0.005%), and failed the tests for disintegration (>15 minutes) and dissolution (only 15% atenolol released at 30 minutes). Conclusion: Although chemical stability was unaffected, storage in compliance aids at 40°C with 75% relative humidity softened atenolol tablets, prolonged disintegration time and hindered dissolution which could significantly reduce bioavailability. This formulation could be suitable for storage in compliance aids at 25°C, but not in hotter, humid weather.

The component polypeptide chains of bovine insulin nucleate or inhibit aggregation of the parent protein in a conformation-dependent manner

Amyloid fibrils are typically rigid, unbrariched structures with diameters of similar to 10 nm and lengths up to several micrometres, and are associated with more than 20 diseases including Alzheimer's disease and type II diabetes. Insulin is a small, predominantly alpha-helical protein consisting of 51 residues in two disulfide-linked polypeptide chains that readily assembles into amyloid fibrils under conditions of low PH and elevated temperature. We demonstrate here that both the A-chain and the B-chain of insulin are capable of forming amyloid fibrils in isolation under similar conditions, with fibrillar morphologies that differ from those composed of intact insulin. Both the A-chain and B-chain fibrils were found to be able to cross-seed the fibrillization of the parent protein, although these reactions were substantially less efficient than self-seeding with fibrils composed of full-length insulin. In both cases, the cross-seeded fibrils were morphologically distinct from the seeding, material, but shared common characteristics with typical insulin fibrils, including a very similar helical repeat. The broader distribution of heights of the cross-seeded fibrils compared to typical insulin fibrils, however, indicates that their underling protofilament hierarchy may be subtly different. In addition, and remarkably in view of this seeding behavior, the soluble forms of the A-chain and B-chain peptides were found to be capable of inhibiting insulin fibril formation. Studies using mass spectrometry suggest that this behavior might be attributable to complex formation between insulin and the A-chain and B-chain peptides. The finding that the same chemical form of a polypeptide chain in different physical states can either stimulate or inhibit the conversion of a protein into amyloid fibrils sheds new light on the mechanisms underlying fibril formation, fibril strain propagation and amyloid disease initiation and progression. (c) 2006 Elsevier Ltd. All rights reserved.

Synthesis and fabrication of a thin film containing silica-encapsulated face-centered tetragonal FePt nanoparticles

Self-assembly of monodisperse, silica-encapsulated, face-centered tetragonal FePt nanoparticles forms closely packed 2D arrays (see figure). Placing monodisperse FePt nanoparticles in silica nanocapsules allows the transition from a disordered face-centered cubic phase to a ferromagnetic crystalline face-centered tetragonal structure at elevated temperature without severe sintering. These materials are potential candidates for the generation of ultrahigh-density magnetic recording media.

Surface science studies of strong metal-oxide interactions on model catalysts

The strong metal support interaction (SMSI) was first described in 1978 by Tauster [1-4]. The effect was observed as a severely negative effect on CO and H2 uptake on the catalyst after high temperature calcination under reducing conditions (heating above ~ 700 K) [1,2]. It also had a negative effect on the reaction rate for reactions, such as alkane hydrogenolysis [5,6]. It appeared that the effect occurred for catalysts comprised of reducible supports which were treated at elevated temperature in reducing conditions [2-4]. A classic support which has manifested this behaviour in many studies is TiO2. Over the years following the first discovery of SMSI it has been recognised that the effect is not always negative – for instance for the CO-H2 reaction for which it appears to have a positive effect [5,6]. Further it was noted that hydrogen reduction was not necessary to observe the effect of CO adsorption suppression, it also occurs by vacuum treatment [7], though it should be noted that vacuum treatment at elevated temperature is, in effect, a reducing environment.

Reversible addition of CO to coordinatively unsaturated high-spin iron(II) complexes

Several new coordinatively unsaturated iron(II) complexes of the types [Fe(EN-iPr)X2] (E = P, S, Se; X = Cl, Br) and [Fe(ON-iPr)2X]X containing bidentate EN ligands based on N-(2-pyridinyl)aminophosphines as well as oxo, thio, and seleno derivatives thereof were prepared and characterized by NMR spectroscopy and X-ray crystallography. Mössbauer spectroscopy and magnetization studies confirmed their high-spin nature with magnetic moments very close to 4.9 μB, reflecting the expected four unpaired d-electrons in all these compounds. Stable low-spin carbonyl complexes of the types [Fe(PN-iPr)2(CO)X]X (X = Cl, Br) and cis-CO,cis-Br-[Fe(PN-iPr)(CO)2X2] (X = Br) were obtained by reacting cis-Fe(CO)4X2 with the stronger PN donor ligands, but not with the weaker EN donor ligands (E = O, S, Se). Furthermore, the reactivity of [Fe(PN-iPr)X2] toward CO was investigated by IR spectroscopy. Whereas at room temperature no reaction took place, at −50 °C [Fe(PN-iPr)X2] added readily CO to form, depending on the nature of X, the mono- and dicarbonyl complexes [Fe(PN-iPr)(X)2(CO)] (X = Cl) and [Fe(PN-iPr)(CO)2X2] (X = Cl, Br), respectively. In the case of X = Br, two isomeric dicarbonyl complexes, namely, cis-CO,trans-Br-[Fe(PN-iPr)(CO)2Br2] (major species) and cis-CO,cis-Br-[Fe(PN-iPr)(CO)2Br2] (minor species), are formed. The addition of CO to [Fe(PN-iPr)X2] was investigated in detail by means of DFT/B3LYP calculations. This study strongly supports the experimental findings that at low temperature two isomeric low-spin dicarbonyl complexes are formed. For kinetic reasons cis,trans-[Fe(PN-iPr)(CO)2Br2] releases CO at elevated temperature, re-forming [Fe(PN-iPr)Br2], while the corresponding cis,cis isomer is stable under these conditions.

Determination of the embedded thermo-optical expansion coefficients of PbTe and ZnSe thin film infrared multilayers

This paper reports the first derived thermo-optical properties for vacuum deposited infrared thin films embedded in multilayers. These properties were extracted from the temperature-dependence of manufactured narrow bandpass filters across the 4-17 µm mid-infrared wavelength region. Using a repository of spaceflight multi-cavity bandpass filters, the thermo-optical expansion coefficients of PbTe and ZnSe were determined across an elevated temperature range 20-160 ºC. Embedded ZnSe films showed thermo-optical properties similar to reported bulk values, whilst the embedded PbTe films of lower optical density, deviate from reference literature sources. Detailed knowledge of derived coefficients is essential to the multilayer design of temperature-invariant narrow bandpass filters for use in non-cooled infrared detection systems. We further present manufacture of the first reported temperature-invariant multi-cavity narrow bandpass filter utilizing PbS chalcogenide layer material.

From insect to man: Photorhabdus sheds light on the emergence of human pathogenicity

Photorhabdus are highly effective insect pathogenic bacteria that exist in a mutualistic relationship with Heterorhabditid nematodes. Unlike other members of the genus, Photorhabdus asymbiotica can also infect humans. Most Photorhabdus cannot replicate above 34°C, limiting their host-range to poikilothermic invertebrates. In contrast, P. asymbiotica must necessarily be able to replicate at 37°C or above. Many well-studied mammalian pathogens use the elevated temperature of their host as a signal to regulate the necessary changes in gene expression required for infection. Here we use RNA-seq, proteomics and phenotype microarrays to examine temperature dependent differences in transcription, translation and phenotype of P. asymbiotica at 28°C versus 37°C, relevant to the insect or human hosts respectively. Our findings reveal relatively few temperature dependant differences in gene expression. There is however a striking difference in metabolism at 37°C, with a significant reduction in the range of carbon and nitrogen sources that otherwise support respiration at 28°C. We propose that the key adaptation that enables P. asymbiotica to infect humans is to aggressively acquire amino acids, peptides and other nutrients from the human host, employing a so called “nutritional virulence” strategy. This would simultaneously cripple the host immune response while providing nutrients sufficient for reproduction. This might explain the severity of ulcerated lesions observed in clinical cases of Photorhabdosis. Furthermore, while P. asymbiotica can invade mammalian cells they must also resist immediate killing by humoral immunity components in serum. We observed an increase in the production of the insect Phenol-oxidase inhibitor Rhabduscin normally deployed to inhibit the melanisation immune cascade. Crucially we demonstrated this molecule also facilitates protection against killing by the alternative human complement pathway.

Associations between elevated atmospheric temperature and human mortality: a critical review of the literature

The effects of the anomalously warm European summer of 2003 highlighted the importance of understanding the relationship between elevated atmospheric temperature and human mortality. This review is an extension of the brief evidence examining this relationship provided in the IPCC’s Assessment Reports. A comprehensive and critical review of the literature is presented, which highlights avenues for further research, and the respective merits and limitations of the methods used to analyse the relationships. In contrast to previous reviews that concentrate on the epidemiological evidence, this review acknowledges the inter-disciplinary nature of the topic and examines the evidence presented in epidemiological, environmental health, and climatological journals. As such, present temperature–mortality relationships are reviewed, followed by a discussion of how these are likely to change under climate change scenarios. The importance of uncertainty, and methods to include it in future work, are also considered.

Global climate change and tree nutrition: effects of elevated CO2 and temperature

Although tree nutrition has not been the primary focus of large climate change experiments on trees, we are beginning to understand its links to elevated atmospheric CO2 and temperature changes. This review focuses on the major nutrients, namely N and P, and deals with the effects of climate change on the processes that alter their cycling and availability. Current knowledge regarding biotic and abiotic agents of weathering, mobilization and immobilization of these elements will be discussed. To date, controlled environment studies have identified possible effects of climate change on tree nutrition. Only some of these findings, however, were verified in ecosystem scale experiments. Moreover, to be able to predict future effects of climate change on tree nutrition at this scale, we need to progress from studying effects of single factors to analysing interactions between factors such as elevated CO2, temperature or water availability.

Effect of elevated CO2 and high temperature on seed-set and grain quality of rice

Hybrid vigour may help overcome the negative effects of climate change in rice. A popular rice hybrid (IR75217H), a heat-tolerant check (N22), and a mega-variety (IR64) were tested for tolerance of seed-set and grain quality to high-temperature stress at anthesis at ambient and elevated [CO2]. Under an ambient air temperature of 29 °C (tissue temperature 28.3 °C), elevated [CO2] increased vegetative and reproductive growth, including seed yield in all three genotypes. Seed-set was reduced by high temperature in all three genotypes, with the hybrid and IR64 equally affected and twice as sensitive as the tolerant cultivar N22. No interaction occurred between temperature and [CO2] for seed-set. The hybrid had significantly more anthesed spikelets at all temperatures than IR64 and at 29 °C this resulted in a large yield advantage. At 35 °C (tissue temperature 32.9 °C) the hybrid had a higher seed yield than IR64 due to the higher spikelet number, but at 38 °C (tissue temperature 34–35 °C) there was no yield advantage. Grain gel consistency in the hybrid and IR64 was reduced by high temperatures only at elevated [CO2], while the percentage of broken grains increased from 10% at 29 °C to 35% at 38 °C in the hybrid. It is concluded that seed-set of hybrids is susceptible to short episodes of high temperature during anthesis, but that at intermediate tissue temperatures of 32.9 °C higher spikelet number (yield potential) of the hybrid can compensate to some extent. If the heat tolerance from N22 or other tolerant donors could be transferred into hybrids, yield could be maintained under the higher temperatures predicted with climate change.

Formulation of a live bacterial vaccine for stable room temperature storage results in loss of acid, bile and bile salt resistance

Live bacterial vaccines have great promise both as vaccines against enteric pathogens and as heterologous antigen vectors against diverse diseases. Ideally, room temperature stable dry formulations of live bacterial vaccines will allow oral vaccination without cold-chain storage or injections. Attenuated Salmonella can cross the intestinal wall and deliver replicating antigen plus innate immune activation signals directly to the intestinal immune tissues, however the ingested bacteria must survive firstly gastric acid and secondly the antimicrobial defences of the small intestine. We found that the way in which cells are grown prior to formulation markedly affects sensitivity to acid and bile. Using a previously published stable storage formulation that maintained over 10% viability after 56 days storage at room temperature, we found dried samples of an attenuated S. typhimurium vaccine lost acid and bile resistance compared to the same bacteria taken from fresh culture. The stable formulation utilised osmotic preconditioning in defined medium plus elevated salt concentration to induce intracellular trehalose accumulation before drying. Dried bacteria grown in rich media without osmotic preconditioning showed more resistance to bile, but less stability during storage, suggesting a trade-off between bile resistance and stability. Further optimization is needed to produce the ultimate room-temperature stable oral live bacterial vaccine formulation.

Acclimation of photosynthesis to elevated CO2 in onion (Allium cepa) grown at a range of temperatures

Onion (Allium cepa) was grown in the field within temperature gradient tunnels (providing about -2.5degreesC to +2.5degreesC from outside temperatures) maintained at either 374 or 532 mumol mol(-1) CO2. Plant leaf area was determined non-destructively at 7 day intervals until the time of bulbing in 12 combinations of temperature and CO2 concentration. Gas exchange was measured in each plot at the time of bulbing, and the carbohydrate content of the leaf (source) and bulb (sink) was determined. Maximum rate of leaf area expansion increased with mean temperature. Leaf area duration and maximum rate of leaf area expansion were not significantly affected by CO2. The light-saturated rates of leaf photosynthesis (A(sat)) were greater in plants grown at normal than at elevated CO2 concentrations at the same measurement CO2 concentration. Acclimation of photosynthesis decreased with an increase in growth temperature, and with an increase in leaf nitrogen content at elevated CO2. The ratio of intercellular to atmospheric CO2 (C-i/C-a ratio) was 7.4% less for plants grown at elevated compared with normal CO2. A(sat) in plants grown at elevated CO2 was less than in plants grown at normal CO2 when compared at the same C-i Hence, acclimation of photosynthesis was due both to stomatal acclimation and to limitations to biochemical CO2 fixation. Carbohydrate content of the onion bulbs was greater at elevated than at normal CO2. In contrast, carbohydrate content was less at elevated compared with normal CO2 in the leaf sections in which CO2 exchange was measured at the same developmental stage. Therefore, acclimation of photosynthesis in fully expanded onion leaves was detected despite the absence of localised carbohydrate accumulation in these field-grown crops.

Acclimation of photosynthesis to elevated CO2 in onion (allium cepa) grown at a range of temperatures

Onion (Allium cepa) was grown in the field within temperature gradient tunnels (providing about -2.5 degrees C to +2.5 degrees C from outside temperatures) maintained at either 374 or 532 mumol mol (-1) CO2. Plant leaf area was determined non-destructively at 7 day intervals until the time of bulbing in 12 combinations of temperature and CO2 concentration. Gas exchange was measured in each plot at the time of bulbing, and the carbohydrate content of the leaf (source) and bulb (sink) was determined. Maximum rate of leaf area expansion increased with mean temperature. Leaf area duration and maximum rate of leaf area expansion were not significantly affected by CO2. The light-saturated rates of leaf photosynthesis (A(sat)) were greater in plants grown at normal than at elevated CO2 concentrations at the same measurement CO2 concentration. Acclimation of photosynthesis decreased with an increase in growth temperature, and with an increase in leaf nitrogen content at elevated CO2. The ratio of intercellular to atmospheric CO2 (C-i/C-a ratio) was 7.4% less for plants grown at elevated compared with normal CO2. A(sat) in plants grown at elevated CO2 was less than in plants grown at normal CO2 when compared at the same C-i Hence, acclimation of photosynthesis was due both to stomatal acclimation and to limitations to biochemical CO2 fixation. Carbohydrate content of the onion bulbs was greater at elevated than at normal CO2. In contrast, carbohydrate content was less at elevated compared with normal CO2 in the leaf sections in which CO2 exchange was measured at the same developmental stage. Therefore, acclimation of photosynthesis in fully expanded onion leaves was detected despite the absence of localised carbohydrate accumulation in these field-grown crops.

A low-temperature ammonium ylid rearrangement: enhanced reactivity engendered by rigidity

Sigmatropic rearrangement of tetrahydropyridine-derived ammonium is a valuable method for the preparation of substituted prolines. These reaction normally require elevated temperatures to proceed, but bicyclic tetrahydropyridine-like ylid I undergoes rearrangement at -15 degrees C; the extra rigidity of the azabicyclo[3.3.0]octene system preorganizes the transition state and lowers the activation energy for rearrangement.