What if there was a stronger pharmaceutical price competition in Spain? When regulation has a similar effect to collusion

This paper examines statins competition in the Spanish pharmaceutical market, where prices are highly regulated, and simulates a situation in which there is unrestricted price competition. A nested logit demand model is estimated with a panel of monthly data for pharmaceuticals prescribed from 1997 to 2005. The simulation indicates that the regulation of prices is similar in its effects to cooperation among producers, since the regulated prices are close to those that would be observed in a scenario of perfect collusion. Freedom to set prices and a regulatory framework with appropriate incentives would result in a general reduction in prices and may make the current veiled competition in the form of discounts to pharmacists become more visible. The decrease in prices would be partially offset by an increase in consumption but the net effect would be an overall decrease in expenditure. The counterfactual set-up would also lead to important changes in the market shares of both manufacturers and active ingredients, and a reversal of generic drugs. Therefore, pro-competitive regulation would be welfare-enhancing but would imply winners and losers.

Analysis of organic volatile residues in 9 mm spent cartridges

Determining the time since discharge of spent cartridges found on a crime scene may be very useful in firearm investigations. The potential of small calibre munitions was barely studied before and this work did therefore focus on that problematic. The first step was to optimize the detection potential of solidphase microextraction (SPME) followed by gas chromatography coupled to a mass spectrometry detector (GC/MS). This allowed determining the organic volatile composition of empty cartridges immediately after a gunshot. Identification of 32 detected compounds was confirmed by the analysis of reference substances. Preliminary aging studies over 32 hours were carried out on selected target compounds to evaluate their potential for the dating of shotguns.

Best Practice Guidance on Joint Working between the HSC and the Pharmaceutical Industry and other relevant organisations (PDF 260KB)

HSS (GEN) 1) 1/95 update. It is intended to replace the guidance previously provided by former HSSBs and Trusts to assist employers and staff in maintaining strict ethical standards in the conduct of HSC business, in this instance, with the pharmaceutical industry

Anionic Sites, Fucose Residues and Class I Human Leukocyte Antigen Fate During Interaction of Toxoplasma gondii with Endothelial Cells

Toxoplasma gondii invades and proliferates in human umbilical vein endothelial cells where it resides in a parasitophorous vacuole. In order to analyze which components of the endothelial cell plasma membrane are internalized and become part of the parasitophorous vacuole membrane, the culture of endothelial cells was labeled with cationized ferritin or UEA I lectin or anti Class I human leukocytte antigen (HLA) before or after infection with T. gondii. The results showed no cationized ferritin and UEA I lectin in any parasitophorous vacuole membrane, however, the Class I HLA molecule labeling was observed in some endocytic vacuoles containing parasite until 1 h of interaction with T. gondii. After 24 h parasite-host cell interaction, the labeling was absent on the vacuolar membrane, but presents only in small vesicles near parasitophorous vacuole. These results suggest the anionic site and fucose residues are excluded at the time of parasitophorous vacuole formation while Class I HLA molecules are present only on a minority of Toxoplasma-containig vacuoles.

A review of coccidiostat residues in poultry

safefood, the Food Safety Promotion Board, is responsible for increasing food safety awareness and for supporting north/south scientific co-operation. safefood is currently funding a project entitled "Poultry Meat: improving food safety by improving chemical residue surveillance". This joint project between the Veterinary Sciences Division, Queen's University, Belfast and the National Food Centre, Teagasc, Dublin, is addressing the problem of anti-coccidial drug residues in poultry meat and eggs through an all-island research and residue testing initiative. The project started in 2001 and will continue until 2004. Poultry have a high susceptibility to the parasitic disease, coccidiosis. Because of this susceptibility, veterinary drugs, commonly known as coccidiostats are routinely used in intensively-reared poultry. The coccidiostats are potent drugs and, where residues occur in food, they may exacerbate certain coronary disease conditions. It is important, therefore, for poultry and egg producers to prevent the occurrence of residues of coccidiostats in food products.

Immunization with synthetic peptides containing a defined malaria epitope induces a highly diverse cytotoxic T lymphocyte response. Evidence that two peptide residues are buried in the MHC molecule.

In the present study, we have explored ways of inducing a CTL response to a previously defined H-2Kd MHC class I restricted epitope in the circumsporozoite (CS) protein of Plasmodium berghei, and studied in detail the fine specificity of the response. We found that the s.c. injection of a variety of synthetic peptides emulsified in Freund's adjuvant efficiently induced a specific CTL response in (BALB/c x C57BL/6)F1 (H-2d x H-2b) mice. In contrast, BALB/c mice responded only marginally, consistent with the possible requirement for a concomitant Th response that would be provided by the C57BL/6 strain. Similar to our previous observations in analyzing CTL clones from sporozoite-immunized mice, the CTL response induced by peptide immunization was in part cross-reactive with an epitope from the Plasmodium yoelii species. The minimal P. berghei CS epitope, the octapeptide PbCS 253-260, was studied in detail by the analysis of a series of variant CS peptides containing single Ala substitutions. The relative antigenic activity for each variant peptide was calculated for 28 different CTL clones. Overall, the response to this P. berghei CTL epitope appeared to be extremely diverse in terms of fine specificity. This was evident among the CTL derived from sporozoite-immunized mice, as well as among those from peptide-immunized animals. The heterogeneity found at the functional level correlates with the highly diverse TCR repertoire that we have found for the same series of CTL clones in a study that is reported separately. The relative competitor activity for each Ala-substituted peptide was also determined in a quantitative functional competition assay. For the residues (Tyr253 and Ile260) within the 8-mer CS peptide, substitution with Ala reduced competitor activity by at least 40-fold, and for two others the reduction was 5- to 10-fold. When the relative antigenic activity for each CTL/peptide combination was normalized to the relative competitor activity of the peptide, a striking pattern emerged. The two residues that most affected competitor activity showed no additional effect on recognition beyond that observed for competition. In marked contrast, Ala substitutions at the other five positions tested varied widely, depending on the CTL/peptide combination. This pattern not only supports a model whereby the Tyr253 and Ile260 residues anchor the peptide to the Kd molecule, but also implies that they are virtually inaccessible to the TCR.

Speciation of antimony (III) and antimony (V) using hydride generation for meglumine antimoniate pharmaceutical formulationsquality control

The pentavalent antimonies, mainly the meglumine antimoniate, are recommends as first-choice medicines for leishmaniasis therapy. In this work we described the development of formulations of meglumine antimoniate injectable medication, as well as the analytical methodology used in the selective determination of Sb(III) and Sb(Total) by hydride generation - inductively coupled plasma atomic emission spectrometry (HG-ICP-AES) and ICP-AES, respectively. On that purpose the analytical methodology was developed focusing on the HG-ICP-AES technique. The formulations using propylene glycol/water as vehicles in a 20:80 proportion were more appropriate for subsequent use in industrial scale. These formulations also showed a lower variation on Sb(III) percentage, no need of buffer solution to stabilize the formulation and no influence of the autoclaving in the quality of the product. The results of the development of the analytical methodology point out the proposed method as an efficient alternative for the determination of Sb(III) in the presence of large quantities of Sb(V) in injectable solutions of meglumine antimoniate, in a selective, linear, accurate and precise manner. In addition, the method showed a low limit of quantification, less interference of the matrix, and more resilience than batch techniques proposed in the Brazilian Pharmacopeia.

Identification of pharmaceutical tablets by Raman spectroscopy and chemometrics

Raman spectroscopy has become an attractive tool for the analysis of pharmaceutical solid dosage forms. In the present study it is used to ensure the identity of tablets. The two main applications of this method are release of final products in quality control and detection of counterfeits. Twenty-five product families of tablets have been included in the spectral library and a non-linear classification method, the Support Vector Machines (SVMs), has been employed. Two calibrations have been developed in cascade: the first one identifies the product family while the second one specifies the formulation. A product family comprises different formulations that have the same active pharmaceutical ingredient (API) but in a different amount. Once the tablets have been classified by the SVM model, API peaks detection and correlation are applied in order to have a specific method for the identification and allow in the future to discriminate counterfeits from genuine products. This calibration strategy enables the identification of 25 product families without error and in the absence of prior information about the sample. Raman spectroscopy coupled with chemometrics is therefore a fast and accurate tool for the identification of pharmaceutical tablets.

Combined simulation and mutagenesis analyses reveal the involvement of key residues for peroxisome proliferator-activated receptor alpha helix 12 dynamic behavior.

The dynamic properties of helix 12 in the ligand binding domain of nuclear receptors are a major determinant of AF-2 domain activity. We investigated the molecular and structural basis of helix 12 mobility, as well as the involvement of individual residues with regard to peroxisome proliferator-activated receptor alpha (PPARalpha) constitutive and ligand-dependent transcriptional activity. Functional assays of the activity of PPARalpha helix 12 mutants were combined with free energy molecular dynamics simulations. The agreement between the results from these approaches allows us to make robust claims concerning the mechanisms that govern helix 12 functions. Our data support a model in which PPARalpha helix 12 transiently adopts a relatively stable active conformation even in the absence of a ligand. This conformation provides the interface for the recruitment of a coactivator and results in constitutive activity. The receptor agonists stabilize this conformation and increase PPARalpha transcription activation potential. Finally, we disclose important functions of residues in PPARalpha AF-2, which determine the positioning of helix 12 in the active conformation in the absence of a ligand. Substitution of these residues suppresses PPARalpha constitutive activity, without changing PPARalpha ligand-dependent activation potential.

Chemical analyses of organic residues in archaeological pottery from Arbon Bleiche 3, Switzerland - evidence for dairying in the late Neolithic

Fatty acids distribution and stable isotope ratios (bulk delta(13)C. delta(15)N and delta(13)C of individual fatty acids) of organic residues from 30 potsherds have been used to get further insights into the diet at the Late Neolithic (3384-3370 BC) site of Arbon Bleiche 3. Switzerland. The results are compared with modern equivalents of animal and vegetable fats, which may have been consumed ill a mixed ecology community having agrarian, breeding, shepherd, gathering, hunting, and fishing activities. The used combined chemical and isotopic approach provides valuable information to complement archaeological indirect evidence about the dietary trends obtained from the analysis of faunal and plant remains. The small variations of the delta(13)C and delta(15)N values within the range expected for degraded animal and plant tissues, is consistent with the archaeological evidence of animals, whose subsistence was mainly based on C(3) plants. The overall fatty acid composition and the stable carbon isotopic compositions of palmitic, stearic and oleic acids of the organic residues indicate that the studied Arbon Bleiche 3 sherds contain fat residues of plant and animal origin, most likely ruminant (bovine and ovine). In several vessels the presence of milk residues provides direct evidence for dairying during the late Neolithic in central Europe. (c) 2005 Elsevier Ltd. All rights reserved.

Characterization of the ligand-binding site of the serotonin 5-HT3 receptor: the role of glutamate residues 97, 224, AND 235.

Ligand-gated ion channels of the Cys loop family are receptors for small amine-containing neurotransmitters. Charged amino acids are strongly conserved in the ligand-binding domain of these receptor proteins. To investigate the role of particular residues in ligand binding of the serotonin 5-HT3AS receptor (5-HT3R), glutamate amino acid residues at three different positions, Glu97, Glu224, and Glu235, in the extracellular N-terminal domain were substituted with aspartate and glutamine using site-directed mutagenesis. Wild type and mutant receptor proteins were expressed in HEK293 cells and analyzed by electrophysiology, radioligand binding, fluorescence measurements, and immunochemistry. A structural model of the ligand-binding domain of the 5-HT3R based on the acetylcholine binding protein revealed the position of the mutated amino acids. Our results demonstrate that mutations of Glu97, distant from the ligand-binding site, had little effect on the receptor, whereas mutations Glu224 and Glu235, close to the predicted binding site, are indeed important for ligand binding. Mutations E224Q, E224D, and E235Q decreased EC50 and Kd values 5-20-fold, whereas E235D was functionally expressed at a low level and had a more than 100-fold increased EC50 value. Comparison of the fluorescence properties of a fluorescein-labeled antagonist upon binding to wild type 5-HT3R and E235Q, allowed us to localize Glu235 within a distance of 1 nm around the ligand-binding site, as proposed by our model.

The impotence of price controls: failed attempts to constrain pharmaceutical expenditures in Greece.

BACKGROUND: While the prices of pharmaceuticals are relatively low in Greece, expenditure on them is growing more rapidly than almost anywhere else in the European Union. OBJECTIVE: To describe and explain the rise in drug expenditures through decomposition of the increase into the contribution of changes in prices, in volumes and a product-mix effect. METHODS: The decomposition of the growth in pharmaceutical expenditures in Greece over the period 1991-2006 was conducted using data from the largest social insurance fund (IKA) that covers more than 50% of the population. RESULTS: Real drug spending increased by 285%, despite a 58% decrease in the relative price of pharmaceuticals. The increase in expenditure is mainly attributable to a switch to more innovative, but more expensive, pharmaceuticals, indicated by a product-mix residual of 493% in the decomposition. A rising volume of drugs also plays a role, and this is due to an increase in the number of prescriptions issued per doctor visit, rather than an increase in the number of visits or the population size. CONCLUSIONS: Rising pharmaceutical expenditures are strongly determined by physicians' prescribing behaviour, which is not subject to any monitoring and for which there are no incentives to be cost conscious.