[Can we transfer the mechanisms of the generics market to biosimilars?]

Personalized medicines such as biologics and their generic equivalents, biosimilars, are pouring onto the pharmaceutical markets. Data of 16 private health insurance companies were used to describe the market shares of selected biosimilars available in 2014 and 2015. The purpose of this study focuses on the question of whether market access of biosimilars will lead to a price competition of the expense of innovation competition. The results show that prescriptions of biosimilars made up 37% of total prescriptions in 2015 compared to 35% in 2014, and that their share of prescription costs went up from 21% to 23% in the same period. Price competition similar to that found in the generic markets has been established for erythropoietin and filgrastim. The same has not been observed for follitropin alfa and somatropin due to the limited number of competitors and products available at this stage. No definitive conclusions can be drown from the results at this stage. Time will tell whether it will be possible for physicians and individuals with private health insurance to fully leverage the savings potential of biosimilars while safeguarding patient safety.

[The relevance of multiple sclerosis drugs in private health insurance (PHI)]. / Die Bedeutung von Multiple-Sklerose-Medikamenten in der PKV.

The development of expenses and prescriptions in the pharmacotherapy for multiple sclerosis (MS) is examined on the basis of prescription data of 14 PHI firms. The drugs for the treatment of MS are among the most top-selling drugs in the PHI. From 2007 to 2012, the expenses increase 2.33-fold. The main cause is the increas of the prescription figures. In 2012, about 8,400 privately insured persons receive an MS drug. The prevalence of MS is 2.3 times higher in women than in men Impro ved diagnostic possibilities and expensive new drugs will lead to a dynamic cost de velopment in the next years.

[Increases in pharmaceutical expenditures of PHI by monoclonal antibodies]. / Ausgabensteigerungen im Arzneimittelbereich der PKV durch monoklonale Antikörper.

The dynamics of one of the most innovative segments of health care and its impact on pharmaceutical expenditure of private health insurance (PHI) is examined on the basis of drug prescription data from private health insurance companies. The study shows that the increase in pharmaceutical expenditure can be explained partly by the new treatment possibilities available with monoclonal antibodies. The per capita expenditure on drugs with monoclonal antibodies increased by 255% from 2006 to 2010 in private health insurance, while the corresponding expenditure of all pharmaceuticals has risen by only 19% in the same period. In the coming years, growth on this scale will be a challenge for all payers in the health system.

[Prevalence of HIV treatment in PHI]. / Behandlungsprävalenz von HIV in der PKV.

The importance of HIV in PHI is examined on the basis of the "AIDS statistics" of the Association of PHI and pharmaceutical data from PHI. The observation period is from 2007 to 2011. We define a HIV case if a private insured person has submitted at least one HIV-related invoice (e.g., an antiretroviral drug) for reimbursement during the observation period. In 2011, 7,624 people in PHI received HIV therapy, that is 32% (+1888) more than in 2007. The number of new HIV cases in 2011 was 673, and thus 12% (-92) lower than in 2007. The proportion of people receiving antiretroviral therapy in PHI is higher than in the general population in Germany. HIV infections occur in all age groups, but peaks in the age group 41 to 50 years old. Men are affected more than women. In contrast, the number of HIV cases among 11- to 15-year-old girls is higher compared to boys of the same age.

[Pharmaceutical prescription for multiple sclerosis : evaluation of pharmaceutical consumption at private health insurance]. / Arzneimittelversorgung bei Multipler Sklerose : Evaluation des Arzneimittelverbrauchs bei der Privaten Krankenversicherung.

BACKGROUND: For persons covered by statutory health insurance (SHI) an increase in the number of defined daily doses (DDD) for pharmaceuticals to treat multiple sclerosis (MS) is known but so far there has been no comparable survey for private health insurance (PHI). Moreover, there are gaps in knowledge of the reasons for the increase and concerning the number of the MS patients in Germany. MATERIAL AND METHODS: The study is based on pharmaceutical data of the PHI in Germany. The projection takes into account the different prevalence and the different male/female relationship in SHI and PHI in an extrapolation to the total population. RESULTS: From 2006 to 2010 the number of DDDs of MS pharmaceuticals increased by approximately 91.6 % (SHI 39.9 %) per insured person. The increase in the PHI is mainly based for on an increase in the number of MS patients. The total number of MS patients in Germany was estimated to be approximately 146,000 whereby some 12,700 MS patients (8.7 %) were insured in PHI. CONCLUSION: There is a need for research into the reasons for the increase in MS patients. The disproportional increase in the PHI compared to SHI could be a result of the increase of insured persons and an increased inclusion of persons with a higher risk of the disease.

Adult fulminant subacute sclerosing panencephalitis: pathological and molecular studies--a case report.

Subacute sclerosing panencephalitis is an uncommon progressive neurological disorder caused by a persistent defective measles virus, typically affecting children. We describe a case of fulminant subacute sclerosing panencephalitis in a 25-year-old male. Brain tissue biopsy showed histologic evidence of encephalitis with eosinophilic intranuclear inclusion bodies (Cowdry Type A and B), intracytoplasmic inclusion bodies, perivascular lymphoplasmacytic infiltration and gliosis. Immunohistochemical studies were positive using an anti-measles antibody. Reverse transcriptase-PCR detected measles virus RNA and phylogenetic analysis indicated a C2 genotype. The rare adult-onset form is often atypical and difficult to diagnose and should be included in the differential diagnosis of subacute "unexplained" neurological diseases and uncommon infectious disorders.

Simulation of congenital heart defects: a novel way of training in echocardiography.

BACKGROUND: Echocardiography is one of the most important diagnostic imaging modalities in paediatric cardiology. Owing to the large number of lesions, achieving expertise often requires years of training. Echocardiography is still taught using the apprenticeship model, which is time- and personnel consuming. OBJECTIVES: To extend the echocardiography simulator EchoCom to enable simulation of congenital heart lesions and validate it for training in paediatric echocardiography. METHODS: The simulator consists of a life-size manikin, a dummy transducer with attached three-dimensional (3D) tracking system and a computer application. Transthoracic real-time (RT) 3D echocardiographic datasets were collected and embedded into the simulator. Two-dimensional images were calculated and resliced from these datasets according to the position of the tracking sensor. Ten RT 3D datasets of congenital heart lesions were selected for validation. Datasets were blinded and without additional information presented to 43 participants who were stratified according to their expertise (12 experts, 16 intermediates, 15 beginners). Participants were asked to list the relevant findings and make a diagnosis. Construct validation was tested comparing diagnostic performance for each group. Face and content validation were tested using a standardised questionnaire. RESULTS: Participants judged the simulator as realistic and useful. The main drawback was the adult size of the manikin. The diagnostic performance of each group differed significantly proving construct validity. CONCLUSIONS: According to this validation the prototype simulator could make a significant contribution to training in the use of echocardiography in congenital heart disease.

[The pharmaceutical cost of elderly people in private health insurance]. / Die Arzneimittelausgaben alterer Menschen in der privaten Krankenversicherung.

In this paper the author analyses the prescription of pharmaceuticals for elderly private insured persons. Data from eight firms form the basis of the survey. The main focus lies in the analysis of the expenditure per capita and the distribution of the pharmaceuticals costs. It will illustrate that costs for elderly private insured persons will have a great impact on the expenditure for the private health insurance companies in the coming years.

EchoComTEE - a simulator for transoesophageal echocardiography.

Transoesophageal echocardiography (TOE) requires extensive hands-on training, and it is for this purpose we have designed EchoComTEE, a simulator for TOE. It consists of a manikin and dummy probe; according to the position of the dummy probe (tracked by an electromagnetic sensor), two-dimensional (2D) images are calculated from three-dimensional (3D) data sets. Echocardiographic images are presented side-by-side with a virtual scene consisting of a 3D heart, probe tip and image plane. In this way the trainee is provided with visual feed-back of the relationship between echocardiogram and image plane position. We evaluated the simulator using a standardised questionnaire. Twenty-five experts and 31 novice users participated in the study. Most experts graded the simulator as realistic and all recommended its use for training. Most novice users felt the simulator supported spatial orientation during TOE and, as anaesthetists often do not have training in transthoracic echocardiography, in this group the TOE simulator might be particularly useful.

Moderate versus deep hypothermia for arterial switch operation.

BACKGROUND: We evaluated the impact of moderate versus deep intraoperative hypothermia on postoperative morbidity in patients receiving a standard arterial switch operation (ASO). METHODS: 71 newborns underwent ASO from 9/98 onwards. Patients were operated using moderate hypothermia (M, 24 degrees C to 30 degrees C, n=21) or deep hypothermia (D, 16-22 degrees C, n=50). Mean patient age was 9.5 (M) versus 10 (D) days, body weight 3.6+/-0.7 (M) versus 3.8+/-0.9 kg (D), P=n. s. Coronary anatomy was complex in 9.5% (M) versus 16% (D) of patients; additional VSD was present in 23.8 (M) versus 38% (D) of the patients, respectively. Mean follow-up is 2.3+/-1.6 years. RESULTS: Intraoperative rectal temperature was 25+/-2 degrees C (M) and 19+/-2 degrees C (D). Cross-clamping time was 95+/-24 (M) versus 108+/-31 min (D), P=n. s. Conventional ultrafiltration was performed at 114+/-46 (M) versus 129+/-69 ml/kg (D), P=n. s. One patient (D) with complex anatomy suffered myocardial ischemia required ECMO support and died. In-hospital mortality was 1.4%. All other patients were safely weaned from extracorporeal circulation with moderate inotropic support. Secondary chest closure was performed in 33% (M) versus 54 % (D) of the patients. Patients were extubated after 7.4 (M) versus 6 (D) days. There was no renal failure and no other serious complications. CONCLUSIONS: ASO can be safely performed using moderate hypothermia, even with complex anatomy, leading to comparatively good results compared to a conventional approach.

Measles outbreak in the Provence-Alpes-Côte d'Azur region, France, January-July 2003.

At the end of May 2003, the Marseilles Hospital Centre's virology laboratory informed the French public heath institute of 5 cases of confirmed measles among young adults living in Marseilles. An investigation was conducted, consulting different community and hospital health services, to determine the virus circulation in the Provence-Alpes-Côte d'Azur (PACA) region by the southern interregional epidemiological cell. The investigation identified 259 cases: 183 clinical, 74 serologically confirmed and 2 epidemiologically linked cases. The first cases were identified during the first six months of 2003, with a peak in April. This outbreak of measles in the PACA region was favoured by poor vaccination coverage, which created groups of susceptible population. The real number of cases was probably higher than the number identified. This investigation has outlined the limitations of the measles surveillance system in France: the sentinel network had not detected any case for this period. France needs to reach the WHO objective of measles elimination by 2010 and the surveillance tools used must be those already used in the most countries that are furthest advanced in the elimination process. To reach this goal, the Direction Générale de la Santé has nominated a working group to be in charge of proposing a national plan to interrupt indigenous measles transmission in France.

Measles outbreak in the Provence - Alpes - Côte d'Azur region, France, January - July 2003.

At the end of May 2003, the Marseilles Hospital Centre's virology laboratory informed the French public heath institute of 5 cases of confirmed measles among young adults living in Marseilles. An investigation was conducted, consulting different community and hospital health services, to determine the virus circulation in the Provence-Alpes-Côte d'Azur (PACA) region by the southern interregional epidemiological cell. The investigation identified 259 cases: 183 clinical, 74 serologically confirmed and 2 epidemiologically linked cases. The first cases were identified during the first six months of 2003, with a peak in April. This outbreak of measles in the PACA region was favoured by poor vaccination coverage, which created groups of susceptible population. The real number of cases was probably higher than the number identified. This investigation has outlined the limitations of the measles surveillance system in France: the sentinel network had not detected any case for this period. France needs to reach the WHO objective of measles elimination by 2010 and the surveillance tools used must be those already used in the most countries that are furthest advanced in the elimination process. To reach this goal, the Direction Générale de la Santé has nominated a working group to be in charge of proposing a national plan to interrupt indigenous measles transmission in France.

Dendritic cells recruitment and in vivo priming of CD8+ CTL induced by a single topical or transepithelial immunization via the buccal mucosa with measles virus nucleoprotein.

The buccal mucosa, a prototype of pluristratified mucosal epithelia, contains a network of directly accessible class II(+) epithelial dendritic cells (DC), similar to skin Langerhans cells. We showed that a single buccal immunization with measles virus nucleoprotein (NP), by either topical application onto or intradermal injection in the buccal mucosa, induced in vivo priming of protective class I-restricted specific CD8(+) CTL. Both routes of immunization with NP induced a rapid recruitment of DC into the mucosa, which peaked at 2 h and decreased by 24 h. Treatment of mice with Flt3 ligand resulted in an increased number of DC in the buccal mucosa and enhanced the frequency of IFN-gamma-producing NP-specific effectors and the NP-specific CTL response generated after buccal immunization with NP. Finally, NP-pulsed bone marrow-derived DC induced NP-specific IFN-gamma-producing cells upon adoptive transfer to naive mice. These data demonstrate that a viral protein delivered to DC of the buccal mucosa induces in vivo priming of protective anti-viral CD8(+) CTL.

Interaction of measles virus (Hallé strain) with CD46: evidence that a common binding site on CD46 facilitates both CD46 downregulation and MV infection.

CD46 acts as a cellular receptor for vaccine strains of measles virus (MV). The MV/CD46 interaction-mediated by the MV attachment glycoprotein, the hemagglutinin (H)-not only facilitates infection but also induces CD46 downregulation. A conflict of opinion exists as to whether a single MVH binding site on CD46, or two separate sites, facilitates the two phenomena. To investigate this conundrum we first tested and compared a panel of CD46-specific monoclonal antibodies (mAbs) for their capacity to block both processes. One (mAb 13/42) abrogated both MV fusion and CD46 downregulation. Mutation of an amino acid (arg59 in the SCR1 of CD46) essential for the epitope of mAb 13/42 resulted in the abrogation of both CD46 downregulation and viral fusion. This strongly suggests that the same MV binding site on CD46 is responsible for both CD46 downregulation and MV infection.

Measles virus infects human dendritic cells and blocks their allostimulatory properties for CD4+ T cells.

Measles causes a profound immune suppression which is responsible for the high morbidity and mortality induced by secondary infections. Dendritic cells (DC) are professional antigen-presenting cells required for initiation of primary immune responses. To determine whether infection of DC by measles virus (MV) may play a role in virus-induced suppression of cell-mediated immunity, we examined the ability of CD1a+ DC derived from cord blood CD34+ progenitors and Langerhans cells isolated from human epidermis to support MV replication. Here we show that both cultured CD1a+ DC and epidermal Langerhans cells can be infected in vitro by both vaccine and wild type strains of MV. DC infection with MV resulted within 24-48 h in cell-cell fusion, cell surface expression of hemagglutinin, and virus budding associated with production of infectious virus. MV infection of DC completely abrogated the ability of the cells to stimulate the proliferation of naive allogeneic CD4+ T cell as early as day 2 of mixed leukocyte reaction (MLR) (i.e., on day 4 of DC infection). Mannose receptor-mediated endocytosis and viability studies indicated that the loss of DC stimulatory function could not be attributed to the death or apoptosis of DC. This total loss of DC stimulatory function required viral replication in the DC since ultraviolet (UV)-inactivated MV or UV-treated supernatant from MV-infected DC did not alter the allostimulatory capacity of DC. As few as 10 MV- infected DC could block the stimulatory function of 10(4) uninfected DC. More importantly, MV-infected DC, in which production of infectious virus was blocked by UV treatment or paraformaldehyde fixation, actively suppressed allogeneic MLR upon transfer to uninfected DC-T-cultures. Thus, the mechanisms which contribute to the loss of the allostimulatory function of DC include both virus release and active suppression mediated by MV-infected DC, independent of virus production. These data suggest that carriage of MV by DC may facilitate virus spreading to secondary lymphoid organs and that MV replication in DC may play a central role in the general immune suppression observed during measles.

Inhibition of HIV-1, HIV-2 and SIV envelope glycoprotein-mediated cell fusion by calmodulin.

Calmodulin, an EF-hand protein, inhibited the fusion between CD4+ human cells and cells stably expressing HIV-1 envelope proteins. Fusion was also inhibited when HIV-1, HIV-2 or SIV envelope glycoproteins were expressed by vaccinia virus (VV) recombinants, but calmodulin did not inhibit syncytia formation induced by measles virus glycoproteins. Calmodulin also inhibited fusion induced by vPE17, a VV-recombinant expressing a truncated form of HIV-1gp160 which lacks the two known calmodulin-binding sites located in the cytoplasmic domain of gp41. The inhibitory activity was specific to calmodulin among the EF-hand proteins. These observations may be important in understanding the mechanism of retroviral envelope glycoprotein-mediated cell fusion. Several possible mechanisms of action are discussed.

DNA immunization circumvents deficient induction of T helper type 1 and cytotoxic T lymphocyte responses in neonates and during early life.

The relative deficiency of T helper type 1 (Th1) and cytotoxic T lymphocyte (CTL) responses in early life is associated with an increased susceptibility to infections by intracellular microorganisms. This is likely to reflect a preferential polarization of immature CD4 T cells toward a Th2 rather than a Th1 pattern upon immunization with conventional vaccines. In this report, it is shown that a single immunization within the first week of life with DNA plasmids encoding viral (measles virus hemagglutinin, Sendai virus nucleoprotein) or bacterial (C fragment of tetanus toxin) vaccine antigens can induce adult-like Th1 or mixed Th1/Th2 responses indicated by production of IgG2a vaccine-specific antibodies and preferential secretion of interferon-gamma (IFN-gamma) compared with interleukin (IL)-5 by antigen-specific T cells, as well as significant CTL responses. However, in spite of this potent Th1-driving capacity, subsequent DNA immunization was not capable of reverting the Th2-biased responses induced after early priming with a recombinant measles canarypox vector. Thus, DNA vaccination represents a novel strategy capable of inducing Th1 or mixed Th1/Th2 and CTL responses in neonates and early life, providing it is performed prior to exposure to Th2-driving conventional vaccine antigens.

Self-association of truncated forms of HIV-1 gp120.

HIV-1 gp120 and truncated forms were expressed in HeLa T4 cells by vaccinia recombinant viruses. The truncated gp120 molecules consisted of N-terminal overlapping envelope proteins of 204, 287 and 393 amino acids respectively. Immunoprecipitation with specific monoclonal antibodies and SDS-PAGE analyses of HIV-1 gp120 revealed bands corresponding to low amounts of secreted and cell-bound stable dimers. In contrast, the truncated forms of gp120 expressed larger amounts of SDS-stable putative dimers and the amounts observed were inversely proportional to their size. The shortest gp120 mutant (204 aa) was found to be secreted almost exclusively as a dimer. The processing of gp120 and its truncated forms was further investigated in the presence of inhibitors of N-glycosylation. Monomers and dimers migrated on gels with the same relative changes, confirming that the protein with the higher molecular weight is a multimer of the smaller one. The putative dimeric form of the truncated gp120s could be stabilized by chemical cross-linking. Finally, the possible existence of an association domain in the N-terminal 204 amino acids (aa) of gp120 is discussed.

Mucosal and systemic immune responses to measles virus haemagglutinin in mice immunized with a recombinant vaccinia virus.

The immune response to a vaccinia virus recombinant expressing the measles virus haemagglutinin (VV-HA) was compared after parenteral or mucosal immunizations in mice. Parenteral immunizations with 10(6) p.f.u. VV-HA induced HA-specific antibody-producing cells (IgG>IgA) and HA-specific class I-restricted cytotoxic T lymphocytes (CTL) in the spleen. In contrast, intranasal administrations of 10(6) p.f.u. of VV-HA induced HA-specific spot-forming cells in the spleen (IgG>IgA) and the lungs (IgA>IgG), and HA-specific CTL in the spleen. Co-immunization by the nasal route with VV-HA and cholera toxin enhanced HA-specific immune responses. Oral immunizations with 10(8) p.f.u. of VV-HA generated low numbers of HA-specific IgA-producing cells in the lamina propria of the gut, and a weak HA-specific CTL activity in the spleen and mesenteric lymph nodes. Oral co-immunization with VV-HA and cholera toxin greatly enhanced the level of HA-specific spot-forming cells in the lamina propria (IgA>IgG). Interestingly, intrajejunal immunizations with 10(8) p.f.u. VV-HA alone induced high levels of anti-HA IgG-producing cells in the spleen and anti-HA IgA-secreting cells in the lamina propria of the gut. These data show that (i) VV-HA by the nasal route is immunogenic and generates a measles-specific mucosal immune response in the lung, which represents the primary site of replication of measles virus and that (ii) VV-HA can also induce measles-specific immunity in the intestine provided that it is protected from degradation in the gastrointestinal tract, or that cholera toxin is used as an adjuvant.