Impact of regulatory measures on antipsychotics drug consumption in Castilla y León, Spain.

OBJECTIVES: Antipsychotics are currently used to treat different diseases; even some off-labelled conditions are treated with this medication. Consumption and cost of antipsychotic drugs sharply increased in Spain after second-generation drugs were marketed; several regulatory measures were adopted to curb this trend. The aim of this study was to examine the impact of these measures upon the use and cost of antipsychotics. STUDY DESIGN: Study of drug use (SDU) from 1995 to 2012. Consumption and cost data were obtained from the CONCYLIA database; this database contains the retail community pharmacies sales of medicinal products reimbursed by the National Health System in Castilla y León (Spain). METHODS: Data are presented as defined daily doses per 1000 inhabitants per day (DID) and day treatment cost (DTC). RESULTS: First-generation antipsychotics prescriptions gradually decreased from 3.0 to 1.8 DID; meanwhile, prescriptions for second-generation antipsychotics considerably increased from 0.3 to 9.9 DID. The use of risperidone dropped after the marketing of its structural derivative paliperidone with a similar efficacy but with a substantially higher cost per day. In 2011 and thereafter, patients in Spain began to pay a part of the medications cost, but this did not decrease antipsychotics consumption. Global cost of antipsychotics only began to fall after measures were adopted to lower the price of medicines because of the economic collapse in Spain after May 2010. CONCLUSION: Several health policy measures have tried to reduce antipsychotics consumption in Spain, special ways of dispensing, marketing of generic drugs and special economic measures for patients. These measures eventually failed to avoid the increase in antipsychotics use. The cost only dropped when lowering prescription drug prices took place.

Hip fracture rates and bisphosphonate consumption in Spain. An ecologic study.

INTRODUCTION: Bisphosphonates are used worldwide to treat osteoporosis and, thus, to prevent fractures. Though they have been proven in clinical trials to avoid some fractures, their effectiveness in reducing hip fractures is unclear. The aim of the present study was to explore the relationship between bisphosphonate use and hip fracture trends in Spain. METHODS: For this purpose, an ecologic study spanning 2002 to 2008 was conducted in Spain. Consumption data were obtained from the Spanish Ministry of Health and Social Policy. The number of hip fractures was obtained from hospital discharges; annual hip fracture rates were determined and standardized using the Spanish 2002 population census. A linear regression was performed between fracture rate and use of bisphosphonates; R(2) and Pearson correlation coefficient were calculated. RESULTS: From 2002 to 2008, dispensed prescriptions of bisphosphonates in Spain increased from 3.28 to 17.66 DDD/1,000 inhabitants per day. In the same period, the crude hip fracture rate increased from 2.85 to 3.02 cases per 1,000 inhabitants older than 50 years; however, when age standardized rates were estimated, the rate declined from 2.85 to 2.79. Analyzed by sex, the standardized rate for men slightly increased from 1.45 to 1.48, while for women the rate significantly dropped from 4.00 to 3.91. CONCLUSION: A small effect of bisphosphonates on hip fracture rates can not be ruled out; however, other factors might partially explain this decline. Assuming this medication was the only cause for hip fracture rate reduction, the elevated medication cost to avoid a single hip fracture makes it necessary to explore less expensive interventions.

Guillain-Barré syndrome and influenza vaccines: current evidence.

OBJECTIVE: Guillain-Barré Syndrome (GBS) as a consequence of influenza vaccination is a relevant topic, yet to be clarified, which raises concern both amongst health care personnel and the general population. Every study and pharmacovigilance system point to need of further research and the importance of continuous monitoring of safety regarding influenza vaccines. The aim of the present study is to investigate the publication of new data since the realisation of our meta-analysis of GBS and influenza vaccines (published in 2015). METHODS: A systematic revision of PubMed, Embase, and Web of Knowledge (WOS) databases has been carried out. These report observational studies assessing GBS risk after the administration of influenza vaccines from May 2014 up to July 20th, 2017. RESULTS: The research yielded 107 articles. Only three studies met established inclusion criteria and referred to an estimation GBS risk after some influenza vaccine. Two studies investigated GBS risk by the pandemic A/H1N1 vaccine, while only one looked into season vaccines. CONCLUSIONS: The present systematic review, conducted after the publication of our previous meta-analysis, seems to confirm its previous results. Therefore, GBS should be considered an infrequent adverse effect of influenza vaccination, which should not negatively influence its acceptance. Unfortunately, very few of the systematically surveyed studies meeting inclusion criteria. This fact sharply contrasts with the current consensus as to the need of continuously monitoring the safety of influenza vaccines.

Drug neosensitization during anticonvulsant hypersensitivity syndrome.

Anticonvulsant hypersensitivity syndrome (AHS) is a rare, severe drug hypersensitivity reaction included in the drug-related rash with eosinophilia and systemic symptoms syndrome (DRESS), in which a transient state of immune suppression and reactivation of latent virus infections have been observed. We describe 5 patients who developed neosensitization to different drugs taken during a previous episode of anticonvulsant-related DRESS, in whom skin prick, intradermal and/or patch tests were performed to confirm the diagnosis of drug hypersensitivity. In 1 patient, transient hypogammaglobulinemia was observed during the AHS. Four of the 5 patients developed a delayed skin eruption or a delayed systemic hypersensitivity reaction after intake of a drug that they had also taken during a previous anticonvulsant DRESS which had occurred months or years earlier; in the fifth, a possible reaction was prevented thanks to the allergy workup. The diagnosis of drug allergy was demonstrated by positive delayed reaction to intradermal test with amoxicillin in 2 cases, positive patch tests to paracetamol and amitriptyline in 2 cases, and by clinical evidence of ceftriaxone erythroderma in one. The possibility of neosensitization to drugs administered during anticonvulsant-related DRESS should be considered. A transient state of immunosuppression induced during the anticonvulsant-related DRESS may trigger latent virus reactivation and massive nonspecific immune system response, which may lead to breakdown of tolerance to other drugs present at that time in the organism.

Decrease of skin and bronchial sensitization following short-intensive scheduled immunotherapy in mite-allergic asthma.

Changes induced by high-dose intensive specific immunotherapy (ISI) were studied in 18 patients with mite-allergic bronchial asthma and compared with 18 control patients. A biologically standardized well-characterized Dermatophagoides pteronyssinus extract of known potency was used both for in vivo tests and ISI. Immediate D pteronyssinus skin tests (measured by parallel-line bioassay) were reduced 20-fold in ISI treated patients, and delayed skin responses significantly decreased and even disappeared following ISI. Bronchial tolerance to D pteronyssinus increased an average of ten times in ISI-treated patients, whereas nonspecific hyperreactivity remained unchanged. ISI induced significant specific IgG and IgG4 increases but no changes were observed in specific IgG1,2 and 3 or in specific IgE. Clinical score did not change significantly after ISI, short ISI schedule with a well-characterized mite extract greatly reduced the degree of mite sensitization (skin and bronchial allergic responses), but clinical disease failed to improve significantly, probably owing to the lack of influence of ISI in nonspecific hyperreactivity.

Urticaria to cetirizine.

A patient with recurrent idiopathic urticaria reported exacerbations after treatment with cetirizine. Prick test to cetirizine was negative. Double-blind challenge tests with mizolastine, loratadine, fexofenadine, dexchlorpheniramine, ebastine, ketotifen, and placebo were negative, whereas hydroxyzine and its active metabolite, cetirizine, reproduced the urticaria. Identification of uncommon adverse reactions to H1 antihistamines is important, particularly because they may mimic the underlying disease.

Successful treatment of chronic idiopathic urticaria associated with thyroid autoimmunity.

The prevalence of thyroid autoimmunity is high in patients with chronic idiopathic urticaria (CIU), but in few selected patients the possible clinical benefit of levothyroxine sodium or antithyroid drugs has been studied. The objective of the present study was to confirm the prevalence of antithyroid antibodies in patients with CIU and to investigate the clinical response to levothyroxine sodium or methimazole. Antithyroglobulin and antiperoxidase antibodies were measured in 170 consecutive patients with CIU. Twenty-five (14.7%) had an antithyroglobulin or antiperoxidase antibody levels > 180 lU/ml and all but three were women. Twenty patients with CIU and thyroid autoimmunity were treated with levothyroxine sodium if hypothyroidism or normal thyroid function were present (18 patients) and with methimazole if hyperthyroidism was detected (two patients). Clinical response was evaluated by a clinical score. Autologous serum skin test before treatment was performed in 18 patients with thyroid autoantibodies. Urticaria resolved rapidly in two patients with Graves' disease. The clinical response of urticaria to levothyroxine sodium treatment was good in 15 patients and partial in two, whereas only one patient showed no improvement in clinical score (p < 0.0005). No changes in the antithyroglobulin or antiperoxidase levels were detected. Five patients reported adverse effects. The autologous serum skin test was positive in 10 patients and negative in eight. After successful treatment the test was repeated in six patients, proving negative in four and significantly diminished in two. We concluded that patients with CIU and thyroid autoimmunity benefit from treatment with levothyroxine sodium or antithyroid drugs. Antithyroid antibodies and positive autologous serum skin test in these patients could be markers of autoimmune disease with several target organs.

Serum sickness-like syndrome due to mosquito bite.

Local inflammatory reactions at the site of a mosquito bite are frequent. Immediate systemic reactions have occasionally been reported. The first case of a patient with relapsing episodes of a serum sickness-like syndrome following mosquito bites is reported herein. A 62-year-old patient came to the emergency room complaining of sudden malaise, chills, fever, headache, cervical lymph node enlargement, arthromyalgia, generalized purpura and leukopenia 6 h after a mosquito bite. He had experienced multiple similar episodes in the last 20 years, also following mosquito bites. Infectious and autoimmune diseases were ruled out. Serum IgE was 9,102 kU/l. Prick test of whole-body Culex pipiens extract was positive. Specific IgE to Aedes communis was 2.25 kU/l. SDS-PAGE immunoblotting of the patient's serum with whole-body C. pipiens extract revealed 43 and 17 kDa IgG-binding proteins and 22 and 17 kDa IgE-binding proteins, neither of which were found with control sera. Skin biopsy was consistent with leukocytoclastic vasculitis. The presence of both mosquito-specific IgE and IgG in the patient's serum suggest a possible cooperative immune response leading to clinical manifestations of serum sickness.

Usefulness of patch tests for diagnosing selective allergy to captopril.

Captopril, enalapril, and lisinopril are angiotensin-converting enzyme (ACE) inhibitors widely prescribed for hypertension and heart failure. Cutaneous side effects of captopril include angio-edema, anaphylactoid reactions, maculopapular eruptions, pitiryasis rosea-like rash, toxic erythema, and exfoliative dermatitis. Some of the immunological captopril-induced cutaneous adverse reactions have been diagnosed in recent years by patch tests. A case of a cutaneous immune adverse reaction to captopril with tolerance to enalapril and lisinopril demonstrated both by patch tests and double-blind challenge tests is reported for the first time. A 71-year-old nonatopic woman suffered a generalized pruriginous maculopapular rash. Two months earlier, she had started oral treatment with captopril 50 mg t.i.d and glibenclamide 5 mg daily. After the rash appeared, she stopped both drugs and the reaction cleared. A skin biopsy from one of the lesions showed perivascular lymphocytic infiltrate of the upper dermis. Skin prick tests with captopril and glibenclamide and patch tests with enalapril, lisinopril, and glibenclamide at 1% and 10% pet., and with mercaptobenzothiazole (a sulfhydryl group-containing chemical at 1% pet were negative. Only patch tests with captopril at 1% and 10% concentrations were positive at 48 h. Oral double-blind challenge tests with glibenclamide, enalapril, lisinopril, and placebo showed good tolerance. The patient was advised to avoid only captopril. Because captopril is the only ACE inhibitor containing a sulfhydryl group and has occasionally been implicated in complex immunological diseases, this chemical group has been considered the culprit of allergic reactions to captopril. The lack of cross-reactivity between captopril, enalapril, and benazepril has been demonstrated in a few patients by patch tests. In our patient, patch tests identified captopril as the drug responsible for a probably immune adverse reaction not due to the sulfhydryl group. Patch tests are useful and safe in the diagnostic work-up of allergic drug reactions and in studies of cross-sensitivity among ACE inhibitors.

Allergic eosinophilic gastroenteritis in a child with Crohn's disease.

A case of a child with Crohn's disease who developed an eosinophilic gastroenteritis is reported. Although symptoms of eosinophilic gastroenteritis at age 8 could mimic those of Crohn's disease, laboratory, radiographic and histologically studies are clearly different. Peripheral blood eosinophilia (7,476 cells per mm3), high serum IgE level (1,050 kU/l) and normal C-reactive protein and erythrocyte sedimentation rate are common in eosinophilic gastroenteritis and uncommon in Crohn's disease. Eosinophilic gastroenteritis was due to bovine serum albumin (BSA) hypersensitivity, confirmed with skin tests, serum levels to specific IgE and a SDS-PAGE IgE-immunoblotting. A strict meat-free diet was started, with progressive relief of symptoms and decrease of eosinophil count twelve months later; the patient became fully symptom-free and eosinophil count was normal.

Influence of mite growth culture phases on the biological standardization of allergenic extracts.

House dust mites are a well known cause of asthma and other respiratory allergies. In order to improve the standardization of allergenic extracts for diagnosis and immunotherapy, it is important to determine the frequency and concentration of the components, both the major and the minor allergens during the growth period of the mite population. In a previous paper we demonstrated that the laboratory cultures of Dermatophagoides pteronyssinus and Dermatophogoides farinae exhibited three well differentiated growth phases: latency, exponential growth, and death of the culture. Biological standardization of extracts from the two mite species were carried out by skin prick tests in a group of 20 patients, using different concentrations of the extracts at the three growth phases. The patient sera were also studied by means of the RAST technique to determine the levels of specific IgE for each phase. The extracts produced from the exponential growth phase of the cultures revealed six times more relative allergenic activity in in vivo studies, and average RAST values were approximately three times higher than those extracts from latency and death phases. The reproducibility of the extract production method was assessed by comparing different batches obtained in similar conditions. The results showed batch-to-batch homogeneity allergenic activity. In conclusion, it was demonstrated that extracts obtained from cultures with the highest concentration of live mites (maximum growth phase) render the best diagnostic results in vivo and in vitro.

Specific immune response to Parietaria judaica plant profilin: a low T cell proliferative response supports high IgE and skin prick test.

BACKGROUND: allergic disease caused by Parietaria judaica (Pj) has been widely documented in Mediterranean area. Profilins have been identified as widely distributed allergenic proteins. The role of Pj profilin in specific immune response in Pj-sensitized patients is unknown. METHODS: skin prick test and determination of specific and total IgE levels in serum were performed in all patients (n = 28) and non-allergic controls (n = 18). Peripheral blood mononuclear cells (PBMC) were isolated from both groups and stimulated with crude extract or highly purified Pj profilin. The production of type I and type II cytokines was determined by specific and polyclonal stimuli in patients and controls. T-cell lines specific to Pj profilin were established and cross-reactivity with another highly purified profilin from Phleum pratense (Phl p) was evaluated. RESULTS: Pj profilin-sensitized patients showed a small but significantly increased in T-cell proliferative response to this profilin compared with non-atopic controls. The production of interleukin (IL)-4 and interferon (IFN)-γ in response to the specific stimulus was undetectable. However, the production of IL-4 in response to a polyclonal stimulus [phytohemagglutinin (PHA)] was significantly higher in atopic patients than in controls. The T-cell response did not correlate with the magnitude of response to skin prick tests with Pj profilin or with Pj-specific serum IgE levels. In addition, the production of IL-4 in response to a polyclonal stimulus (PHA) did not correlate with the individual skin prick tests to Pj profilin or with Pj-specific IgE levels in serum. The T-cell lines tested showed no cross-reactivity with Phl p profilin. CONCLUSIONS: our results suggest that Pj profilin is partly responsible for the T-cell-mediated response in patients allergic to Pj. The high skin reactivity to Pj profilin is these patients was accompanied by a small increase in the T-cell response to this profilin. The response was highly specific since Pj profilin specific T-cell lines showed no cross-reactivity with a highly homologous profilin from Phl p. The lack of correlation between the proliferative T-cell response and polyclonal IL-4 production with allergen-specific serum IgE and skin reactivity probably indicates that some of the responding T-cells may be involved in immune reactions other than those supporting IgE production.

[Sensitization to chymopapain in patients treated with chemonucleolysis]. / Sensibilización a la quimopapaína en pacientes tratados con quimionucleólisis.

BACKGROUND: Chemonucleolysis (intradisk administration of chymopapain) is a procedure to treat intervertebral disk hernia. Recently, its use has been questioned due to the development of anaphylactic reactions in patients sensitized to chymopapain. The prevalence of sensitization to chymopapain has been evaluated before and after chemonucleolysis, and the possibility to establish risk groups through the allergy history has been assessed. METHODS: 104 consecutive patients who were candidates to chemonucleolysis were evaluated with an allergy questionnaire, cutaneous tests to aeroallergens and to chymopapain, and chymopapain-specific IgE. The two latter tests were repeated one month after chemonucleolysis. RESULTS: Only 2 patients (1.9%) showed evidence of chymopapain sensitization before the procedure. Sixteen patients (16%) were sensitized after chemonucleolysis. None of the possible risk factors evaluated in the allergy questionnaire (atopy, drug allergy, papaya occupational exposure or use of additives, cosmetics or drugs containing papaine) were significantly related with the risk of sensitization to chymopapain. CONCLUSIONS: The prevalence of chymopapain sensitization in the study group was low. The allergy questionnaire (atopy, drug allergy, use of papaya, occupational history did not identify sensitized patients. Cutaneous tests and specific IgE are the best method to detect chymopapain sensitization. The remarkable rate of sensitization after chemonucleolysis may partially limit the usefulness of the procedure.

[Outbreak of asthma caused by soybean dust allergy. Clinical and immunologic study of the affected patients]. / Epidemia de asma alérgica a polvo de soja. Estudio clínico e inmunológico de los pacientes afectados.

BACKGROUND: To study the clinical and immunological data of patients affected by a soybean asthma outbreak in Tarragona, Spain. PATIENTS AND METHODS: Characteristics of previous asthma, emergency rooms records and immediate outcome of 15 patients who attended emergency room departments the epidemic day were recorded. Functional respiratory studies, skin prick tests to aeroallergens, and prick tests, specific IgE and immunoblotting to soybean extracts were performed in all patients. RESULTS: Thirteen patients were sensitized to soybean proteins. All of them were atopic (most sensitized to house dust mites) and half had started asthma symptoms after their thirties. The epidemic crisis was particularly severe in patients over 50 years, daily chronic asthma, severe obstructive pattern and/or non receiving steroids. Four patients were admitted to intensive care units. Seven patients showed asthma exacerbations (late reactions) 24 h after the beginning of the epidemic crisis. Specific IgE against a 5-6 kD and a 15.5-17 kD soybean proteins was detected in the sera of 8 patients and 10 patients, respectively. CONCLUSIONS: The outbreak affected atopic patients exposed to soybean dust. The severity of the crisis was related with the previous severity of asthma. Besides the well known 5-6 kD allergenic soybean protein, the 15.5-17 kD protein seems also to be implicated in the sensitization of most of these patients.