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This study aimed to assess the cost-utility and budget impact of dual to single HER2 targeted neoadjuvant therapy for HER2-positive breast cancer in Sri Lanka. A five-health state Markov model with lifetime horizon was used to assess the cost-utility of neoadjuvant trastuzumab (T) plus pertuzumab (P) or lapatinib (L) compared to single therapy of T with chemotherapy (C), in public healthcare system and societal perspectives. Input parameters were estimated using local data, network meta-analysis, published reports and literature. Costs were adjusted to year 2021 (1USD = LKR194.78). Five-year budget impact for public healthcare system was assessed. Incremental cost-effectiveness ratios in societal perspective for neoadjuvantLTC plus adjuvantT (strategy 3), neoadjuvantPTC plus adjuvantT (strategy 2), neoadjuvantLTC plus adjuvantLT (strategy 5), and neoadjuvantPTC plus adjuvantPT (strategy 4) compared to neoadjuvantTC plus adjuvantT (strategy 1) were USD2716, USD5600, USD6878, and USD12127 per QALY gained, respectively. One GDP per-capita (USD3815) was considered as the cost-effectiveness threshold for the analysis. Even though only the ICER for strategy 3 was cost-effective, uncertainty of efficacy parameter was revealed. For strategy 2 neoadjuvant PTC plus adjuvant T, a 25% reduction of neoadjuvant regimen cost was required to be cost effective for use in early HER2 positive breast cancer.
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Neoplasias de la Mama , Análisis Costo-Beneficio , Lapatinib , Terapia Neoadyuvante , Receptor ErbB-2 , Trastuzumab , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/economía , Neoplasias de la Mama/metabolismo , Femenino , Receptor ErbB-2/metabolismo , Terapia Neoadyuvante/economía , Trastuzumab/uso terapéutico , Trastuzumab/economía , Sri Lanka , Lapatinib/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/economía , Cadenas de Markov , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/economía , Años de Vida Ajustados por Calidad de Vida , Presupuestos , Persona de Mediana EdadRESUMEN
BACKGROUND: Imported malaria continues to be reported in Sri Lanka after it was eliminated in 2012, and a few progress to life-threatening severe malaria. METHODS: Data on imported malaria cases reported in Sri Lanka from 2013 to 2023 were extracted from the national malaria database maintained by the Anti Malaria Campaign (AMC) of Sri Lanka. Case data of severe malaria as defined by the World Health Organization were analysed with regard to patients' general characteristics and their health-seeking behaviour, and the latter compared with that of uncomplicated malaria patients. Details of the last three cases of severe malaria in 2023 are presented. RESULTS: 532 imported malaria cases were diagnosed over 11 years (2013-2023); 46 (8.6%) were severe malaria, of which 45 were Plasmodium falciparum and one Plasmodium vivax. Most severe malaria infections were acquired in Africa. All but one were males, and a majority (87%) were 26-60 years of age. They were mainly Sri Lankan nationals (82.6%). Just over half (56.5%) were treated at government hospitals. The average time between arrival of the person in Sri Lanka and onset of illness was 4 days. 29 cases of severe malaria were compared with 165 uncomplicated malaria cases reported from 2015 to 2023. On average both severe and uncomplicated malaria patients consulted a physician equally early (mean = 1 day) with 93.3% of severe malaria doing so within 3 days. However, the time from the point of consulting a physician to diagnosis of malaria was significantly longer (median 4 days) in severe malaria patients compared to uncomplicated patients (median 1 day) (p = 0.012) as was the time from onset of illness to diagnosis (p = 0.042). All severe patients recovered without sequelae except for one who died. CONCLUSIONS: The risk of severe malaria among imported cases increases significantly beyond 5 days from the onset of symptoms. Although patients consult a physician early, malaria diagnosis tends to be delayed by physicians because it is now a rare disease. Good access to expert clinical care has maintained case fatality rates of severe malaria at par with those reported elsewhere.
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Enfermedades Transmisibles Importadas , Sri Lanka/epidemiología , Humanos , Masculino , Adulto , Persona de Mediana Edad , Femenino , Adulto Joven , Enfermedades Transmisibles Importadas/epidemiología , Enfermedades Transmisibles Importadas/parasitología , Enfermedades Transmisibles Importadas/diagnóstico , Malaria Falciparum/epidemiología , Malaria Vivax/epidemiología , Anciano , Adolescente , Malaria/epidemiología , Malaria/prevención & control , Erradicación de la Enfermedad/estadística & datos numéricosRESUMEN
BACKGROUND: Sri Lanka has maintained a rigorous programme to prevent the re-establishment of malaria ever since the disease was eliminated in October 2012. It includes efforts to sustain case surveillance to ensure early diagnosis and management of malaria. Yet, in April of 2023 the death occurred of an individual with imported malaria. CASE PRESENTATION: The deceased was a 37-year-old Sri Lankan male who returned to Sri Lanka on the 10th of April after a business trip to several countries including Tanzania. He was febrile on arrival and consulted three Allopathic Medical Practitioners in succession in his home town in the Western Province of Sri Lanka, over a period of 5 days starting from the very day that he arrived in the country. Malaria was not tested for at any of these consultations and his clinical condition deteriorated. On the evening of 14th of April he was admitted to the medical intensive care unit of a major private hospital in the capital city of Colombo with multiple organ failure. There, on a request by the treating physician blood was tested for malaria and reported early the next morning as Plasmodium falciparum malaria with a high parasitaemia (> 10%). The patient died shortly after on the 15th of April before any anti-malarial medication was administered. The deceased had been a frequent business traveller to Africa, but with no past history of malaria. He had not taken chemoprophylaxis for malaria on this or previous travels to Africa. DISCUSSION: The patient's P. falciparum infection progressed rapidly over 5 days of arriving in Sri Lanka leading to severe malaria without being diagnosed, despite him seeking healthcare from three different Medical Practitioners. Finally, a diagnosis of malaria was made on admission to an intensive care unit; the patient died before anti-malarial medicines were administered. CONCLUSIONS: This first death due to severe P. falciparum malaria reported in Sri Lanka after elimination of the disease was due to the delay in diagnosing malaria.
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Antimaláricos , Malaria Falciparum , Malaria , Masculino , Humanos , Adulto , Sri Lanka , Plasmodium falciparum , Antimaláricos/uso terapéutico , Malaria/diagnóstico , Malaria/tratamiento farmacológico , Malaria/prevención & control , Malaria Falciparum/diagnóstico , Malaria Falciparum/tratamiento farmacológico , Malaria Falciparum/prevención & control , TanzaníaRESUMEN
BACKGROUND: Malaria was eliminated from Sri Lanka in 2012, and since then 50-60 imported malaria cases have been reported yearly. The country has remained malaria-free since, except for a single case of indigenous malaria in 2018. Blood donors are routinely screened for malaria, and transfusion malaria has not been reported in the country since 1966. CASE PRESENTATION: A 17-year-old splenectomized beta thalassaemia patient developed a transfusion-induced Plasmodium falciparum malaria infection following a blood transfusion 18 days earlier. The blood donor was an armed forces personnel who returned from South Sudan following a United Nations peace-keeping mission. The blood recipient's malaria infection took a complicated clinical course with elevated liver enzymes, lowered blood pressure and a prolonged parasite clearance time of 7 days but he recovered fully after two courses of artemether-lumefantrine interrupted by a course of intravenous artesunate. The prolonged parasite clearance is likely due to lack of splenic clearance of dead or damaged intra-erythrocytic parasites (due to a splenectomy) rather than to the parasite strain being resistant to artemisinin or the partner drug. This is corroborated by the fact that the blood donor's infection responded to artemether-lumefantrine with parasites being cleared on day 3. The blood donor who had not displayed signs or symptoms of malaria, had been screened for malaria on arrival in Sri Lanka and was negative on both microscopy and RDT. At the point of blood donation a blood smear examined microscopically was also reported negative for malaria, but retrospectively, the preserved smear of the donor's blood was found to contain P. falciparum parasites at a very low density. The donor when tested after the transfusion-induced case was diagnosed, also tested positive for malaria and was treated. CONCLUSIONS: After malaria elimination, transfusion-induced malaria from blood donors returning from malaria endemic countries poses a threat to preventing the re-establishment of the disease. Improved surveillance of arrivals in Sri Lanka from malaria endemic countries using more sensitive methods for screening than microscopy may be required to reduce this risk. More stringent criteria for selecting blood donors, and more effective methods of screening donors for malaria than microscopy may also be necessary.
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Transfusión Sanguínea , Sangre/parasitología , Malaria Falciparum/complicaciones , Talasemia beta/complicaciones , Adolescente , Humanos , Malaria Falciparum/sangre , Malaria Falciparum/prevención & control , Sri Lanka , Talasemia beta/sangreRESUMEN
Treatment failure to intralesional sodium stibogluconate (IL-SSG) is a health challenge for cutaneous leishmaniasis (CL) in Sri Lanka. A randomized controlled proof of principle clinical trial, with two arms (viz., radio frequency-induced heat therapy [RFHT] by a ThermoMed™ device (Model 1.8, Thermosurgery Technologies, Inc., Phoenix, AZ) and thermotherapy by a handheld exothermic crystallization thermotherapy for CL [HECT-CL] device) was conducted on 40 CL treatment failures to IL-SSG, from three hospitals in Tangalle, Hambantota, and Anuradhapura, from January 2017 to January 2018, followed up for 180 days post-thermotherapy with a final follow-up in February 2020. Intention-to-treat cure rates were calculated at day 90 (initial cure rate) and at day 180 (final cure rate) posttreatment. Radio frequency-induced heat therapy group: the initial cure rate was 100% (20/20) and the final cure rate was 95% (19/20), with one patient relapsing. The HECT-CL group: both the initial and final cure rates were 80% (16/20), with no relapses and one excluded from the trial. In February 2020 (1.6-3 years posttreatment), 27 traceable patients (RFHT = 16, HECT-CL = 11) remained healed. Second-degree burns were observed with RFHT in 65% (13/20), with HECT-CL in 15% (3/20), which completely resolved subsequently. The cure rates between the two treatment groups were comparable (P = 0.15). Radio frequency-induced heat therapy consumed less time and required only a single hospital visit. Handheld exothermic crystallization thermotherapy for CL is potentially usable at community settings with both being less costly than IL-SSG. This study is the first proof that thermotherapy is an efficacious and safe treatment for CL patients in Sri Lanka, complicated by treatment failure to IL-SSG.
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Gluconato de Sodio Antimonio/uso terapéutico , Antiprotozoarios/uso terapéutico , Hipertermia Inducida/métodos , Leishmaniasis Cutánea/tratamiento farmacológico , Leishmaniasis Cutánea/terapia , Adolescente , Adulto , Anciano , Niño , Femenino , Humanos , Inyecciones Intralesiones , Masculino , Persona de Mediana Edad , Sri Lanka , Insuficiencia del Tratamiento , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: The quality of life in many patients is affected by skin lesions. Cutaneous leishmaniasis (CL), the commonest form of leishmaniasis, is no exception. In Sri Lanka, CL is an emerging parasitological condition with over 3,000 cases within the last decade. Lesions are often seen on exposed parts of the body which may cause social stigma, and hence a study was done to assess the changes in quality of life of CL patients. METHOD: A total of 294 patients (200 civilians and 94 army personnel) answered a previously validated Sinhala self-administered Dermatology Life Quality Index (DLQI) questionnaire and an interviewer-administered questionnaire. RESULTS: From the majority of the civilian population, 47% had no effect on their quality of life due to CL lesions, 33.5% were affected in a small way, 12.5% were affected moderately, 6.5% suffered in a large way, and 0.5% (one patient) were extremely affected due a large ulcerative lesion being on the face. The effect on quality of life was negligible in the majority of army patients as well (35.1% no effect, 31.9% small effect), with a few patients affected moderately and very largely (22.3 and 10.6%, respectively). The most affected domain in patients was symptoms and feeling 1.27 ± 1.400 (mean ± SD), and the least was the relationships domain 0.27 ± 0.625. CONCLUSION: CL does not seem to affect the quality of life in the majority of Sri Lankan patients when compared to CL in other parts of the world or other skin diseases.
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Leishmaniasis Cutánea/psicología , Personal Militar/psicología , Calidad de Vida , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Leishmaniasis Cutánea/complicaciones , Masculino , Persona de Mediana Edad , Estigma Social , Sri Lanka , Encuestas y Cuestionarios , Evaluación de Síntomas , Adulto JovenRESUMEN
Leishmania donovani causes cutaneous leishmaniasis (CL) in Sri Lanka. Standard treatment is multiple, painful doses of intralesional sodium stibogluconate (IL-SSG). Treatment failures are increasingly reported, hence the need to investigate alternatives. Efficacy, safety, and cost-effectiveness of thermotherapy were assessed for the first time for L. donovani CL. A single blinded noninferiority randomized controlled trial was conducted on new laboratory-confirmed CL patients with single lesions (N = 213). Selected patients were randomly assigned to 1) test group (N = 98; single session of radiofrequency-induced heat therapy (RFHT) given at 50°C for 30 seconds) and 2) control group (N = 115; 1-3 mL IL-SSG given weekly, until cure/10 doses). Patients were followed-up fortnightly for 12 weeks to assess clinical cure. Cost of treatment was assessed using scenario building technique. Cure rates by 8, 10, and 12 weeks in RFHT group were 46.5%, 56.5%, and 65.9% as opposed to 28%, 40.8%, and 59.4% in IL-SSG group, with no major adverse events. Cure rate by RFHT was significantly higher at 8 weeks (P = 0.009, odds ratio [OR]: 2.236, confidence interval [CI]: 1.217-4.108) and 10 weeks (P = 0.035, OR: 1.881, CI: 1.044-3.388), but comparable thereafter. Cost of RFHT was 7 times less (USD = 1.54/patient) than IL-SSG (USD = 11.09/patient). A single application of RFHT is safe, cost-effective, and convenient, compared with multiple doses of IL-SSG in the treatment of L. donovani CL. Therefore, RFHT would be considered noninferior as per trial outcome when compared with standard IL-SSG therapy with multiple benefits for the patient and the national health care system.
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Hipertermia Inducida , Leishmania donovani , Leishmaniasis Cutánea/terapia , Leishmaniasis Visceral/terapia , Adolescente , Adulto , Gluconato de Sodio Antimonio/administración & dosificación , Gluconato de Sodio Antimonio/uso terapéutico , Niño , Femenino , Humanos , Leishmaniasis Cutánea/parasitología , Leishmaniasis Cutánea/patología , Leishmaniasis Visceral/parasitología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: The standard dose of rituximab used in rheumatoid arthritis (RA) is 1000 mg but recent studies have shown that low dose (500 mg) is also effective. Efficacy of low dose rituximab in rheumatoid arthritis (RA) refractory to first-line non-biologic Disease Modifying Anti Rheumatic Drugs (DMARDs), compared to leflunomide is unknown. In a tertiary care referral setting, we conducted a randomized, double blind controlled clinical trial comparing the efficacy and safety of low-dose rituximab-methotrexate combination with leflunomide-methotrexate combination. METHODS: Patients on methotrexate (10-20 mg/week) with a Disease Activity Score (DAS) > 3.2 were randomly assigned to rituximab (500 mg on days 1 and 15) or leflunomide (10-20 mg/day). The primary end-point was ACR20 at 24 weeks. Sample of 40 had 70% power to detect a 30% difference. ACR50, ACR70, DAS, EULAR good response, CD3 + (T cell), CD19 + (B cell) and CD19 + CD27+ (memory B cell) counts, tetanus and pneumococcal antibody levels were secondary end points. RESULTS: Baseline characteristics were comparable in the two groups. At week 24, ACR20 was 85% vs 84% (p = 0.93), ACR50 was 60% vs. 64% (p = 0.79) and ACR70 was 35% vs 32% (P = 0.84), in rituximab and in leflunomide groups respectively. Serious adverse events were similar. With rituximab there was significant reduction in B cells (p < 0.001), memory B cells (p < 0.001) and pneumococcal antibody levels (P < 0.05) without significant changes in T cells (p = 0.835) and tetanus antibody levels (p = 0.424) at 24 weeks. With leflunomide, significant reduction in memory B cells (p < 0.01) and pneumococcal antibody levels (p < 0.01) occurred without significant changes in B cells (P > 0.05), T cells (P > 0.05) or tetanus antibody levels (P > 0.05). CONCLUSIONS: Leflunomide-methotrexate combination is as efficacious as low-dose rituximab-methotrexate combination at 24 weeks, in RA patient's refractory to initial DMARDs. The high responses seen in both groups have favorable cost implications for patients in developing countries. Changes in immune parameters with leflunomide are novel and need further characterization. TRIAL REGISTRATION: The trial was registered with the Sri Lanka Clinical Trials Registry (SLCTR), a publicly accessible primary registry linked to the registry network of the International Clinical Trials Registry Platform of the WHO (WHO-ICTRP) (registration number: SLCTR/2008/008 dated 16th May 2008).
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Antirreumáticos/administración & dosificación , Artritis Reumatoide/sangre , Artritis Reumatoide/tratamiento farmacológico , Isoxazoles/administración & dosificación , Metotrexato/administración & dosificación , Rituximab/administración & dosificación , Adulto , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Leflunamida , Linfocitos/efectos de los fármacos , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Resultado del TratamientoRESUMEN
Leishmaniasis is caused by parasitic protozoa of the genus Leishmania. Cutaneous leishmaniasis (CL) is endemic in Sri Lanka with over 3000 cases during the last decade and numbers are increasing. Treatment options available in Sri Lanka for CL include intralesional/intramuscular sodium stibogluconate and cryotherapy. Eight cases of treatment failure with standard therapy are reported from the Dermatology Clinic, Teaching Hospital Anuradhapura. Therapeutic regimes aim for clinical healing, these patients responded poorly to anti-leishmanial therapy, indicating the need for close monitoring, explore alternative treatment options and to investigate for drug resistance in parasites.
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This document is intended as a guide to the protocol development for trials of prophylactic vaccines. The template may serve phases I-IV clinical trials protocol development to include safety relevant information as required by the regulatory authorities and as deemed useful by the investigators. This document may also be helpful for future site strengthening efforts.
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Investigación Biomédica/métodos , Ensayos Clínicos como Asunto , Vacunas/efectos adversos , Humanos , Vacunas/administración & dosificaciónRESUMEN
BACKGROUND: Acute paracetamol poisoning is a rapidly increasing problem in Sri Lanka. The antidotes are expensive and yet no health economic evaluation has been done on the therapy for acute paracetamol poisoning in the developing world. The aim of this study is to determine the cost effectiveness of using N-acetylcysteine over methionine in the management of acute paracetamol poisoning in Sri Lanka. METHODS: Economic analysis was applied using public healthcare system payer perspective. Costs were obtained from a series of patients admitted to the National Hospital of Sri Lanka with a history of acute paracetamol overdose. Evidence on effectiveness was obtained from a systematic review of the literature. Death due to hepatotoxicity was used as the primary outcome of interest. Analysis and development of decision tree models was done using Tree Age Pro 2008. RESULTS: An affordable treatment threshold of Sri Lankan rupees 1,537,120/death prevented was set from the expected years of productive life gained and the average contribution to GDP. A cost-minimisation analysis was appropriate for patients presenting within 10 hours and methionine was the least costly antidote. For patients presenting 10-24 hours after poisoning, n-acetylcysteine was more effective and the incremental cost effectiveness ratio of Sri Lankan rupees 316,182/life saved was well under the threshold. One-way and multi-way sensitivity analysis also supported methionine for patients treated within 10 hours and n-acetylcysteine for patients treated within 10-24 hours as preferred antidotes. CONCLUSIONS: Post ingestion time is an important determinant of preferred antidotal therapy for acute paracetamol poisoning patients in Sri Lanka. Using n-acetylcysteine in all patients is not cost effective. On economic grounds, methionine should become the preferred antidote for Sri Lankan patients treated within 10 hours of the acute ingestion and n-acetylcysteine should continue to be given to patients treated within 10-24 hours.
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Acetaminofén/envenenamiento , Acetilcisteína/economía , Antiinflamatorios no Esteroideos/envenenamiento , Antídotos/economía , Metionina/economía , Acetaminofén/economía , Acetilcisteína/administración & dosificación , Antiinflamatorios no Esteroideos/economía , Antídotos/administración & dosificación , Enfermedad Hepática Inducida por Sustancias y Drogas/economía , Enfermedad Hepática Inducida por Sustancias y Drogas/mortalidad , Análisis Costo-Beneficio , Árboles de Decisión , Humanos , Metionina/administración & dosificación , Sri Lanka , Factores de TiempoRESUMEN
OBJECTIVE: To document the types and severity of adverse drug reactions to diethylcarbamazine and albendazole in randomly selected urban populations from Colombo and rural populations from Gampaha, Sri Lanka. METHODS: Interviewers administered a pre-tested questionnaire to elicit information about the type and severity of adverse drug reactions experienced by recipients. Seeking medical treatment and requiring hospital admission for the adverse drug reactions were used as indicators for severity. The sample population was selected using the cluster sampling method. RESULTS: Two thousand three hundred and nineteen persons aged 10 to 90 years (median 40.0) responded to the questionnaire; 63.9% of them had received and ingested the drugs. 12.6% reported that they had experienced adverse drug reactions, the proportion being similar in urban and rural areas (chi2 = 0.05; p = 0.82). Commonly reported reactions were drowsiness (34.7%), headache (23.1%), gastrointestinal symptoms (18.7%) and dizziness or faintness (11.9%). However, most symptoms were mild (96.3%) and did not interfere with daily activities or require medical attention. 3.2% said that they sought medical advice for their symptoms; one person (0.5%) who had severe abdominal pain was hospitalized. CONCLUSIONS: Fewer people experienced adverse drug reactions than in previous years, possibly due to lower microfilariaemia prevalence after several rounds of mass drug administration against filariasis. Community awareness of adverse drug reactions is essential for improving compliance and for the success of the filariasis elimination programme.
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Sistemas de Registro de Reacción Adversa a Medicamentos , Albendazol/efectos adversos , Dietilcarbamazina/efectos adversos , Filariasis Linfática/tratamiento farmacológico , Filaricidas/efectos adversos , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Niño , Filariasis Linfática/epidemiología , Filariasis Linfática/prevención & control , Femenino , Humanos , Masculino , Persona de Mediana Edad , Cooperación del Paciente , Sri Lanka/epidemiología , Encuestas y Cuestionarios , Resultado del TratamientoRESUMEN
Bell's palsy has been reported as an adverse event following immunization (AEFI). Review of the published literature reveals that several characteristics have been used to describe Bell's palsy, which differ significantly from author to author. Evidently, the definition of "Bell's palsy" remains controversial, and consensus between different medical subspecialties is urgently needed. The Brighton Collaboration has formed an international working group with representatives of neurology, otorhinolaryngology, pediatrics, electrophysiology, pharmacology, pharmaceutical and biotech industry as well as regulatory agencies to create a case definition of Bell's palsy as an AEFI.
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Parálisis de Bell/etiología , Inmunización/efectos adversos , Potenciales de Acción , Parálisis de Bell/diagnóstico , Parálisis de Bell/virología , Niño , Humanos , Imagen por Resonancia MagnéticaRESUMEN
The current system of pharmacovigilance encourages reporting of adverse drug reactions (ADRs) mainly from healthcare professionals. Underreporting is a major problem, more so in the developing world than in the developed world. Less than 3% of reports added to the WHO database in the year 2000 originated from developing countries, although around 80% of the global population lives in the developing world [corrected]. Also a considerable time lag still exists in recognition of serious ADRs. Hence, there is a need for a different approach to pharmacovigilance. We present an overview of possible reasons for underreporting by healthcare professionals with particular emphasis on the developing world, and the potential benefits of encouraging consumer reporting. Only a few countries accept consumer reports. We suggest an independent consumer reporting system for hypothesis generation to complement the present health professional-based system. We also highlight the low priority given by multinational pharmaceutical companies to the developing countries regarding new safety information. The important questions are whether the resources available would be sufficiently robust to sustain such a system in the developing world, and whether it will be sufficiently robust and sensitive for the early detection of signals.