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1.
Anticancer Res ; 40(10): 5853-5860, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988915

RESUMO

BACKGROUND/AIM: The optimal treatment sequencing for asymptomatic de novo metastatic rectal cancer is unclear. The aim of this study was to investigate the role of upfront radiotherapy, with or without chemotherapy on risk for local complications, in patients with asymptomatic advanced metastatic rectal cancer treated with palliative intention. PATIENTS AND METHODS: All patients with de novo metastatic rectal cancer diagnosed between January 2008 and December 2017 in two healthcare regions in Sweden (Örebro län, Sörmland) were identified and data were extracted from electronic medical records. Patients were divided into 3 groups based on treatment sequence: upfront radiotherapy, upfront chemotherapy, and only palliative surgery. RESULTS: In total, 102 patients were included in the study cohort, 30 patients in upfront radiotherapy group, 54 in upfront chemotherapy, and 18 in only palliative surgery group. Patients with only upfront CT [odds ratio (OR)= 5.10; 95% confidence interval (CI)=1.24-20.91, p=0.024] had a higher risk to suffer from a local complication compared to those who received upfront radiotherapy. Cause-specific Cox regression analysis among patients who received oncological therapy revealed that female patients [cause-specific hazard ratio (csHR)=3.61; 95% confidence interval (CI)=1.67-7.81] and upfront chemotherapy [csHR=1.85; 95% CI=1.11-3.77] were associated with increased cumulative incidence of local complication over time, whereas primary surgery with ostomy or stent with lower risk [csHR=0.45; 95% CI=0.21-0.99]. CONCLUSION: Patients who received upfront radiotherapy, with or without chemotherapy, had fewer local complications due to primary tumor compared to patients who only received chemotherapy. This could indicate that radiotherapy to the primary tumor could be discussed with the patients as a first treatment option for asymptomatic metastatic rectal cancer to prevent local complications later during the disease.


Assuntos
Doenças Assintomáticas/terapia , Doenças Raras/radioterapia , Neoplasias Retais/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Assintomáticas/epidemiologia , Estudos de Coortes , Terapia Combinada , Feminino , Humanos , Masculino , Oncologia/tendências , Pessoa de Meia-Idade , Cuidados Paliativos , Modelos de Riscos Proporcionais , Doenças Raras/tratamento farmacológico , Doenças Raras/patologia , Doenças Raras/cirurgia , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/patologia , Neoplasias Retais/cirurgia , Suécia/epidemiologia
2.
Viruses ; 12(9)2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32972027

RESUMO

Traditionally, drug discovery utilises a de novo design approach, which requires high cost and many years of drug development before it reaches the market. Novel drug development does not always account for orphan diseases, which have low demand and hence low-profit margins for drug developers. Recently, drug repositioning has gained recognition as an alternative approach that explores new avenues for pre-existing commercially approved or rejected drugs to treat diseases aside from the intended ones. Drug repositioning results in lower overall developmental expenses and risk assessments, as the efficacy and safety of the original drug have already been well accessed and approved by regulatory authorities. The greatest advantage of drug repositioning is that it breathes new life into the novel, rare, orphan, and resistant diseases, such as Cushing's syndrome, HIV infection, and pandemic outbreaks such as COVID-19. Repositioning existing drugs such as Hydroxychloroquine, Remdesivir, Ivermectin and Baricitinib shows good potential for COVID-19 treatment. This can crucially aid in resolving outbreaks in urgent times of need. This review discusses the past success in drug repositioning, the current technological advancement in the field, drug repositioning for personalised medicine and the ongoing research on newly emerging drugs under consideration for the COVID-19 treatment.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos , Pneumonia Viral/tratamento farmacológico , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Reposicionamento de Medicamentos/economia , Reposicionamento de Medicamentos/tendências , Humanos , Pandemias , Pesquisa Farmacêutica , Pneumonia Viral/epidemiologia , Medicina de Precisão , Doenças Raras/tratamento farmacológico
5.
Artigo em Inglês | MEDLINE | ID: mdl-32357397

RESUMO

This study aimed to identify orphan drug accessibility and impact on pharmaceutical budgets in South Korea by analyzing the status of orphan drug designation, approval, reimbursement, and pharmaceutical expenditure. We analyzed the dataset on orphan drugs designated, approved, and reimbursed from 2007 to 2019 based on long-term real-world data. The designated and approved orphan drugs were 165 and 156, respectively, and 88 out of 156 approved products were reimbursed. Total expenditure on orphan drugs increased annually to account for about 1.44% of total pharmaceutical expenditure in 2018. Orphan drug expenditure per patient increased on average by 8.7% per year. The average annual cost of orphan drugs was USD 27,000-USD 47,000, with the maximum value of USD 260,000-USD 560,000. As there are a number of orphan drugs that have not yet been reimbursable after approval, a reimbursement policy should be established that considers the characteristics of orphan drugs. Since the rapid increase in orphan drug expenditure can be a potential threat to the insurance budget, budget management should also be considered. In conclusion, it is necessary to take preemptive measures to manage the health insurance budget efficiently while improving patient accessibility to orphan drugs.


Assuntos
Análise de Dados , Acesso aos Serviços de Saúde , Produção de Droga sem Interesse Comercial , Doenças Raras , Orçamentos , Humanos , Doenças Raras/tratamento farmacológico , República da Coreia
8.
Bull Cancer ; 107(4): 506-516, 2020 Apr.
Artigo em Francês | MEDLINE | ID: mdl-32145961

RESUMO

A subgroup of androgen receptor-expressing tumors represents approximately 30 % of all triple negative tumors. The androgen receptor and its signaling pathways have a central biological role in this tumor entity. These triple negative androgen receptor-positive tumors occur in older patients and do not appear to have a better prognosis compared to other triple negative tumors. In addition to androgen receptor-expression, these tumors are genomically characterized by a high frequency of PIK3CA activating mutation. Three clinical trials reported efficacy data for anti-androgens (bicalutamide, abiraterone acetate and enzalutamide) based on strong preclinical rationale. These trials report clinical benefit rates in about one in five patients. These encouraging but still limited results make a case for the identification of predictive response factors and therapeutic combinations to improve response rates. This review will provide an update on the biological and clinical knowledge of this tumoral subgroup that opens the way to non-cytotoxic anti-androgen therapies.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Doenças Raras/metabolismo , Receptores Androgênicos/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Acetato de Abiraterona/uso terapêutico , Fatores Etários , Idoso , Anilidas/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/genética , Ensaios Clínicos como Assunto , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Previsões , Humanos , Mutação , Nitrilos/uso terapêutico , Feniltioidantoína/análogos & derivados , Feniltioidantoína/uso terapêutico , Prognóstico , Doenças Raras/tratamento farmacológico , Transdução de Sinais , Compostos de Tosil/uso terapêutico
9.
Bull Cancer ; 107(4): 410-416, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32145962

RESUMO

Tumor profiling has been shown to benefit patients with rare or refractory metastatic cancer, but several limitations hamper its use in daily clinical practice. We aim to assess the added benefit of a comprehensive tumor profiling, including factors predictive of response to targeted and cytotoxic therapy, in the treatment of refractory or rare solid tumors outside of a formal clinical trial. Patients were included between 2013 and 2017. Multiplatform comprehensive tumor profiling (CTP) was performed on FFPE specimens. Tumor response was evaluated by imaging using the RECIST criteria version 1.1. The PFS ratio was defined as PFS under CTP-guided therapy (PFS2)/PFS under previous standard therapy (PFS1). A clinical benefit was identified if the PFS ratio exceeded the 1.3 threshold value. In total, 184 patients were enrolled among whom 104 were evaluable for the PFS ratio. Objective response rates (ORR) were equal to 25% (CI95: 16.6-33.4%) and 36.5% (CI95: 27.2-45.8%) on the last therapy before CTP and on the CTP-guided therapy respectively (P-value=0.058 on paired proportion comparison test). The proportion of patients achieving a PFS2/PFS1 ratio≥1.3 was equal to 50%. The median PFS1 was statistically lower than PFS2 (120 days compared to 184 days respectively, P-value log rank 0.01). These results confirm the feasibility and the added benefit of a CTP in patients with refractory tumors in daily clinical practice especially in patients not able to enter a clinical trial.


Assuntos
Antineoplásicos/uso terapêutico , Terapia de Alvo Molecular/métodos , Proteínas de Neoplasias/genética , Neoplasias/tratamento farmacológico , Neoplasias/genética , Doenças Raras/tratamento farmacológico , Doenças Raras/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/antagonistas & inibidores , Tomada de Decisão Clínica , Estudos de Viabilidade , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Hibridização In Situ/métodos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas de Neoplasias/análise , Proteínas de Neoplasias/antagonistas & inibidores , Neoplasias/mortalidade , Probabilidade , Intervalo Livre de Progressão , Análise Serial de Proteínas/métodos , Doenças Raras/mortalidade , Critérios de Avaliação de Resposta em Tumores Sólidos , Taxa de Sobrevida , Adulto Jovem
11.
Pediatrics ; 145(4)2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32127360

RESUMO

BACKGROUND: Orphan drug development is crucial for children, who are disproportionately affected by rare diseases. Data are lacking on the number, nature, and benefit of recently approved pediatric orphan indications. METHODS: We classified the 402 orphan indications the US Food and Drug Administration approved between 2010 and 2018 as "pediatric" if they were approved for children only or targeted pediatric diseases. We determined the number of unique diseases targeted by pediatric orphan indications and calculated the proportion that were for (1) novel drugs, (2) non-novel drugs approved to treat ≥1 common disease, and (3) non-novel drugs approved only to treat rare diseases. Among pediatric orphan indications eligible for US Food and Drug Administration breakthrough designation (granted to drugs potentially representing major therapeutic advances), we calculated the proportion receiving this designation. RESULTS: Of the 402 orphan indications, 136 (33.8%) were pediatric. These 136 indications targeted 87 unique diseases; 21 diseases were targeted by ≥1 indication. Of the 136 pediatric orphan indications, 60 (44.1%) were for novel drugs, 45 (33.1%) were for non-novel drugs approved to treat ≥1 common disease, and 31 (22.8%) were for non-novel drugs approved only to treat rare diseases. Among 97 indications eligible for breakthrough designation, 20 (20.6%) received this designation. CONCLUSIONS: Recent orphan drug development has increased the availability of treatments for pediatric rare diseases. Most pediatric orphan indications expanded use of existing drugs, and many targeted the same disease. Some indications may represent breakthroughs, but substantial unmet need for treatments remains for most pediatric rare diseases.


Assuntos
Aprovação de Drogas/estatística & dados numéricos , Produção de Droga sem Interesse Comercial/estatística & dados numéricos , Doenças Raras/tratamento farmacológico , Criança , Rotulagem de Medicamentos/estatística & dados numéricos , Humanos , Produção de Droga sem Interesse Comercial/classificação , Estados Unidos
12.
Pharmaceut Med ; 34(1): 19-29, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32048213

RESUMO

BACKGROUND: Growth in development, approvals, and revenue of drugs treating rare diseases (orphan drugs) has been increasing over the last four decades, which has drawn substantial attention to these products. Much of this growth has been attributed to the incentives created by the Orphan Drug Act, which includes a seven-year exclusivity period for the approval of rare disease indications. OBJECTIVE: This study aims to compare the effective market exclusivity period of small molecule new molecular entities (NMEs) for rare (orphan) and non-rare (non-orphan) diseases approved by the U.S. Food and Drug Administration (FDA) from 2001-2012. While the overall length of a drug's effective market exclusivity period has been explored previously, there is little empirical research evaluating the differences in its duration between drugs for rare and non-rare diseases. METHODS: Data sources utilized in this analysis included the NME Drug and New Biologic Approvals Reports, Orange Book, Orphan Drug Product Designation Database, Drugs@FDA and IQVIA's National Sales Perspective. We computed the effective market exclusivity period for each NME as the time from NME approval until approval of the first generic competitor. We then regressed the effective market exclusivity period for each NME, on orphan disease status, and other NME market factors using a Cox proportional hazards model. Subsequently, we calculated regression-adjusted median effective market exclusivity periods for both orphan and non-orphan NMEs to estimate effective exclusivity extensions from orphan status. RESULTS: We find that only individual NMEs approved for the treatment of both orphan and non-orphan indications lower the hazard of generic entry (hazard ratio 0.464, p = 0.030) in comparison with non-orphan NMEs with a single indication. The associated additional median survival time for these NMEs is 1.9 years. CONCLUSIONS: NMEs' orphan status per se is not associated with a reduction in the hazard of generic entry and longer effective market exclusivity periods in comparison with non-orphan NMEs. Only NMEs that were approved for the treatment of both orphan and non-orphan diseases experience lower hazard of generic entry and longer exclusivity periods compared with non-orphan drugs with a single indication.


Assuntos
Aprovação de Drogas/organização & administração , Doenças Raras/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/economia , Indústria Farmacêutica , Medicamentos Genéricos , Humanos , Produção de Droga sem Interesse Comercial , Modelos de Riscos Proporcionais , Estados Unidos , United States Food and Drug Administration
14.
Am J Case Rep ; 21: e919781, 2020 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-31911575

RESUMO

BACKGROUND Adenoid cystic carcinoma (ACC) is a very rare tumor with a high risk of loco-regional recurrence and potential distant metastases. Until now, only a few cases of renal metastases from ACC have been reported in the literature. CASE REPORT A 64-year-old, Caucasian, non-smoker female, 8 months after being treated by radio-chemotherapy for a squamous cell nasal cavity tumor, presented two renal lesions associated with lung and vertebral metastases. Histology was consisted with a metastasis from an ACC. The histological revision of the primary nasal tumor confirmed a squamous cells carcinoma with an adenoid cystic component that metastasized to the kidney. Renal lesions appeared hypometabolic at the ¹8F-fluorodeoxyglucose (¹8F-FDG) PET scan mimicking a primary renal tumor. The patient underwent a systemic, palliative chemotherapy by a weekly carboplatin/paclitaxel/cetuximab regimen that was well tolerated and allowed a lasting tumor control. CONCLUSIONS The particularity of this case relies on the rarity of renal metastasis from ACC, its difficult diagnosis, and the complexity of its management, as no standard chemotherapy has been validated for metastatic ACC, yet. In our case, a weekly carboplatin/paclitaxel/cetuximab regimen was administered leading to a durable tumor stabilization with an excellent patient's quality of life.


Assuntos
Carcinoma Adenoide Cístico/patologia , Carcinoma de Células Escamosas/patologia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/secundário , Neoplasias Nasais/patologia , Carboplatina/uso terapêutico , Carcinoma Adenoide Cístico/terapia , Carcinoma de Células Escamosas/terapia , Cetuximab/uso terapêutico , Quimioterapia Combinada , Feminino , Fluordesoxiglucose F18 , Humanos , Pessoa de Meia-Idade , Cavidade Nasal , Neoplasias Nasais/terapia , Paclitaxel/uso terapêutico , Cuidados Paliativos , Tomografia por Emissão de Pósitrons , Doenças Raras/tratamento farmacológico
15.
Am J Case Rep ; 21: e919616, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31919337

RESUMO

BACKGROUND Pseudolymphoma is a rare disorder that can mimic lymphoma both clinically and histologically. It usually affects middle-aged females. Since pseudolymphoma is a rare disorder not only is diagnosing the condition difficult, but there is also a lack of standardized treatment guidelines. In the literature, anti-CD20 monoclonal antibody rituximab is described as an effective treatment option. CASE REPORT 46-year-old female fell ill suddenly with swelling and enlargement of her chin. Multiple skin biopsies were done, which were re-evaluated multiple times as well. Each ended with a new diagnosis for the patient. Finally, in the last revision of biopsy material, pseudolymphoma was confirmed. The patient received multiple courses of corticosteroid treatments - locally and systemically - without long lasting effect. After diagnosis of pseudolymphoma, the patient was started on intravenous rituximab and this treatment was effective. CONCLUSIONS Cutaneous pseudolymphoma is a diagnostic challenge. Rituximab is a treatment option for refractory pseudolymphoma. Since there are no treatment guidelines for pseudolymphoma, more clinical studies are needed to establish best treatment options for these patients. Therefore, each reported clinical case is important.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Pseudolinfoma/diagnóstico , Pseudolinfoma/tratamento farmacológico , Rituximab/uso terapêutico , Dermatopatias/diagnóstico , Dermatopatias/tratamento farmacológico , Biópsia , Queixo/fisiopatologia , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Humanos , Linfoma Cutâneo de Células T/diagnóstico , Pessoa de Meia-Idade , Pseudolinfoma/patologia , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológico , Dermatopatias/patologia
16.
Nat Rev Drug Discov ; 19(2): 93-111, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31836861

RESUMO

Most rare diseases still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to catalyse the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs. With this in mind, we discuss here the technological basis and rare disease applicability of the main therapeutic modalities, including small molecules, monoclonal antibodies, protein replacement therapies, oligonucleotides and gene and cell therapies, as well as drug repurposing. For each modality, we consider its strengths and limitations as a platform for rare disease therapy development and describe clinical progress so far in developing drugs based on it. We also discuss selected overarching topics in the development of therapies for rare diseases, such as approval statistics, engagement of patients in the process, regulatory pathways and digital tools.


Assuntos
Aprovação de Drogas , Desenvolvimento de Medicamentos , Reposicionamento de Medicamentos/estatística & dados numéricos , Produção de Droga sem Interesse Comercial/estatística & dados numéricos , Doenças Raras/tratamento farmacológico , Humanos
18.
Genes (Basel) ; 10(12)2019 11 27.
Artigo em Inglês | MEDLINE | ID: mdl-31783696

RESUMO

The amount of data collected and managed in (bio)medicine is ever-increasing. Thus, there is a need to rapidly and efficiently collect, analyze, and characterize all this information. Artificial intelligence (AI), with an emphasis on deep learning, holds great promise in this area and is already being successfully applied to basic research, diagnosis, drug discovery, and clinical trials. Rare diseases (RDs), which are severely underrepresented in basic and clinical research, can particularly benefit from AI technologies. Of the more than 7000 RDs described worldwide, only 5% have a treatment. The ability of AI technologies to integrate and analyze data from different sources (e.g., multi-omics, patient registries, and so on) can be used to overcome RDs' challenges (e.g., low diagnostic rates, reduced number of patients, geographical dispersion, and so on). Ultimately, RDs' AI-mediated knowledge could significantly boost therapy development. Presently, there are AI approaches being used in RDs and this review aims to collect and summarize these advances. A section dedicated to congenital disorders of glycosylation (CDG), a particular group of orphan RDs that can serve as a potential study model for other common diseases and RDs, has also been included.


Assuntos
Aprendizado Profundo , Doenças Raras/diagnóstico , Ensaios Clínicos como Assunto , Descoberta de Drogas , Humanos , Medicina de Precisão , Doenças Raras/tratamento farmacológico
19.
PLoS One ; 14(12): e0225500, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800621

RESUMO

Using the English Wikipedia network of more than 5 million articles we analyze interactions and interlinks between the 34 largest pharmaceutical companies, 195 world countries, 47 rare renal diseases and 37 types of cancer. The recently developed algorithm using a reduced Google matrix (REGOMAX) allows us to take account both of direct Markov transitions between these articles and also of indirect transitions generated by the pathways between them via the global Wikipedia network. This approach therefore provides a compact description of interactions between these articles that allows us to determine the friendship networks between them, as well as the PageRank sensitivity of countries to pharmaceutical companies and rare renal diseases. We also show that the top pharmaceutical companies in terms of their Wikipedia PageRank are not those with the highest market capitalization.


Assuntos
Indústria Farmacêutica , Internacionalidade , Internet , Neoplasias/tratamento farmacológico , Doenças Raras/tratamento farmacológico , Algoritmos , Indústria Farmacêutica/economia , Humanos , Marketing , Estatísticas não Paramétricas
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