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1.
Med Princ Pract ; 2024 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-38471490

RESUMO

Alzheimer's disease (AD) is the most common cause of neurodegenerative impairment in elderly people. Clinical characteristics include short-term memory loss, confusion, hallucination, agitation, and behavioural disturbance. Owing to evolving research in biomarkers AD can be discovered at early onset, but the disease is currently considered a continuum, which suggests that pharmacotherapy is most efficacious in the preclinical phase, possibly 15 - 20 years before discernible onset. Present developments in AD therapy aim to respond to this understanding and go beyond the drug families that relieve clinical symptoms. Another important factor in this development is the emergence of precision medicine that aims to tailor treatment to specific patients or patient subgroups. This relatively new platform would categorize AD patients on the basis of parameters like clinical aspects, brain imaging, genetic profiling, clinical genetics and epidemiological factors. This review enlarges on recent progress in the design and clinical use of antisense molecules, antibodies, antioxidants, small molecules and gene editing to stop AD progress and possibly reverse the disease on the basis of relevant biomarkers.

2.
Med Princ Pract ; 32(6): 313-322, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37788649

RESUMO

Alzheimer's disease (AD) is a disabling neurodegenerative disease. The prognosis is poor, and currently there are no proven effective therapies. Most likely, the etiology is related to cerebral inflammatory processes that cause neuronal damage, resulting in dysfunction and apoptosis of nerve cells. Pathogens that evoke a neuroinflammatory response, collectively activate astrocytes and microglia, which contributes to the secretion of pro-inflammatory cytokines. This leads to the deposit of clustered fragments of beta-amyloid and misfolded tau proteins which do not elicit an adequate immune reaction. Apart from the function of astrocytes and microglia, molecular entities such as TREM2, SYK, C22, and C33 play a role in the physiopathology of AD. Furthermore, bacteria and viruses may trigger an overactive inflammatory response in the brain. Pathogens like Helicobacter pylori, Chlamydia pneumonia, and Porphyromonas gingivalis (known for low-grade infection in the oral cavity) can release gingipains, which are enzymes that can damage and destroy neurons. Chronic infection with Borrelia burgdorferi (the causative agent of Lyme disease) can co-localize with tau tangles and amyloid deposits. As for viral infections, herpes simplex virus 1, cytomegalovirus, and Epstein-Barr virus can play a role in the pathogenesis of AD. Present investigations have resulted in the development of antibodies that can clear the brain of beta-amyloid plaques. Trials with humanized aducanumab, lecanemab, and donanemab revealed limited success in AD patients. However, AD should be considered as a continuum in which the initial preclinical phase may take 10 or even 20 years. It is generally thought that this phase offers a window for efficacious treatment. Therefore, research is also focused on the identification of biomarkers for early AD detection. In this respect, the plasma measurement of neurofilament light chain in patients treated with hydromethylthionine mesylate may well open a new way to prevent the formation of tau tangles and represents the first treatment for AD at its roots.


Assuntos
Doença de Alzheimer , Infecções por Vírus Epstein-Barr , Doenças Neurodegenerativas , Humanos , Infecções por Vírus Epstein-Barr/complicações , Doenças Neurodegenerativas/complicações , Herpesvirus Humano 4/metabolismo , Peptídeos beta-Amiloides/metabolismo , Microglia/metabolismo , Microglia/patologia
3.
Med Princ Pract ; 32(3): 155-165, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37285828

RESUMO

In 2020, more than 9 million patients suffering from Parkinson's disease (PD) were reported worldwide, and studies predict that the burden of this disease will grow substantially in industrial countries. In the last decade, there has been a better understanding of this neurodegenerative disorder, clinically characterized by motor disturbances, impaired balance, coordination, memory difficulties, and behavioral changes. Various preclinical investigations and studies on human postmortem brains suggest that local oxidative stress and inflammation promote misfolding and aggregation of alpha-synuclein within Lewy bodies and cause nerve cell damage. Parallel to these investigations, the familial contribution to the disease became evident from studies on genome-wide association in which specific genetic defects were linked to neuritic alpha-synuclein pathology. As for treatment, currently available pharmacological and surgical interventions may improve the quality of life but do not stop the progress of neurodegeneration. However, numerous preclinical studies have provided insights into the pathogenesis of PD. Their results provide a solid base for clinical trials and further developments. In this review, we discuss the pathogenesis, the prospects, and challenges of synolytic therapy, CRISPR, gene editing, and gene- and cell-based therapy. We also throw light on the recent observation that targeted physiotherapy may help improve the gait and other motor impairments.


Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/terapia , Doença de Parkinson/genética , Doença de Parkinson/patologia , alfa-Sinucleína , Estudo de Associação Genômica Ampla , Qualidade de Vida , Encéfalo
5.
Med Princ Pract ; 31(4): 303-312, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35636395

RESUMO

In mammalian cells, DNA damage response initiates repair by error-free homologous recombination (HRR) or by error-prone non-homologous end joining (NHEJ). DNA damage is detected by PARP proteins that facilitate this repair, both in normal cells and in cancer cells. Cells containing BRCA1/2 mutations have an HRR-deficient repair mechanism which may result in unrepaired one-ended double-strand breaks and stalled replication forks, considered as the most lethal cell damage. Here, we review the state of the art of the role of Poly (ADP-ribose) polymerase (PARP) inhibitors as a precision-targeted anticancer drug in BRCA1/2-mutated female breast cancer. Although knowledge is incomplete, it is assumed that the main role of the archetype PARP1 in the cell nucleus is to detect and adhere to single-strand breaks. This mediates possible damage repair, after which cells may continue replication; this process is called synthetic lethality. As for PARP clinical monotherapy, progression-free survival has been observed using the FDA- and EMA-approved drugs olaparib and talazoparib. In the case of combined drug therapy, a synergy has been demonstrated between veliparib and platinum drugs. Information regarding adverse effects is limited, but hematological effects have been described. However, there is need for multicenter trials, preferably conducted without commercial guidance and funding. Some of the available trials reported resistance to PARP inhibitors. In this review, we also describe the various causes of resistance to PARP inhibitors and research indicating how resistance can be overcome.


Assuntos
Neoplasias da Mama , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Feminino , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Poli(ADP-Ribose) Polimerases/uso terapêutico , Comportamento de Redução do Risco
6.
Med Princ Pract ; 31(1): 20-28, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-34923496

RESUMO

The musical composers in the Romantic Era (1800-1910) strived for compositions that expressed human life, including happiness, harmony, and despair. They lived in a period in which freedom of thought, expression of emotion, and inspiration by nature predominated. During this period, intensive trading with other parts of the world brought new microorganisms along, which made infections and epidemics very common. This article serves to address the cause of death and relevant biographic data of a number of well-known Romantic composers. Primarily, this review refers to clinically significant findings using reports that were retrieved from PubMed, Embase, and Google over the 19th, 20th, and 21st centuries till 14th June 2021. This text dwells on diseases and the cause of death of ten composers, namely Mozart, Beethoven, Chopin, Schubert, Schumann, Mendelssohn, Brahms, Liszt, Mahler, and Bruckner. It is evident that from the perspective of modern medicine, symptoms and forensic facts are not complete, but witnesses' reports and recent medical research have provided passable and plausible clarity. Although many questions will remain unanswered, it appears that the diseases of these composers and their causes of death have their origins in alcohol abuses, age, epidemics (like tuberculosis), and syphilis.


Assuntos
Música , Sífilis , Causas de Morte , Emoções , Humanos , Música/psicologia , Sífilis/história
7.
Med Princ Pract ; 30(5): 401-411, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33761499

RESUMO

A significant number of studies suggest that coffee consumption reduces cancer risk. This beneficial effect is usually ascribed to the presence of polyphenolic antioxidants and anti-inflammatory agents, including caffeine, cafestol, kahweol, and chlorogenic acids. To summarize recent literature on this subject, we performed a bibliographic search in PubMed and Embase over the period January 2005 to December 2020 to identify cohort studies and meta-analysis (with data collection ensuring quality of selected reports) that could provide quantitative data on the relationship between coffee consumption and common cancers. The totality of eligible scientific articles supports the evidence that coffee intake is inversely associated with risk of hepatocellular cancer and, to a slight extent, risk of breast cancer among postmenopausal women. As to the association with other organs, including the esophagus, pancreas, colorectum, kidneys, bladder, ovaries, and prostate, the results are less clear as reports reveal conflicting results or statistically nonsignificant data. Therefore, this overview does not provide broad-based conclusions. Important uncertainties include general study design, inhomogeneous patient sampling, different statistical analysis (deliberate), misreporting of socioeconomic status, education, coffee-brewing methods, consumption of caffeinated or decaffeinated coffee, smoking habits, and alcohol intake. Clearly, more epidemiologic research needs to be conducted before solid science-based recommendations can be made with regard to coffee consumption.


Assuntos
Cafeína/administração & dosagem , Café , Neoplasias , Cafeína/efeitos adversos , Humanos , Neoplasias/epidemiologia , Neoplasias/prevenção & controle
8.
Med Princ Pract ; 25(2): 101-9, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26571215

RESUMO

Screening mammography offers the possibility of discovering malignant diseases at an early stage, which is consequently treated early, thereby reducing the mortality rate. However, ionizing radiation as used in low-dose X-ray mammography may be associated with a risk of radiation-induced carcinogenesis. In the context of the harmful effects of ionizing radiation, this article reviewed novel radiobiological data and provided a simulation of the relative incidence of radiation-induced breast cancer due to screening against a background baseline incidence in a population of 100,000 individuals. The use of modern digital mammographic technology was assumed, giving rise to a glandular dose of 2.5 mGy from a 2-view per breast image. Assuming no latency time, this led to a ratio of induced incidence rate over baseline incidence rate of about 1.6‰ for biennial screening in women aged 50-74 years, although it cannot be excluded that the dose and dose rate effectiveness factor values relying on new radiobiological insights may lower this number to about 0.7‰. This carcinogenic risk is considered small in relation to the potential beneficial effects of screening, especially as latency time was not taken into consideration. However, individuals who are known to be carriers of risk-increasing genetic variations and/or have an inherited disposition of breast cancer should avoid ionizing radiation as much as possible and should be referred to ultrasound or magnetic resonance imaging. In addition, a significant, but difficult to quantify, risk of cancer is present for individuals who suffer from hypersusceptibility to ionizing radiation.


Assuntos
Neoplasias da Mama/etiologia , Neoplasias da Mama/prevenção & controle , Mamografia/efeitos adversos , Neoplasias Induzidas por Radiação/etiologia , Adulto , Idoso , Relação Dose-Resposta à Radiação , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Induzidas por Radiação/prevenção & controle , Doses de Radiação , Tolerância a Radiação
9.
Med Princ Pract ; 23(5): 403-12, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25060169

RESUMO

According to the first publication in 1993 by Rauscher et al. [Nature 1993;365:611], the Mozart effect implies the enhancement of reasoning skills solving spatial problems in normal subjects after listening to Mozart's piano sonata K 448. A further evaluation of this effect has raised the question whether there is a link between music-generated emotions and a higher level of cognitive abilities by mere listening. Positron emission tomography and functional magnetic resonance imaging have revealed that listening to pleasurable music activates cortical and subcortical cerebral areas where emotions are processed. These neurobiological effects of music suggest that auditory stimulation evokes emotions linked to heightened arousal and result in temporarily enhanced performance in many cognitive domains. Music therapy applies this arousal in a clinical setting as it may offer benefits to patients by diverting their attention from unpleasant experiences and future interventions. It has been applied in the context of various important clinical conditions such as cardiovascular disorders, cancer pain, epilepsy, depression and dementia. Furthermore, music may modulate the immune response, among other things, evidenced by increasing the activity of natural killer cells, lymphocytes and interferon-γ, which is an interesting feature as many diseases are related to a misbalanced immune system. Many of these clinical studies, however, suffer from methodological inadequacies. Nevertheless, at present, there is moderate but not altogether convincing evidence that listening to known and liked music helps to decrease the burden of a disease and enhances the immune system by modifying stress.


Assuntos
Estimulação Acústica/psicologia , Emoções , Musicoterapia , Música/psicologia , Adulto , Nível de Alerta , Cognição , Humanos
10.
Med Princ Pract ; 22(5): 427-37, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23363934

RESUMO

Positron emission tomography (PET) with [¹8F]fluoro-2-deoxy-D-glucose (FDG) has proven to be a valuable diagnostic modality in various diseases. Its accuracy has been improved with the hybrid PET/computed tomography (CT) technique because of precise anatomic location of areas of abnormal FDG accumulation. This integrated PET/CT modality has been widely adopted, particularly in oncology. This paper reviews the role of FDG-PET/CT imaging in breast cancer, non-small-cell lung cancer, colorectal cancer, head and neck cancer as well as lymphoma on the basis of recent key articles. Special attention is paid to preoperative diagnostic workup, evaluation of treatment response and survival prognosis. Experience from specialized centers indicates that there is strong evidence for the clinical effectiveness of FDG-PET/CT in staging, restaging and the prediction of response to therapy in the above-mentioned malignancies. It is concluded that this imaging modality contributes considerably to improved patient management and paves the way to personalize cancer treatment in a cost-effective way.


Assuntos
Fluordesoxiglucose F18 , Imagem Multimodal/métodos , Neoplasias/patologia , Neoplasias/terapia , Compostos Radiofarmacêuticos , Feminino , Humanos , Gradação de Tumores , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X , Resultado do Tratamento
11.
Med Princ Pract ; 21(6): 508-15, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-22472997

RESUMO

Over the past two decades technical advances and improvements have made computed tomography (CT) a valuable and essential tool in the array of diagnostic imaging modalities. CT uses ionizing radiation (X-rays) which may damage DNA and increase the risk of carcinogenesis. This is especially pertinent in pediatric CT as children are more radiosensitive and have a longer life expectancy than adults. The purpose of this paper is to review and elucidate the potential harmful effects of ionizing radiation in terms of solid cancer induction from pediatric CT scanning. In the light of scientific and technical developments, we will also discuss the possible strategies and ongoing efforts to reduce CT radiation exposure in pediatric patients. In this context, we will not ignore the fact that a well-justified CT scan may exceed its risk and have a favorable impact.


Assuntos
Relação Dose-Resposta à Radiação , Neoplasias Induzidas por Radiação/etiologia , Pediatria , Radiação Ionizante , Tomografia Computadorizada por Raios X/efeitos adversos , Fatores Etários , Criança , Proteção da Criança , Humanos , Lesões por Radiação/etiologia , Proteção Radiológica/métodos , Radiometria , Risco , Segurança
12.
Acta Radiol ; 52(7): 767-73, 2011 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-21742785

RESUMO

The considerable rise of computed tomography (CT) procedures over the past few decades has urged responsible authorities and researchers to evaluate the risk of carcinogenesis in the population in relation to the radiation dose delivered to the patient. A single patient undergoing CT may receive a radiation equivalent dose that varies between about 2 mSv (head ) to about 20 mSv (CT-based coronary angiography). Whereas the latter represents a substantial dose delivered to one patient it is, however, population-wise far below the area of the so-called low doses, i.e. 50 mSv in children and 100 mSv in adults. While at effective doses above 50 mSv the risk of cancer induction increases linearly with dose, this dose-response relation has not been demonstrated at doses below 50 mSv. Below 50 mSv no convincing epidemiological evidence for cancer risk exists. Calculations on this risk are based on scientifically questionable, if not invalid, extrapolations of data from higher doses. However, the failure to demonstrate that a risk of cancer exists does not mean that there is no risk. This paper summarizes the data mentioned in various articles from recent literature discussing cancer risks due to CT and puts the results of these studies in perspective of current scientific knowledge in the field of radiation protection. For this we follow the lead of the ICRP and UNSCEAR. Furthermore, we review the strategies and efforts of various national and international bodies and manufacturers of CT apparatus to lower the radiation dose to the patient.


Assuntos
Neoplasias Induzidas por Radiação/etiologia , Doses de Radiação , Tomografia Computadorizada por Raios X/efeitos adversos , Adulto , Criança , Humanos , Neoplasias Induzidas por Radiação/prevenção & controle , Proteção Radiológica/métodos , Radiometria
13.
Med Princ Pract ; 20(2): 103-11, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21252562

RESUMO

The lower occurrence of cancer and cardiovascular disease in the population around the Mediterranean basin has been linked to the dietary habits of the region. Indeed, this so-called Mediterranean diet is essentially different from the diets consumed in Western and Northern European countries and is rich in nuts, fruits, vegetables, legumes, whole-wheat bread, fish, and olive oil, with moderate amounts of red wine, which is mainly consumed during meals. Although a variety of cultural and religious traditions exist among the peoples of the Mediterranean area, olive oil, fish, and red wine hold a traditional and central position in the culinary routines of the region. The components of the diet contain an ample source of molecules with antioxidant and anti-inflammatory actions, among which omega-3 fatty acids, oleic acid, and phenolic compounds hold a prominent place. This review will summarize the results of important epidemiological studies that have investigated the protective effect of fish and olive oil on the risk of breast, prostate, and colorectal cancer and of wine on the risk of cardiovascular disease. The present review also aims to elucidate the various mechanisms by which various dietary components exhibit their beneficial action. In this respect, emphasis will be placed on the properties of omega-3 fatty acids from fish, oleic acid from olive oil, and phenolic compounds from olive oil and red wine.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antioxidantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Dieta Mediterrânea , Neoplasias/prevenção & controle , Doenças Cardiovasculares/dietoterapia , Doenças Cardiovasculares/epidemiologia , Flavonoides/uso terapêutico , Saúde Global , Nível de Saúde , Humanos , Neoplasias/dietoterapia , Neoplasias/epidemiologia , Estado Nutricional , Ácido Oleico/uso terapêutico , Azeite de Oliva , Fenóis/uso terapêutico , Óleos de Plantas/uso terapêutico , Polifenóis , Fatores de Risco
14.
Adv Drug Deliv Rev ; 63(7): 547-54, 2011 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-20933557

RESUMO

Molecular imaging techniques are increasingly being used as valuable tools in the drug development process. Radionuclide-based imaging modalities such as single-photon emission computed tomography (SPECT) and positron emission tomography (PET) have proven to be useful in phases ranging from preclinical development to the initial stages of clinical testing. The high sensitivity of these imaging modalities makes them particularly suited for exploratory investigational new drug (IND) studies as they have the potential to characterize in vivo pharmacokinetics and biodistribution of the compounds using only a fraction of the intended therapeutic dose (microdosing). This information obtained at an early stage of clinical testing results in a better selection among promising drug candidates, thereby increasing the success rate of agents entering clinical trials and the overall efficiency of the process. In this article, we will review the potential applications of SPECT imaging in the drug development process with an emphasis on its applications in exploratory IND studies.


Assuntos
Desenho de Fármacos , Drogas em Investigação/administração & dosagem , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Ensaios Clínicos como Assunto/métodos , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Drogas em Investigação/farmacocinética , Humanos , Tomografia por Emissão de Pósitrons/métodos , Distribuição Tecidual
15.
J Nucl Med ; 51(5): 775-81, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20395330

RESUMO

UNLABELLED: Early assessment of the efficacy of treatment is important in patients with breast cancer, whose routine adjuvant regimen frequently includes chemotherapy. Irrespective of the exact mechanisms involved in induction, the common early phenotypic marker of apoptosis is the expression on the outer cell membrane surface of phosphatidylserine, which avidly binds annexin V. (99m)Tc-labeled annexin V has been proposed for in vivo scintigraphic detection of apoptosis, albeit with contradicting results. This study was performed to define the time course of apoptosis induced by the chemotherapeutic agent paclitaxel in a model of virus-induced murine breast cancer. METHODS: The RIII virus induces an estrogen-dependent, slow-growing breast cancer; BALB-c/cRIII female mice with breast tumors averaging 10 mm were studied, both in baseline conditions and at various times after the intravenous administration of paclitaxel (equivalent to a human dose of 20 mg/70 kg of body weight). The biodistribution of (99m)Tc-annexin V was evaluated at baseline and then at 1, 3, 6, and 24 h after paclitaxel administration. Apoptotic and antiapoptotic markers were also evaluated in tumor samples obtained at the same time points: DNA breaks (terminal deoxynucleotidyl transferase biotin-dUTP nick-end labeling [TUNEL]), active caspase-3, apoptosis-inducing factor, and Bcl-2 protein. RESULTS: Baseline uptake of (99m)Tc-annexin V in breast tumors was about 2-fold higher than the uptake in normal breast tissue (demonstrating some ongoing apoptosis); tracer uptake increased at 1 and 3 h after paclitaxel administration (to almost double the baseline value) and then declined to levels even lower than baseline. Although no activation of the apoptosis-inducing factor mechanism was detected, a peak in TUNEL-positive tumor cells was reached 3 h after paclitaxel administration (to more than 6-fold the baseline level). The antiapoptotic marker Bcl-2 exhibited a biphasic pattern, with a maximum drop at 3 h, followed by return toward baseline levels at 6 h. CONCLUSION: These results define the time course of various biologic events taking place in this model of murine breast cancer after a proapoptotic insult (single-dose paclitaxel). Although confirming that in vivo uptake of (99m)Tc-annexin V reflects the degree of apoptosis, the study also suggests that the apoptotic response to antitumor therapy may differ from tumor type to tumor type. Therefore, contradicting results previously reported may depend on an inadequate time window chosen for imaging with (99m)Tc-annexin V.


Assuntos
Antineoplásicos Fitogênicos/uso terapêutico , Neoplasias Mamárias Experimentais/diagnóstico por imagem , Neoplasias Mamárias Experimentais/tratamento farmacológico , Paclitaxel/uso terapêutico , Animais , Anexina A5/farmacocinética , Apoptose/efeitos dos fármacos , Fator de Indução de Apoptose/metabolismo , Western Blotting , Caspase 3/metabolismo , Feminino , Marcação In Situ das Extremidades Cortadas , Neoplasias Mamárias Experimentais/virologia , Vírus do Tumor Mamário do Camundongo , Camundongos , Camundongos Endogâmicos BALB C , Transplante de Neoplasias , Compostos de Organotecnécio/farmacocinética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Cintilografia , Compostos Radiofarmacêuticos/farmacocinética , Distribuição Tecidual
16.
Drug News Perspect ; 22(4): 205-13, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19536365

RESUMO

The primary pathological hallmark of Alzheimer's disease (AD) is neurodegeneration by neuronal cell death caused by the development of aggregates of beta- amyloid peptide. Epidemiologically, low fish intake and low blood levels of the omega-3 polyunsaturated fatty acid docosahexaenoic acid (DHA) have been related to an increased risk of AD. Test animals on dietary DHA depletion show learning and memory deficits, whereas their brains show inflammatory and oxidative damage to neurons and synaptic defects. The behavioral defects could be reversed by DHA supplementation exemplified by improved cognitive function. Mechanistically, these phenomena have been explained by the antiinflammatory action of DHA. This immunomodulation has been ascribed to incorporation of increased amounts of DHA in cell membrane phospholipids, leading to decreased production of proinflammatory omega-6 eicosanoids. The latter molecules may cause vascular damage which promotes the clinical signs of AD. This review will provide an overview on the available knowledge with regard to the role of DHA in AD with a focus on mechanistic and epidemiological investigations.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Ácidos Docosa-Hexaenoicos/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Doença de Alzheimer/fisiopatologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ensaios Clínicos como Assunto , Ácidos Docosa-Hexaenoicos/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Peixes , Humanos , Camundongos , Alimentos Marinhos
17.
Drug News Perspect ; 22(3): 151-60, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19440558

RESUMO

It has been determined that patients suffering from mild cognitive impairment (MCI) may progress to Alzheimer's disease (AD), which offers a window for therapeutic intervention to slow or halt disease progression. Thus, the detection of prodromal AD is essential to initiate early treatment. The key pathologic hallmark of AD is amyloid beta peptide 42 (Abeta(42)). Probably because of its direct contact with brain tissue, levels of Abeta(42) in combination with phosphorylated tau determined in cerebrospinal fluid (CSF) appear to be useful markers of the disease. In addition, structural and functional brain imaging with magnetic resonance techniques and metabolic imaging with positron emission tomography have been shown to provide useful disease markers. These imaging markers include diminished global brain and hippocampus volume, grey matter loss in the mediotemporal lobe, functional neuronal disconnections and regional hypometabolism. To date, the combination of CSF Abeta(42) and tau parameters provide a sensitivity and a specificity of > 80%. In this article we summarize key aspects of diagnostic markers for AD based on published knowledge. We also dwell on the potential usefulness of these markers for treatment monitoring and in the process of developing and evaluating novel drugs.


Assuntos
Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/análise , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Doença de Alzheimer/fisiopatologia , Peptídeos beta-Amiloides/sangue , Biomarcadores/sangue , Biomarcadores/líquido cefalorraquidiano , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Descoberta de Drogas , Humanos , Imageamento por Ressonância Magnética , Fragmentos de Peptídeos/sangue , Tomografia por Emissão de Pósitrons
18.
Cancer Biother Radiopharm ; 24(2): 215-27, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19409044

RESUMO

The multidrug resistance (MDR) phenotype in cancer is closely related with the overexpression of P-glycoprotein (Pgp) and multidrug resistance protein-1 (MRP1). Although conferring resistance to a similar spectrum of drugs, these proteins present distinct transport mechanisms and have their own substrates. In this work, we compared the functional properties of Pgp and MRP1 in the transport kinetics of two cationic lipophilic tracers, [(99m)Tc]sestamibi and [(99m)Tc]tetrofosmin, in cellular models of resistance. Cellular transport kinetics of both tracers was evaluated in Small-cell lung cancer cell line H69 and in its drug-resistant sublines, H69LX4 and H69AR, overexpressing Pgp and MRP1, respectively. Studies were performed in the absence and in the presence of MDR modulators. Kinetic parameters extracted from time-activity curves were analyzed through receiver-operating characteristics curve analysis. The uptake and the efflux rate of both radiotracers were significantly higher (p < 0.05) in sensitive cells. However, MRP1 was more effective than Pgp in removing tracers from the intracellular medium. The addition of verapamil and PSC833 significantly reduced the efflux rate and restored the accumulation of both tracers in H69LX4 cells. Only verapamil was effective in the inhibition of MRP1; however, the effects were more pronounced with [(99m)Tc]sestamibi, when compared to [(99m)Tc]tetrofosmin. Outward transport of radiotracers by MRP1 was dependent on the intracellular glutathione levels. We concluded that both tracers can detect Pgp- and MRP1-mediated drug resistance, based on transport kinetics; however, MRP1 is more effective than Pgp on outward transport of radiotracers. We postulate that this finding can be useful to distinguish between the two resistance mechanisms.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Compostos Organofosforados/farmacocinética , Compostos de Organotecnécio/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio Tc 99m Sestamibi/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Transporte Biológico , Linhagem Celular Tumoral , Ciclosporinas/farmacologia , Resistencia a Medicamentos Antineoplásicos , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/antagonistas & inibidores , Curva ROC , Cintilografia , Carcinoma de Pequenas Células do Pulmão/diagnóstico por imagem , Carcinoma de Pequenas Células do Pulmão/metabolismo , Células Tumorais Cultivadas , Verapamil/farmacologia
19.
Curr Pharm Des ; 15(9): 928-34, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19275656

RESUMO

The advances of nuclear medicine imaging instrumentation and radiopharmaceutical sciences allow their involvement in the developmental processes of therapeutic drugs. New chemical entities, meant as potential drugs, need to comply with the proof-of-principle. Tomographic imaging methods as PET, SPECT and CT have been used for small animal and human studies at an early stage of drug development. Using a drug candidate in a radiolabeled form in obtaining quantitative imaging data provides opportunity for a complete morphological and functional overview of targeting properties and overall pharmacokinetics. This can be helpful in go/no-go decision making. Microdosing, using e.g.1% of the proposed dose of the radiolabeled potential drug plays an important part in this early development and notably reduces the risk of serious adverse effects in human volunteers or patients. This paper primarily focuses on the way in which microdosing and SPECT imaging may contribute to the development of drugs. Furthermore, this paper illustrates how these techniques may help to eliminate weak drug candidates at early stage, making time and funds available for potential lead compounds. Eventually this approach facilitates and accelerates new drug approval. The present paper highlights how these techniques make drug development easier in the field of oncology and neurology.


Assuntos
Desenho de Fármacos , Radioisótopos , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Biomarcadores/metabolismo , Ensaios Clínicos como Assunto , Sistemas de Liberação de Medicamentos , Humanos , Marcação por Isótopo/métodos , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Tecnologia Farmacêutica/métodos
20.
J Nucl Med ; 49(5): 776-87, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18413380

RESUMO

This review outlines the technical aspects and diagnostic performance parameters of nuclear medicine procedures used on patients with disorders of the lower gastrointestinal tract, with the exclusion of techniques using tumor-seeking radiopharmaceuticals. Chronic disorders of the lower gastrointestinal tract often reduce the quality of life because of discomfort from constipation or diarrhea. Five classes of radionuclide procedures are used to characterize these disorders: transit scintigraphy, searches for ectopic gastric mucosa in Meckel's diverticulum, scintigraphy of active inflammatory bowel disease, scintigraphic defecography, and scintigraphy to detect sites of gastrointestinal bleeding. Protocols for these procedures and their relative merit in patient management are discussed, with special emphasis on their potential for semiquantitative assessment of the pathophysiologic parameter investigated. Quantitation is particularly relevant for prognostic purposes and for monitoring the efficacy of therapy.


Assuntos
Trato Gastrointestinal Inferior/diagnóstico por imagem , Trato Gastrointestinal Inferior/patologia , Cintilografia/métodos , Constipação Intestinal/diagnóstico por imagem , Constipação Intestinal/patologia , Defecografia , Diarreia/diagnóstico por imagem , Diarreia/patologia , Hemorragia/diagnóstico por imagem , Hemorragia/patologia , Humanos
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