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1.
Biomed Pharmacother ; 174: 116376, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38508080

RESUMO

Alzheimer's disease (AD) is a very common neurodegenerative disorder associated with memory loss and a progressive decline in cognitive activity. The two major pathophysiological factors responsible for AD are amyloid plaques (comprising amyloid-beta aggregates) and neurofibrillary tangles (consisting of hyperphosphorylated tau protein). Polyphenols, a class of naturally occurring compounds, are immensely beneficial for the treatment or management of various disorders and illnesses. Naturally occurring sources of polyphenols include plants and plant-based foods, such as fruits, herbs, tea, vegetables, coffee, red wine, and dark chocolate. Polyphenols have unique properties, such as being the major source of anti-oxidants and possessing anti-aging and anti-cancerous properties. Currently, dietary polyphenols have become a potential therapeutic approach for the management of AD, depending on various research findings. Dietary polyphenols can be an effective strategy to tackle multifactorial events that occur with AD. For instance, naturally occurring polyphenols have been reported to exhibit neuroprotection by modulating the Aß biogenesis pathway in AD. Many nanoformulations have been established to enhance the bioavailability of polyphenols, with nanonization being the most promising. This review comprehensively provides mechanistic insights into the neuroprotective potential of dietary polyphenols in treating AD. It also reviews the usability of dietary polyphenol as nanoformulation for AD treatment.


Assuntos
Doença de Alzheimer , Polifenóis , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/dietoterapia , Doença de Alzheimer/metabolismo , Polifenóis/farmacologia , Humanos , Animais , Fármacos Neuroprotetores/uso terapêutico , Fármacos Neuroprotetores/farmacologia , Nanopartículas/química , Dieta , Peptídeos beta-Amiloides/metabolismo , Disponibilidade Biológica
2.
Curr Pharm Des ; 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321896

RESUMO

Coleus amboinicus Benth., also known as Plectranthus amboinicus (Lour.) Spreng., is a perennial plant from the Lamiaceae family commonly found in tropical and warm regions of Africa, Asia, and Australia. Folk medicine commonly employs this remedy to address various ailments, including but not limited to asthma, headaches, skin disorders, coughs, constipation, colds, and fevers. Several phytoconstituents from various phytochemical classes, such as phenolics, terpenoids, phenolic acids, flavonoids, flavones, and tannins, have been identified in Coleus amboinicus up to the present time. Numerous pharmacological properties of Coleus amboinicus crude extracts have been documented through both in vitro and in vivo studies, including but not limited to antitumor, antibacterial, antifungal, antiprotozoal, anti-inflammatory, antioxidant, antidiabetic, wound healing, analgesic, antirheumatic, and various other therapeutic effects. Due to its extensive history of traditional usage, the diverse array of bioactive phytochemicals, and numerous established pharmacological activities, Coleus amboinicus is widely regarded as having significant potential for clinical applications and warrants further exploration, development, and exploitation through research. With this context, the present study gathers information on the occurrence, biological description, cultivation, and nutritional values of Coleus amboinicus. Furthermore, it thoroughly discusses various phytoconstituents, along with their classes, present in Coleus amboinicus, followed by detailed descriptions of their pharmacological activities based on recent literature.

3.
Eur J Med Res ; 29(1): 26, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38183131

RESUMO

This review article explores the dynamic field of radiopharmaceuticals, where innovative developments arise from combining radioisotopes and pharmaceuticals, opening up exciting therapeutic possibilities. The in-depth exploration covers targeted drug delivery, delving into passive targeting through enhanced permeability and retention, as well as active targeting using ligand-receptor strategies. The article also discusses stimulus-responsive release systems, which orchestrate controlled release, enhancing precision and therapeutic effectiveness. A significant focus is placed on the crucial role of radiopharmaceuticals in medical imaging and theranostics, highlighting their contribution to diagnostic accuracy and image-guided curative interventions. The review emphasizes safety considerations and strategies for mitigating side effects, providing valuable insights into addressing challenges and achieving precise drug delivery. Looking ahead, the article discusses nanoparticle formulations as cutting-edge innovations in next-generation radiopharmaceuticals, showcasing their potential applications. Real-world examples are presented through case studies, including the use of radiolabelled antibodies for solid tumors, peptide receptor radionuclide therapy for neuroendocrine tumors, and the intricate management of bone metastases. The concluding perspective envisions the future trajectory of radiopharmaceuticals, anticipating a harmonious integration of precision medicine and artificial intelligence. This vision foresees an era where therapeutic precision aligns seamlessly with scientific advancements, ushering in a new epoch marked by the fusion of therapeutic resonance and visionary progress.


Assuntos
Medicina de Precisão , Compostos Radiofarmacêuticos , Humanos , Compostos Radiofarmacêuticos/uso terapêutico , Inteligência Artificial
4.
Curr Drug Deliv ; 21(5): 662-682, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37357524

RESUMO

Hypertension is a critical health problem. It is also the primary reason for coronary heart disease, stroke, and renal vascular disease. The use of herbal drugs in the management of any disease is increasing. They are considered the best immune booster to fight against several types of diseases. To date, the demand for herbal drugs has been increasing because of their excellent properties. This review highlights antihypertensive drugs, polyphenols, and synbiotics for managing hypertension. Evidence is mounting in favour of more aggressive blood pressure control with reduced adverse effects, especially for specific patient populations. This review aimed to present contemporary viewpoints and novel treatment options, including cutting-edge technological applications and emerging interventional and pharmaceutical therapies, as well as key concerns arising from several years of research and epidemiological observations related to the management of hypertension.


Assuntos
Hipertensão , Humanos , Hipertensão/tratamento farmacológico , Hipertensão/induzido quimicamente , Anti-Hipertensivos/uso terapêutico , Anti-Hipertensivos/farmacologia , Pressão Sanguínea
5.
AAPS PharmSciTech ; 24(8): 233, 2023 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-37973643

RESUMO

Blood cancer, also known as hematological malignancy, is one of the devastating types of cancer that has significantly paved its mortality mark globally. It persists as an extremely deadly cancer type and needs utmost attention owing to its negligible overall survival rate. Major challenges in the treatment of blood cancer include difficulties in early diagnosis, as well as severe side effects resulting from chemotherapy. In addition, immunotherapies and targeted therapies can be prohibitively expensive. Over the past two decades, scientists have devised a few nanoparticle-based drug delivery systems aimed at overcoming this challenge. These therapeutic strategies are engineered to augment the cellular uptake, pharmacokinetics, and effectiveness of anticancer drugs. However, there are still numerous types of nanoparticles that could potentially improve the efficacy of blood cancer treatment, while also reducing treatment costs and mitigating drug-related side effects. To the best of our knowledge, there has been limited reviews published on the use of nano-based drug delivery systems for the treatment of hematological malignancies. Therefore, we have made a concerted effort to provide a comprehensive review that draws upon recent literature and patents, with a focus on the most promising results regarding the use of nanoparticle-based approaches for the treatment of hematological malignancies. All these crucial points covered under a common title would significantly help researchers and scientists working in the area.


Assuntos
Antineoplásicos , Neoplasias Hematológicas , Nanopartículas , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Neoplasias Hematológicas/tratamento farmacológico
7.
Artigo em Inglês | MEDLINE | ID: mdl-37880560

RESUMO

Cervical cancer (CC) is the fourth most common malignancy in female patients. "Human papillomavirus" (HPV) contamination is a leading cause of all forms of cervical cancer, accounting for an expected 570,000 reported incidents in 2018. Two HPV strains (16 and 18) are responsible for 70% of CC and pre-cancerous cervical abnormalities. CC is one of the foremost reasons for the malignancy death rate in India among women ranging from 30 to 69 years of age in India, responsible for 17% of all cancer deaths. Currently approved cervical cancer treatments are associated with adverse reactions that might harm the lives of women affected by this disease. Consequently, probiotics can play a vital role in the treatment of CC. It is reflected from various studies regarding the role of probiotics in the diagnosis, prevention or treatment of cancer. In this review article, we have discussed the rationale of probiotics for treatment of CC, the role of probiotics as effective adjuvants in anti-cancer therapy and the combined effect of the anti-cancer drug along with probiotics to minimize the side effects due to chemotherapy.

8.
Front Immunol ; 14: 1264502, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37818370

RESUMO

The outbreak of a fatal black fungus infection after the resurgence of the cadaverous COVID-19 has exhorted scientists worldwide to develop a nutshell by repurposing or designing new formulations to address the crisis. Patients expressing COVID-19 are more susceptible to Mucormycosis (MCR) and thus fall easy prey to decease accounting for this global threat. Their mortality rates range around 32-70% depending on the organs affected and grow even higher despite the treatment. The many contemporary recommendations strongly advise using liposomal amphotericin B and surgery as first-line therapy whenever practicable. MCR is a dangerous infection that requires an antifungal drug administration on appropriate prescription, typically one of the following: Amphotericin B, Posaconazole, or Isavuconazole since the fungi that cause MCR are resistant to other medications like fluconazole, voriconazole, and echinocandins. Amphotericin B and Posaconazole are administered through veins (intravenously), and isavuconazole by mouth (orally). From last several years so many compounds are developed against invasive fungal disease but only few of them are able to induce effective treatment against the micorals. Adjuvant medicines, more particularly, are difficult to assess without prospective randomized controlled investigations, which are challenging to conduct given the lower incidence and higher mortality from Mucormycosis. The present analysis provides insight into pathogenesis, epidemiology, clinical manifestations, underlying fungal virulence, and growth mechanisms. In addition, current therapy for MCR in Post Covid-19 individuals includes conventional and novel nano-based advanced management systems for procuring against deadly fungal infection. The study urges involving nanomedicine to prevent fungal growth at the commencement of infection, delay the progression, and mitigate fatality risk.


Assuntos
COVID-19 , Mucormicose , Micoses , Humanos , Anfotericina B/farmacologia , Anfotericina B/uso terapêutico , Mucormicose/tratamento farmacológico , Virulência , Micoses/tratamento farmacológico
9.
Cancer Med ; 12(18): 18797-18825, 2023 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-37668041

RESUMO

BACKGROUND: Cancer treatment is still a global health challenge. Nowadays, chemotherapy is widely applied for treating cancer and reducing its burden. However, its application might be in accordance with various adverse effects by exposing the healthy tissues and multidrug resistance (MDR), leading to disease relapse or metastasis. In addition, due to tumor heterogeneity and the varied pharmacokinetic features of prescribed drugs, combination therapy has only shown modestly improved results in MDR malignancies. Nanotechnology has been explored as a potential tool for cancer treatment, due to the efficiency of nanoparticles to function as a vehicle for drug delivery. METHODS: With this viewpoint, functionalized nanosystems have been investigated as a potential strategy to overcome drug resistance. RESULTS: This approach aims to improve the efficacy of anticancer medicines while decreasing their associated side effects through a range of mechanisms, such as bypassing drug efflux, controlling drug release, and disrupting metabolism. This review discusses the MDR mechanisms contributing to therapeutic failure, the most cutting-edge approaches used in nanomedicine to create and assess nanocarriers, and designed nanomedicine to counteract MDR with emphasis on recent developments, their potential, and limitations. CONCLUSIONS: Studies have shown that nanoparticle-mediated drug delivery confers distinct benefits over traditional pharmaceuticals, including improved biocompatibility, stability, permeability, retention effect, and targeting capabilities.

10.
J Health Popul Nutr ; 42(1): 74, 2023 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-37501216

RESUMO

BACKGROUND: Magnesium (Mg) has gained much importance recently because of its unique range of biological functions. It is one of the most significant micronutrients in biological systems. This review aims to outline the immune-regulating actions of Mg and its crucial role in regulating inflammation and immune response to infectious agents and malignancies. METHODS: We conducted a literature review on MEDLINE, PubMed, EMBASE, Web of Science to determine the impact of Mg on immune regulation in three settings of inflammation, infection, and cancer. We thoroughly examined all abstracts and full-text articles and selected the most relevant ones for inclusion in this review. RESULTS: Mg has long been associated with immunological responses, both nonspecific and specific. It plays a pivotal role in diverse immune responses by participating in multiple mechanisms. It facilitates substance P binding to lymphoblasts, promotes T helper, B cell, and macrophage responses to lymphokines, and facilitates antibody-dependent cytolysis and immune cell adherence. Besides, Mg serves as a cofactor for C'3 convertase and immunoglobulin synthesis. It additionally boasts a significant anti-cancer effect. Chronic Mg deficiency leads to enhanced baseline inflammation associated with oxidative stress, related to various age-associated morbidities. A deficiency of Mg in rodents has been observed to impact the cell-mediated immunity and synthesis of IgG adversely. This deficiency can lead to various complications, such as lymphoma, histaminosis, hypereosinophilia, increased levels of IgE, and atrophy of the thymus. The immunological consequences of Mg deficiency in humans can be influenced by the genetic regulation of Mg levels in blood cells. Mg can also mediate cell cycle progression. There has been a renewed interest in the physiology and therapeutic efficacy of Mg. However, the in-depth mechanisms, their clinical significance, and their importance in malignancies and inflammatory disorders still need to be clarified. CONCLUSIONS: Mg is essential for optimal immune function and regulating inflammation. Deficiency in Mg can lead to temporary or long-term immune dysfunction. A balanced diet usually provides sufficient Mg, but supplementation may be necessary in some cases. Excessive supplementation can have negative impacts on immune function and should be avoided. This review provides an update on the importance of Mg in an immune response against cancer cells and infectious agents and how it regulates inflammation, oxidative stress, cell progression, differentiation, and apoptosis.


Assuntos
Doenças Transmissíveis , Neoplasias , Humanos , Magnésio , Inflamação
11.
Virusdisease ; : 1-19, 2023 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-37363362

RESUMO

Over 98% of cervical cancers (CC) are caused by regular infections with "high risk" genotype of the human papilloma virus (HPV). However, this is not always the causative factor. Therefore, production of HPV vaccinations represents a significant chance to minimize the risk of CC. Phase III studies for a number of preventative HPV vaccines based on L1-virus-like particle (VLPs) have just been completed and the preliminary results are very convincing. However, there are a lot of practical concerns that need to be resolved before the use of these vaccinations. These vaccines were challenged with obvious queries such as protection time, subject receiving vaccines, time of vaccination, and how to include them into ongoing screening programs. Although these vaccines were 90% effective at preventing HPV infection as these offered only modest advantages for the removal of pre-existing infections. New advancements in the creation of therapeutic vaccinations have been explored for further improvement and post-vaccination surveillance. Therapeutic vaccines attempted to boost cell-mediated immunities and these are detrimental to the infected cell as opposed to neutralizing antibodies (different from prophylactic vaccines).

12.
Anticancer Agents Med Chem ; 23(16): 1866-1879, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37365788

RESUMO

OBJECTIVE: Curcumin has the propensity to inhibit cancer growth, slow cancer development, increase chemotherapy effectiveness, and shield healthy cells from radiation treatment harm. As a result of curcumin's ability to block several signaling pathways, cervical cancer cells can once again proliferate normally. To optimize topically applied curcumin-loaded solid lipid nanoparticles (SLNPs) for the treatment of cervical cancer, this study set out to establish the relationship between design variables and experimental data. It also performed in vitro characterizations to determine the formulation's efficacy and safety. METHODS: Curcumin-loaded SLNPs were constructed and optimized using a systematic design of experiment (DoE) technique. SLNPs that were loaded with curcumin were produced utilizing a cold emulsification ultrasonication process. Using the Box Behnken Design, it was determined how independent variables (factors) like the quantity of lipid (A), the quantity of phospholipid (B), and the concentration of surfactant (C) affected the responses of the dependent variables (responses), such as particle size (Y1), polydispersity index (PDI) (Y2), and entrapment efficiency (EE) (Y3) (BBD). RESULTS: The ideal formulation (SLN9) was chosen using the desirability technique based on 3-D surface response graphs. Using polynomial equations and three-dimensional surface plots, the influence of independent factors on the dependent variables was evaluated. The observed responses were almost equal to the levels that the optimal formulation expected. The improved SLNP gel's shape and other physicochemical characteristics were also assessed, and they were determined to be ideal. The sustained release profile of the produced formulations was validated by in vitro release tests. Studies on hemolysis, immunogenic response, and in vitro cell cytotoxicity demonstrate the efficacy and safety of the formulations. CONCLUSION: To improve the treatment effect, chitosan-coated SLNPs may carry encapsulated curcumin to the desired location and facilitate its localization and deposition in the desired vaginal tissue.


Assuntos
Curcumina , Nanopartículas , Neoplasias do Colo do Útero , Feminino , Humanos , Curcumina/farmacologia , Curcumina/química , Lipídeos/química , Neoplasias do Colo do Útero/tratamento farmacológico , Nanopartículas/química , Tensoativos/química , Tamanho da Partícula , Portadores de Fármacos/química
13.
Naunyn Schmiedebergs Arch Pharmacol ; 396(11): 2769-2792, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37219615

RESUMO

Lung cancer is the most common type of cancer, with over 2.1 million cases diagnosed annually worldwide. It has a high incidence and mortality rate, leading to extensive research into various treatment options, including the use of nanomaterial-based carriers for drug delivery. With regard to cancer treatment, the distinct biological and physico-chemical features of nano-structures have acquired considerable impetus as drug delivery system (DDS) for delivering medication combinations or combining diagnostics and targeted therapy. This review focuses on the use of nanomedicine-based drug delivery systems in the treatment of lung cancer, including the use of lipid, polymer, and carbon-based nanomaterials for traditional therapies such as chemotherapy, radiotherapy, and phototherapy. The review also discusses the potential of stimuli-responsive nanomaterials for drug delivery in lung cancer, and the limitations and opportunities for improving the design of nano-based materials for the treatment of non-small cell lung cancer (NSCLC).


Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Nanopartículas , Neoplasias , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Nanopartículas/química , Neoplasias/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Portadores de Fármacos/química
14.
Chem Biol Interact ; 368: 110231, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36288778

RESUMO

The human microbiota is fundamental to correct immune system development and balance. Dysbiosis, or microbial content alteration in the gut and respiratory tract, is associated with immune system dysfunction and lung disease development. The microbiota's influence on human health and disease is exerted through the abundance of metabolites produced by resident microorganisms, where short-chain fatty acids (SCFAs) represent the fundamental class. SCFAs are mainly produced by the gut microbiota through anaerobic fermentation of dietary fibers, and are known to influence the homeostasis, susceptibility to and outcome of many lung diseases. This article explores the microbial species found in healthy human gastrointestinal and respiratory tracts. We investigate factors contributing to dysbiosis in lung illness, and the gut-lung axis and its association with lung diseases, with a particular focus on the functions and mechanistic roles of SCFAs in these processes. The key focus of this review is a discussion of the main metabolites of the intestinal microbiota that contribute to host-pathogen interactions: SCFAs, which are formed by anaerobic fermentation. These metabolites include propionate, acetate, and butyrate, and are crucial for the preservation of immune homeostasis. Evidence suggests that SCFAs prevent infections by directly affecting host immune signaling. This review covers the various and intricate ways through which SCFAs affect the immune system's response to infections, with a focus on pulmonary diseases including chronic obstructive pulmonary diseases, asthma, lung cystic fibrosis, and tuberculosis. The findings reviewed suggest that the immunological state of the lung may be indirectly influenced by elements produced by the gut microbiota. SCFAs represent valuable potential therapeutic candidates in this context.


Assuntos
Asma , Microbioma Gastrointestinal , Humanos , Disbiose/metabolismo , Ácidos Graxos Voláteis/metabolismo , Ácidos Graxos Voláteis/uso terapêutico , Pulmão/metabolismo , Asma/tratamento farmacológico
15.
Chem Biol Interact ; 363: 110000, 2022 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-35671828

RESUMO

Extrachromosomal DNA (ecDNA) is often found in cancerous cells, and numerous scientific investigations have already shown that ecDNA-mediated oncogene amplification which contributes to cancer therapy resistance. This ecDNA is found to be essential for enhancing gene transcription and resistance to chemotherapeutic drugs, as well as promoting tumor heterogeneity and reversing tumor phenotypes, suggesting that it plays a key role in carcinogenesis. The ecDNA induces tumors to become hostile which results in a lower survival rate and chemotherapy tolerance. It also holds the potential as a target for treatment or diagnostic procedure of tumors. The review describes the properties and origins of ecDNA, as well as how it affects carcinogenesis, its function in cancer etiology and progression, and its therapeutic value. Propagation of oncogenes and resistance genes situated in extra-chromosomal DNA has been discovered to become one of the primary causes of intra-tumor genetic heterogeneity and may result in a threshold of probable evolutionary adaptation in many investigations.


Assuntos
Neoplasias , Oncogenes , Carcinogênese/genética , Transformação Celular Neoplásica/genética , DNA , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/patologia
16.
Recent Pat Nanotechnol ; 16(3): 207-218, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-33726660

RESUMO

Oleosomes are oil-containing micro-carriers of natural origin that are comprised of special oleosin proteins embedded with a monolayer of phospholipids having a triacylglycerol core. Due to their unique structure and non-toxicity in the biological system, these oil carriers are becoming very eye-catching for formulation development in the field of pharmacy. Consequently, oleosome offers emoliency, occlusivity, self-emulsification, anti-oxidant, and film-forming properties, which leads to controlled and sustained release of encapsulated bio-actives. It is also feasible to load oil-soluble ingredients, such as fragrance, vitamins (retinol), and lipophilic drug moieties inside the core. Being a natural carrier, it shows some stability issues (leakage of oil from the core, oxidation of the loaded oil, aggregation of oil droplets), which are controllable. In this review, we have focused on the various stability issues, the techniques (coating, surface modification, solvents) and how to overcome those problems, and how to load any lipophilic drug into the oil core, and we have also linked patent research works in the field of formulation development.


Assuntos
Gotículas Lipídicas , Farmácia , Portadores de Fármacos , Sistemas de Liberação de Medicamentos , Emulsões/química , Excipientes , Patentes como Assunto , Preparações Farmacêuticas
17.
Curr Drug Res Rev ; 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34802415

RESUMO

Several current studies have highlighted the high occurrence of coagulopathy in nCOVID-19 infection. The corona virus often prompts hypercoagulability along with both microangiopathy and local thrombus development, and systemic coagulation limitation which causes large vessel thrombosis and key thromboembolic issues such as pulmonary embolism in seriously ill hospitalized patients. Based on recent reports, the most severely ill patients present with coagulopathy, and disseminated intravascular coagulation (DIC)-like massive intravascular clot formation is frequently seen in this cohort. Therefore, coagulation tests may be considered useful to discriminate severe cases of nCOVID-19. The clinical presentation of nCOVID-19-associated coagulopathy is organ dysfunction primarily, while hemorrhagic events are less frequent. Changes in hemostatic biomarkers represented by increase in D-dimer and fibrin/fibrinogen degradation products indicate the essence of coagulopathy is massive fibrin formation. Overall, the patients have an increase in venous and arterial thrombotic events especially in ICU patients. Routine thromboprophylaxis with low molecular weight heparin is recommended in all hospitalized patients to reduce the incidence of thrombosis. Though, the importance of thromboembolic impediments has not been extensively spotlighted, thus the rationale of this article is to provide recent information about this severe difficulty. In this article the mechanism of coagulopathy, associated problems and possible therapeutics has been reviewed.

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