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FUTURE ASPECTS IN DENGUE FEVER THERAPY

 

Clinical courses

Dengue fever is a viral caused disease that is spread by the bite of mosquito Aedes aegypti. There are 4 distinct, but closely related, serotypes of the virus that cause dengue (DEN-1, DEN-2, DEN-3 and DEN-4)

Symptoms

  • Sudden high fever (104-105 degree, 4 to 7 days after the infection)
  • A flat red rash may appear over most of the body 2-5 days after the fever starts.
  • Fatigue, headache, joint aches, muscle aches, nausea, vomiting, swollen lymph nodes, dehydration, thrombocytopenia.
  • Dengue causes liver involvement in a number of patients. Hepatomegaly and elevations in aspartate(AST) and alanine transaminase (ALT) are common. Postulated mechanisms for liver injury includes direct damage or various immune mediated effects mainly through cytokines, T cells, apoptosis or free radicals[1].

DENV life cycle
To date, many research studies have been conducted to understand the life cycle of dengue virus, especially the viral protein processing and the genome replication. Dengue virus binds to its receptor, and this process is mediated by envelop protein (E). In mammalian cell, DEN 1–4 serotypes bind with Heparan sulfate, nLc4Cer, DC-SIGN/L-SIGN and Mannose receptors. DEN-2 serotype also binds with HSP70/HSP90, GRP78, CD14- associated protein and two unknown proteins having trypsin resistance and trypsin sensitive properties. DEN 1–3 serotypes as well bind with Laminin receptor[2]. DEN 2–4 serotypes also bind with an unknown protein having the property of serotype specific binding. After initial attachment of the virus with particular receptors on the surface of host cell, the viral particle is fused into acidic lysosomes through receptor-mediated endocytosis[3]. After that, viral particle is uncoated and the RNA is released in host cell where it directs the synthesis of viral proteins. Once all the essential proteins are synthesized, viral RNA starts copying to generate a minus strand, which is then transcribed to new plus stranded molecules. In only few hours after infection, tens of thousands copies of viral molecules are produced from a single viral molecule leading to cell damage and in severe cases to death. Viral-encoded RNA-dependent RNA polymerases (RdRps) and other cellular factors are responsible for catalyzing the infection cycle of dengue virus[4].

DENV Cell entry receptors
Dengue virus replication cycle.
Prevention & treatment
To date, there is no specific treatment available for dengue virus infection. There are three ways to solve the problem of dengue infection. The First is to use a preventive measure by avoiding contact with infected mosquitoes. Aedes mosquitoes bite during daytime and its  contact can be avoided by: properly managing waste and improving storage of water, removing all sources of stagnant water, using household pesticides to kill mosquitoes, using mosquito coils and nets, wearing longsleeved shirts, socks and trousers and using insect repellent to avoid mosquitoes. Insecticide treated nets (ITNs) are available to protect young children, pregnant women, old people, in addition to others who may rest during the day. The Second is vaccination, which is currently not available and the Third is drug therapy but no antiviral drugs are available to target dengue virus [5]. However, supportive care and treatment can save a patient infected with dengue fever. Fever can be treated by anti-pyretics, like paracetamol. Joint pain can be treated by analgesics or painkiller tablets. In case of DHF/DSS, patients must be hospitalized. Dehydration can be prevented by oral rehydration therapy and if oral intake is impossible then intravenous fluid replacement can be used to prevent shock in infected patients. If platelet level drops below 20,000 or if there is significant bleeding, then platelet transfusion is recommended. Drugs such as aspirin, brufen and non-steroidal anti- inflammatory should be avoided as they may worsen the bleeding tendency. Any medicine that decreases the platelet level should be avoided.


Role of Papaya in Dengue fever
Botanical Name: Carica papaya
Family Name: Caricaceae

Common Name: Papaya, Paw Paw, Kates, Papaw
Part Used: Leaves, Fruits, bark

With the rising number of people catching dengue fever, the demand for papaya leaf juice has soared. Thrombocytopenia is one of the clinical manifestations in dengue fever and contributes to the plasma leakage and haemorrhage in the presence of enhanced vascular permeability[6]. Thrombocytopenia in dengue is considered to be an immune related, molecular mimcry involving dengue viral particles and the platelet leads to auto-destruction of the platelets by immunoglobulin M(IgM) antibodies.Interstingly, C.papaya leaves juice have demonstrated a positive effect on increasing platelet count in healthy mice. C. papaya leaves extract prepared in water has been tested against dengue fever. After the administration of aqueous extract in dengue infected patient, the platelet count increased from 55x103/μL to 168x103/μL, White blood cells from 3.7x103/μL to 7.7x103/μL and neutrophils from 46% to 78%[7]. Carica papaya leaf juice showed a significant inhibition of haemolysis invitroand could have a potential therapeutic effect on disease processes causing destabilization of biological membranes may effectively enhance the survival of platelets[8]. Thus carica papya can be used to target dengue fever.


Conclusion
Dengue infection has emerged as a major health concern in Southeast Asia, the pacific and America. Dengue virus has become a serious issue in India as it has caused many endemics starting since 1994 . Developing tetravalent vaccine against all four dengue serotypes is quite challenging. To date, there is no licensed vaccine available for dengue virus. Therefore, there is an urgent need to develop an alternative solution to combat this endemic infection. Currently, there are no antiviral compounds available against dengue virus and there is a need to develop antiviral compounds that can target all four serotypes of dengue with same efficiency. Several medicinal plants have been tested against dengue virus entry and replication; many of them showed significant inhibitory effects. Nevertheless, it will be very exciting to see these medicinal plants as potential DENV inhibitors to progress through clinical developments and, hopefully, provide dengue patients with much needed, more effective therapies.

REFERENCES
1. Guzman MG, Kouri G: Dengue: an update. Lancet Infect Dis 2002, 2:33–42. Dengue infection has emerged as a major health concern       
2. WHO: Dengue Haemorrhagic Fever: Diagnosis, Treatment, Prevention and Control. 2nd edition. Geneva: World Health Organization; 1997 in Southeast Asia, the pacific and America.
3. Jahan F: Dengue Fever (DF) in Pakistan. Asia Pac Fam Med 2011, 10:1. has become a serious issue in Pakistan as it has caused  
4. Hidari KI, Suzuki T: Dengue virus receptor. Trop Med Health 2011, 39:37–43. many endemics starting from 1994 to 2011.
5. Selisko B, Guillemot J-C, Alvarez K, Canard B: Opportunities in the  development of ANTI-dengue drugs. Geneva: 2006.
6. Tang LI, Ling AP, Koh RY, Chye SM, Voon KG: Screening of anti-dengue activity in methanolic extracts of medicinal plants. BMC Complement Altern Med 2012, 12:3.
7. Huet J, Looze Y, Bartik K, Raussens V, Wintjens R, Boussard P: Structural characterization of the papaya cysteine proteinases at low pH. Biochem  Biophys Res Commun 2006, 341:620–626.
8. Ahmad N, Fazal H, Ayaz M, Abbasi BH, Mohammad I, Fazal L: Dengue fever   treatment with Carica papaya leaves extracts. Asian Pac J Trop Biomed 2011, 330:333.

About Author:
Shuja Nazimudin K.H
Assistant Professor
Department of Pharmacology
MGR Medical University
coolshuj2u@gmail.com

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