Snake bite

Snake bite is an acute life threatening medical emergency often faced by farmers and farm
labourers. Early diagnosis of envenoming by venomous snake and its rational and accurate
management may save life. Rural Indian victims of snake bite are reported earlier due to easily
available transport including auto and jeeps and constructed approachable roads to the majority of
villages. Irrespective of early reporting, the fatality in venomous snake envenoming is due to nonavailability
of medical officers at primary health Center (PHC), inadequate facilities including antisnake
venom (ASV), and resuscitation trolley: working laryngoscope, endo tracheal tubes, Ambu
bag, ventilator and other emergency medicine. Many times the medical officer is a freshly passed
graduate and has not seen and treated the venomous snake bites before. This adds to the morbidity
and mortality. Because of expensive ASV and it not being easily available to private hospitals,
many doctors avoid admitting the case due to threat of anaphylaxis. Moreover the poor rural
population cannot afford expensive ASV and treatment at private hospitals. Snake bite should be
declared as an occupational hazard. ASV should be available free of cost to victims admitted to
private hospitals. ASV is always in short supply. To avoid the crisis of ASV supply, peripheral
doctors should be trained regarding management of snake bite and indications of ASV. Availability
of snake venom antigen detection kit (ELISA Mono-specific) is a must. Antivenin producers in
India should be encouraged to prepare antivenom from venom obtained from snakes caught from
relevant areas of the country.

Introduction

Venomous snake bite is an important public health hazard in tropical and subtropical countries. In rural areas snake bite poisoning is a leading cause of premature death of young earning
member of the family. In India 35,000-50,000 lives are lost per year due to venomous snake bite. More than 2000 deaths per year are reported from Maharashtra. This is the tip of the iceberg as
the majority of snake bite deaths go unreported as many villagers go to traditional healers like
mantriks and tantriks. Moreover snake bite is not a notified disease in medical fraternity. It is
surprising that, snake bite poisoning is seldom mentioned as a priority for health research in a
developing country like India. The grant allocated for snake bite is many times less than the grant
allocated to amoebic dysentery (with a negligible fatality as compared to snake bite). Unfortunately
public health authorities, nationally and internationally, have given little attention to this grave, life
threatening medical problem, relegating snake bite envenoming to the category of a major neglected
disease of the 21st century. There should be more encouragement from government and other
funding agencies for conducting research. Moreover there are very few medical scientists taking
interest or carrying out research in this field.
Most of the venomous species of snakes are “sit and wait” predators wherein they lie camouflaged
lying in wait for their potential victim and they strike when the prey comes within their striking
distance. The snake usually then lets go allowing the venom to take effect after which they follow
their prey by following its scent trail. So after a human strike, it is very likely that the snake will be
found in the 30 foot radius and it should be remembered that they are no less dangerous after the
first strike. So victim should be moved away from the area.

Andrographis paniculata (Kalmegh)

                  Andrographis paniculata

Scientific classification
Kingdom:	Plantae
(unranked):	Angiosperms
(unranked):	Eudicots
(unranked):	Asterids
Order:	Lamiales
Family:	Acanthaceae
Genus:	Andrographis
Species:	A. paniculata

 Andrographis paniculata is a herbaceous plant in the family  Acanthaceae, native to India and Sri Lanka.

It is widely cultivated in Southern and Southeastern Asia, where it is used to treat infections and some diseases, often being used before antibiotics were created. Mostly the leaves and roots were used for medicinal purposes.

Andrographis paniculata is a plant that has been effectively used in traditional Asian medicines for centuries. Its perceived “blood purifying” property results in its use in diseases where blood “abnormalities” are considered causes of disease, such as skin eruptions, boils, scabies, and chronic undetermined fevers. "e aerial part of the plant, used medicinally, contains a large number of chemicalconstituents, mainly lactones, diterpenoids, diterpene glycosides, flavonoids, and flavonoid glycosides. Controlled clinical trials report its safe and effective use for reducing symptoms of uncomplicated upper respiratory tract infections.

 Since many of the disease conditions commonly treated with A. paniculata in traditional medical systems are considered self-limiting, its purported benefits need critical evaluation. "is review summarizes current scientific findings and suggests further research to verify the therapeutic efficacy of A. paniculata. A. paniculata, known on the Indian subcontinent as Chirayetah and Kalmegh in Urdu and Hindi languages, respectively, is an annual plant, 1-3 ft high, that is one of the most commonly used plants in the traditional systems of Unani and Ayurvedic medicines. It is called Creat in English and is known as the “king of bitters.” It grows in hedge rows throughout the plains of India and is also cultivated in gardens. [Kabeeruddin (1937) & Dymock (1972)] It also grows in many other Asian countries and is used as a traditional herbal medicine in China, Hong Kong, the Philippines, Malaysia, Indonesia, and "Tailand" aerial parts are most commonly used; however, the whole plant or roots are mentioned for certain limited purposes in some manuscripts. Traditionally, the plant was used as an infusion, decoction, or powder, either alone or in combination with other medicinal plants. In modern times, and in many controlled clinical trials, commercial preparations have tended to be standardized extracts of the whole plant. Since many disease conditions commonly treated with A. paniculata in traditional medical systems are considered self-limiting, its purported benefits need critical evaluation. "is review summarizes current scientific findings and suggests areas where further research is needed.

Distribution

A. paniculata is distributed in tropical Asian countries, often in isolated patches. It can be found in a variety of habitats, such as plains, hillsides, coastlines, and disturbed and cultivated areas such as roadsides, farms, and wastelands. Native populations of A. paniculata are spread throughout south India and Sri Lanka which perhaps represent the center of origin and diversity of the species. The herb is an introduced species in northern parts of India, Java, Malaysia, Indonesia, the West Indies, and elsewhere in the Americas. The species also occurs in Hong Kong, Thailand, Brunei, Singapore, and other parts of Asia where it may or may not be native. The plant is cultivated in many areas, as well.

Unlike other species of the genus, A. paniculata is of common occurrence in most places in India, including the plains and hilly areas up to 500 m, which accounts for its wide use. Since time immemorial, village and ethnic communities in India have been using this herb for treating a variety of ailments.

Uses in Traditional Medical Systems     

A.     paniculata has been reported as having antibacterial, antifungal, antiviral, choleretic, hypoglycemic, hypocholesterolemic, and adaptogenic effects.[Bhatnagar., et al., 1961) .

In the Unani system of medicine, it is considered aperient, anti-inflammatory, emollient, astringent, diuretic, emmenagogue, gastric and liver tonic, carminative, antihelmintic, and antipyretic. Due to its “blood purifying” activity it is recommended for use in cases of leprosy, gonorrhea, scabies, boils, skin eruptions, and chronic and seasonal fevers.[ Kabeeruddin & Kitabul  1937] Juice or an infusion of fresh  leaves is given to infants to relieve griping, irregular bowel habits, and loss of appetite.[Dymock & Chopra  et al. 1972] "e leaves and root are also used in general debility, during convalescence after fevers, for dyspepsia associated with gaseous distension, and in advanced stages of dysentery.[ Khory RN & Katrak NN. 1972 ]

In China, the herb derived from the leaves or aerial parts of A. paniculata is known as Chuanxinlian, Yijianxi or Lanhelian. It is described as bitter and cold, is considered to be antipyretic, detoxicant, anti-inflammatory, and detumescent,

and is thought to remove “pathogenic heat” from the blood. A. paniculata is used for the treatment of pharyngolaryngitis, diarrhea, dysentery, cough with thick sputum, carbuncle, sores, and snake bites.[ Chang and But  1987]

 Various preparations and compound formulas of the herb have been used to treat infectious and non-infectious diseases, with significant effective rates reported for conditions such as epidemic encephalitis B, suppurative otitis media, neonatal subcutaneous annular ulcer, vaginitis, cervical erosion, pelvic inflammation, herpes zoster, chicken pox, mumps, neurodermatitis, eczema, and burns. [ Chang and But  1987]

Modern Uses

A primary modern use of A. paniculata is for the prevention and treatment of the common cold. It appears to have antithrombotic actions, suggesting a possible benefit in cardiovascular disease.[Amroyan  et al. 1999] Pharmacological and clinical studies suggest the potential for beneficial effects in diseases like cancer 

(See et al., 2002, Sheeja,2007, Shi, 2008, Yang 2009)  and HIV infections. (Calabrese et al., 2000)

Medicinal use

Since ancient times, A. peniculata is used in traditional Siddha and Ayurvedic systems of medicine as well as in tribal medicine in India and some other countries for multiple clinical applications. From a biomedicinal perspective, the therapeutic value of Kalmegh is due to its mechanism of action which is perhaps by enzyme induction. The plant extract exhibits antityphoid and antifungal activities. Kalmegh is also reported to possess antihepatotoxic, antibiotic, antimalarial, antihepatitic, antithrombogenic, antiinflammatory, [ Thiyagarajan et al. 2011] anti-snake venom, and antipyretic properties to mention a few, besides its general use as an immunostimulant agent.[ Burgos el al (2009)] A study conducted at Bastyr University, showed a significant rise in the mean CD4 lymphocyte level of HIV subjects after administration of 10 mg/kg andrographolide, (Chang & But., 1987) the chief constituent extracted from the leaves of the plant.

The herb has shown an ability to reduce inflammation and viral infection, and is used as a principal ingredient in traditional Chinese medicinal formulas against cold infection. [Kate Wright (2009)]

In one Chilean study, the herb had a significant drying effect on the nasal secretions of cold sufferers who took 1,200 milligrams of andrographis extract daily for five days. [Cáceres &  Hancke (1999)] A systematic review of the literature and meta-analysis of randomized controlled trials also suggested the herb alone or in combination with eleuthero may be an appropriate alternative treatment of uncomplicated acute upper respiratory tract infection., [Poolsup et al (2004) & Schulz V (2010) ]

The herb is the well-known as Kalmegh 'green chiretta', and forms the principal ingredient of a household medicine ('alui'), used as a bitter tonic and febrifuge.

The Tamils have been using Nilavempu - as it is called in Tamil - for centuries. In Siddha medicine, Andrographis Paniculata is used widely to treat fevers like chikenguinea, swine-flu, typhoid etc.

A recent study found Andrographis paniculata as effective as mesalazine (mesalamine) in ulcerative colitis. [Tang & Targan (2011)] Further, andrographolide inhibits interleukin-6 expression and suppresses prostate cancer cell growth in vitro.[ hun JY & Tummala R (2010)]

Andrographis has been shown to be a safe traditional remedy for upper respiratory tract diseases [Coon JT, Ernst E(2004)] The herb has been shown to inhibit RANTES secretion in inflamed bronchial cells. RANTES is a chemo attractant for eosinophils, monocytes and lymphocytes that is stored in, and released by, platelets and activated T-cells [Ko & Wei BL(2006)]. In related research: Andrographolide, an active ingredient in Andrographis, has been shown to be responsible for the herb's inflammatory modulating actions, including the reduction of cytokine and peritoneal deposition of neutrophils, and modulation of lung inflammation in vivo. Extracts of Andrographis exhibit potent inflammatory modulating and antioxidant actions in mouse models. [Sheeja K & Shihab PK(2006)]

Phytochemistry

Andrographolide is the major constituent extracted from the leaves of the plant which is a bicyclic diterpenoid lactone. This bitter principle was isolated in pure form by Gorter (1911). Such other activities as liver protection under various experimental conditions of treatment with galactosamine [Saraswat et al., 1995], paracetamol [Visen et al., 1993] etc. are also attributed to Andrographolide. The hepatoprotective action of andrographolide is related to the activity of certain metabolic enzymes [Choudhury and Poddar, 1984, 1985; Choudhury et al., 1987]. Systematic studies on chemistry of A. paniculata have been carried out. [Chao & Lin (2010)]

Some known constituents are:

• "14-Deoxy-11-dehydroandrographolide     -  Plant
• 14-Deoxy-11-oxoandrographolide              - Plant
• 5-Hydroxy-7,8,2',3'-Tetramethoxyflavone  - Plant
• Andrographine                                             - Root
• Andrographolide                                          - Plant
• Neoandrographolide                                    - Plant
• Panicoline                                                    - Root
• Paniculide-A                                                - Plant
• Paniculide-B                                                - Plant

 

Mechanisms of Action

Hepatoprotective Effects

A. paniculata is extensively used as a hepatostimulant and hepatoprotective agent in Indian systems of medicine. [Trivedi & Rawal (2001)] A. paniculata is also an ingredient in several polyherbal preparations used as hepatoprotectants in India, [Ram VJ.(2001)]one of which has been reported as efficacious in chronic hepatitis B virus infection. [Rajkumar (2007)]

Antimicrobial and Antiparasitic Effects

A. paniculata has been extensively used to treat a variety of conditions of infectious origin in traditional systems of medicine. Modern research has investigated it for activity against various bacteria, viruses, and parasites. Crude powder suspended in water was reported to be devoid of in vitro antibacterial activity against Salmonella, Shigella, Escherichia coli, gram A Streptococci, and Staphylococcus aureus, even at a concentration of 25 mg/mL crude powder. Administration of a single oral dose of powder, up to 6 g, to healthy volunteers in a randomized crossover manner or daily administration of 0.12-24 g/kg body weight to rats for six months also failed to show any ex vivo antibacterial activity.[Leelarasamee et al (1990)]

Cardiovascular Effects

Aqueous extract of A. paniculata produced a dose-dependent fall in systolic blood pressure of both spontaneously hypertensive rats (SHRs) and normotensive Wistar-Kyoto rats, with a corresponding significant decrease in plasma angiotensin converting enzyme (ACE) activity and lipid peroxidation in kidneys in extract-treated SHRs. Decreases in ACE activity and lipid peroxidation were not significantly altered in normotensive Wistar-Kyoto rats. [Zhang & Tan (1996)]

Antihyperglycemic and Hypoglycemic Effects

Water extract of A. paniculata significantly prevents orally administered glucose-induced hyperglycemia in nondiabetic rabbits without affecting epinephrine-induced hyperglycemia. Chronic administration of the extract for six weeks also showed no effect on fasting blood glucose level. However, ethanol extract, administered orally twice daily for 14 days to streptozotocin induced diabetic rats significantly reduced fasting serum glucose and increased body weight in a dose-dependent manner [ Borhanuddin  et al (1994)] . The extract also significantly lowered levels of thiobarbituric acid-reactive substances in liver and kidney compared to vehicle-treated rats, while significantly increasing the activity of superoxide dismutase and catalase enzymes and hepatic glutathione concentrations in diabetic rats. [Zhang  & Tan ( 2000)]

1. Kabeeruddin M. Kitabul Advia. Vol 2. Delhi, India: Aligarh Barqi Press; 1937:148.

2. Dymock W. Pharmacographia Indica. Karachi, Pakistan: "e Institute of Health and Tibbi Research, Hamdard National Foundation; 1972:45.

3. Bhatnagar SS, Santapau H, Desa JD, et al. Biological activity of Indian medicinal plants. I. Antibacterial, antitubercular and antifungal action. Indian J Med Res 1961;49:799-813.

4. Chopra RN, Chopra IC, Handa KL, Kapur LD. Indigenous Drugs of India. Calcutta, New Delhi, India: Academic Publishers; 1982:238.

5. Khory RN, Katrak NN. Materia Medica of India and !eir !erapeutics. Delhi , India: Neeraj Publishing House; 1984:64.

6. Chang HM, But PPH. Pharmacology and Applications of Chinese Materia Medica. English translation by

Shem Chang-Shing Yeung, Sih Cheng-Yao and Lai-Ling Wang (Chinese Medicinal Material Research Centre, "e Chinese University of Hong Kong), Singapore: World Scientific Publishing Co. Pte. Ltd; 1987;2:918-928.

7. Amroyan E, Gabrielian E, Panossian A, et al. Inhibitory effect of andrographolide from Andrographis paniculata on PAF-induced platelet aggregation. Phytomedicine 1999;6:27-31

8. See D, Mason S, Roshan R. Increased tumor necrosis factor alpha (TNF-alpha) and natural killer

cell (NK) function using an integrative approach in late stage cancers. Immunol Invest 2002;31:137-153.

9. Sheeja K, Guruvayoorappan C, Kuttan G. Antiangiogenic activity of Andrographis paniculata extract and andrographolide. Int Immunopharmacol 2007;7:211-221.

10. Shi MD, Lin HH, Lee YC, et al. Inhibition of cell-cycle progression in human colorectal carcinoma Lovo cells by andrographolide. Chem Biol Interact 2008;174:201-210.

11. Yang L, Wu D, Luo K, et al. Andrographolide enhances 5-fluorouracil-induced apoptosis via caspase-8-dependent mitochondrial pathway involving p53 participation in hepatocellular carcinoma (SMMC-7721) cells. Cancer Lett 2009;276:180-188.

12. Zhao F, He EQ, Wang L, Liu K. Anti-tumor activities of andrographolide, a diterpene from Andrographis paniculata, by inducing apoptosis and inhibiting VEGF level. J Asian Nat Prod Res 2008;10:467-473

13. Calabrese C, Berman SH, Babish JG, et al. A phase I trial of andrographolide in HIV positive patients and normal volunteers. Phytother Res 2000;14:333-338.

14.^ C.V., Thiyagarajan P., Deepak H.B., Agarwal A. , "In vitro modulation of LPS/calcimycin induced inflammatory and allergic mediators by pure compounds of Andrographis paniculata (King of bitters) extract Chandrasekaran" International Immunopharmacology 2011 11:1 (79-84)

15.^ Burgos R.A., Hancke J.L., Bertoglio J.C., Aguirre V., Arriagada S., Calvo M., Cáceres D.D. "Efficacy of an Andrographis paniculata composition for the relief of rheumatoid arthritis symptoms: A prospective randomized placebo-controlled trial" Clinical Rheumatology 2009 28:8 (931-946)

16. Calabrese, Carlo; Berman, Sheryl H.; Babish, John G.; Ma, Xinfang; Shinto, Lynne; Dorr, Melissa; Wells, Kameron; Wenner, Cynthia A. et al (2000). "A phase I trial of andrographolide in HIV positive patients and normal volunteers". Phytotherapy Research 14 (5): 333–8

17. Kate Wright (2009). "Natural Anti-Viral Support for Coughs and Congestion"^]

18. Poolsup, N.; Suthisisang, C.; Prathanturarug, S.; Asawamekin, A.; Chanchareon, U. (2004). "Andrographis paniculata in the symptomatic treatment of uncomplicated upper respiratory tract infection: systematic review of randomized controlled trials". Journal of Clinical Pharmacy and Therapeutics 29 (1): 37–45. doi:10.1046/j.1365-2710.2003.00534.x. PMID 14748896.

19.Schulz V. "Extract from Andrographis herb for the symptomatic treatment of acute upper respiratory tract infections: Results of a placebo-controlled study in India with 223 patients" Zeitschrift fur Phytotherapie 2010 31:3 (141-142)

20.hun JY, Tummala R, Nadiminty N, Lou W, Liu C, Yang J, Evans CP, Zhou Q, Gao AC.,"Andrographolide, an herbal medicine, inhibits interleukin-6 expression and suppresses prostate cancer cell growth.", Genes Cancer. 2010 Aug 1;1(8):868-876 C

21.Cáceres, DD; Hancke, JL; Burgos, RA; Sandberg, F; Wikman, GK (1999). "Use of visual analogue scale measurements (VAS) to asses the effectiveness of standardized Andrographis paniculata extract SHA-10 in reducing the symptoms of common cold. A randomized double blind-placebo study". Phytomedicine 6 (4): 217–23. PMID 10589439.

22.Tang T., Targan S.R., Li Z.-S., Xu C., Byers V.S., Sandborn W.J. ,"Randomised clinical trial: Herbal extract HMPL-004 in active ulcerative colitis - A double-blind comparison with sustained release mesalazine." Alimentary Pharmacology and Therapeutics 2011 33:2 (194-202)

23.Coon JT, Ernst E. Andrographis paniculata: a systematic review of safety and efficacy, Planta, 2004 Apr. Pubmed ID: 15095142

24.Ko HC, Wei BL, Chiou WF. The effect of medicinal plants used in Chinese folk medicine on RANTES, Ethnopharmacol, 2006 Mar 17. Pubmed ID: 16621378.

25.Sheeja K, Shihab PK, Kuttan G. Antioxidant and inflammatory modulating activities of the plant Andrographis paniculata Nees, Immunopharmacol Immunotoxicol. 2006. Pubmed ID: 16684672

26.Govindarajan M, Sivakumar R. " Adulticidal and repellent properties of indigenous plant extracts against Culex quinquefasciatus and Aedes aegypti (Diptera: Culicidae).Parasitol Res. 2011 Oct 20

27.Chao W-W., Lin B.-F. "Isolation and identification of bioactive compounds in Andrographis paniculata (Chuanxinlian) Chinese Medicine 2010 5 Article Number 17

28. Leelarasamee A, Trakulsomboon S, Sittisomwong N. Undetectable anti-bacterial activity of Andrographis paniculata (Burma) wall. ex ness. J MedAssoc !ai 1990;73:299-304

29. Zhang CY, Tan BK. Hypotensive activity of aqueous extract of Andrographis paniculata in rats. Clin Exp Pharmacol Physiol 1996;23:675-678.

30. Borhanuddin M, Shamsuzzoha M, Hussain AH. Hypoglycemia effects of Andrographis paniculata Nees on non-diabetic rabbits. Bangladesh Med Res Counc Bull 1994;20:24-26.

31. Zhang XF, Tan BK. Antihyperglycemic and anti-oxidant properties of Andrographis paniculata in normal and diabetic rats. Clin Exp Pharmacol Physiol 2000;27:358-363.

32. Chang HM, But PPH. Pharmacology and Applications of Chinese Materia Medica. English translation byShem Chang-Shing Yeung, Sih Cheng-Yao and Lai-Ling Wang (Chinese Medicinal Material Research Centre, "e Chinese University of Hong Kong), Singapore: World Scientific Publishing Co. Pte. Ltd; 1987;2:918-928.

33. Rajkumar JS, Sekar MG, Mitra SK. Safety and efficacy of oral HD-03/ES given for six months in patients with chronic hepatitis B virus infection. World J Gastroenterol 2007;13:4103-4107.

34. Trivedi NP, Rawal UM. Hepatoprotective and antioxidant property of Andrographis paniculata (Nees) in BHC-induced liver damage in mice. Indian J Exp Biol 2001;39:41-46.

35. Ram VJ. Herbal preparations as a source of hepatoprotective agents. Drug News Perspect 2001;14:353-363.