Thursday, September 24, 2015

Caripill: A Pill with Papaya Leaf Extract to Fight Dengue

Micro Labs (Bengluru, India), a fully integrated generic manufacturing pharma company recently launched Caripill, which helps to increase the platelet count in patients suffering from dengue.  Approved by the scientific and regulatory authority, the pill is made from Carica Papaya leaf extract and reportedly does not have any side-effects.

Caripill: Papaya Leaf Extract in a Pill

What is Dengue?

Dengue is an acute viral infection with potential fatal complications. Dengue viruses (DV or DENV) belong to family Flaviviridae and there are four serotypes of the virus referred to as DV-1, DV-2, DV-3 and DV-4. DV is a positive stranded encapsulated RNA virus and is composed of three structural protein genes, which encode the nucleocapsid or core (C) protein, a membrane-associated (M) protein, an enveloped (E) glycoprotein and seven non-structural (NS) proteins. It is transmitted mainly by Aedes aegypti mosquito and also by Ae. Albopictus. An incubation period varying from 3 to 14 days is followed by a febrile illness consisting of sudden-onset fever, headache, myalgia, arthralgia and rash. Thrombocytopenia is a common feature of the illness. The patient develops hemorrhagic manifestations such as petechiae and bleeding through the nose, gastrointestinal tract and gums. A number of atypical manifestations have also been reported in the literature, which include encephalitis, encephalopathy, myocarditis, hepatitis and cholecystitis [1].
All four serotypes can cause full spectrum of disease from a subclinical infection to a mild self limiting disease, the dengue fever (DF) and a severe disease that may be fatal, the dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). Though, the most common virus responsible for dengue is DV- 2 (dengue virus-2). WHO currently estimates there may be 50-100 million dengue infections and half a million DHF worldwide every year, with an average case fatality rate of around 5% [2].

Four main characteristic manifestations of dengue illness are [3]: 
a:  continuous high fever lasting 2-7 days;
b:  haemorrhagic tendency as shown by a positive tourniquet test, petechiae or epistaxis;
c:   thrombocytopoenia (platelet count less than 100 x 109 /L); and
d: evidence of plasma leakage manifested by haemo-concentration (an increase in haematocrit 20% above average for age, sex and population), pleural effusion and ascites, etc.
Whether papaya leaves are effective in controlling dengue or not? Whether Ayurveda, one of the oldest medicine systems from India advocate the usage of papaya leafs in curing dengue? Such questions were answered in modern perspective [4]. Carica papaya belongs to family Caricaceae. It is an erect, fast-growing and unbranched tree or shrub indigenous to Central America and cultivated in Mexico and most tropical countries for its edible fruits. The author has pointed about four trials, where papaya leaves, seeds etc where proven to be effective against dengue and toxic to Aedes aegypti mosquito, which is a vector for the etiologic agents of both yellow and dengue fever.
Carica papaya leaf has been used traditionally in the treatment of dengue. The leaf has been investigated for its potential against DF. The aqueous extract of leaves of this plant exhibited potential activity against DF by increasing the platelet (PLT) count, white blood cells (WBC) and neutrophils (NEUT) in blood samples of a 45-year-old patient bitten by carrier mosquitoes [9]. After 5 days of oral administration of 25 mL aqueous extract of Carica papaya leaves to the patient twice daily, the PLT count increased from 55 × 103/µL to 168 × 103/µL, WBC from 3.7 × 103/µL to 7.7 × 103/µL and NEUT from 46.0 to 78.3 %. Increased platelets could lead to reduced bleeding, thus avoiding progression to the severe illness of DHF.

Currently available treatment for dengue:
1. The standard treatment protocol for management of Dengue includes symptomatic treatment with fluid management. This is the best option, if detected on time.
2. Drugs like Eltrombopag and Romiplastim are available for increasing the platelet counts, but they pretty costly options. Again, very much avoidable.
3. Using corticosteroid is advised by some as it is supposed to halt further platelet destruction but generally not preferred. The side-effects are pretty bad enough. Moreover, it is an immunosuppressant, it will "hide" any other secondary infection.
4. Platelet transfusion if the platelet count goes below 20000 /µl, where such is advocated.

Caripill costs Rs 25 per tablet with the dosage of administering one pill (1100 mg) three times a day, for five days.

Phase trial that sealed the deal [3]
Concept: A multi-centric open labeled, randomized, comparative pilot study was conducted at two centres of Bengaluru metropolis. The Carica papaya leaf extract was formulated in appropriate dosage form of tablet in the strength of 1100mg. A total of 30 subjects (n=30) diagnosed as dengue cases by NS1 antigen test were enrolled and randomized in this study. Exclusion and Inclusion criteria were followed and those meeting all the inclusion criteria’s were allowed to participate. A clinical diagnosis of DF and DHF was made by the clinician based upon the patient’s presentation and blood investigations. A rapid dengue test (NS1 Ag) was used to confirm the dengue case.
Method: Of the total subjects 14 were randomized to study group where in addition to the routine standard supportive management of dengue the investigational drug Carica papaya leaf extract 1100mg tid for 5 days was administered. The remaining 16 in control group received the routine standard supportive management of dengue, only. All the subjects were followed up every day for five days and their platelet counts were monitored daily.
a: At baseline, mean Platelet Count was 64.79 among test group, which was comparable with 65.94 among control group and the difference was not statistically significant.
b: After the treatment at the end of Day 5, mean Platelet Count showed a significant increase of 61.6% in Test group and an insignificant rise of 1.0% in Control group from baseline.
c: If compared change was more in Test group than Control group and the difference was statistically significant.

Sideeffects: In the published text the authors [3] have not mentioned any adverse event (AE) reported by the participants. Subsequent self-study and information from various users have pointed cases of nausea, vomiting, abdominal pain, heartburn, dyspepsia happening with them.
Individuals with bleeding disorders or those taking blood thinning drugs such as aspirin or warfarin, should avoid Caripill. Monitor blood glucose levels regularly. There is no special warning found for Caripill usage in pregnancy but it is better to start this medication under medical supervision if you are pregnant.
{If you have some information to share on an adverse reaction with Caripill, please fill the same in comment field. It will be updated and shared to benefit all.}

The authors conclude as "Papaya extract no doubt offers a cheap and possibly effective treatment for dengue. Various clinical and preclinical studies conducted have demonstrated a positive effect in dengue cases with thrombocytopenia. The current pilot study also demonstrates the same positive beneficial trend in increasing the platelets significantly. However, large scale randomized clinical trials are necessary to further establish its pivotal role in the management of dengue."
Being a product of extensive research and clinical trials conducted by Micro Labs, the pill has proved its safety and efficacy in about one lakh patients across India, claims a company release.

1. Cho Paknikar, S. S.; et. al. Papaya Extract to Treat Dengue: A Novel Therapeutic Option? Ann Med Health Sci Res 2014, 4(3), 320-324. (FMO only)
2. WHO. 2. Dengue: Guidelines for diagnosis, treatment, prevention, and control in sub-Saharan Africa and 13 countries in South America. Geneva: World Health Organization; 2009, 2012(FMO only)
3. Nagabhushan, K. H.; et. al. A Pilot Study to Evaluate the Effectiveness of Carica Papaya Leaf Extract in Increasing the Platelet Count in Cases of Dengue with Thrombocytopenia. Indian Medical Gazette 2015, 109-116. (FMO only)
4. Manohar, P. R.; et. al. Papaya, dengue fever and Ayurveda. Anc Sci Life 2013, 32(3), 131-133. (FMO only)
5. Ahmad, N.; et. al. Dengue fever treatment with Carica papaya leaves extracts. Asian Pac J Trop Biomed 20111(4), 330-333. (FMO only)