Efficacy & safety of Carica papaya leaf extract (CPLE) in severe thrombocytopenia (≤30,000/μl) in adult dengue – Results of a pilot study

Abstract

Severe thrombocytopenia in dengue often prompts platelet transfusion primarily to reduce bleeding risk. In India, about 11-43% of dengue patients report receiving platelet transfusions which is considered scarce and expensive especially in resource limited settings. Herein, we evaluated the efficacy and safety of Carica papaya leaf extract (CPLE) in the management of severe thrombocytopenia (�30,000/μL) in dengue infection. 51 laboratory confirmed adult dengue patients with platelet counts �30,000/μL were randomly assigned to either treatment (n = 26) or placebo (n = 24) group. By day 3, CPLE treated patients reported significantly (p = 0.007) increased platelet counts (482%± 284) compared to placebo (331%±370) group. In the treatment group, fewer patients received platelet transfusions (1/26 v/s 2/24) and their median time for platelets to recover to � 50,000/μL was 2 days (IQR 2-3) compared to 3 days (IQR 2-4) in placebo. Overall, CPLE was safe and well tolerated with no significant decrease in mean hospitalization days. Plasma cytokine profiling revealed that by day 3, mean percent increase in TNFα and IFNγ levels in treatment group was less compared to that observed in placebos; (TNFα: 58.6% v/s 127.5%; p = 0.25 and IFNγ: 1.93% v/s 62.6% for; p = 0.12). While a mean percent increase in IL-6 levels occurred in placebos (15.92%±29.93%) by day 3, a decrease was noted in CPLE group (12.95%±21.75%; p = 0.0232). Inversely, CPLE treated patients reported a mean percent increase compared to placebo by day 3 (143% ±115.7% v/s 12.03%± 48.4%; p = 0.006). Further, by day 3, a faster clearance kinetics of viral NS1 antigenemia occurred-mean NS1 titers in treatment group decreased to 97.3% compared to 88% in placebos (p = 0.023). This study demonstrates safety and efficacy of CPLE in increasing platelet counts in severe thrombocytopenia in dengue infections. A possible immunomodulatory and antiviral activity may be attributed to CPLE treatment. These findings merit validation in larger prospective studies.

Potential Medicinal Plants for the Treatment of Dengue Fever and Severe Acute Respiratory Syndrome-Coronavirus

“…It therefore could prevent the complications of thrombocytopenia [ 94 ], and shorten the length of hospital stay in these patients [ 95 ]. Similar outcomes were also reported by a recent study [ 96 ] that also showed C. papaya treatment reduced plasma tumor necrosis factor-α, interferon-γ, and interleukin-6 as well as mean dengue non-structural protein 1 (NS1). The findings confirmed the immunomodulatory property of the plant seen in the animal study.…”

Network analysis, sequence and structure dynamics of key proteins of coronavirus and human host, and molecular docking of selected phytochemicals of nine medicinal plants

“…In vitro antiviral activity of Irvingia gabonensis extract against human immunodeficiency virus (HIV) has been reported (Abdurahman et al, 1995). In vitro and pilot study have reported antiviral activity of Carica papaya leaves aqueous extract against dengue virus (Sathyapalan et al, 2020;Sharma et al, 2019;Joseph et al, 2015), through inhibition of the viral non-structural 2B and 3 (NS2B-NS3) protease complex which is crucial for virus replication (Senthilvel et al, 2013) and this is similar to the mechanism reported for simeprevir (Verbinnen et al, 2015) and clemizole (Einav et al, 2008). Carica papaya and Corchorus olitorius have been used to treat asthma properties in Nigerian traditional medicine (Erinoso & Aworinde, 2012).…”

The plausible mechanisms of action of Carica papaya on Dengue infection: A comprehensive review

“…Apart from increase in the thrombocyte, the study also suggested the improvement of the symptoms in dengue might due to the anti-hemolytic activity of papaya too [12] . In another study by Sathyapalan et al (2020), the patients with severe thrombocytopenia who has taken 1100 mg of papaya leaf extract in tablet three times a day for 5 days showed an increase in the platelet count in the first 4 days and then the platelet count is maintained on day 5 compared to the placebo group in which the platelet count increases slowly and the platelet count drops on day 5. This indicates that the Carica papaya leaf extract has the capability to maintain the platelet count where it promotes the production of platelets and could be used in severe condition, thus proving the reliability as an alternative treatment for dengue patients [24] .…”

“…Research have been done to investigate the beneficial effect of papaya leaf extract as an immune-boosting impact to the dengue patients. A study by Sathyapalan et al (2020) proposed that oral administration of 1100 mg of papaya leaf extract in tablet three times a day for 5 days in human has initiated and activated the coagulation and inflammation pathways lead to the release of proinflammatory cytokines such as TNG-alpha, IFN-gamma and IL-6, that further inhibit the thrombocytopenia in patients [24] . Similarly, another research team has proposed that the unripe papaya leaf juice extract (10% v/v) which consists of major compound papain, may enhance IL-6 secretion and lead to the proliferation, maturation and differentiation of multipotential heamatopoietic progenitors and then increase in thrombocyte production in mesenchymal stem cells and haematopoietic cells.…”