Journal of Family Medicine and Primary Care

INVITED ARTICLE
Year
: 2020  |  Volume : 9  |  Issue : 5  |  Page : 2172--2175

COVID-19: Older drugs for a novel disease—Chloroquine, hydroxychloroquine, and possible Pentoxifylline—set to start the second innings?


Pugazhenthan Thangaraju1, Meenalotchini P Gurunthalingam1, Shobanbabu Varthya2, Sajitha Venkatesan3, Eswaran Thangaraju4,  
1 Department of Pharmacology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
2 Department of Pharmacology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India
3 Department of Microbiology, All India Institute of Medical Sciences, Raipur, Chhattisgarh, India
4 Associate Professor, Department of EEE, AKT Memeorial College of Engineering and Technology, Kallakurichi, Tamil Nadu, India

Correspondence Address:
Dr. Pugazhenthan Thangaraju
Assistant professor, Department of Pharmacology, All India Institute of Medical Sciences, Raipur - 492 099, Chhattisgarh
India

Abstract

Currently no drug is approved for the prophylaxis and management of COVID 19. Lots of activities on vaccine and trials with drugs are underway. Some evidence have shown positive results using older established drug in the management of severe cases. We are also of same view and opinion to adopt some emergency measure by pharmacological intervention till a newer drug available in the market.



How to cite this article:
Thangaraju P, Gurunthalingam MP, Varthya S, Venkatesan S, Thangaraju E. COVID-19: Older drugs for a novel disease—Chloroquine, hydroxychloroquine, and possible Pentoxifylline—set to start the second innings?.J Family Med Prim Care 2020;9:2172-2175


How to cite this URL:
Thangaraju P, Gurunthalingam MP, Varthya S, Venkatesan S, Thangaraju E. COVID-19: Older drugs for a novel disease—Chloroquine, hydroxychloroquine, and possible Pentoxifylline—set to start the second innings?. J Family Med Prim Care [serial online] 2020 [cited 2020 Jul 15 ];9:2172-2175
Available from: http://www.jfmpc.com/text.asp?2020/9/5/2172/285129


Full Text



 Introduction



The world tuned into a panic mode after the emergence of the Novel Coronavirus in Wuhan, Hubei Province, China in December 2019. The World Health Organisation (WHO) officially named the new coronavirus infection disease as “Corona Virus Disease 2019, COVID-19” on February 11, 2020. It declared the virus a “global health emergency” in late January 2020. On March 11, 2020, the WHO declared the coronavirus outbreak a pandemic.[1]

These corona viruses constitute a larger family of viruses that is common for both pathology of animals and humans. This novel coronavirus also called the SARS-CoV-2 presents with the signs and symptoms similar to the earlier breakouts like SARS-CoV (2003) and the MERS-CoV (2015). But the COVID-19 is spreading at a faster pace than its predecessors the SARS-CoV and MERS-CoV and has infected more than 1,00,000 people all over the world as of today.[2] Evidences show that the COVID-19 can be transmitted to other people by pre-symptomatic or mildly ill people making it spread at a faster pace.[3] Hence there is a need to treat the infected people at an early stage to break the cycle of transmission.

The WHO has issued strategies to control the spread of the infection by non-pharmacological methods, but yet to release a standard treatment protocol to treat the COVID-19.[4] The Ministry of AYUSH, Government of India has released the strategies to control and prevent the spread of the COVID-19.[5] The strategies released by the Ministry of AYUSH are precautionary and prophylactic methods.Any development of new drugs against the disease will take time which is what we don't have right now.

Studies of yesteryears have shown that the age-old drug Chloroquine, a 4-aminoquinoline has antiviral actions along with its antimalarial and antiinflammatory actions. Chloroquine reduces the hospital stay and improve the prognosis during the treatment of the coronavirus infection. It is cheaper and easily available in the market. Hence chloroquine can be considered as a treatment option for treating the novel coronavirus infection.

Rays of hope have arisen as reports of successfully treating a patient of COVID-19 from Rajasthan, India came into news amidst all the negative news.[6] According to the reports, a group of Italian tourists landed in india tested positive for COVID-19. Among them one female patient who tested positive earlier turned negative after treatment with a cocktail regimen of antiHIV drugs Lopinavir and Ritonavir, antiinfluenza drug Oseltamavir and antimalarial drug Chloroquine. The same cocktail regimen is being administerd to her husband who is under non-invasive ventilatory support. According to the treating physicians, the condition of the patient is stable. The delay in his recovery is vowed to be due to the lung condition which he was already suffering from.

India's research institute of excellence namely the Indian Medical Research Council (ICMR) recently has comeout with a treatment protocol for COVID-19 with stringent inclusion criteria.[7] Very recently an article concluded that there is no benefit observed with lopinavir–ritonavir treatment as efficacy beyond the routiene standard care of maangement in an hospitalized adult patients with severe Covid-19.[8]

Another age old drug which we propose for considering in the treatment of COVID-19 is Pentoxifylline. Similar to chloroquine, Pentoxifylline also has antiviral and anti-inflammatory actions which will be beneficial in the treatment of the novel coronavirus.

Hence we focuss upon the treatment strategy of the novel coronavirus with the already available drugs like the Chloroquine and Pentoxifylline instead of waiting for a novel drug in particular to the severe cases. The main purpose of this article is that the “primary care physician should be aware about the fact of using these drugs, their rationale and possible advserse and contraindications”. Eventhough the malarial drugs have been used for several decades and the primary care physicians are the frontliner in treating malaria, the knowledge in case of its usage in COVID-19 will help in clarification of the queries raised by the patients also.

 Chloroquine Antiviral Action



Chloroquine belongs to the 4-aminoquinoline group of drugs. It is being used in the prophylaxis and treatment of malaria. It also has good immunomodulatory activity and used in the treatment of various autoimmune diseases like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE). Chloroquine being a weak base gets concentrated in the acidic vesicles like the lysosomes, Golgi vesicles, and endosomes. The chloroquine once inside the acidic vesicles increases the pH of the vesicles and disrupt the structure of the vesicles.[9] The rise in the pH of the vesicles disrupts the enzymes involved in protein synthesis. This, in turn, interferes in the replication of cellular DNA. Many in-vitro and in-vivo studies have shown various mechanisms by which chloroquine exerts antiviral activity on various viruses.[10],[11],[12],[13],[14],[15],[16],[17] They act by changing the endosomal pH (inhibits viruses such as the avian leucosis virus, Bornavirus, and the Zika virus), inhibiting the viral gene expression by inhibit the replication of the virus, by changing the glycosylation pattern of HIV-1 gp 120 envelope and thereby inhibiting its replication and by inhibiting the autophagy. Vertical transmission of Zika virus from the mother to the fetus may be cut off by Chloroquine that was shown in animal experiments. Chloroquine has proved to have significant antiviral activity against many of the viruses, including the SARS virus in various in-vitro experiments and trials. But when similar experiments were tried in-vivo, the antiviral activity of chloroquine was not significant as compared with those of the in-vitro studies. But, in a recent study from china chloroquine was used in more than 100 patients of COVID-19 with severe pneumonia.[18] They have demonstrated that chloroquine was found to be superior in inhibiting the pneumonia exacerbation that was seen positive in improvement in lung Images. They also concluded that it promoted for early viral negative conversion that helped in the shortening of the the disease.[18]

Keyaerts et al. 2004,[14] observed that chloroquine inhibits the replication of SARS in the Vero E6 cells. The study conducted by Xu et al. 2020[19] compared the structures of SARS and SARS-CoV2. The results were encouraging which showed that both the viruses shared similarities in structure and the Van der Wal forces bonding. The above two studies further encourages the addition of the age old antimalarial chloroquine for COVID-19. In China, more than 10 clinical trials are underway that have included chloroquine for treatment of COVID-19.[20] The Guangdong provincial science and technology department has released the expert consensus on chloroquine phosphate for new coronavirus pneumonia[21] which has included chloroquine phosphate in the treatment regimen of COVID 19.

Another salts of chloroquine, hydroxychloroquine in a non-randomized study conducted has shown an remarkable disappearance or reduction of the viral load when combined with antibiotic Azithromycin in COVID-19 positive patients.[22] It was also inferred that more than 50 clinical trials are registered to check the efficacy of hydroxychloroquine in the treatment strategy of COVID.[23]

 Pentoxyphylline for Covid-19



Pentoxyphylline, is a methyl-xanthine which inhibits Phosphodiesterase-4 (PDE 4). It is approved by the food and drugs administration (FDA) for the treatment of intermittent claudication in pateints of chronic occlusive arterial disease of the limbs.[24] The PDE 4 is the regulator of the cyclic AMP (cAMP) metabolism which is involved in the proinflammtory action. Pentoxifylline exerts anti-inflammatory action by inhibiting the cAMP metabolismwhich in turn reduces the production of the proinflammatory cytokines, the TNF-alpha and INF gamma. This increase in the cAMP is the reason for the bronchodilatory action of pentoxifylline.[25] The antiviral activity of this drug is due to the down regulation of the NF kappa B and the NFAT transcription factors which are necessary for the viral replications.[25] Studies of Russian scientists demonstrate the in-vitro antiviral activity of pentoxifylline against many viruses including the acyclovir resistant herpes simplex virus, vaccinia virus, rota virus, the tick-borne encephalitis virus, the Japanese encephalitis virus, and the West Nile virus.[26]

In a randomized controlled trial conducted by Ardizzoia et al.,[27] where the effect of pentoxifylline and standard care combination was compared with the standard care of cancer patients with respiratory distress syndrome, the patient group with pentoxifylline were observed to have improvement in the symptoms without any toxic effects.

As the COVID-19 damage the lung which eventually lead on to acute respiratory distress, pentoxifylline with the antiinflammtory action, which helps in the improvement of ARDS and antiviral activity may be considered as one of the “ideal candidates” for the treatment of COVID-19.

 Conclusion



The antiviral and antiinflammatory actions of the two age old drugs, the chloroquine[28] and the pentoxifylline, along with their immunomodulatory effect, make them a good choice for considering these drugs in the treatment of the COVID-19. In addition both the drugs are inexpensive, easily available with minimum side effects make them ideal to be considered as adjuvant drugs in combination with the propsed antiviral drugs. The antiinflammatory and immunomodulatory actions of these drugs could play an important role in the treatment of the respiratory distress due to the COVID 19.

Key points

Currently there is no approved standard WHO or ICMR pharmacological treatment options for COVID-19With available scientific evidences from other parts of the world, Chloroquine and hydroxychloroquine could be used with all necessary cautions based in its mechanismsPentoxyfylline is hypothesized for the same with possible mechanism of actionEssential knowledge by the family primary care physician regarding Chloroquine/hydroxychloroquine is highly manadatory in time of [andemic and panicityQTc should be evaluated by the primary care physician before prescribing chloroquine or hydroxychloroquine in case of treatment or prophylaxis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Corana gloabal health emergency. Available from: https://www.who.int/dg/speeches/d etail/who-director-general-s-open ing-remarks-at-the-media-briefin g-on-covid-19---11-march-2020. [Retreieved on 2020 Mar 19].
2WHO Corana updates. Available from: https://www.who.int/docs/default-sou rce/coronaviruse/situat ion-reports/20200313-sitr ep-53-covid-19.pdf?sfv rsn=adb3f72_2.[Retreieved on 2020 Mar 19].
3Transmission among people. Available from: https://www.cdc.gov/coronavirus/2019-ncov/prepare/trans mission. html. [Retrieved on 2020 Mar 19].
4Technical guidance in management of patient. Available from: https://www.who.int/emergencies/di seases/novel-coronavirus-2019/technical-guidan ce/patient-management. [Retrieved on 2020 Mar 19].
5AYUSH advisory on prophylaxis and treatment. Available from: https://pib.gov.in/PressRelea sePage.aspx?PRID=1600895. [Retrieved on 2020 Mar 19].
6Treated Italian patient. Available from: https://timesofindia.indiatim es.com/city/jaipur/city-docs-cu re-corona-patient-with-hiv-drugs/articlesho wprint/74584859.cms. [Retrieved on 2020 Mar 1903].
7Bhatnagar T, Murhekar MV, Soneja M, Gupta N, Giri S, Wig N, et al. Lopinavir/ritonavir combination therapy amongst symptomatic coronavirus disease 2019 patients in India: Protocol for restricted public health emergency use. Indian J Med Res. Epub ahead of print.doi: 10.4103/ijmr.IJMR_502_20.
8Cao B, Wang Y, Wen D, Liu W, Wang J, Fan G, et al. A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19 [published online ahead of print, 2020 Mar 18].N Engl J Med 2020. NEJMoa2001282. doi: 10.1056/NEJMoa2001282.
9Savarino A, Boelaert JR, Cassone A, Majori G, Cauda R. Effects of chloroquine on viral infections: An old drug against today's diseases? Lancet Infect Dis2003;3:722-7.
10Inglot AD. Comparison of the antiviral activity in vitro of some non-steroidal anti inflammatorydrugs. J Gen Virol1969;4:203-14
11Miller DK, Lenard J. Antihistaminics, local anesthetics, and other amines as antiviral agents. Proc Natl Acad Sci USA1981;78:3605-9.
12Shimizu Y, Yamamoto S, Homma M, Ishida N. Effect of chloroquine on the growth of animal viruses. Arch Gesamte Virusforsch1972;36;93-104.
13Keyaerts E, Vijgen L, Maes P, Neyts J, Van Ranst M.In vitro inhibition of severe acute respiratory syndrome coronavirus by chloroquine. Biochem Biophys Res Commun2004;323:264-8.
14Keyaerts E, Li S, Vijgen L, Rysman E, Verbeeck J, Van Ranst M,et al. Antiviral activity of chloroquine against human coronavirus OC43 infection in newborn mice. Antimicrob Agents Chemother2009;53:3416-21.
15Tan YW, Yam WK, Sun J, Chu JJH. An evaluation of chloroquine as a broad-acting antiviral against hand, foot and mouth disease. Antiviral Res2018;149:143-9.
16Li C, Zhu X, Ji X, Quanquin N, Deng YQ, Tian M, et al. Chloroquine, a FDA-approved drug, prevents Zika virus infection and its associated congenital microcephaly in mice.EBioMedicine 2017;24:189-94.
17Yan Y, Zou Z, Sun Y, Li X, Xu KF, Wei Y,et al. Anti-malaria drug chloroquine is highly effective in treating avian influenza A H5N1 virus infection in an animal model. Cell Res2013;23:300-2.
18Gao J, Tian Z, Yang X. Breakthrough: Chloroquine phosphate has shown apparent efficacy in treatment of COVID-19 associated pneumonia in clinical studies. Biosci Trends2020;16:14:72-3.
19Xu X, Chen P, Wang J, Feng J, Zhou H, Li X, et al. Evolution of the novel coronavirus from the ongoing Wuhan outbreak and modeling of its spike protein for risk of human transmission. Sci China Life Sci 2020;63:457-60.
20Chloroquine clinical trials in COVID-19. Available from: https://clinicaltrials.gov/ct2/results? cond=COVID19 and ter m=chloroquine&cn try=&state=&city=&dist=.[Retreived on 2020 Apr 13].
21Guangdong Provincial Science and Technology Department and Guangdong Provincial Health and Health Commission's Multicenter Collaboration Group on Chloroquine Phosphate for New Coronavirus Pneumonia. Expert consensus on chloroquine phosphate for new coronavirus pneumonia [J/OL]. Zhonghua Jie He He Hu Xi Za Zhi 2020;23:E019. doi: 10.3760/cma.j.issn. 1001-0939.2020.0019. (2020-02-20). Available from: http://rs.yiigle.com/yu fabiao/1182323.htm. [Internet pre-publishing].
22Gautret P, Lagier JC, Parola P, Hoang VT, Meddeb L, Mailhe M, et al. Hydroxychloroquineand azithromycin as a treatment of COVID-19: Results of anopen-label non-randomized clinical trial. Int J Antimicrob Agents2020:105949. doi: 10.1016/j.ijantimicag. 2020.105949.
23Hydroxychloroquine clinical trials in COVID -19. Available from: https://clinicaltrials. gov/ct2/results? term=hydroxychloroquine and cond=COVID and flds=aby &Search=Apply&age_v=& gndr=& type=and rslt=. [Retreived on 2020 Apr 13].
24Pentoxifylline. Available from: https://www.accessdata.fda.gov/drugsa tfda_docs/label/2012/018631s039lbl.pdf. [Retrieved on 2020 Apr 27].
25Bermejo Martín JF, Jimenez JL, MuEóz-FernándezA. Pentoxifylline and SARS. Med Sci Monit 2003;9:SR41-6. Available from: http://www. MedSciMonit.com/pub/vol_9/no_6/3738.pdf/.
26Amvros'eva TV, Votiakov VI, Andreeva OT, Vladyko GV, Nikolaeva SN, Orlova SV,et al. New properties of trental as an inhibitor of viral activity with a wide range of activity.[Article in Russian]. Vopr Virusol 1993;38:230-3.3. Vasil'ev VS, Pron'ko NV: Use of trental in combined treatment
27Ardizzoia A, Lissoni P, Tancini G, Paolorossi F, Crispino S, Villa S,et al. Respiratory distress syndrome in patients with advanced cancer treated with pentoxifylline: A randomized study. Support Care Cancer 1993;1:331-3.
28Connolly KM, Stecher VJ, Danis E, Pruden DJ, LaBrie T. Alteration of interleukin-1 activity and the acute phase response in adjuvant arthritic rats treated with disease modifying antirheumatic drugs. Agents Actions 1988;25:94-105.