Clinical Modification with Early Treatment in COVID-19

to ABSTRACT Coronavirus disease (COVID-19) is caused by SARS-COV2 and represents a global public health problem. E l use of ivermectin for the treatment of SARS-COV2 the World Health Organization encourages concerns the use of therapy untested in the context of randomized clinical trial. Azithromycin has shown success in the SARS-COV2 . The low molecular weight heparins have decreased mortality COVID-19, and l Rivaroxaban is an alternative pathway oral for use. E l objective was to evaluate the percentage of patients diagnosed with COVID-19 that modify their clinical evolution under treatment comparative early intervention. Material and Methods: Design randomized experimental, single - blind, prospective, longitudinal and open in 114 patients with COVID-19 UMF No. 13 and No. 20 of November to December 2020 , prior informed consent is given medication randomized 67 patients (Azithromycin / Ivermectin a / Ribaroxaban ) vs. 47 (Azithromycin / Ribaroxaban ); followed by video call for 14 days with evaluation of the outcome of clinical symptoms such as headache, cough, fever, conjunctivitis, myalgia, arthralgia, rhinorrhea, odynophagia, anosmia, chest pain, dyspnea, using statistics with Student’s t test , survival tables, using SPSS version 21. Results: There was an improvement in the modification of the clinical evolution of the symptoms of patients with COVID-19 with double therapy in 95.7% (n = 44) vs. 90.8% with triple therapy (n = 59) with therapeutic failure in 4.3 % (n = 2) vs. 9.2% (n = 6) respectively, with a value of p = 0.327.

evaluate the effectiveness of Ivermectin in the treatment of SARS-CoV-2 [10]. Authors report that Azithromycin has in vitro effects on SARS-CoV-2 [11,12]. In addition, the mechanism of action is like that of an anti-inflammatory drug, reducing the mediators of the secretory phenotype associated with senescence (SASP), such as IL-1beta and IL-6 [13,14].
In a Randomized Clinical Trial where dual therapy was given that included Azithromycin, 83% of the virologically cured patients were shown on day 4 of treatment of patients with COVID-19 [15].
Studies derived from COVID-19 conclude that initial treatment with Low Molecular Weight Heparins (LMWH) reduces mortality by 48% at 7 days and 37% at 28 days and achieves a significant improvement in the blood pressure / oxygen ratio. Inspired fraction of O2 (PaO2 / FiO2) by mitigating microthrombus formation and associated pulmonary coagulopathy. For this reason, the studies derived from COVID-19 use LMWH in all cases during admission in prophylactic doses for at least 7 days [16]. The use of Rivaroxaban 10 mg once daily has been compared with LMWH in the prevention of VTE (venous thromboembolism) after major orthopedic surgery [17]. Rivaroxaban is potent, oral, highly selective, a direct factor Xa inhibitor, and effective for primary and secondary thromboprophylaxis, [18,19] therefore, the hypothesis of this study is whether there will be a modification in the clinical

Materials and Methods
The present study is a randomized, single-blind, prospective,

Procedure
If the patient, with prior informed consent, agreed to participate in the study after the positive COVID19 test, patients with Mild Clinical Phase Covid-19, they were instructed to take medications according to the groups that will be managed and according to those prescribed by the doctor Researcher, it could be previous randomization assigned to Group A with taking the following medications: Paracetamol 500mg orally 1 tablet every 8 hours for 3 days in case of fever equal to or greater than 38.3 °C, Azithromycin 500mg tablets will take 1 tablet single dose the first day and then half a tablet (250mg) orally every 24 for 4 days, Ivermectin tablets of 200mcg which will be calculated according to your weight and dose, will be every 24 hours for 2 days and Rivaroxaban tablets of 10mg will take 1 every 24 hours for 10 days. If it was Group B, take Paracetamol 500mg orally 1 tablet every 8 hours for 3 days in case of fever equal to or greater than 38.3 °C, Azithromycin 500mg tablets will take 1 tablet single dose the first day and then half a tablet via orally every 24 hours for 4 days and Rivaroxaban 10mg tablets will take 1 every 24 hours for 10 days.

Randomization
For the conformation of the groups, random numbers generated by lottery were used in which the patient, as he arrived, took a piece of paper which had the number of the group to which it will be assigned. Performing a type of randomization by blocks, participants, respectively. The mechanism used to implement the random assignment sequence was the use of two containers that will include 67 blue boxes and another of 47 orange boxes with the identification of the color to the assigned treatment, which was carried out by a doctor. The personnel who generated the random allocation sequence was a physician (considered the only role in the study) and who selected the participants and assigned the participants to the interventions was an associate investigator (considered the only role in the study). The study was kept blinded after assigning the interventions to the given patient who does not know what treatment he is receiving and to the treatment group A or B that was assigned.

Discussion
In the present study, we could consider the efficacy of Ivermectin against SARS-Cov-2 [20] given that the group of patients with triple therapy presented only 10% therapeutic failure in all patients operated on with conventional dose therapy in humans, a possible explanation This is what is referred to by a study in the experimental phase indicating that ivermectin has an anti-inflammatory effect in the inhibition of nitric oxide, prostaglandins E2 induced by the activation of macrophage lipopolysaccharides, at a dose of 0.5 and 2ug / ml [21] and in lung tissue in mice, the administration of 2mg / kg of ivermectin suppresses mucus hypersecretion, the recruitment of immune cells and the production of cytokines and IgE / IgG1 in the bronchoalveolar lavage in the lower respiratory tract. Khan, et al. [22] refers to a 1% therapeutic failure in all patients treated with ivermectin at 12 mg orally once a day during their hospital stay [23].
In the present study, the inclusion of patients with double or triple therapy was observed during the mild clinical phase of COVID-19, with initiation of therapy on the 4th day of the COVID-19 disease vs. another study including patients in a moderate clinical phase with a 9-day hospital stay [24]. In relation to Azithromycin that is within the two therapies (double and triple), only 3 (2.6%) patients died, a characteristic that was also observed in presenting the with remote electronic monitoring for 35 days [26].

Limitations
In the present study, the sample size was insufficient to obtain a statistically significant difference on the type of therapy implemented, however, according to the hypothesis of the study about a modification in the clinical evolution ≥ 25% of patients with COVID-19 under a treatment with double or triple therapy for 14 days followed by video call, practically in the symptoms cough, headache, odynophagia, anosmia, myalgia, chest pain and movement dyspnea, a percentage> 25% was reached in the median of patients due to symptoms in both therapies.

Conclusion
In the present study, a percentage of patients with a diagnosis of COVID-19 that modify their clinical evolution greater than 90% was achieved for both early intervention therapies, with a clinical but not statistical difference in the type of therapy, still achieving an impact on the therapeutic approach of patients with SARS-Cov2 for the improvement of health, however it is necessary to carry out more randomized clinical trials involving these therapies and to replicate these results.

Thanks
To the Head Delegate of the North Delegation who contributed to making this article a reality and to the Head of Medical Benefits who, together with the work team in charge, led to the successful completion of this research study.