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New positive ivermectin evidence 121gamers 33 Views • 4 months ago

A Pilot, Randomised, Placebo-Controlled, Double-Blind Trial of a Single Oral Dose of Ivermectin for Post-Exposure Prophylaxis of SARS-CoV-2

https://www.mdpi.com/1999-4923/17/9/1205

People who took one small oral dose of ivermectin after exposure,

took longer to test positive and had more time alive and free of symptoms.

Multiple reports from in vitro infectious models document Ivermectin’s antiviral properties

https://pmc.ncbi.nlm.nih.gov/a....rticles/PMC7564151/p

Ivermectin has broad-spectrum antiviral activity.

Randomised, double-blind, placebo-controlled

Single oral dose of Ivermectin as prophylaxis for SARS-CoV-2

Trial to evaluate the effectiveness of a single oral low dose of Ivermectin

Ability to prevent SARS-CoV-2 infection?

Ability to reduce symptoms if infection did occur?

Methods

Asymptomatic community-dwelling adults

Enrolled within 72 h of close contact with a case of SARS-CoV-2.

Single oral 200 µg/kg dose of Ivermectin or placebo.

65Kg woman given 13mg

80Kg man given 16mg

The primary outcome

Conversion to a positive PCR or RAT test within 14 days of close contact.

Secondary outcomes

(for those who tested positive)

Days alive free of symptoms in the 14 and 28 days following ivermectin

Days from close contact until a positive PCR or RAT

Results

N = 536 (86 met inclusion criteria and were randomised)

68 adhered and were included in the analysis.

Ivermectin arm

11/36 tested positive

Placebo arm

11/32 tested positive

So, ivermectin did not prevent people testing positive

Days from close contact until a positive PCR or RAT

Increased by 2.3 days in ivermectin group.

P = 0.033

So, ivermectin lengthened the incubation period

Viral load needed to precipitate clinical disease took longer to develop – indicating an antiviral effect.

Infection may have been prevented from primary contact, - indicating an antiviral effect.

Days alive free of symptoms

Increased by 2.5 days in ivermectin group.

P = 0.036

So ivermectin delayed onset of symptoms in people who tested positive

(Longer asymptomatic period)

Controlling included

Age, prior SARS-CoV-2 infection, body mass index, hypertension, lung disease

Conclusions

We did not demonstrate that a single oral low dose of Ivermectin administered to asymptomatic adults within 72 h of close contact with a case of
SARS-CoV-2 prevents conversion to a positive PCR or RAT.

(may have done with a larger sample size)

Amongst those who did convert to a positive PCR or RAT

Ivermectin significantly lengthened the time from close contact to conversion

Ivermectin increased the number of days alive free of symptoms

More details

Initiation of this trial in late 2021

Discovery in 1975

Massively used around the world

Nobel Prize in 2015

Very low incidence of serious adverse side effects

No instance of resistance reported in over 25 years.

Ivermectin can bind to and inhibit the nuclear transport roles of the host importin α (IMPα) protein,

which is known to mediate the nuclear import of various viral proteins and key host factors.

Other quite distinct antiviral actions of Ivermectin have been proposed

High (therapeutic) concentrations collect in the lungs, stable for more than 30 days in cattle

Trial was based on the strong clinical retrospective association of statistically significantly lower mortality in patients who received oral Ivermectin (200 μg/kg) compared with usual care

https://www.sciencedirect.com/....science/article/pii/

Ivermectin patients 15% mortality

Controls, 25.2% mortality

In subjects with severe pulmonary disease

Ivermectin patients, mortality 38.8%
Controls, 80.7% mortality

Ivermectin and mebendazole, 84% benefit in cancer 121gamers 37 Views • 4 months ago

Ivermectin and Mebendazole in Cancer Patients

https://zenodo.org/records/19455636

The Clinical Benefit Ratio

Complete Response + Partial Response + Stable Disease / Total Patients

(CBR) was 84.4%

Overall, it is estimated that annual costs of standard chemotherapies average $111,000 per year.

Background: Drug repurposing offers a pathway to identify accessible, low-toxicity cancer therapies.

Ivermectin and mebendazole have demonstrated multi-target anti-cancer activity.

This paper evaluates real-world patient-reported outcomes, safety, and adherence in a cohort of cancer patients utilizing this combination protocol.

Methods:

Prospective observational cohort of 197 cancer patients,

who were prescribed ivermectin and mebendazole off-label through telemedicine (platform by licensed U.S. healthcare providers)

Participants received compounded oral capsules containing 25 mg ivermectin and 250 mg mebendazole.

Data were collected via voluntary, standardized digital surveys at baseline and at approximately 6-month follow-up.

Of the initial cohort (N = 197), baseline characteristics, including cancer type and disease status, were assessed.

A total of 122 participants completed the follow-up survey (61.9% response rate)

Results:

Mean age of 67 years, (52.3% male, 47.7% female).

Cancer types included
Prostate 27.9%
Breast 18.3%
Lung 8.6%
Colon 5.1%
Urologic 4.6%
Pancreatic 3.0%
Liver 2.5%
Gynaecologic 2.5%
Hematologic 2.5%
Median duration since initial diagnosis, 1.2 years

37.1% experiencing active disease progression.

6-month follow-up

Medication adherence, 86.9%

Full initial 90-capsule ivermectin-mebendazole prescription.

The Clinical Benefit Ratio

Complete Response + Partial Response + Stable Disease / Total Patients

(CBR) was 84.4%

Notably, 48.4% of cohort, strongest positive outcomes:

Regression, 15.6%

No current evidence of disease (NED), 32.8%

Disease stability, 36.1%

Disease progression, 15.6%

No significant dose-response association was observed for cancer outcomes (p = 0.91),

without a clear dose-response gradient for efficacy.

Side effects

Mild side effects (primarily gastrointestinal), 25.4%

(93.6% of those affected continued treatment through minor dose adjustments)

Concurrent conventional therapies

Chemotherapy, 27.9%
Radiation therapy, 21.3%
Surgery, 19.7%

Adjunctive interventions such as supplement use, 49.2%
Dietary modification, 37.7%

Conclusions: In this prospective real-world cohort, the combination of ivermectin and mebendazole was associated with high rates of self-reported clinical benefit, with nearly half of participants reporting tumours regression or no current evidence of disease across a heterogeneous population of cancer patients.

These findings provide a compelling clinical signal that these well-tolerated, repurposed agents may offer therapeutic benefit.

However, observational design, reliance on self-reported outcomes, and potential for selection bias and uncontrolled confounding, these findings should be interpreted as hypothesis-generating.

Urgent prospective, randomized, placebo-controlled clinical trials

Validate these observations and further define optimal dosing strategies.

Mechanism (pharmacodynamics)

Ivermectin and mebendazole are antiparasitic agents,

demonstrated highly promising anti-cancer activity.

Ivermectin

Shown to exert over 14 distinct anti-cancer mechanisms across more than 12 cancer types,

inhibiting cancer cell proliferation, metastasis, angiogenesis, mitochondrial function.

Has demonstrated excellent safety in cancer patients (including those actively undergoing chemotherapy)

Ivermectin and mebendazole selectively target cancer stem cells

Mebendazole

Microtubule disruption, leading to effective cell cycle arrest

Potent induction of apoptosis

Significant inhibition of tumour growth

Inhibition of angiogenesis

Disruption of glucose uptake

When used together

Target non-overlapping pathways, resulting in synergistic tumour regression,

cancer stem cell depletion, and reversal of multidrug resistance in multiple in vitro and in vivo models

Biodistribution, ivermectin and mebendazole document excellent tissue penetration

Ivermectin research 121gamers 28 Views • 4 months ago

With Professor Colleen Aldous
Critical appraisal of multidrug therapy in the ambulatory
management of patients with COVID-19 and hypoxemia
Part II: Causal inference using the Bradford Hill criteria

https://www.jstage.jst.go.jp/a....rticle/antibiotics/7

We continue the critical appraisal of three published case series of 119 COVID-19 patients with hypoxemia, treated in the United States, Zimbabwe, and Nigeria with similar ivermectin-based multidrug treatments, to assess the available evidence supporting a causal relationship between treatment and reduction in hospitalizations and mortality. A narrative review was conducted to assess the Bradford Hill criteria for a causal association. We used a previously proposed refinement of the Bradford Hill criteria that reorganized them into three categories of direct, mechanistic, and
parallel evidence. The efficacy of the two most aggressive ivermectin-based
multidrug protocols is supported by the Bradford Hill criteria for temporality,
strength of association, biological gradient, biological plausibility, coherence, consistency, and analogy. The causal relation between the treatment of hypoxemic COVID-19 patients using these protocols and the reduction in hospitalizations and mortality is supported as an inference to the best explanation.

Critical appraisal of multidrug therapy in the ambulatory
management of patients with COVID-19 and hypoxemia
Part I. Evidence supporting the strength of association

https://faculty.utrgv.edu/elef....therios.gkioulekas/p

On March 11, 2020, Coronavirus Disease 2019 (COVID-19), the disease caused by the Severe Acute Respiratory Coronavirus 2 (SARS-CoV-2), was declared a pandemic by the World Health Organization (WHO) [1]. Worldwide, 768,187,096 confirmed cases of COVID-19 and 6,945,714 deaths have been reported to the WHO as of June 21 2023, amounting to an average Case Fatality Rate (CFR) of 0.9% [2]. During 2020, while several governments and public health agencies were focused on contagion control and in-hospital patient care, several medical doctors from all around the world innovated and discovered early outpatient multidrug treatments using several repurposed medications in combination [3–15]. In the United States, several independent efforts coalesced into the formulation of a sequenced multidrug protocol [10, Fig. 3] (hereafter, McCullough protocol), which is based on the pathophysiological understanding of COVID-19 as a triphasic illness with three overlapping phases: (1) viral proliferation; (2) hyperinflammatory cytokine storm (COVID-19 pneumonia); and (3) thrombosis. McCullough’s protocol proposed a combination antiviral therapy for treating the viral proliferation phase, immunomodulators for treating the cytokine storm, and antiplatelet agents and antithrombotics for handling the thrombotic stage, based on risk stratification and how the disease presents in each individual patient. Thus, the McCullough protocol is an algorithmic treatment using sequenced multiple drugs in combination and customized to the individual patient and their response to treatment; no single drug is necessary nor sufficient to achieve treatment efficacy towards reducing hospitalizations and deaths. A recently published update of the McCullough protocol [16, Fig. 3] introduced some adjustments including virucidal nasal washes and oral gargles [17–24]. A large case series of 869 high-risk patients [25, 26], who were treated using an early version of the McCullough protocol, has been compared against population-level and historical controls [27], showing the existence of efficacy with respect to the reduction of mortality and hospitalizations, which is also resilient with respect to random selection bias, provided that patients are treated early enough within the first 3 to 5 days from the onset of illness. Indeed, an earlier study by Fazio et al.[28] showed that the ideal window of opportunity for initiating an effective early outpatient treatment of COVID-19 to prevent hospitalization is approximately within the first 3 days.