Preclinical data

Extensive preclinical studies have demonstrated the efficacy and safety of arvidal in various formulations, including intramuscular solution, inhalation solution, and nasal spray. These studies highlight its potential in the treatment of acute respiratory viral infections (ARVI), caused by pathogens such as influenza virus strain A/Puerto Rico/8/34 (H1N1), Hong Kong A/H3N2 influenza strain, and human adenoviruses (serogroups 5 and 7). In addition to its antiviral efficacy, arvidal has been shown to normalize virus-induced cytokine production and stimulate the secretion of key molecules with antiviral activity, including INF-γ, INF-β, and IL-28A. These findings underscore its promise as a therapeutic agent in the fight against viral infections.

Accordion with Filtering

In vitro evaluation of the antiviral activity of ARVIDAL's active pharmaceutical ingredient

#Efficacy studies #In vitro #API

Study goal:
To evaluate the antiviral activity of arvidal in vitro against the relevant strains of influenza virus (A/Puerto Rico/8/34 (H1N1)) and adenovirus (human adenovirus type 5 strain).
Study endpoints:

Determination of cytotoxicity of ARVIDAL's active pharmaceutical ingredient (API) by MTT test (a colorimetric assay for assessing cell metabolic activity).
Assessment of ARVIDAL's antiviral activity in comparison with Remantadin (rimantadine hydrochloride) against A/Puerto Rico/8/34 (H1N1) influenza virus in MDCK (Madin-Darby Canine Kidney) cell line by hemagglutination assay.
Assessment of ARVIDAL's antiviral activity in comparison with acyclovir against human adenovirus type 5 strain in Vero cells (a cell line obtained from the kidney epithelium of the African green monkey) by specific cytopathic effect (CPE) test.
Assessment of immunomodulating activity: in vitro evaluation of the ARVIDAL's effect on virus-induced cytokine production (CXCL-10, IFN-γ, IL-1, TNF-α, IL-10, IL-12, IL-8, GM-CSF, IL-6, IL-28A, IFN-β) in donors’ peripheral blood monocytes.

Main Results:

Evaluation of the cytotoxic properties of ARVIDAL's API on MDCK cells showed no reduction in absorbance (=no cytotoxic effect) up to the maximum dose used (30 μg/mL), which allows to evaluate ARVIDAL's CC50 (50 % cytotoxic concentration) at over 30 μg/mL.
arvidal reduces the infectious activity of adenovirus and influenza virus in cell cultures. This effect was more pronounced for influenza virus (the concentration of drug required for 50% virus inhibition in vitro IC50 = 0.8 μg/mL, and the selectivity index (SI) > 37.5) and to a certain degree less pronounced for adenovirus (IC50 = 2.5 μg/mL, SI = 12). Reference drugs rimantadine hydrochloride and acyclovir did not exhibit antiviral properties, as the selected viruses showed insensitivity to these drugs.
Tests on human peripheral blood monocytes demonstrated that arvidal can activate factors of innate immunity and stimulate monocyte-mediated response to the virus, which does not occur in the absence of the drug.

Evaluation of the antiviral activity of ARVIDAL's active pharmaceutical ingredient with nasal and intramuscular administration at different doses and concentrations in an influenza pneumonia model in mice

#Efficacy studies #In vivo #API

Study goal:
To assess ARVIDAL's antiviral activity under intranasal and intramuscular administration in influenza pneumonia model in mice.
Study endpoints:

Evaluation of the antiviral activity of the arvidal API at different doses of intranasal and intramuscular administration in a model of A/Puerto Rico/8/34 (H1N1) influenza pneumonia in Balb/c mice.
Evaluation of the antiviral activity of the arvidal API at different concentrations and dosage regimens in comparison with intragastrical administration of TamifluTM (oseltamivir phosphate) and Kagocel® (interferon inducer) in the mice model of influenza pneumonia, caused by A/Puerto Rico/8/34 (H1N1) strain. The antiviral activity was assessed through calculations of animal mortality and the index of protection (IP).

Main Results:

arvidal was administered to mice intramuscularly and nasally once a day for 6 days (24 h and 1 h before the challenge and for 5 days after the challenge) at doses of 0.01, 0.1 and 1 mg/kg. The animal model of lethal influenza pneumonia demonstrated that arvidal exhibits a protective effect, reducing the mortality.
arvidal exhibited the greatest activity when administered by intramuscular injection at a dose of 0.1 mg/kg (IP = 43.8 %, p = 0.008).
In the 2nd study arvidal was administered one or three times per day for 6 days intranasally or in combination with spraying on the posterior pharyngeal wall (PPW) at doses of 0.2 and 0.5 mg/kg. Comparator drugs were given intragastrically at 24 h (Kagocel®) and 1 h (TamifluTM, Kagocel®) before challenge and for 5 days after challenge. By the end of the study, the body weight of animals receiving TamifluTM and arvidal 0.1 % (nasally + PPW once daily) and 0.08 % (nasally once daily) was significantly (p < 0.05) higher than in the control group. Animal model of lethal influenza pneumonia demonstrated that arvidal exhibited a protective effect by reducing animal mortality. The ARVIDAL's greatest efficacy was recorded for when given in combined manner: administered nasally and applied to the posterior pharyngeal wall at a dose of 0.5 mg/kg as 0.1 % solution (index of protection (IP) = 46.2 %, p < 0.0001). The second most efficient method of administration was nasal administration once daily at a dose of 0.2 mg/kg as 0.08 % solution. In terms of efficacy, this method was identical to the comparator drug Kagocel® (in both cases, IP = 34.6 %, p = 0.049 and 0.01 respectively, fig. 1).

Figure 1. Kaplan—Meier curves for the mortality dynamics in mice during lethal influenza pneumonia with nasal administration of ARVIDAL® at different concentrations relative to TamifluTM and Kagocel®

Study of specific activity of the dosage form arvidal, 0.2 % topical spray, in A/H1N1 influenza, A/H3N2 influenza, and ARVI

#Efficacy studies #In vivo #Nasal spray

Study goal:
To assess the specific antiviral activity of the finished dosage form arvidal, 0.2 % spray solution, administered intranasally in combination with posterior pharyngeal wall spraying at various doses, in influenza pneumonia and ARVI models.
Study endpoints:

Assessment of the specific antiviral activity of the dosage form arvidal, 0.2 % spray solution, in prevention mode (24, 4, and 1 hour before infection) and in treatment mode (2 times daily for 7 days after infection).
Evaluation at doses of 0.3 mg/kg/day, 0.6 mg/kg/day and 1.2 mg/kg/day in comparison with placebo (saline solution) and intramuscular administration of Arvidal in mice infected with influenza A/Puerto Rico/8/34 (H1N1), A/H3N2, and human adenovirus.

Main Results:

Survival analysis showed a dose-dependent effect with the best results at 1.2 mg/kg/day of arvidal.
The combination of nasal administration and posterior pharyngeal wall spraying showed the best therapeutic and preventive effects across all models tested.

Study of specific activity of the dosage form arvidal, 0.05 % inhalation solution, in A/H1N1 influenza, A/H3N2 influenza, and ARVI

#Efficacy studies #In vivo #Solution for inhalation

Study goal:
To assess the specific antiviral activity of the dosage form arvidal, 0.05 % inhalation solution, administered by inhalation at various doses, in influenza pneumonia and ARVI models.
Study endpoints:

Assessment of the antiviral activity of arvidal, 0.05 % inhalation solution, administered twice daily for 7 days after infection.
Evaluation of different doses: 0.4 mg/kg/day, 0.8 mg/kg/day, and 1.6 mg/kg/day in comparison with placebo (normal saline solution) and intramuscular administration of Arvidal in mice infected with A/H1N1 and A/H3N2 influenza strains and human adenovirus.

Main Results:

Animals treated with arvidal exhibited improved body weight restoration compared to the placebo group.
The best efficacy results were seen at doses of 0.8 mg/kg/day and 1.6 mg/kg/day.

Evaluation of the acute toxicity of the active pharmaceutical ingredient of arvidal in rats

#Safety studies #In vivo #API

Study goal:
To determine tolerable, toxic and lethal doses of the active pharmaceutical ingredient (API) of arvidal after single-dose administration by inhalation or by application to oral and nasal mucosa of male and female rats.
Study endpoints:

Signs of toxicity or death after a single administration by inhalation of 160 mg/kg of the arvidal API via a nebulizer during 14 days of monitoring.
Signs of toxicity or death after application to oral and nasal mucosa of 5 doses of 500 μL of the arvidal API each during 14 days of monitoring.

Main Results:

No fatalities were observed even at the maximum inhalation dose (160 μg/kg), and the mucosal application of up to 20 mg/kg showed no abnormalities in the rats.

Evaluation of the chronic toxicity of the active pharmaceutical ingredient of arvidal in rabbits (by inhalation over 3 months)

#Safety studies #In vivo #API

Study goal:
To evaluate chronic toxicity of the active pharmaceutical ingredient of arvidal after daily administration by inhalation to Soviet Chinchilla rabbits of both sexes for three months and during a subsequent one-month follow-up period.
Study endpoints:

Evaluation of toxicity signs and the local irritant effect of arvidal at different daily inhalation doses: therapeutic dose (TD, 0.95 mg/kg), 5xTD (4.75 mg/kg), and 10xTD (9.5 mg/kg).

Evaluation of the chronic toxicity of the active pharmaceutical ingredient of arvidal in rabbits (by application to mucous membranes over 3 months)

#Safety studies #In vivo #API

Study goal:
To evaluate the chronic toxicity of the active pharmaceutical ingredient of arvidal, including evaluation of the local irritant effect after daily application to oral and nasal mucous membranes to Soviet Chinchilla rabbits for three months and during a subsequent one-month follow-up period.
Study endpoints:

Evaluation of toxicity signs and the local irritant effect of arvidal at daily application to mucous membranes at a dose equal to a therapeutic dose (TD, 0.52 mg/kg);
Evaluation of toxicity signs and the local irritant effect of arvidal at daily application to oral and nasal mucous membranes at a dose equal to 5xTD (2.6 mg/kg);
Evaluation of toxicity signs and the local irritant effect of arvidal at daily application to oral and nasal mucous membranes at a dose equal to 10xTD (5.2 mg/kg).

Main Results:

Daily application of arvidal API to mucous membranes over 3 months at 1xTD, 5xTD, and 10xTD did not cause death of animals and did not affect general physiological parameters, feed or water consumption. The overall condition, appearance and mobility of the rabbits were satisfactory throughout the experiment and did not differ between the treatment and control groups. The substance had no effect on the body weight dynamics at any of the doses.
No signs of irritant effects were observed by macroscopic examination of mucous membranes at the site of application (nasal and oral cavity), as well as lungs, bronchi, trachea and oesophagus at the end of the 3-month dosing period and after the end of follow-up.

To summarize the results, arvidal API does not affect the organs and systems of rabbits of either sex.

Evaluation of the chronic toxicity of the active pharmaceutical ingredient of arvidal in rats (by inhalation over 3 months)

#Safety studies #In vivo #API

Study goal:
To evaluate chronic toxicity of the active pharmaceutical ingredient of arvidal after daily administration by inhalation to outbred rats of both sexes for three months and during a subsequent one-month follow-up period.
Study endpoints:

Evaluation of toxicity signs and the local irritant effect of arvidal at daily administration by inhalation at a dose equal to a therapeutic dose (TD, 1.8 mg/kg);
Evaluation of toxicity signs and the local irritant effect of arvidal at daily administration by inhalation at a dose equal to 5xTD (9 mg/kg);
Evaluation of toxicity signs and the local irritant effect of arvidal at daily administration by inhalation at a dose equal to 10xTD (18 mg/kg).

Main Results:

Daily administration of arvidal by inhalation over 3 months at 1xTD, 5xTD and 10xTD to rats of both sexes did not cause animal fatalities and did not affect general physiological parameters, feed or water consumption. The overall condition, appearance and mobility of the rats did not differ between the treatment and control groups. The weight gain of animals in all groups was similar to control animals.
Pathomorphological examination revealed no differences in relative organ weights between treatment groups and control groups after 3 months of dosing and after the end of the follow-up period. Histopathological evaluation demonstrated that the API did not cause pathological changes in the examined organs at any of the doses used either in males or in females.
Macroscopic examination of the respiratory tract (trachea, bronchi and lungs) revealed no signs of local irritant effect. Absence of local irritant effect was also confirmed by histological evaluation. The data suggest arvidal is safe when administered by inhalation.

Evaluation of the chronic toxicity of the active pharmaceutical ingredient of arvidal in rats (by application to mucous membranes over 3 months)

#Safety studies #In vivo #API

Study goal:
To evaluate the chronic toxicity of the active pharmaceutical ingredient of arvidal, including evaluation of the local irritant effect after daily application to oral and nasal mucous membranes to rats of both sexes for three months and during a subsequent one-month follow-up period.
Study endpoints:

Evaluation of toxicity signs and the local irritant effect of arvidal at daily application to mucous membranes at a dose equal to a therapeutic dose (TD, 0.96 mg/kg);
Evaluation of toxicity signs and the local irritant effect of arvidal at daily application to oral and nasal mucous membranes at a dose equal to 5xTD (4.8 mg/kg);
Evaluation of toxicity signs and the local irritant effect of arvidal at daily application to oral and nasal mucous membranes at a dose equal to 10xTD (9.6 mg/kg).

Main Results:

Daily administration of the arvidal API by application to oral and nasal mucosa over 3 months at 1xTD, 5xTD and 10xTD did not cause the death of animals and did not affect general physiological parameters, feed or water consumption. The overall condition, appearance and mobility of the rats were satisfactory and did not differ between the treatment and control groups.
The substance had no effect on the body weight dynamics at any of the doses. It did not impact the locomotor or exploratory activity of rats.
Pathomorphological examination revealed no differences in relative organ weights between treatment and control groups after 3 months of dosing and after the end of the follow-up period. According to histopathological evaluation the API did not cause pathological changes in the organs examined at any of the doses neither in males, nor in females. No signs of irritant effects were observed by macroscopic examination of mucous membranes at the site of application (nasal and oral cavity) as well as lungs, bronchi, trachea and oesophagus at the end of the 3-month dosing period and after the end of follow-up.

arvidal API, applied to oral and nasal mucosa over 3 months at 1xTD, 5xTD and 10xTD did not affect the organs and systems of rats of both sexes.

Chronic toxicity study of the finished dosage form arvidal in rabbits (mucosal application for 3 months)

#Safety studies #In vivo #Nasal spray

Study goal:
To evaluate chronic toxicity of the finished dosage form arvidal, including the evaluation of local irritation, after daily mucosal application in the oral and nasal cavity to Soviet Chinchilla rabbits of both sexes for three months and during a subsequent one-month follow-up period.
Study endpoints:

Evaluation of toxicity signs and the local irritant effect of the finished dosage form arvidal at daily application to mucous membranes at a dose equal to a therapeutic dose (TD, 0.52 mg/kg);
Evaluation of toxicity signs and the local irritant effect of the finished dosage form arvidal at daily application to oral and nasal mucous membranes at a dose equal to 5xTD (2.6 mg/kg);
Evaluation of toxicity signs and the local irritant effect of the finished dosage form arvidal at daily application to oral and nasal mucous membranes at a dose equal to 10xTD (5.2 mg/kg).

Main Results:

Daily mucosal application of the finished dosage form arvidal for 3 months at 1xTD, 5xTD and 10xTD did not cause the death of animals and did not affect general physiological parameters, feed or water consumption. The overall health status, appearance and mobility of the rabbits were satisfactory.
The drug had no effect on the body weight dynamics at any of the doses. The finished dosage form arvidal did not affect the cardiovascular system, respiratory system, locomotor and exploratory activities, biochemical parameters and excretory system of rabbits.
Pathomorphological studies revealed no differences in relative organ weights between treatment groups and control groups after 3 months of dosing, as well as at the end of the follow-up period.
Histopathological evaluation of rabbits receiving mucosal applications of the finished dosage form arvidal for 3 months showed that the product did not cause pathological changes in the studied organs at all tested doses, both in male and female rabbits.
No signs of irritation were observed by macroscopic examination of mucous membranes at the site of application (nasal and oral cavity) as well as lungs, bronchi, trachea and oesophagus at the end of the dosing period and at the end of follow-up.

The results suggest that the finished dosage form of arvidal does not affect organs and systems in both male and female rabbits. Thus, arvidal, 0.2 % solution, nasal and oral spray, can be recommended for further clinical studies.

Chronic toxicity study of the finished dosage form arvidal in rabbits (administration by inhalation for 3 months)

#Safety studies #Solution for inhalation

Study goal:
To evaluate chronic toxicity of the finished dosage form arvidal, including the evaluation of local irritation, after daily inhalations using a 0.05 % solution to Soviet Chinchilla rabbits of both sexes for three months and during a subsequent one-month follow-up period.
Study endpoints:

Evaluation of toxicity signs and the local irritant effect of the finished dosage form arvidal at daily inhalations at a therapeutic dose (TD, 0.95 mg/kg);
Evaluation of toxicity signs and the local irritant effect of the finished dosage form arvidal at daily inhalations at a dose equal to 5xTD (4.75 mg/kg);
Evaluation of toxicity signs and the local irritant effect of the finished dosage form arvidal at daily inhalations at a dose equal to 10xTD (9.5 mg/kg).

Main Results:

Daily inhalations of the finished dosage form arvidal for 3 months at 1xTD, 5xTD and 10xTD did not cause the death of animals and did not affect general physiological parameters, feed or water consumption. The overall health status, appearance and mobility of the rabbits did not differ in treatment and control groups.
arvidal had no effect on the body weight dynamics at any of the doses. Inhalations of the finished dosage form arvidal did not affect the cardiovascular system, respiratory system, locomotor and exploratory activities, biochemical parameters and excretory system of rabbits.
Pathomorphological studies revealed no differences in relative organ weights between treatment groups and control groups after 3 months of dosing, as well as at the end of the follow-up period.
Histopathological evaluation of rabbits inhaling the finished dosage form arvidal for 3 months showed that the product did not cause pathological changes in the studied organs at all tested doses, both in male and female rabbits.
Macroscopic and histopathological examination of the respiratory tract (local irritation), i.e. trachea, bronchi, lungs, showed no signs of irritation.

The results suggest that the finished dosage form arvidal does not affect organs and systems in both male and female rabbits. Thus, arvidal, 0.05 % inhalation solution, can be recommended for further clinical studies.

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