Toxicity and toxicokinetic study of RPh201 in Sprague-Dawley rats

Ramot, Yuval; Hazan, Zadik; Lucassen, Andre; Adamsky, Konstantin; Kumar, D P Santhosh; Vijayasarathi, S. K.; Krishnappa, H.; Seervi, Madhav; Nyska, Abraham

doi:10.1016/j.fct.2017.12.036

Cited by 7 publications

(10 citation statements)

References 44 publications

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“…However, information on its long-term safety profile is limited. We have recently reported that RPh201 was found to have no adverse effects in Sprague-Dawley rats when administered subcutaneously (Ramot et al 2017). In this study, injection site reactions were observed to be of greater severity in the high-dose group, but they were of mild severity and reversible.…”

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confidence: 42%

Toxicity and Toxicokinetic Study of Subcutaneously Administered RPh201 in Minipigs

et al. 2018

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Mastic gum extracts are widely used as herbal remedies and are being tested for several clinical indications. Nevertheless, information on their safety is limited. RPh201 is an extract of the mastic gum, formulated and stabilized in a proprietary method, which is being developed as a novel drug candidate for neurological indications. The aim of this study was to assess the systemic toxic potential of RPh201, administered twice weekly by subcutaneous injections to minipigs, after 39 weeks of administration followed by a recovery period of 6 weeks. No clinical or dose-related signs were observed, but treatment-related findings were seen at the injection sites of the high-dose animals, composed of abscesses, chronic inflammation, and subcutaneous fibrosis. Abscesses >30 mm in size, graded as marked severity, were confined to the high-dose group and were considered as adverse. Minimal-slight subcutaneous and lymph nodes abscesses seen in control, low, and intermediate doses, related to the vehicle (cottonseed oil), were not considered as adverse. Additionally, minimal-to-slight cystic spaces or vacuolation related to the vehicle were observed in the skin, lymph nodes, kidney, and lungs. These findings were considered not to be adverse. The no-observed-adverse-effect level was considered to be 12.5 mg/kg/occasion.

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confidence: 42%

Toxicity and Toxicokinetic Study of Subcutaneously Administered RPh201 in Minipigs

et al. 2018

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“…The dose of RPh201 was chosen based on previously conducted studies in rat models of stroke and vascular dementia (unpublished data). The current dosage is 16-120 times less than the doses used in the toxicology study in rats and is approximately equivalent to the 20 mg of RPh201 used in clinical trials according to the published dose conversion methods between rat and human (Nair and Jacob, 2016;Ramot et al, 2018b;Rath et al, 2019). Rats were then divided into two cohorts for neurological function, histopathology, and immunochemistry evaluations at 2 weeks (35 days after MCAO, n = 5/group for ischemic rats, n = 4 for Sham rats) and 16 weeks (133 days after MCAO, n = 15/group for ischemic rats, n = 9 for Sham rats) after initiation of treatment.…”

Section: Experimental Design and Treatmentsmentioning

confidence: 99%

Delayed (21 Days) Post Stroke Treatment With RPh201, a Botany-Derived Compound, Improves Neurological Functional Recovery in a Rat Model of Embolic Stroke

et al. 2020

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Background: Despite the recent advances in the acute stroke care, treatment options for long-term disability are limited. RPh201 is a botany-derived bioactive compound that has been shown to exert beneficial effects in various experimental models of neural injury. The present study evaluated the effect of delayed RPh201 treatment on long term functional recovery after stroke. Methods: Adult male Wistar rats subjected to embolic middle cerebral artery occlusion (MCAO) were randomized into the following experimental groups (n = 20/group): (1) RPh201 treatment, and (2) Vehicle (cottonseed oil). RPh201 (20 µl) or Vehicle were subcutaneously administered twice a week for 16 consecutive weeks starting at 21 days after MCAO. An array of behavioral tests was performed up to120 days after MCAO. Results: Ischemic rats treated with RPh201 exhibited significant (p < 0.05) improvement of neurological function measured by adhesive removal test, foot-fault test, and modified neurological severity score at 90 and 120 days after MCAO. Immunohistochemistry analysis showed that RPh201 treatment robustly increased neurofilament heavy chain positive axons and myelin basic protein densities in the periinfarct area by 61% and 31%, respectively, when compared to the Vehicle treatment, which were further confirmed by Western blot analysis. The RPh201 treatment did not reduce infarct volume. Conclusion: Our data demonstrated that RPh201 has a therapeutic effect on improvement of functional recovery in male ischemic rats even when the treatment was initiated 21 days post stroke. Enhanced axonal and myelination densities by RPh201 in ischemic brain may contribute to improved stroke recovery.

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“…Local injection site reactions were observed in all animals, with comparable severity and frequency in the placebo and high‐dose groups. However, given the relative increase in tissue reaction in the high‐dose group, these changes were attributed to RPh201 administration …”

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confidence: 99%

“…In vitro and in vivo animal toxicology studies of RPh201 dosed for up to 39 weeks revealed no genotoxic effects, local dermal irritation, corrosion, sensitization, adverse clinical or behavioral signs, or effects on the respiratory and central nervous systems. 33 Abscesses >30 mm in size, graded as marked severity, were confined to the high-dose group and were considered as adverse. 34 Local injection site reactions were observed in all animals, with comparable severity and frequency in the placebo and high-dose groups.…”

mentioning

confidence: 99%

“…However, given the relative increase in tissue reaction in the highdose group, these changes were attributed to RPh201 administration. 33 Recent in vitro studies of RPh201 demonstrated transdifferentiation of the human retina epithelium cell line ARPE-19 into neuronal cells. In in vivo models, RPh201 promoted neurogenesis and synaptogenesis, and enhanced functional recovery of cognition, memory, and sensorimotor deficits in vascular dementia and stroke (middle cerebral artery occlusion) rat models (unpublished data).…”

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A First‐in‐Human Phase 1 Randomized Single and Multiple Ascending Dose Study of RPh201 in Healthy Volunteers

Hazan

Adamsky

Lucassen

et al. 2019

Clinical Pharm in Drug Dev

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RPh201 is a drug extracted from gum mastic that has been studied for its anti‐inflammatory and antibacterial properties. Preclinical studies of RPh201 demonstrated neuroprotective and neuroenhancing effects. Toxicology studies in animals did not reveal safety concerns or genotoxic effects. This single‐center, phase 1, randomized, placebo‐controlled, double‐masked study in healthy volunteers assessed the safety and tolerability of RPh201, and determined the highest tolerated dose. There were 2 parts: a single ascending dose (SAD) stage, followed by a multiple ascending dose (MAD) stage. Three dosing arms were included in each stage (5 mg, 10 mg, and 20 mg). Safety data in the lower dosing arms were evaluated before higher doses were initiated. Eighteen participants were randomized in the SAD stage: 12 to RPh201 (4 at each dose) and 4 to placebo. Twenty‐one participants were randomized in the MAD stage, of which 13 received RPh201. All 18 participants in the SAD stage completed treatment. Sixteen of the 21 participants in the MAD stage completed treatment. The most frequently reported adverse events were local injection site pain and erythema. No deaths or adverse events related to changes in vital signs or electrocardiograms were reported. No occurrences of suicidal behavior or ideation were reported.

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Toxicity and toxicokinetic study of RPh201 in Sprague-Dawley rats

Cited by 7 publications

References 44 publications

Toxicity and Toxicokinetic Study of Subcutaneously Administered RPh201 in Minipigs

Toxicity and Toxicokinetic Study of Subcutaneously Administered RPh201 in Minipigs

Delayed (21 Days) Post Stroke Treatment With RPh201, a Botany-Derived Compound, Improves Neurological Functional Recovery in a Rat Model of Embolic Stroke

A First‐in‐Human Phase 1 Randomized Single and Multiple Ascending Dose Study of RPh201 in Healthy Volunteers

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