Safety-Toxicology Review

Tollovid: Brief Introduction

Tollovid is a botanically – sourced commercial product that is available as a supplement and sold directly to consumers in the US and certain European markets, and has a Certificate of Free Sale. Tollovid is delivered in capsule format and contains Lithospermum erythrorhizon (sometimes called Gromwell) root extract which demonstrates potent protease inhibitory activity, but is not supplemented with highly purified shikonin as is Tollovir. The recommended dose is 3 capsules 4 times daily for 5 days.

The main botanical ingredients of Tollovid are derived from organic extracts of Lithospermum  erythrorhizon roots, a plant species that is a member of the Lithospermeae tribe of the Boraginaceae plant family, and which is highly related to its ‘cousin’, Arnebia euchroma. Both species are noted for their important roles in Traditional Chinese Medicine, and have a long history of safety and tolerability.

Classification of Lithospermum and Arnebia
(From NCBI: txid 34254 and 373122)


12 capsules/day contain up to approximately 3.6 g of Gromwell Root (Lithospermum erythrorhizon) powder (ethanol extract), amounting to approximately 36-50 mg/kg/day of root extract for an average adult weighing 70-100 kg.

Toxicology, PK, ADME Publications

Summary Tables of Studies
Studies Using Root Extracts

 

 

Studies with Root Extracts:

Safety/Toxicology

  • In dogs, the no adverse effect level was 100 mg/kg/day of a hexane extract of Lithospermum containing acetyl shikonin, given for 28 days (Nam et al 2015).
  • In Wistar rats, no tox at 800 mg/kg/day of an ethanol extract of Arnebia given for 6 months (Su et al, 2013).
  • In Sprague Dawley rats, no adverse effect level at more than 400 mg/kg/day of ethanol extract from Lithospermum given for 28 days (Han et al 2015).
  • In Fischer 344 rats, NOAEL of orally administered Lithospermum aqueous extract was higher than 2000 mg/kg/day over 13 weeks (Kim et al, 2019).
  • In Sprague Dawley rats, effects seen on fertility at 720 and 1080 mg/kg/day of ‘acetyl shikonin extract’ (DMSO?) from zicao (Lithospermum), but no such effects at 120 or 360 mg/kg/day. (He et al., 2016).
 

Pharmacokinetics
PK data are available from studies in beagles, and indicate that shikonin (hexane extract of Lithospermum) accumulates with repeated dosing over the course of 28 days. Note that Tollovid’s recommended dosing is for 5 days. (Nam et al 2015, see right)


ADME

Finally, Zhang et al (2020) reviewed studies concerning the  distribution, absorption, and elimination of a single derivative of root extract, acetylshikonin as an index analyte. The applicability to Tollovid, therefore, is unclear. Nonetheless, results indicate that:

(In mice) ...[3H]-acetylshikonin was mainly distributed in the stomach and intestine, secondarily in the gallbladder, liver, kidneys, lungs, and least in the brain and spinal cord. The cumulative excretion rate of faeces and urine was nearly 80% within 48 h, mainly through faecal excretion. These results indicated that acetylshikonin had a wide distribution and poor absorption in mice. The binding rate of acetylshikonin to human plasma proteins was high. In general, acetylshikonin has a wide distribution, poor absorption, and high binding rate to human plasma proteins.

Observations

  • Studies use various root extracts
  • Extracts are not uniform, as some are hexane, some are ethanol, one is aqueous, one benzene, etc
  • Botanic sources can differ. Some are from Lithospermum, some are from Arnebia.
  • There is little to no information on the actual shikonin content of the root extracts; most just say xyz extract containing Shikonin, meaning that exposure to shikonin and its derivatives may not be uniform across experiments.
  • Note that our active compound is contained in root extract, but is not shikonin, although shikonin itself does have activity
  • No formal toxicology studies have been performed with Tollovid itself, although a substantial literature is available on its constituents (see above discussion)

How Tollovid™ Uses 3CL Protease Inhibitors to Fight Infections