In Vivo Evaluation of the Acute Systemic Toxicity of (1S,2E,4R,6R,7E,11E)-Cembratriene-4,6-diol (4R) in Sprague Dawley Rats
Abstract
:1. Introduction
2. Materials and Methods
2.1. Test Substance and Vehicle
2.2. Test Animals
2.3. Single-Dose Toxicity Study Design
2.4. Gross Necropsy
2.5. Histopathology
2.6. Blood Collection
2.7. Statistical Analysis
3. Results
3.1. Body Weight and Clinical Signs of Toxicity
3.2. Hematological Changes
3.3. Biochemical Changes
3.4. Gross Organ and Histopathological Examination
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Ciereszko, L.S.; Odense, P.H.; Schmidt, R.W. Chemistry of coelenterates. II. Occurrence of taurobetaine and creatine in gorgonians. Ann. N. Y. Acad. Sci. 1960, 90, 920–922. [Google Scholar] [CrossRef]
- Rodriguez, A.D. The natural products chemistry of West Indian gorgonian octocorals. Tetrahedron 1995, 51, 4571–4618. [Google Scholar] [CrossRef]
- Ferchmin, P.A.; Pagan, O.R.; Ulrich, H.; Szeto, A.C.; Hann, R.M.; Eterovic, V.A. Actions of octocoral and tobacco cembranoids on nicotinic receptors. Toxicon 2009, 54, 1174–1182. [Google Scholar] [CrossRef] [Green Version]
- Eklund, A.M.; Berg, J.E.; Wahlberg, I. Tobacco chemistry. 73. 4,6,8-trihydroxy-11-capnosene-2,10-dione, a new cembrane-derived bicyclic diterpenoid from tobacco. Acta Chem. Scand. 1992, 46, 367–371. [Google Scholar] [CrossRef] [Green Version]
- Yan, N.; Du, Y.; Liu, X.; Zhang, H.; Liu, Y.; Zhang, Z. A Review on Bioactivities of Tobacco Cembranoid Diterpenes. Biomolecules 2019, 9, 30. [Google Scholar] [CrossRef] [Green Version]
- Aqil, F.; Zahin, M.; El Sayed, K.A.; Ahmad, I.; Orabi, K.Y.; Arif, J.M. Antimicrobial, antioxidant, and antimutagenic activities of selected marine natural products and tobacco cembranoids. Drug Chem. Toxicol. 2011, 34, 167–179. [Google Scholar] [CrossRef]
- El Sayed, K.A.; Sylvester, P.W. Biocatalytic and semisynthetic studies of the anticancer tobacco cembranoids. Expert Opin. Investig. Drugs 2007, 16, 877–887. [Google Scholar] [CrossRef]
- Ebrahim, H.Y.; Mohyeldin, M.M.; Hailat, M.M.; El Sayed, K.A. (1S,2E,4S,7E,11E)-2,7,11-Cembratriene-4,6-diol semisynthetic analogs as novel c-Met inhibitors for the control of c-Met-dependent breast malignancies. Bioorganic Med. Chem. 2016, 24, 5748–5761. [Google Scholar] [CrossRef] [Green Version]
- Hailat, M.M.; Ebrahim, H.Y.; Mohyeldin, M.M.; Goda, A.A.; Siddique, A.B.; El Sayed, K.A. The tobacco cembranoid (1S,2E,4S,7E,11E)-2,7,11-cembratriene-4,6-diol as a novel angiogenesis inhibitory lead for the control of breast malignancies. Bioorganic Med. Chem. 2017, 25, 3911–3921. [Google Scholar] [CrossRef]
- El Sayed, K.A.; Laphookhieo, S.; Baraka, H.N.; Yousaf, M.; Hebert, A.; Bagaley, D.; Rainey, F.A.; Muralidharan, A.; Thomas, S.; Shah, G.V. Biocatalytic and semisynthetic optimization of the anti-invasive tobacco (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol. Bioorganic Med. Chem. 2008, 16, 2886–2893. [Google Scholar] [CrossRef]
- Chen, Y. Organophosphate-induced brain damage: Mechanisms, neuropsychiatric and neurological consequences, and potential therapeutic strategies. Neurotoxicology 2012, 33, 391–400. [Google Scholar] [CrossRef] [PubMed]
- Ferchmin, P.A.; Lukas, R.J.; Hann, R.M.; Fryer, J.D.; Eaton, J.B.; Pagan, O.R.; Rodriguez, A.D.; Nicolau, Y.; Rosado, M.; Cortes, S.; et al. Tobacco cembranoids block behavioral sensitization to nicotine and inhibit neuronal acetylcholine receptor function. J. Neurosci. Res. 2001, 64, 18–25. [Google Scholar] [CrossRef] [PubMed]
- Ferchmin, P.A.; Hao, J.; Perez, D.; Penzo, M.; Maldonado, H.M.; Gonzalez, M.T.; Rodriguez, A.D.; de Vellis, J. Tobacco cembranoids protect the function of acute hippocampal slices against NMDA by a mechanism mediated by alpha4beta2 nicotinic receptors. J. Neurosci. Res. 2005, 82, 631–641. [Google Scholar] [CrossRef]
- Eterovic, V.A.; Del Valle-Rodriguez, A.; Perez, D.; Carrasco, M.; Khanfar, M.A.; El Sayed, K.A.; Ferchmin, P.A. Protective activity of (1S,2E,4R,6R,7E,11E)-2,7,11-cembratriene-4,6-diol analogues against diisopropylfluorophosphate neurotoxicity: Preliminary structure-activity relationship and pharmacophore modeling. Bioorganic Med. Chem. 2013, 21, 4678–4686. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Ferchmin, P.A.; Perez, D.; Castro Alvarez, W.; Penzo, M.A.; Maldonado, H.M.; Eterovic, V.A. gamma-Aminobutyric acid type A receptor inhibition triggers a nicotinic neuroprotective mechanism. J. Neurosci. Res. 2013, 91, 416–425. [Google Scholar] [CrossRef] [Green Version]
- Hu, J.; Ferchmin, P.A.; Hemmerle, A.M.; Seroogy, K.B.; Eterovic, V.A.; Hao, J. 4R-Cembranoid Improves Outcomes after 6-Hydroxydopamine Challenge in Both In vitro and In vivo Models of Parkinson’s Disease. Front. Neurosci. 2017, 11, 272. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Martins, A.H.; Hu, J.; Xu, Z.; Mu, C.; Alvarez, P.; Ford, B.D.; El Sayed, K.; Eterovic, V.A.; Ferchmin, P.A.; Hao, J. Neuroprotective activity of (1S,2E,4R,6R,-7E,11E)-2,7,11-cembratriene-4,6-diol (4R) in vitro and in vivo in rodent models of brain ischemia. Neuroscience 2015, 291, 250–259. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Eterovic, V.A.; Perez, D.; Martins, A.H.; Cuadrado, B.L.; Carrasco, M.; Ferchmin, P.A. A cembranoid protects acute hippocampal slices against paraoxon neurotoxicity. Toxicol. Vitr. Int. J. Publ. Assoc. BIBRA 2011, 25, 1468–1474. [Google Scholar] [CrossRef] [Green Version]
- Ferchmin, P.A.; Andino, M.; Reyes Salaman, R.; Alves, J.; Velez-Roman, J.; Cuadrado, B.; Carrasco, M.; Torres-Rivera, W.; Segarra, A.; Martins, A.H.; et al. 4R-cembranoid protects against diisopropylfluorophosphate-mediated neurodegeneration. Neurotoxicology 2014, 44, 80–90. [Google Scholar] [CrossRef] [Green Version]
- Velez-Carrasco, W.; Green, C.E.; Catz, P.; Furimsky, A.; O’Loughlin, K.; Eterovic, V.A.; Ferchmin, P.A. Pharmacokinetics and Metabolism of 4R-Cembranoid. PLoS ONE 2015, 10, e0121540. [Google Scholar] [CrossRef]
- Single Dose Acute Toxicity Testing for Pharmaceuticals, Guidance for Industry. In e Federal Register on August 26, 1996 (61 FR 43934). 1996. Available online: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/single-dose-acute-toxicity-testing-pharmaceuticals (accessed on 9 February 2022).
- Bittner, B.; Richter, W.; Schmidt, J. Subcutaneous Administration of Biotherapeutics: An Overview of Current Challenges and Opportunities. BioDrugs 2018, 32, 425–440. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Dancygier, H.; Schirmacher, P. Liver Cell Degeneration and Cell Death. In Clinical Hepatology; Springer: Berlin/Heidelberg, Germany, 2010. [Google Scholar] [CrossRef]
- Richardson, K.J.; Schwinck, J.L.; Robinson, M.V. Organophosphate poisoning. Nurse Pr. 2021, 46, 18–21. [Google Scholar] [CrossRef]
- Grob, D. Anticholinesterase intoxication in man and its treatment. In Handbuch der Experimentellen Pharmakologie; Heffter, A., Heubner, W., Koelle, G.B., Eds.; Springer: Berlin/Heidelberg, Germany, 1963; Volume XV, pp. 989–1027. [Google Scholar]
- Miyaki, K.; Nishiwaki, Y.; Maekawa, K.; Ogawa, Y.; Asukai, N.; Yoshimura, K.; Etoh, N.; Matsumoto, Y.; Kikuchi, Y.; Kumagai, N.; et al. Effects of sarin on the nervous system of subway workers seven years after the Tokyo subway sarin attack. J. Occup. Health 2005, 47, 299–304. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Yokoyama, K.; Araki, S.; Murata, K.; Nishikitani, M.; Okumura, T.; Ishimatsu, S.; Takasu, N. A preliminary study on delayed vestibulo-cerebellar effects of Tokyo Subway Sarin Poisoning in relation to gender difference: Frequency analysis of postural sway. J. Occup. Env. Med. 1998, 40, 17–21. [Google Scholar] [CrossRef] [PubMed]
- Broderick, G.; Ben-Hamo, R.; Vashishtha, S.; Efroni, S.; Nathanson, L.; Barnes, Z.; Fletcher, M.A.; Klimas, N. Altered immune pathway activity under exercise challenge in Gulf War Illness: An exploratory analysis. Brain Behav. Immun. 2013, 28, 159–169. [Google Scholar] [CrossRef] [PubMed]
- Broderick, G.; Kreitz, A.; Fuite, J.; Fletcher, M.A.; Vernon, S.D.; Klimas, N. A pilot study of immune network remodeling under challenge in Gulf War Illness. Brain Behav. Immun. 2011, 25, 302–313. [Google Scholar] [CrossRef] [PubMed]
- Gasparyan, A.Y.; Ayvazyan, L.; Mikhailidis, D.P.; Kitas, G.D. Mean platelet volume: A link between thrombosis and inflammation? Curr. Pharm. Des. 2011, 17, 47–58. [Google Scholar] [CrossRef]
- Slavka, G.; Perkmann, T.; Haslacher, H.; Greisenegger, S.; Marsik, C.; Wagner, O.F.; Endler, G. Mean platelet volume may represent a predictive parameter for overall vascular mortality and ischemic heart disease. Arter. Thromb Vasc. Biol. 2011, 31, 1215–1218. [Google Scholar] [CrossRef] [Green Version]
- Hosten, A.O. BUN and Creatinine. In Clinical Methods: The History, Physical, and Laboratory Examinations; Walker, H.K., Hall, W.D., Hurst, J.W., Eds.; Butterworths: Boston, UK, 1990. [Google Scholar]
- Kaiser, C.; Knight, A.; Nordstrom, D.; Pettersson, T.; Fransson, J.; Florin-Robertsson, E.; Pilstrom, B. Injection-site reactions upon Kineret (anakinra) administration: Experiences and explanations. Rheumatol. Int. 2012, 32, 295–299. [Google Scholar] [CrossRef] [Green Version]
- Knop, K.; Hoogenboom, R.; Fischer, D.; Schubert, U.S. Poly(ethylene glycol) in drug delivery: Pros and cons as well as potential alternatives. Angew. Chem. Int. Ed. Engl. 2010, 49, 6288–6308. [Google Scholar] [CrossRef]
- Carpenter, C.P.; Shaffer, C.B. A study of the polyethylene glycols as vehicles for intramuscular and subcutaneous Injection. J. Am. Pharm. Assoc. Am. Pharm. Assoc. 1952, 41, 27–29. [Google Scholar] [CrossRef] [PubMed]
Body Weight (g) | ||||||
---|---|---|---|---|---|---|
Sex | 4R Dose (mg/kg) | Number Dosed | Day 1 | Day 3 | Day 8 | Mortality (Dead/Total) |
Male | 0 | 5 | 253.8 ± 12.5 | 270.6 ± 15.1 | 312.6 ± 19.0 | 0% (0/5) |
6 | 5 | 257.0 ± 22.7 | 274.4 ± 20.3 | 305.8 ± 22.1 | 0% (0/5) | |
24 | 5 | 258.6 ± 18.1 | 276.0 ± 19.7 | 312.5 ± 14.0 | 0% (0/5) | |
98 | 5 | 252.2 ± 12.76 | 265.6 ± 10.6 | 299.6 ± 12.1 | 0% (0/5) | |
Female | 0 | 5 | 171.4 ±13.4 | 185.2 ± 14.2 | 203.0 ± 14.0 | 0% (0/5) |
6 | 5 | 173.8 ± 13.0 | 181.4 ± 16.6 | 202.2 ± 20.5 | 0% (0/5) | |
24 | 5 | 164.8 ± 32.1 | 185.8 ± 20.7 | 204.0 ± 17.6 | 0% (0/5) | |
98 | 5 | 181.6 ± 7.7 | 191.6 ± 2.5 | 211.8 ± 4.8 | 0% (0/5) |
Observation | |||||
---|---|---|---|---|---|
Sex | Dose (mg/kg) | Normal | Alopecia | Discolored—Red | Eschar Formation |
Male | 0 | 5 | 0 | 0 | 0 |
6 | 2 | 3 (D5, D8) | 3 (D8) | 2 (D8) | |
24 | 0 | 5 (D4, D8) | 4 (D8) | 5 (D6, D8) | |
98 | 0 | 3 (D4, D8) | 2 (D8) | 5 (D6, D8) | |
Female | 0 | 1 | 3 (D8) | 2 (D8) | 3 (D8) |
6 | 3 | 2 (D5, D8) | 1 (D8) | 2 (D6, D8) | |
24 | 0 | 5 (D3, D8) | 2 (D8) | 5 (D6, D8) | |
98 | 0 | 5 (D3, D8) | 0 | 5 (D8) |
Day 3 | Day 8 | |||||||
---|---|---|---|---|---|---|---|---|
Group (mg/kg) | ||||||||
Parameters | 0 | 6 | 24 | 98 | 0 | 6 | 24 | 98 |
Male | ||||||||
WBC (×103/µL) | 16.55 ± 4.2 | 14.69 ± 1.9 | 15.74 ± 2.6 | 15.18 ± 1.7 | 15.15 ± 3.6 | 18.54 ± 5.9 | 16.02 ± 4.5 | 15.54 ± 1.5 |
PLC (×103/µL) | 1022 ± 160 | 905 ± 124.9 | 1105 ± 208.7 | 996 ± 111.3 | 1275 ± 176 | 1199 ± 296 | 1433 ± 360.8 | 1304 ± 154.9 |
AEO (×103/µL) | 0.28 ± 0.2 | 0.40 ± 0.1 | 0.16 ± 0.06 | 0.30 ± 0.05 | 0.32 ± 0.1 | 0.35 ± 0.1 | 0.35 ± 0.3 | 0.35 ± 0.1 |
ANS (×103/µL) | 3.67 ± 1.8 | 4.00 ± 1.8 | 5.12 ± 1.6 | 3.55 ± 0.9 | 2.72 ± 0.8 | 3.93 ± 2.3 | 5.18 ± 1.7 | 3.20 ± 1.1 |
ALY (×103/µL) | 11.85 ± 2.2 | 9.69 ± 1.2 | 9.67 ± 1.3 | 10.50 ± 1.5 | 11.57 ± 2.8 | 13.36 ± 3.8 | 9.89 ± 3.06 | 11.53 ± 2.1 |
AMO (×103/µL) | 0.67 ± 0.2 | 0.53 ± 0.2 | 0.73 ± 0.2 | 0.77 ± 0.1 | 0.46 ± 0.2 | 0.70 ± 0.2 | 0.53 ± 0.2 | 0.41 ± 0.1 |
ABA (×103/µL) | 0.08 ± 0.05 | 0.07 ± 0.01 | 0.06 ± 0.02 | 0.06 ± 0.01 | 0.07 ± 0.02 | 0.10 ± 0.06 | 0.06 ± 0.02 | 0.06 ± 0.01 |
MCH (pg) | 19.3 ± 0.3 | 19.8 ± 0.7 | 19.8 ± 0.2 | 19.5 ± 0.4 | 19.7 ± 0.2 | 19.9 ± 0.7 | 20.2 ± 0.3 | 19.7 ± 0.3 |
PNS (%) | 21.2 ± 5.8 | 26.4 ± 10.4 | 32.0 ± 7.7 | 23.3 ± 5.03 | 17.9 ± 2.4 | 20.1 ± 7.8 | 32.1 ± 7.7 * | 20.7 ± 7.4 |
HCT (%) | 42.2 ± 2.2 | 41.1 ± 1.1 | 40.7 ± 0.9 | 41.4 ± 1,8 | 41.0 ± 3.9 | 44.7 ± 3.1 | 42.4 ± 3.1 | 43.8 ± 3.8 |
RDW (%) | 13.5 ± 0.3 | 13.2 ± 0.9 | 13.0 ± 0.6 | 12.8 ± 0.4 | 16.5 ± 1.08 | 14.8 ± 1.8 | 15.2 ± 0.9 | 15.2 ± 1.2 |
PLY (%) | 72.7 ± 6.7 | 66.9 ± 12.1 | 62.0 ± 8.08 | 69.2 ± 5.7 | 76.4 ± 3.1 | 73.8 ± 8.1 | 62 ± 8.3 | 73.9 ± 8.9 |
PMO (%) | 4.0 ± 0.6 | 3.5 ± 1.5 | 4.6 ± 0.9 | 5.1 ± 0.7 | 3.0 ± 0.8 | 3.6 ± 0.5 | 3.5 ± 1.5 | 2.7 ± 0.9 |
PEO (%) | 1.7 ± 1.1 | 2.7 ± 0.7 | 1.0 ± 0.4 | 2.0 ± 0.4 | 2.3 ± 1.2 | 2.0 ± 0.8 | 2.0 ± 1.3 | 2.2 ± 1.03 |
PBA (%) | 0.5 ± 0.2 | 0.5 ± 0.09 | 0.4 ± 0.12 | 0.4 ± 0.1 | 0.5 ± 0.09 | 0.5 ± 0.1 | 0.4 ± 0.05 | 0.4 ± 0.07 |
RET (%) | 5.87 ± 0.6 | 6.26 ± 1.4 | 5.90 ± 0.8 | 5.27 ± 0.2 | 12.20 ± 0.8 | 9.99 ± 1.6 | 10.71 ± 2.2 | 10.98 ± 1.5 |
MCV (fL) | 64.9 ± 0.6 | 65.2 ± 2.3 | 66.1 ± 1.0 | 65.3 ± 1.6 | 66.8 ± 0.9 | 67.6 ± 1.8 | 67.2 ± 0.8 | 66.6 ± 1.42 |
MPV (fL) | 8.3 ± 0.5 | 9.2 ± 0.6 * | 8.5 ± 0.4 | 9.0 ± 0.2 | 8.2 ± 0.4 | 8.6 ± 0.6 | 8.2 ± 1.3 | 8.5 ± 0.3 |
HGB (g/dL) | 12.5 ± 0.7 | 12.4 ± 0.5 | 12.2 ± 0.2 | 12.4 ± 0.5 | 12.1 ± 1.1 | 13.2 ± 1.08 | 12.8 ± 0.2 | 13.0 ± 1.2 |
REA (109/L) | 382.6 ± 56 | 396 ± 86.3 | 362.6 ± 50.04 | 336.2 ± 27 | 745.6 ± 58 | 656.4 ± 79 | 675.3 ± 124 | 720.3 ± 93.1 |
RBC (106/µL) | 6.50 ± 0.2 | 6.30 ± 1.1 | 6.15 ± 0.081 | 6.34 ± 0.27 | 6.13 ± 0.5 | 6.62 ± 0.5 | 6.32 ± 0.1 | 6.58 ± 0.5 |
Female | ||||||||
WBC (×103/µL) | 16.38 ± 2.1 | 15.75 ± 2.9 | 17.27 ± 3.08 | 15.00 ± 2.0 | 12.83 ± 6.3 | 14.88 ± 3.3 | 14.65 ± 2.3 | 13.28 ± 1.7 |
PLC (×103/µL) | 1012 ± 156 | 1207 ± 114.8 | 1010 ± 137.4 | 1125 ± 74.3 | 1394 ± 349 | 1479 ± 235 | 1273 ± 231 | 1626 ± 129 |
AEO (×103/µL) | 0.36 ± 0.1 | 0.17 ± 0.058 * | 0.24 ± 0.047 | 0.15 ± 0.103 * | 0.27 ± 0.1 | 0.22 ± 0.06 | 0.25 ± 0.084 | 0.18 ± 0.1 |
ANS (×103/µL) | 3.72 ± 1.0 | 2.88 ± 1.2 | 3.07 ± 0.8 | 2.60 ± 0.7 | 2.11 ± 1.1 | 2.85 ± 1.1 | 2.21 ± 0.5 | 2.39 ± 0.9 |
ALY (×103/µL) | 11.50 ± 1.7 | 12.03 ± 2.8 | 13.26 ± 2.5 | 11.22 ± 2.1 | 10.06 ± 4.9 | 11.38 ± 2.9 | 11.70 ± 2.1 | 10.32 ± 1.2 |
AMO (×103/µL) | 0.71 ± 0.2 | 0.60 ± 0.2 | 0.60 ± 0.1 | 0.96 ± 0.3 | 0.33 ± 0.3 | 0.37 ± 0.2 | 0.43 ± 0.1 | 0.34 ± 0.06 |
ABA (×103/µL) | 0.09 ± 0.02 | 0.07 ± 0.03 | 0.10 ± 0.04 | 0.05 ± 0.03 | 0.06 ± 0.04 | 0.06 ± 0.02 | 0.08 ± 0.01 | 0.04 ± 0.01 |
MCH (pg) | 20.1 ± 0.5 | 19.6 ± 0.6 | 19.9 ± 1.05 | 20.0 ± 0.8 | 20.6 ± 0.3 | 20.0 ± 0.5 | 20.7 ± 1.1 | 20.5 ± 0.4 |
PNS (%) | 22.7 ± 5.5 | 18.5 ± 8.8 | 17.8 ± 4.2 | 17.5 ± 5.8 | 16.8 ± 5.4 | 19.3 ± 7.4 | 15.2 ± 4.4 | 17.8 ± 4.9 |
HCT (%) | 43.0 ± 2.1 | 40.7 ± 1.0 | 39.8 ± 2.2 * | 42.2 ± 1.1 | 40.2 ± 4.7 | 39.5 ± 1.5 | 40.5 ± 2.2 | 40.7 ± 1.3 |
RDW (%) | 11.9 ± 0.4 | 12.5 ± 1.0 | 11.8 ± 0.4 | 11.9 ± 0.4 | 15.3 ± 0.7 | 15.4 ± 1.4 | 16.3 ± 2.0 | 16.2 ± 1.9 |
PLY (%) | 70.2 ± 6.0 | 76.1 ± 8.9 | 76.7 ± 4.4 | 74.4 ± 5.0 | 78.3 ± 4.7 | 76.4 ± 7.5 | 79.7 ± 5.7 | 77.9 ± 5.2 |
PMO (%) | 4.4 ± 1.3 | 3.8 ± 0.6 | 3.5 ± 1.0 | 6.5 ± 2.8 | 2.2 ± 0.9 | 2.3 ± 0.8 | 2.9 ± 0.9 | 2.6 ± 0.6 |
PEO (%) | 2.2 ± 0.8 | 1.2 ± 0.5 | 1.5 ± 0.4 | 1.0 ± 0.7 | 2.3 ± 1.3 | 1.6 ± 0.7 | 1.8 ± 0.6 | 1.3 ± 0.6 |
PBA (%) | 0.5 ± 0.1 | 0.4 ± 0.1 | 0.5 ± 0.1 | 0.3 ± 0.1 | 0.4 ± 0.1 | 0.4 ± 0.09 | 0.5 ± 0.1 | 0.4 ± 0.05 |
RET (%) | 4.12 ± 0.7 | 5.43 ± 0.8 | 3.89 ± 1.7 | 4.82 ± 1.3 | 12.99 ± 1.8 | 11.85 ± 1.5 | 13.39 ± 4.0 | 12.93 ± 2.7 |
MCV (fL) | 65.3 ± 1.3 | 64.6 ± 1.3 | 65.0 ± 3.3 | 65.8 ± 2.4 | 68.4 ± 1.1 | 67.1 ± 1.4 | 68.9 ± 3.1 | 68.7 ± 1.8 |
MPV (fL) | 7.8 ± 0.4 | 8.0 ± 0.7 | 8.7 ± 0.3 * | 8.5 ± 0.2 | 7.9 ± 0.6 | 7.1 ± 0.3 * | 8.2 ± 0.4 | 7.8 ± 0.3 |
HGB (g/dL) | 13.2 ± 0.6 | 12..3 ± 0.3 | 12.2 ± 0.8 | 12.8 ± 0.4 | 12.1 ± 1.4 | 11.8 ± 0.3 | 12.2 ± 0.7 | 12.2 ± 0.3 |
REA (109/L) | 271.9 ± 56 | 316.6 ± 57.6 | 235.5 ± 100.2 | 307.7 ± 82 | 755.7 ± 87 | 698.3 ± 93 | 791.0 ± 244 | 765.5 ± 160 |
Day 3 | Day 8 | |||||||
---|---|---|---|---|---|---|---|---|
Group (mg/kg) | ||||||||
Parameters | 0 | 6 | 24 | 98 | 0 | 6 | 24 | 98 |
Male | ||||||||
ALB (×103/µL) | 3.8 ±0.82 | 3.8 ± 0.1 | 3.6 ± 0.16 | 3.4 ± 0.16 * | 4.0 ± 0.31 | 4.0 ± 0.46 | 3.9 ± 0.13 | 3.9 ± 0.27 |
BUN (×103/µL) | 14 ± 2.0 | 16 ± 1.9 | 14 ± 1.9 | 15 ± 1.9 | 20 ± 2.9 | 19 ± 2.8 | 15 ± 2.4 * | 13 ± 0.8 ** |
CRE (×103/µL) | 0.24 ± 0.01 | 0.22 ± 0.02 | 0.24 ± 0.02 | 0.22 ± 0.03 | 0.29 ± 0.01 | 0.27 ± 0.01 | 0.22 ± 0.02 ** | 0.23 ± 0.01 ** |
AST (U/L) | 90 ± 9.0 | 86 ± 4.2 | 99 ± 10.1 | 90 ± 8.6 | 77 ± 0.4 | 77 ± 5.1 | 83 ± 10.5 | 81 ± 9.3 |
ALT (U/L) | 48 ± 5.2 | 51 ± 7.0 | 54 ± 9.0 | 45 ± 4.0 | 43 ± 2.2 | 44 ± 6.0 | 43 ± 6.5 | 42 ± 5.0 |
ALP (U/L) | 255 ± 47 | 227 ± 42.3 | 224 ± 27.0 | 234 ± 16.7 | 257 ± 35.4 | 215 ± 33.8 | 228 ± 44.5 | 232 ± 19.1 |
SOD (mEq/L) | 145 ± 1.3 | 146 ± 0.4 | 147 ± 0.8 | 146 ± 1.1 | 142 ± 1.0 | 142 ± 0.5 | 144 ± 1.0 ** | 145 ± 1.1 ** |
POT (mEq/L) | 6.6 ± 0.39 | 6.4 ± 0.28 | 6.4 ± 0.17 | 6.4 ± 0.28 | 6.8 ± 0.40 | 6.8 ± 0.40 | 6.2 ± 0.48 | 6.6 ± 0.46 |
CHL (mEq/L) | 100 ± 1.1 | 100 ± 1.4 | 102 ± 1.6 * | 102 ± 0.9 | 100 ± 1.5 | 99 ± 1.3 | 100 ± 1.7 | 100 ± 1.4 |
CHO (mg/dL) | 92 ± 10.3 | 79 ± 19.0 | 80 ± 16.3 | 86 ± 12.0 | 75 ± 8.4 | 70 ± 12.8 | 75 ± 15.7 | 92 ± 10.3 |
TRI (mg/dL) | 153 ± 52.3 | 128 ± 55.7 | 103 ± 38.3 | 75 ± 17.4 | 145 ± 22.9 | 120 ± 26.1 | 122 ± 84.3 | 126 ± 24.5 |
GLU (mg/dL) | 132 ± 7.9 | 133 ± 14.4 | 137 ± 10.3 | 136 ± 6.5 | 175 ± 49.9 | 196 ± 35.1 | 143 ± 16.6 | 132 ± 7.9 |
CAL (mg/dL) | 12.0 ± 0.34 | 12.0 ± 0.23 | 12.1 ± 0.29 | 12.6 ± 0.4 * | 12.4 ± 0.75 | 13.0 ± 0.09 | 12.8 ± 0.19 | 12.0 ± 0.34 |
PHO (mg/dL) | 11.2 ± 0.26 | 11.3 ± 0.97 | 11.1 ± 0.56 | 11.9 ± 0.38 | 12.8 ± 1.73 | 13.2 ± 1.35 | 12.3 ± 0.92 | 11.2 ± 0.26 |
TPR (mg/dL) | 5.7 ± 0.28 | 5.6 ± 0.18 | 5.5 ± 0.24 | 5.5 ± 0.34 | 5.8 ± 0.32 | 5.9 ± 0.51 | 5.8 ± 0.24 | 5.7 ± 0.28 |
GLO (g/dL) | 1.9 ± 0.21 | 1.9 ± 0.15 | 1.9 ± 0.23 | 2.2 ± 0.32 | 1.8 ± 0.09 | 1.9 ± 0.11 | 1.9 ± 0.29 | 1.9 ± 0.21 |
Female | ||||||||
ALB (×103/µL) | 4.2 ± 0.27 | 4.2 ± 0.24 | 3.9 ± 0.35 | 3.9 ± 0.15 | 4.4 ± 0.4 | 4.6 ± 0.22 | 4.4 ± 0.19 | 4.2 ± 0.19 |
BUN (×103/µL) | 14 ± 2.0 | 15 ± 1.9 | 14 ± 2.5 | 15 ± 3.5 | 17 ± 2.3 | 16 ± 2.3 | 16 ± 3.9 | 14 ± 1.4 |
CRE (×103/µL) | 0.22 ± 0.03 | 0.23 ± 0.03 | 0.23 ± 0.03 | 0.22 ± 0.03 | 0.29 ± 0.09 | 0.25 ± 0.06 | 0.28 ± 0.03 | 0.24 ± 0.02 |
AST (U/L) | 90 ± 9.0 | 86 ± 4.2 | 99 ± 10.1 | 90 ± 8.6 | 77 ± 0.4 | 77 ± 5.1 | 83 ± 10.5 | 81 ± 9.3 |
ALT (U/L) | 48 ± 5.2 | 51 ± 7.0 | 54 ± 9.0 | 45 ± 4.0 | 43 ± 2.2 | 44 ± 6.0 | 43 ± 6.5 | 42 ± 5.0 |
ALP (U/L) | 255 ± 47.0 | 227 ± 42.3 | 224 ± 27.0 | 234 ± 16.7 | 257 ± 35.4 | 215 ± 33.8 | 228 ± 44.5 | 232 ± 19.1 |
SOD (mEq/L) | 145 ± 1.3 | 144 ± 1.2 | 146 ± 0.7 | 146 ± 1.1 | 142 ± 0.7 | 142 ± 1.7 | 143 ± 1.1 | 145 ± 0.9 ** |
POT (mEq/L) | 6.2 ± 0.40 | 6.4 ± 0.27 | 6.3 ± 0.67 | 6.5 ± 0.41 | 6.5 ± 030 | 6.5 ± 0.46 | 6.3 ± 0.67 | 6.6 ± 0.50 |
CHL (mEq/L) | 100 ± 0.8 | 100 ± 1.5 | 102 ± 0.8 * | 101 ± 0.9 | 100 ± 2.1 | 99 ± 0.8 | 102 ± 1.2 | 100 ± 0.5 |
TRI (mg/dL) | 91 ± 20.4 | 74 ± 29.9 | 73 ± 13.3 | 64 ± 12.2 | 90 ± 22.9 | 84 ± 38.7 | 66 ± 14.1 | 78 ± 42.4 |
CHO (mg/dL) | 85 ± 15.9 | 82 ± 6.3 | 72 ± 6.5 | 75 ± 9.5 | 79 ± 14.9 | 80 ± 4.5 | 78 ± 8.5 | 76 ± 12.2 |
GLU (mg/dL) | 130 ± 13.4 | 133 ± 6.3 | 139 ± 8.2 | 130 ± 4.4 | 164 ± 58.3 | 149 ± 42.7 | 159 ± 27.4 | 125 ± 10.2 |
CAL (mg/dL) | 12.1 ± 0.29 | 12.2 ± 0.41 | 11.9 ± 0.25 | 12.6 ± 0.42 | 12.5 ± 0.56 | 12.7 ± 0.67 | 12.7 ± 0.30 | 12.8 ± 0.30 |
PHO (mg/dL) | 10.5 ± 0.5 | 10.0 ± 1.05 | 10.0 ± 0.27 | 11.0 ± 0.67 | 11.7 ± 2.54 | 11.5 ± 1.62 | 12.3 ± 1.80 | 11.2 ± 0.55 |
TPR (mg/dL) | 6.1 ± 0.42 | 5.9 ± 0.16 | 5.7 ± 0.32 | 6.0 ± 0.22 | 6.0 ± 0.48 | 6.2 ± 0.29 | 6.1 ± 0.31 | 6.2 ± 0.28 |
GLO (g/dL) | 1.9 ± 0.17 | 1.7 ± 0.11 | 1.8 ± 0.26 | 2.0 ± 0.23 | 1.6 ± 0.15 | 1.5 ± 0.17 | 1.7 ± 0.20 | 1.8 ± 0.19 |
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Sabeva, N.; Pagán, O.R.; Ferrer-Acosta, Y.; Eterović, V.A.; Ferchmin, P.A. In Vivo Evaluation of the Acute Systemic Toxicity of (1S,2E,4R,6R,7E,11E)-Cembratriene-4,6-diol (4R) in Sprague Dawley Rats. Nutraceuticals 2022, 2, 60-70. https://doi.org/10.3390/nutraceuticals2020005
Sabeva N, Pagán OR, Ferrer-Acosta Y, Eterović VA, Ferchmin PA. In Vivo Evaluation of the Acute Systemic Toxicity of (1S,2E,4R,6R,7E,11E)-Cembratriene-4,6-diol (4R) in Sprague Dawley Rats. Nutraceuticals. 2022; 2(2):60-70. https://doi.org/10.3390/nutraceuticals2020005
Chicago/Turabian StyleSabeva, Nadezhda, Oné R. Pagán, Yancy Ferrer-Acosta, Vesna A. Eterović, and Peter A. Ferchmin. 2022. "In Vivo Evaluation of the Acute Systemic Toxicity of (1S,2E,4R,6R,7E,11E)-Cembratriene-4,6-diol (4R) in Sprague Dawley Rats" Nutraceuticals 2, no. 2: 60-70. https://doi.org/10.3390/nutraceuticals2020005