Kharasch ED - "Metabolism and toxicity of the new anesthetic agents" Acta Anaesthesiol Belg 47(1):7-14 (1996)
"Peak serum fluoride concentrations occur within one hour after sevoflurane anesthesia, are usually in the range of 20-40 microM, and decline rapidly. Fluoride concentrations have exceeded 50 microM in approximately 7% of sevoflurane patients."
Holaday DA, Smith FR - "Clinical characteristics and biotransformation of sevoflurane in healthy human volunteers" Anesthesiology 54(2):100-6 (1981)
https://pubs.asahq.org/anesthesiology/a ... rmation-of
"After an hour of exposure arterial blood scrum inorganic fluoride concentrations averaged 22 μM and plasma nonvolatile organic fluorine concentrations averaged 9.1 mg/I, or 61.3 μM. Uptakes of sevoflurane averaged 94 (±63 SD) mmol. Following exposure 37 (±12) mmol of unaltered sevoflurane were estimated to be excreted in exhaled air and 0.90 mmol of inorganic fluoride and 163 mg, or 1.43 (±0.26) mmol of organic fluorine were excreted in the urine."
Taylor B, Scott TE, Shaw J, Chockalingam N - "Renal safety of critical care sedation with sevoflurane: a systematic review and meta-analysis" J Anesth 37(5):794-805 (2023) doi: 10.1007/s00540-023-03227-y.
https://link.springer.com/article/10.10 ... 23-03227-y
"Levels of serum inorganic fluoride were significantly elevated in patients where sevoflurane was used."
Chung W, Park S, Hong J, Park S, Lee S, Heo J, Kim D, Ko Y - "Sevoflurane exposure during the neonatal period induces long-term memory impairment but not autism-like behaviors" Paediatr Anaesth 25(10):1033-45 (2015)
https://pubmed.ncbi.nlm.nih.gov/26095314/
Wang HV, Forestier S, Corces VG - "Exposure to sevoflurane results in changes of transcription factor occupancy in sperm and inheritance of autism" Biol Reprod 105(3):705-719 (2021)
https://pubmed.ncbi.nlm.nih.gov/33982067/
Zhang L, Xu L - "Fgf2 and Ptpn11 play a role in cerebral injury caused by sevoflurane anesthesia" Medicine (Baltimore) 102(45):e36108 (2023). doi: 10.1097/MD.0000000000036108
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10637467/
"Gene Expression Heatmap showed that the core genes (Fgf2, Pdgfra, Ptpn11, Slc2a1) were highly expressed in sevoflurane anesthesia brain tissue samples. CTD Analysis showed that the 4 core genes (Fgf2, Pdgfra, Ptpn11, Slc2a1) were associated with neurodegenerative diseases, brain injuries, memory disorders, cognitive disorders, neurotoxicity, drug-induced abnormalities, neurological disorders, developmental disorders, and intellectual disabilities."
- Ptpn11 --> Protein Tyrosine Phosphatase, Non-Receptor Type 11 -> regulated by thyroid hormone
Slc2a1 --> Solute Carrier Family 2 Member 1, also known as Glucose Transporter 1 (GLUT1) -> regulated by thyroid hormone
Fgf2 --> Fibroblast Growth Factor 2 -> regulated by thyroid hormone
Pdgfra --> Platelet-Derived Growth Factor Receptor Alpha -> regulated by thyroid hormone
Sevoflurane & Gq/11
Minami K, Sudo Y, Yokoyama T, Ogata J, Takeuchi M, Uezono Y - "Sevoflurane inhibits the µ-opioid receptor function expressed in Xenopus oocytes" Pharmacology 88(3-4):127-32 (2011) doi: 10.1159/000330096
https://pubmed.ncbi.nlm.nih.gov/21912198/
"Further, the mechanism of inhibition by sevoflurane would be mediated by PKC."
Nakayama T, Hayashi M, Warner DO, Jones KA - "Anesthetics inhibit membrane receptor coupling to the Gq/11 heterotrimeric G protein in airway smooth muscle" Anesthesiology 103(2):296-305 (2005). doi: 10.1097/00000542-200508000-00013. PMID: 16052112.
https://pubmed.ncbi.nlm.nih.gov/16052112/
Nakayama T, Penheiter AR, Penheiter SG, Chini EN, Thompson M, Warner DO, Jones KA - "Differential effects of volatile anesthetics on M3 muscarinic receptor coupling to the Galphaq heterotrimeric G protein" Anesthesiology 105(2):313-24 (2006). doi: 10.1097/00000542-200608000-00014
https://pubs.asahq.org/anesthesiology/a ... thetics-on
"Halothane and sevoflurane but not isoflurane inhibit acetylcholine-promoted Galphaq guanosine nucleotide exchange."
Animal Models in ASD
Li Z, Zhu YX, Gu LJ, Cheng Y - "Understanding autism spectrum disorders with animal models: applications, insights, and perspectives" Zool Res 42(6):800-824 (2021)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8645879/
Sadamatsu M, Kanai H, Xu X, Liu Y, Kato N - "Review of animal models for autism: implication of thyroid hormone" Congenit Anom (Kyoto) 46(1):1-9 (2006)doi: 10.1111/j.1741-4520.2006.00094.x.
https://pubmed.ncbi.nlm.nih.gov/16643592/
Proposal to use the rat with mild and transient neonatal hypothyroidism as a novel model for autism.
Valproic Acid
Choi CS, Gonzales EL, Kim KC, Yang SM, Kim JW, Mabunga DF, Cheong JH, Han SH, Bahn GH, Shin CY - "The transgenerational inheritance of autism-like phenotypes in mice exposed to valproic acid during pregnancy" Sci Rep 6:36250 (2016)
https://pubmed.ncbi.nlm.nih.gov/27819277/
Nicolini C, Fahnestock M - "The valproic acid-induced rodent model of autism" Exp Neurol 299(Pt A):217-227 (2018)
https://pubmed.ncbi.nlm.nih.gov/28472621/
- SEE also:
MHRA update on new study on risk in children born to men taking valproate
https://www.gov.uk/government/news/mhra ... -valproate
Valproic Acid & Gq/11
Hoshi N - "M-Current Suppression, Seizures and Lipid Metabolism: A Potential Link Between Neuronal Kv7 Channel Regulation and Dietary Therapies for Epilepsy" Front Physiol 11:513 (2020)
https://pubmed.ncbi.nlm.nih.gov/32523549/
Tokuoka SM, Saiardi A, Nurrish SJ - "The mood stabilizer valproate inhibits both inositol- and diacylglycerol-signaling pathways in Caenorhabditis elegans" Mol Biol Cell 19(5):2241-50 (2008)
https://pubmed.ncbi.nlm.nih.gov/18287529/
"VPA reduces levels of DAG and inositol-1-phosphate, but phosphatidylinositol-4,5-bisphosphate (PIP(2)) is slightly increased, suggesting that phospholipase C-mediated hydrolysis of PIP(2) to form DAG and IP(3) is defective in the presence of VPA."
Kelly E, Sharma D, Wilkinson CJ, Williams RSB - "Diacylglycerol kinase (DGKA) regulates the effect of the epilepsy and bipolar disorder treatment valproic acid in Dictyostelium discoideum" Dis Model Mech 11(9):dmm035600 (2018)
https://pubmed.ncbi.nlm.nih.gov/30135067/
"Finally, we show that VPA, lithium and novel epilepsy treatments function through DAG regulation, and the presence of DGKA is necessary for compound-specific increases in DAG levels following treatment."
Chen G, Manji HK, Wright CB, Hawver DB, Potter WZ - "Effects of valproic acid on beta-adrenergic receptors, G-proteins, and adenylyl cyclase in rat C6 glioma cells" Neuropsychopharmacology 15(3):271-80 (1996)
https://www.nature.com/articles/1380468.pdf
"..As can be seen in Figures 3 and 4, chronic incubation of C6 cells with VPA (0.5 mM) resulted in a significant decrease in the cholera toxin-catalyzed [12P]ADP-ribosylation of Gs 45, which was also apparent after 3 days of VPA incubation. Chronic incubation of C6 cells with YPA (0.5 m1v1) for 3 or more days also resulted in a significant reduction in the cholera toxin catalyzed [12P]ADP-ribosylation of Gs 52 (Figures 3 and 4). The pertussis toxin-catalyzed ['2P]ADP-ribosvlations of G(Xi/o were not altered at any time point studied."
Valproic Acid & Thyroid
Zhang YX, Shen CH, Lai QL, Fang GL, Ming WJ, Lu RY, Ding MP - "Effects of antiepileptic drug on thyroid hormones in patients with epilepsy: A meta-analysis" Seizure 35:72-9 (2016)
https://pubmed.ncbi.nlm.nih.gov/26803280/
"...and valproic acid (VPA) use was associated with decreased T4 and increased TSH."
Guzeva VI, Guzeva VV - "The effect of antiepileptic therapy on the level of hormones in the blood serum of girls with epilepsy" Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(4 Pt 2):23-9. Russian. PMID: 24874333.
https://pubmed.ncbi.nlm.nih.gov/24874333/
"The highest content of TSH was found in girls, aged 8-17 years, treated with valproate."
Doneray H, Kara IS, Karakoc A, Tan H, Orbak Z - "Serum thyroid hormone profile and trace elements in children receiving valproic acid therapy: a longitudinal and controlled study" J Trace Elem Med Biol 26(4):243-7 (2012)
https://pubmed.ncbi.nlm.nih.gov/22683050/
"TSH level was significantly increased in the patient group whereas FT4 was significantly decreased."
Eirís-Puñal J, Del Río-Garma M, Del Río-Garma MC, Lojo-Rocamonde S, Novo-Rodríguez I, Castro-Gago M - "Long-term treatment of children with epilepsy with valproate or carbamazepine may cause subclinical hypothyroidism" Epilepsia 40(12):1761-6 (1999)
https://pubmed.ncbi.nlm.nih.gov/10612341/
"The increase in TSH levels was particularly marked in VPA-treated children, accounting for 26% of patients with subclinical hypothyroidism."
Sahu JK, Gulati S, Kabra M, Arya R, Sharma R, Gupta N, Kaleekal T, Reeta Kh, Gupta YK - "Evaluation of subclinical hypothyroidism in ambulatory children with controlled epilepsy on valproate monotherapy" J Child Neurol 27(5):594-7 (2012)
https://pubmed.ncbi.nlm.nih.gov/22114214/
"There was a significantly high (P = .012) prevalence of subclinical hypothyroidism (26%) in those receiving valproate monotherapy compared with healthy controls (7.7%)...Results of the present study suggest higher prevalence of subclinical hypothyroidism in children with controlled epilepsy on long-term valproate monotherapy."
Cansu A, Serdaroğlu A, Camurdan O, Hirfanoğlu T, Bideci A, Gücüyener K - "The evaluation of thyroid functions, thyroid antibodies, and thyroid volumes in children with epilepsy during short-term administration of oxcarbazepine and valproate" Epilepsia 47(11):1855-9 (2006)
https://onlinelibrary.wiley.com/doi/10. ... 06.00821.x
(Increase in TSH)
Zhao Y, Wen SW, Qin Y, Liu Y, Gao Y, Retnakaran R, Zhang R, Zhai D - "Association between valproate treatment for acute phase schizophrenia and risk of new onset hypothyroidism" Schizophr Res 235:12-16 (2021)
https://pubmed.ncbi.nlm.nih.gov/34298238/
"Similar with lithium, valproate as adjunctive drug is associated with increased risk of new onset hypothyroidism during acute phase treatment for schizophrenia."
Yılmaz U, Yılmaz TS, Akıncı G, Korkmaz HA, Tekgül H - "The effect of antiepileptic drugs on thyroid function in children" Seizure 23(1):29-35 (2014)
https://pubmed.ncbi.nlm.nih.gov/24091037/
"Valproate-treated patients had decreased fT4 and increased TSH levels at months 1, 6, and 12."
Güngör O, Özkaya AK, Temiz F - "The effect of antiepileptic drugs on thyroid hormonal function: valproic acid and phenobarbital." Acta Neurol Belg. 120(3):615-619 (2020)
https://pubmed.ncbi.nlm.nih.gov/29508221/
"When compared with the pre-treatment values, there was a statistically significant difference in the incidence of subclinical hypothyroid in the valproic acid group and no significant difference in the phenobarbital group."
Kim SH, Chung HR, Kim SH, Kim H, Lim BC, Chae JH, Kim KJ, Hwang YS, Hwang H - "Subclinical hypothyroidism during valproic acid therapy in children and adolescents with epilepsy" Neuropediatrics 43(3):135-9 (2012)
"Serum VPA level and daily dose of VPA were correlated with TSH level. Subclinical hypothyroidism developed frequently in children and adolescents during VPA therapy."
Attilakos A, Katsarou E, Prassouli A, Mastroyianni S, Voudris K, Fotinou A, Garoufi A - "Thyroid function in children with epilepsy treated with sodium valproate monotherapy: a prospective study" Clin Neuropharmacol 32(1):32-4 (2009)
https://pubmed.ncbi.nlm.nih.gov/18978499/
"Thyroxine and free thyroxine levels were significantly decreased, whereas TSH levels were significantly increased at 6, 12, and 24 months of VPA therapy. Triiodothyronine levels were significantly decreased only at 24 months of therapy. Thirteen children (43.3%) at 6 months, 14 children (46.6%) at 12 months, and 15 children (50%) at 24 months of treatment had TSH values greater than 5 mIU/mL. Normal serum TSH levels were restored in all 8 children examined at 3 months after withdrawal of medication."
Park YM, Kang SG, Lee BH, Lee HJ - "Decreased thyroid function in Korean women with bipolar disorder receiving valproic acid" Gen Hosp Psychiatry. 33(2):200.e13-5 (2011)
https://www.sciencedirect.com/science/a ... 431000246X
"Furthermore, VPA therapy is associated with increased thyroid stimulating hormone (TSH) levels, an effect that is not reversible following withdrawal of the medication in girls [10]. In contrast, VPA does not appear to exert any significant effects on thyroid function in men [5]....We report here two female patients with bipolar disorder who developed abnormal thyroid function after short-and long-term administration of VPA."
Vainionpää LK, Mikkonen K, Rättyä J, Knip M, Pakarinen AJ, Myllylä VV, Isojärvi JI. - "Thyroid function in girls with epilepsy with carbamazepine, oxcarbazepine, or valproate monotherapy and after withdrawal of medication" Epilepsia 45(3):197-203 (2004)
https://onlinelibrary.wiley.com/doi/ful ... m%3Apubmed
"The VPA-treated girls with epilepsy had normal serum T4 and FT4 concentrations, but slightly increased TSH levels (3.3; SD, 1.5 mU/L; p < 0.01) compared with the control girls (2.5; SD, 1.0 mU/L)."
Isojärvi JI, Pakarinen AJ, Ylipalosaari PJ, Myllylä VV - "Serum hormones in male epileptic patients receiving anticonvulsant medication" Arch Neurol. 47(6):670-6 (1990)
https://pubmed.ncbi.nlm.nih.gov/2135734/
(Increased TSH, blunted TSH response to TRH stimulation)
rT3
Visser WE, de Rijke YB, van Toor H, Visser TJ - "Thyroid status in a large cohort of patients with mental retardation: the TOP-R (Thyroid Origin of Psychomotor Retardation) study" Clin Endocrinol (Oxf) 75(3):395-401 (2011)
https://pubmed.ncbi.nlm.nih.gov/21535074/
"Antiepileptic drugs (AEDs) use affected thyroid hormones (T4: 102·1 ± 1·2 vs 83·9 ± 1·2 nmol/l, P < 1 × 10(-24) ; FT4: 18·0 ± 0·2 vs 16·1 ± 0·2 pmol/l, P < 1 × 10(-9) ; T3: 1·72 ± 0·02 vs 1·57 ± 0·02 nmol/l, P < 1 × 10(-9) ; and rT3: 0·37 ± 0·01 vs 0·27 ± 0·01 nmol/l, P < 1 × 10(-28) in subjects without vs with AEDs).
Bentsen KD, Gram L, Veje A - "Serum thyroid hormones and blood folic acid during monotherapy with carbamazepine or valproate. A controlled study" Acta Neurol Scand 67(4):235-41 (1983)
https://pubmed.ncbi.nlm.nih.gov/6407268/
"Valproate caused a decrease in T4, FT4 and T3." [rT3 first increased (one month treatment), then decreased (3 month treatment)] -> Dose and time dependent Gq/11 activation
More On Sevoflurane Effects on TH
Marana E, Colicci S, Meo F, Marana R, Proietti R - "Neuroendocrine stress response in gynecological laparoscopy: TIVA with propofol versus sevoflurane anesthesia" J Clin Anesth 22(4):250-5 (2010) doi: 10.1016/j.jclinane.2009.07.011
https://www.sciencedirect.com/science/a ... 8010000929
RCT; TSH levels increased while FT3 levels decreased significantly relative to basal values. In both groups, perioperative FT4 levels significantly increased compared with preoperative values.
