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European Review for Medical and Pharmacological Sciences 2011; 15: 931-936 safety: clinical evidences

G. CARLOMAGNO, V. UNFER

AGUNCO Obstetrics & Gynecology Center, Rome (Italy)

Abstract. – Myo-inositol is a six carbon ent required by the human cells for the growth cyclitol that contains five equatorial and one axi- and survival in the culture. In humans and other al hydroxyl groups. Myo-inositol has been classi- species, Myo-inositol can be converted to either fied as an sensitizing agent and it is L- or D-chiro-inositol by epimerases. Early stud- commonly used in the treatment of the Polycys- Ovary Syndrome (PCOS). However, despite ies showed that inositol urinary clearance was al- its wide clinical use, there is still scarce informa- tered in type 2 diabetes patients, the next step tion on the myo-inositol safety and/or side ef- was to link impaired inositol clearance with in- fects. The aim of the present review was to sum- sulin resistance (for a review see1). Because of marize and discuss available data on the myo-in- these properties, inositol have been classified as ositol safety both in non-clinical and clinical set- “insulin sensitizing agent”2. tings. The main outcome was that only the highest In the recent years, inositol has found more dose of myo-inositol (12 g/day) induced mild and more space in the reproductive clinical prac- gastrointestinal side effects such as nausea, fla- tice3-6. Indeed, since the main therapy for Poly- tus and diarrhea. The severity of side effects did cystic Ovary Syndrome (PCOS) is the use of in- not increase with the dosage. sulin sensitizing agent inositol is mainly use as a chronic treatment for this disease2,5,7,8. Further- Key Words: more, recently it was proposed as a preventing Myo-inositol, PCOS, Side effects, Dosage, NTDs. agent for -resistant neural tube defects (NTDs)9,10. The toxicity of Myo-inositol has not been di- rectly investigated. However, a number of studies have been conducted to investigate the efficacy of myo-inositol in preventing the pathological Introduction changes associated with experimental dia- betes11,12 (and other pathology models) and as a Myo-inositol (also known as inositol, hexahy- cancer chemoprevention agent13-16. The data of droxycyclohexane, or cis-1,2,3,5-trans-4,6-cyclo- these studies provide useful data for evaluating hexanehexol) is a six carbon cyclitol that con- the toxicity of myo-inositol. The relevant studies tains five equatorial hydroxyl groups and one in will be described and discussed hereafter. axial position. The main source of myo-inositol With the present review we aim to summarize is the diet, indeed it is found in a wide variety of some data that are availed in the literature in both foods such as whole grains, , and fruits. non clinical and clinical settings. Myo-inositol can also be synthesized from glu- cose, the immediate precursor being fructose 6- Non Clinical Studies phosphate, which is converted to myo-inositol by Pugliese et al11 investigated the potential effect a cyclase. Myo-inositol is a precursor in the of myo-inositol on diabetes-induced vascular cycle. It is a source of sever- functional changes. Myo-inositol was adminis- al second messengers including diacylgycerol, tered to diabetic rats as supplement in the diet, which regulates some members of the protein ki- ranging from 0.5, 1, or 2% (w/w). Vascular func- nase C family, inositol-1,4,5-triphosphate, which tional changes were evaluated by examining: (1) modifies intracellular levels, and phos- 131I-labeled bovine serum albumin (BSA) perme- phatidylinositol-3,4,5-biphosphate, which is in- ation of vessels in multiple tissues, (2) glomeru- volved in the . It is a compo- lar filtration rate (GFR), estimated as renal plas- nent of membranes and is an essential nutri- ma clearance of 57Co-labeled EDTA, (3) regional

Corresponding Author: Gianfranco Carlomagno, Ph.D.; e-mail: [email protected] 931 G. Carlomagno, V. Unfer

blood flows, measured with 15-microns 85Sr-la- chemical changes triggered by kainate-induced beled microspheres, and 4) endogenous albumin status epilepticus (SE) in rats. The effects of and IgG urinary excretion rates, quantified by ra- myo-inositol were investigated after both acute dial immunodiffusion assay. After 1 month of in- (1 day) and sub-acute (28 days) administration. duced-diabetes, 131I-BSA tissue clearance in- For the acute administration the study was per- creased significantly (2- to 4-fold) in the anterior formed on three different groups, (1) male Wistar uvea, choroid-sclera, retina, sciatic nerve, aorta, rats received intraperitoneal injection of kainic new granulation tissue, diaphragm, and kidney acid (10 mg/kg). Six hours following the treat- but was unchanged in skin, forelimb muscle, and ment, rats received myo-inositol 30 mg/kg, by in- heart. Myo-inositol-supplemented diets reduced jection; (2) rats received only 30 mg/kg myo-in- diabetes-induced increases in 131I-BSA clearance ositol (by injection); (3) rats treated with only (in a dose-dependent manner) in all tissues. saline as controls. However, only in new granulation tissue and di- For the sub-acute study also three different aphragm did the 2% myo-inositol diet complete- groups were analysed (1) rats were treated on ly normalize vascular albumin permeation. Dia- day 1 with kainate received twice a day myo-in- betes-induced increases in GFR and in urinary ositol for 28 days; (2) rats were not treated with albumin and IgG excretion were also substantial- kainate on day 1 and received myo-inositol for ly reduced or normalized by dietary myo-inositol 28 days; (3) rats were not treated with kainate supplements. Increased blood flow in anterior and received saline instead of myo-inositol as uvea, choroid-sclera, kidney, new granulation tis- controls. Changes in proteins expression in the sue, and skeletal muscle in streptozotocin-D hippocampus and neocortex, were evaluated. (STZ-D) rats also was substantially reduced or Proteins studied were: GLUR1, subunit of gluta- normalized by the 2% myo-inositol diet. Notably, mate receptors, calcium/calmodulin-dependent the Authors noted that myo-inositol had minimal protein kinase II (CaMKII); and heat shock pro- if any effects on the above parameters in control tein 90. No changes were found in the acute ex- rats. periments. However, on 28th day of experiment Coppey et al12 studied whether administration the amounts of GLUR1 and CaMKII were of myo-inositol could prevent the detrimental strongly reduced in the hippocampus of KA changes of motor nerve conduction velocity, en- treated animals but MI significantly halted this doneurial blood flow and endothelium-dependent reduction. Notably, in the group that received vascular relaxation of arterioles induced by ex- myo-inositol alone didn’t show change in the perimental diabetes animal model. Diabetic male amounts of studies proteins. rats of 8-9 weeks old were fed with 1% by weight of myo-inositol as a Chronic Studies and Carcinogenesis for a period of about 8 weeks. Administration of Liao et al18 studied the effects of myo-inositol myo-inositol completely reversed the decrease in and hexaphosphate inositol (HI) on the carcino- intracellular myo-inositol content caused by ex- genesis associated to ulcerative colitis (UC) in a perimental diabetes. Treating diabetic rats with newly developed mouse model. Female C57BL/6 myo-inositol improved the reduction of en- mice were subjected to long-term, cyclic dextran doneural blood flow and motor nerve conduction sulphate sodium (DSS) treatment and fed a 2- velocity and prevented the metabolic derange- fold -enriched diet. In this long-term study of ments associated with either activation of the chronic UC and associated colorectal carcino- or increased non-enzymatic gly- genesis, mice were randomized into six groups. cation. Myo-inositol treatment did not prevent Group 1, Group 2 and Group 3 were adminis- the gross signs of diabetes-associated toxicity, tered water, 1% inositol and 1% HI, respectively, such as decrease in body weight change, increase in the drinking water throughout the experiment in blood or serum free fatty acids (FFA) as negative controls (n = 5 mice per group). and triglycerides (TG). In the myo-inositol Group 4, Group 5 and Group 6 mice were sub- group, the values of these parameters were the jected to cyclic DSS treatment. Group 4 received same as the in the diabetic untreated group. This no further treatment (positive control), whereas clearly shows that myo-inositol did cause no fur- groups 5 and 6 mice were administered 1% myo- ther functional impairment in diabetic rats. inositol or 1% HI, respectively in the drinking Solomonia et al17 investigated whether treat- fluid. The study lasted 255 days. Myo-inositol ment with myo-inositol could influence the bio- and HI did not induce any change in body weight

932 Inositol safety: clinical evidences or food consumption, both in DSS-treated and the above parameters in control or diabetic rats. untreated mice. In mice not treated with DSS, However, retinal capillary basement membrane myo-inositol or HI did not induce any change in width (CBMW) was increased significantly (ap- body weight, food consumption or mortality, as proximately 50% versus controls) after 9 months compared to negative controls receiving water. of diabetes and in the control group myo-inositol No colorectal tumors were found in mice receiv- increased CBMW to the level of untreated dia- ing Myo-inositol of HI. The colons of these mice betic rats (myo-inositol had no effect on CBMW were morphologically normal. Myo-inositol 1% in each diabetic group). The number of retinal caused a significant reduction of tumour frequen- capillaries containing pericyte nuclei and peri- cy, tumour multiplicity and tumour volume. The cyte capillary coverage were increased in untreat- Authors’ conclusion is that inositol compounds ed as well as myo-inositol-treated diabetic rats may act as preventive agents for chronic inflam- and in the myo-inositol-treated control group. mation-carcinogenesis. The inhibition of UC-as- Glomerular CBMW was increased after 5 and 9 sociated carcinogenesis by inositol compounds months of diabetes versus age-matched controls, might relate to their function on the modulation and was increased even more by myo-inositol. of macrophage mediated inflammation, nitro-ox- Mesangial fractional volume of the glomerulus idative and cell proliferation in UC-associ- was increased 36% by diabetes and was de- ated carcinogenesis. creased slightly but significantly by myo-inosi- Kassie et al14-16 have examined the inhibitory tol. These results indicate that diets supplement- capacity of myo-inositol (56 µmoles/g diet, i.e., ed with 2% myo-inositol cause capillary base- 10 mg/g or 1% diet), in combination with N- ment membrane thickening and pericyte changes acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cys- in retinal capillaries of normal rats. Myo-inositol teine (PEITC-NAC) on tobacco carcinogen-in- supplementation cause further thickening of duced lung adenocarcinoma in mice. They found glomerular CBM in diabetic rats and is ineffec- that none of the chemopreventive agents, alone tive in preventing or reversing diabetes-induced or in combination, significantly reduced body retinal CBM thickening. weight gain of the mice. The absolute and rela- tive weights of liver and kidney of mice from the Safety data in Humans from treatment groups were similar to those of the Clinical Trials control group. In addition, histopathologic exam- Besides animal model studies, several clinical ination of the studied organs reveal no abnormal- trials have been carried out in order to evaluate ities except a dose-dependent increase in the fre- the effects of myo-inositol in pathologic condi- quency of eosinophilic bodies within the cyto- tions, mainly neuropsychiatric disease (depres- plasm of urinary bladder epithelial cells. sion, Alzheimer disease, ) and Tilton et al19 focused in studying the effects of polycystic ovary syndrome (PCOS)20,21. The du- dietary myo-inositol supplementation on dia- ration of myo-inositol exposure in these trials betes-induced vascular structural lesions in retina ranged from 1 to 12 months. The doses ranged and kidney. The study lasted for a period of 9 from 4 to 30 g/day. months during which diabetic-induced male The safety data of the trials report mild side Sprague-Dawley rats were assigned in three dif- effects such as, nausea and one of flatus and mild ferent groups: 1) rats were fed with 2% myo-in- insomnia only at 12 g/day or higher. Results are ositol diet for 9 months; 2) rats were left untreat- shown in Table I. ed for 5 months then treated with myo-inositol for the 4 months; 3) rats were left untreated for 9 months. Controls included untreated and myo-in- ositol-treated groups. As expected, weight gain Summary was impaired and plasma glucose, glycosylated hemoglobin, food consumption, urine volume, Non Clinical Data and albuminuria were increased significantly in Data from sub-acute studies indicate that a di- diabetic versus age-matched control rats. Plasma et containing up to 2% w/w causes no toxic ef- myo-inositol levels were increased approximate- fects in rats. ly five-fold in controls and approximately six- to Pugliese et al: the Authors noted that myo-in- eightfold in diabetic rats treated with myo-inosi- ositol had minimal if any effects on the above pa- tol. In general, myo-inositol did not affect any of rameters in control rats.

933 G. Carlomagno, V. Unfer and one of flatus inositol. The (at her request) to receive the same mild other patient showed weeks after increase several discontinuation of inositol. while taking Inositol month only for the first experienced panic attacks dizziness and 4 placebo7 inositol 2 mild increases in glycemia after 4 week 1 transient, although the patient continued Placebo-controlled trials Placebo-controlled 30 g/day were flatulence, loose stool, or diarrhea Patients afety tolerability 16 From 12 to 1 month most frequently reported symptoms The disorders 8 inositol binge eating type II diabetes men without agoraphobia MTD 10 18 g/day 3 months Mild gastrointestinal symptoms were disorder Safety data from Clinical trials. Study Pathology (inositol group) Dose Duration Dropouts Adverse events Papaleo et al, 2008Papaleo Gerli et al, 2007Agostini et al, 2006 PCOS Erectile dysfunction in PCOs 88 30 45 4 g/day 1 month 4 g/day 4 g/day None 12 months 14 weeks None patients complained of mild insomnia Two None Levine J et al, 1997Levine 13 12 g/day 1 month 11 1 nausea and 1 flatus Barak Y et al, 1996Allan SJ et al, 2004 Alzheimer's disease Psoriasis, bipolar 12 15 inositol + 6 g/dayBenjamin J et al, 1995 disorder with or Panic 1 month 21 6 g/day 1 month 12 g/day None 1 month patients complained of sleepiness Two Fux M et al, 1996 J et al, 1996.Levine Obsessive-compulsive Stephen Lam et al, 2006 Antidepressant S 13 18+36 18 g/day 6 weeks 18 g/day 1 month _ _ Palatnik A et al, 2001Palatnik Depression panicGelber D et al, 2001 and Bulimia nervosa 25 24 18 g/day 18 g/day 1 month 6 weeks 4 had no 3 subjects nausea, tiredness, headache, _ Table I. Table

934 Inositol safety: clinical evidences

Coppey et al: Authors clearly show that myo- perinsulinemia and hormonal parameters in over- inositol did not cause any further functional im- weight patients with polycystic ovary syndrome. pairment in diabetic rats. Gynecol Endocrinol 2008; 24: 139-144. Solomonia et al: Rats not treated with kainate, 8) MINOZZI M, D'ANDREA G, UNFER V. Treatment of administration of myo-inositol did not produce hirsutism with myo-inositol: a prospective clini- any change in the amounts of GLUR1 and cal study. Reprod Biomed Online 2008; 17: 579- CaMKII. 582. 9) CAVALLI P, C OPP AJ. Inositol and folate resistant Human (Clinical) Data neural tube defects. J Med Genet 2002; 39: E5. In the reported studies more than 250 subjects 10) CAVALLI P, T EDOLDI S, RIBOLI B. Inositol supplementa- have been exposed to myo-inositol for varying tion in pregnancies at risk of apparently folate-re- periods. sistant NTDs. Birth Defects Res A Clin Mol Tera- Clinical trial data indicate that adverse events tol 2008; 82: 540-542. related to myo-inositol treatment are: 11) PUGLIESE G, TILTON RG, SPEEDY A, SANTARELLI E, EADES Gastrointestinal symptoms (nausea, flatus, DM, PROVINCE MA, KILO C, SHERMAN WR, WILLIAMSON loose stools, diarrhoea) at dose of 12 g/day or JR. Modulation of hemodynamic and vascular fil- higher. Furthermore the severity of adverse tration changes in diabetic rats by dietary myo-in- events stays the same also at 30 g/day. ositol. Diabetes 1990; 39: 312-322. Notably the dosage of 4 g/day of inositol com- 12) COPPEY LJ, GELLETT JS, DAVIDSON EP, DUNLAP JA, monly used in clinics is completely free of side YOREK MA. Effect of treating streptozotocin-in- effects. duced diabetic rats with sorbinil, myo-inositol or aminoguanidine on endoneurial blood flow, motor nerve conduction velocity and vascular function of epineurial arterioles of the sciatic nerve. Int J Exp Diabetes Res 2002; 3: 21-36. References 13) VUCENIK I, SHAMSUDDIN AM. Cancer inhibition by inositol hexaphosphate (IP6) and inositol: from laboratory to clinic. J Nutr 2003; 133: 3778S- 1) LARNER J. D-chiro-inositol¬–its functional role in in- 3784S. sulin action and its deficit in insulin resistance. Int J Exp Diabetes Res 2002; 3: 47-60. 14) KASSIE F, M ATISE I, NEGIA M, LAHTI D, PAN Y, S CHERBER R, UPADHYAYA P, H ECHT SS. Combinations of N- 2) BLOOMGARDEN ZT, FUTTERWEIT W, P ORETSKY L. Use of Acetyl-S-(N-2-Phenethylthiocarbamoyl)-L-Cys- insulin-sensitizing agents in patients with polycys- teine and myo-inositol inhibit tobacco carcinogen- tic ovary syndrome. Endocr Pract 2001; 7: 279- induced lung adenocarcinoma in mice. Cancer 286. Prev Res (Phila) 2008; 1: 285-297. 3) COLONE M, MARELLI G, UNFER V, B OZZUTO G, MOLI- 15) KASSIE F, M ELKAMU T, E NDALEW A, UPADHYAYA P, L UO X, NARI A, STRINGARO A. Inositol activity in oligoas- HECHT SS. Inhibition of lung carcinogenesis and thenoteratospermia–an in vitro study. Eur Rev critical cancer-related signaling pathways by N- Med Pharmacol Sci 2010; 14: 891-896. acetyl-S-(N-2-phenethylthiocarbamoyl)-l-cysteine, 4) GERLI S, PAPALEO E, FERRARI A, DI RENZO GC. Ran- indole-3-carbinol and myo-inositol, alone and in domized, double blind placebo-controlled trial: ef- combination. Carcinogenesis 2010; 31: 1634- fects of myo-inositol on ovarian function and 1641. metabolic factors in women with PCOS. Eur Rev 16) KASSIE F, K ALSCHEUER S, MATISE I, MA L, MELKAMU T, Med Pharmacol Sci 2007; 11: 347-354. UPADHYAYA P, H ECHT SS. Inhibition of vinyl carba- 5) PAPALEO E, UNFER V, B AILLARGEON JP, DE SANTIS L, FUSI mate-induced pulmonary adenocarcinoma by in- F, B RIGANTE C, MARELLI G, CINO I, REDAELLI A, FERRARI dole-3-carbinol and myo-inositol in A/J mice. Car- A. Myo-inositol in patients with polycystic ovary cinogenesis 2010; 31: 239-245. syndrome: a novel method for ovulation induction. Gynecol Endocrinol 2007; 23: 700-703. 17) SOLOMONIA R, MIKAUTADZE E, NOZADZE M, KUCHI- ASHVILI N, LEPSVERIDZE E, KIGURADZE T. Myo-inositol 6) PAPALEO E, UNFER V, B AILLARGEON JP, FUSI F, O CCHI F, treatment prevents biochemical changes trig- DE SANTIS L. Myo-inositol may improve oocyte gered by kainate-induced status epilepticus. Neu- quality in intracytoplasmic sperm injection cycles. rosci Lett 2010; 468: 277-281. A prospective, controlled, randomized trial. Fertil Steril 2009; 91: 1750-1754. 18) LIAO J, SERIL DN, YANG AL, LU GG, YANG GY. Inhibi- tion of chronic ulcerative colitis associated adeno- 7) GENAZZANI AD, LANZONI C, RICCHIERI F, J ASONNI VM. carcinoma development in mice by inositol com- Myo-inositol administration positively affects hy- pounds. Carcinogenesis 2007; 28: 446-454.

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