Oral hyaluronan relieves knee pain: a review

Oe, Mariko; Tashiro, Toshiyuki; Yoshida, Hideto; Nishiyama, Hiroshi; Masuda, Yasunobu; Maruyama, Koh; Koikeda, Takashi; Maruya, Reiko; Fukui, Naoshi

doi:10.1186/s12937-016-0128-2

Nutrition Journal

Table 2 Safety tests of hyaluronan

From: Oral hyaluronan relieves knee pain: a review

Test procedures		Subjects	Route	Results	References
Randmized, double-blind, placebo-controlled trial		Human	Oral administration, 60 mg/day for 2 weeks	No adverse event related to hyaluronan.	[34]
		Human	Oral administration, 48 mg/day for 2 months	No adverse event related to hyaluronan.	[35]
		Human	Oral administration, 240 mg/day for 8 weeks	No adverse event related to hyaluronan.	[36]
		Human	Oral administration, 200 mg/day for 8 weeks	No adverse event related to hyaluronan.	[37]
		Human	Oral administration, 60 mg/day for 4 months	No adverse event related to hyaluronan.	[39]
		Human	Oral administration, 200 mg/day for 12 months	No adverse event related to hyaluronan.	[41]
		Human	Oral administration, 52 mg/day for 3 months	No adverse event related to hyaluronan.	[42]
		Human	Oral administration, 52 mg/day for 3 months	No adverse event related to hyaluronan.	[43]
		Human	Oral administration for 4 weeks (225 mg/day for first 2 weeks, 150 mg/day for last 2 weeks)	No adverse event related to hyaluronan.	[46]
single-dose toxicity study		Mouse	Oral administration	LD50 (mg/kg) > 2400	[48]
		Mouse	Oral administration	LD50 (mg/kg) > 500	[49]
		Rat	Oral administration	LD50 (mg/kg) > 800	[48]
		Rat	Oral administration	LD50 (mg/kg) > 200	[50]
		Rabbit	Oral administration	LD50 (mg/kg) > 1000	[48]
Repeated-dose toxicity study		Rat	Subcutaneous administration for 13 weeks with 4 weeks recovery test	NOAEL 50 mg/kg/day	[51]
		Beagle dog	Subcutaneous administration for 13 weeks with 4 weeks recovery test	NOAEL 10 mg/kg/day	[52]
		Rat	Oral administration for 30 days	NOAEL 1500 mg/kg/day	[53]
		Rat	Oral administration for 90 days	NOAEL 1333 mg/kg/day	[54]
		Rat	Oral administration for 90 days	NOAEL 1000 mg/kg/day	[55]
		Rat	Oral administration 28 days	NOAEL 3500 mg/kg/day	[56]
		Rat	Intraperitoneal administration 90 days	NOAEL 9 mg/kg/day	[57]
		Rat	Intraperitoneal administration for 3 months	NOAEL 60 mg/kg/day	[58]
		Rat	Oral administration for 13 weeks	NOAEL 12.5 mg/kg/day	[59]
		Rat	Oral administration for 90 days with 28 days recovery test	NOAEL 48 mg/kg/day	[60]
		Beagle dog	Intra-articular administration for 6 months	NOAEL 12 mg/kg/day	[61]
Reproductive and developmental toxicity studies		Rat	Subcutaneous administration	NOAEL 50 mg/kg/day	[62–64]
		Rat	Oral administration	NOAEL 670 mg/kg/day	[65]
		Rat	Subcutaneous administration	NOAEL 50 mg/kg/day	[66–68]
		Rabbit	Subcutaneous administration	NOAEL 50 mg/kg/day	[69]
Mutagenicity test	Reverse mutation test	Bacteria(Ames test)	1000 μg/plate	Negative	[70]
	Chromosomal aberration test	Mammalian cultured cell	1.00 mg/mL	Negative	[71]
	Chromosomal aberration test	Mammalian cultured cell	1000 μg/plate	Negative	[72]
	Micronucleus test	Mouse	300 mg/kg	Negative	[73]
	Micronucleus test	Mouse	Intraperitoneal administration, 30 mg/kg	Negative	[74]
Antigenicity study		Mouse, Rat	Intraperitoneal administration, 100 μg/個体	Negative	[75]
		Guinea pig	Intraperitoneal administration, 100 μg/個体	Negative	[75]
		Rabbit	Intramuscularl administration, 30 mg/kg	Negative	[76]
Influence on cancer cell		Mouse, cell	Oral administration, 200 mg/day	No influence on cancer cell	[77]

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