Table 2.

Bioactivities and potential mechanisms of melatonin.

Study Type	Subjects	Dose (mg/kg b.w.)/(Dose Dependent)	Potential Mechanisms (Melatonin (Mel) and/or Its Metabolites)	Reference
Antioxidant Activities
			Directly scavenging free radical
In vivo	Mouse	10 mg/kg b.w.	Increasing the efficiency of electron transport chain: - lowering electron leakage and reducing free radical generation	[122]
In vitro	Human umbilical artery segment	10−6, 10−5, 10−4 M (dose dependent)	Significantly scavenging the hydroxyl radical	[127]
			Cascade effects: removing free radicals efficiently than other reductants:
In vivo	Rat	43 μmol/kg b.w.	- more efficient than Vitamin C	[128]
	Rat	2 μmol/kg b.w.	- more efficient than Vitamin E	[125]
	Mouse	5 mg/kg b.w.	- more efficient than Vitamin E	[325]
In vitro	Incubation medium	1–1000 mM	- more efficient than Vitamin C & Vitamin E	[123]
			Some metabolites more potent than its precursor in reducing oxidative stress:
	Fenton reaction-based assay	AFMK: 0.017–0.067 mM AMK: up to 0.2 mM	- the order of efficacy of scavenging ∙OH: AMK > AK > AFMK	[130]
N/A	N/A	N/A	- C3-OHM is 2–3 fold more potent than Mel in reducing hypervalent hemoglobin (Tan & Reiter, unpublished observations).	[131]
			Modulating and activating other enzymes
			Downregulating pro-oxidative enzymes
In vitro & in vivo	Rat striatum	M & AMK: 10−11–10−3 M (dose dependent in vitro)	- Mel & AMK inhibiting nNOS activity - AMK more potent in inhibiting nNOS activity than Mel (in vivo)	[142]
In vitro	MCF-7 cells	1 nM	Inhibiting the mRNA expression of COX 1 and COX-2 in MCF-7 cells	[143]
			Stimulating the synthesis of other antioxidants
In vitro	ECV304 cells	1 μM	- Inducing γ-GCS expression to promote GSH synthesis	[124]
In vitro	2 neuronal cell lines: PC12 cells & SK-N-SH	1 nM	- Regulating AOEs gene expression - Increasing mRNA of SODs and GPx	[144]
			Preventing antioxidant enzymes from oxidative stress
In vitro	human BM-MSCs	0 to 1000 μM (dose dependent 10–100 μM)	- significantly restoring SOD (p < 0.05) and CAT (p < 0.01) - increasing GSH (p < 0.01) with pre-treatment of Mel	[145]
In vivo	Sprague-Dawley rats	10 mg/kg b.w.	GSH-Rd activity was completely or partially restored by Mel treatment	[146]
In vitro & in vivo	Sprague–Dawley rats	0–0.1 mM (dose dependent in vitro) 10 mg/kg b.w.	G6PG activity dose-dependent in vitro (increased below 0.08 mM Mel concentration and reached a plateau above 0.1 mM) G6PG activity time-dependent (in vivo)	[147]
			Synergistically working with other reductants
			Combining with other antioxidants to remove radicals synergistically
In vitro	Rat liver homogenates	2.5–1600 μM	- dramatically enhancing the protective effects after combining	[148]
Anti-inflammatory Activities
			NF-κB signaling pathway involved mechanisms
			Modulating NF-κB and its downstream pro-inflammatory target genes
In vitro	Human colon cancer cell lines SW620 and LOVO	1 mmol/L	- iNOS	[70]
In vitro	RAW 264.7 macrophages	0.5, 1, 2 mM (dose dependent)	- COX-2, PGE2	[158]
In vitro	Human neuroblastoma dopamine SH-SY5Y cell lines	1, 10, 100 or 1000 nM	- TNF-α	[159]
In vitro	Rat astrocytoma C6 cells	50–200 μM (dose dependent)	- GFAP	[160]
In vitro & in vivo	CHON-001 human chondrocyte cell line Rabbit with osteoarthritis (OA)	0.1, 1, 10, 100 ng (dose- and time-dependent) 20 mg/kg	Protecting cells by blocking the activated NF-κB as well as the phosphorylation of PI3K/Akt, p38, ERK, JNK and MAPK	[161]
In vitro	BV2 murine microglial cell line	1 mM	Downregulating chemokine expression	[162]
In vivo	Rats	5 mg/kg	Inhibiting the inflammatory reaction	[163]
In vivo & in vitro	Female BALB/c mice MMECs	5, 10, 20 mg/kg 25, 50, 100 μM (dose dependent)	Suppressing NF-κB activation and activating PPAR-γ	[164]
In vitro	Mast cells (RBL-2H3)	100 nM and 1 mM (dose dependent)	Inhibiting IKK/NF-κB signal transduction	[165]
			SIRT1 pathway involved mechanisms
In vitro & in vivo	BV2 cell lysates PND7 rat brain	100 µM 10 mg/kg	Activating SIRT1/Nrf2 signaling pathway to reduce oxidative stress damage	[168]
			Other possible mechanisms
In vivo	Pediatric patients	10 mg (09:00 h) 60 mg ( 21:00 h )	Regulating the expression of other pro-inflammatory genes	[150]
In vitro	Mouse Gsk3b knockout (Gsk3b−/−) and wild-type (Gsk3b+/+) MEF cells	10 nM	Inhibiting the expression of inflammatory chemokines/cytokines	[169]
In vivo	Plasmodium	10 µM (time dependent)	Inducing temporal up-regulation of gene expression related to UPS	[170]
In vivo	C57BL mice	10 mg/kg i.p.	Downregulating mRNA of E2F2 and H2-Ab1	[171]
In vivo	Rats	5, 15, and 25 mg/kg (dose-dependent)	Activating the expression of NDRG2, which was involved in cellular differentiation, development, anti-apoptosis, anti-inflammatory cytokine, and antioxidant	[172]
In vivo	Carp	10−4–10−12 M	Maintaining the pro- and anti- inflammatory balance during infection by influencing leukocyte migration and apoptosis	[151]
Enhancing Immune Activities
			Reciprocally regulating the nervous, endocrine, and immune systems
In vivo & In vitro	Mice Thymus and spleen cells	4–5 mL/day/mouse 1.5 pg/ml to 1.5 pgg/ml	Regulating thymocyte apoptosis	[174]
In vivo	Mice	1.5 pg/mL to 1.5 pg/mL	The concentration of melatonin correspond with the change of seasons	[175]
			Inhibiting the production of cAMP, cGMP and DAG, and improving the immunity
In vitro	Human blood lymphocyte	N/A (dose-dependent)	Inhibiting adenylyl cyclase and the stimulating phospholipase C	[183]
In vivo	Golden hamsters	25 μg/100 g/hamster/day	Improving immune responses	[184]
			Protecting the immune organs, tissues and cells
			Reversing the weight loss of thymuses and spleens in pinealectomized animals
In vivo & In vitro	Mice Thymus and spleen cells	4–5 mL/day/mouse 1.5 pg/mL to 1.5 pg/mL	- thymus	[175]
In vivo	Syrian hamsters	25 μg	- spleen	[188]
In vivo	Pediatric patients	N/A	Increasing tonsillar size	[189]
			Improving proliferation, increasing activity and inhibiting apoptosis of immune cells
In vitro	cultured monocytes	N/A	- monocyte	[190]
In vivo	ICR mice	10 or 50 mg/kg	- natural killer (NK) cells	[191]
In vitro	Neutrophils & peripheral blood mononuclear cells	10 mM	- neutrophils	[192]
In vivo	Wistar albino rats	10 mg/kg	Increasing the sensitivity of the immune cells to some cytokines	[193]
In vitro & In vitro	Thymocytes of Barbari goats Thymus	500 pg/mL 500 pg/mL	Restoring the suppressed immunity of T-cell cultured by developing some hormonal microcircuit (gonadal steroid and melatonin) in lymphatic organs	[194]
			Modulating immune mediator production
In vitro	Human mononuclear cells	10−8 M	Increasing IL-2, IFN-γ and IL-6 in monocytes	[195]
In vitro	Neutrophils & peripheral blood mononuclear cells	10 mM	Mel & AFMK: decreasing IL-8 and TNF-α in neutrophils	[192]
In vitro	RAW264.7 cells	10, 100 or 1000 μM	Decreasing IL-1β, IL-6, IL-8, IL-10 and TNF-α in macrophages	[196]
			Regulating the ROS production in the essential immune cells
In vitro	Human monocytes	10−12 M and above	Activating monocytes (above the activation threshold of 5 × 10−11 M)	[199]
In vitro	Lung neutrophils	0.01, 0.1, 1 mM (dose-dependent)	Activating neutrophils	[200]
In vivo	Hamsters	25 μg/100 g b.w.	Attenuating oxidative load	[201]
In vivo	Wild birds	25 μg/100 g/day	Alleviating oxidative damage and suppressing the immune status induced by stress	[202].
In vitro & in vivo	Heart tissue of C57BL/6 C57BL/6J mice	3 or 4 doses of melatonin 30 mg/kg	Suppressing systemic innate immune activation by blocking the NF-κB/NLRP3 connection through a sirtuin1-dependent pathway	[154].
Improving Circadian Rhythm and Sleep
In vivo	C3H & C57BL mice	N/A	Being involved in the control of clock gene protein levels in the adrenal cortex of mice	[211]
In vivo	Soay sheep	N/A	Resetting circadian rhythms in the pituitary pars tuberalis	[212]
In vivo	Mice (C3H/HeJCrl and C57BL/6NCrl)	N/A	Influencing PER1 and CRY2 protein levels Playing a role in rhythmic regulation of pCREB levels in the mammalian retina	[213]
In vitro & in vivo	COS7 cells Lambs	N/A	Activating Npas4	[215]
In vivo	Hamster	20 μg/day	Coordinating the diurnal rhythm in neuronal remodeling	[217]
In vivo	Mice	6 μg/day for 2 weeks	Increasing amplitude in expressional rhythms Altering the expression of genes of serotonergic neurotransmission Improve the depression-like behavior	[218]
In vivo	23 patients	N/A	Being positive correlated with sleep parameters	[220]
Anticancer Activities
			Effects on tumor cell cycle, incl. growth, proliferation, metabolism and apoptosis
In vitro & In vivo	Human gastric cancer cell lines (AGS and MKN) Male BALB/c nude mice	5 mg/kg/twice/week for 33 days 1 µM to 2 mM (dose-/time- dependent, 15 min to 24 h)	Inhibiting gastric tumor growth and peritoneal metastasis Inhibiting C/EBPβ and NF-κB Inducing ER stress and inhibiting EMT	[232]
In vitro	T47D-BAF co-cultured	20 nM	Suppressing breast cancer cell proliferation and inhibiting aromatase	[238]
In vitro & in vivo	Prostate cancer cells TRAMP male mice	1 mM 200 µg/mL	Reducing glucose uptake and modifying the expression of GLUT1 transporter Attenuating glucose-induced tumor progression and prolonging the lifespan	[233]
In vitro	Hypoxic prostate cancer cell line PC-3 cells	1 mM	Anti-angiogenic property Upregulating miRNA3195 and miRNA 374b and downregulating 16 miRNAs	[239]
In vitro	Colorectal cancer LoVo cells	0.1–2.0 mM (dose-dependent)	Suppressing cell proliferation and inducing apoptosis Inducing dephosphorylation and nuclear import of histone deacetylase 4 (HDAC4) Decreasing H3 acetylation by inactivating CaMKIIα and reducing bcl-2 expression	[240]
In vitro	Breast cancer cell line SK-BR-3 & MDA-MB-231	2 mM	Changing the protein levels of Survivin, Bcl-2, and Bax Affecting cyt c release from the mitochondria to the cytosol Enhancing apoptotic cell death via sustained upregulation of Redd1 expression and inhibition of mTORC1 upstream of the activation of the p38/JNK pathways	[234]
			Effects on invasion and metastasis of tumor cells
In vitro	HepG2 liver cancer cells	1 mM	Exhibiting anti-invasive and antimetastatic activities by suppressing the activity of MMP-9 Reducing IL-1β-induced HepG2 cells MMP-9 gelatinase activity and inhibiting cell invasion and motility through downregulation of MMP-9 gene expression and upregulation of the MMP-9-specific inhibitor tissue inhibitor of TIMP-1 Suppressing IL-1β-induced NF-κB translocation and transcriptional activity	[241]
In vitro	Renal cell carcinoma cells (Caki-1 and Achn)	0.5–2 mM	Reducing the migration and invasion Inhibiting MMP-9 by reducing p65- and p52-DNA-binding activities Regulating MMP-9 transactivation and cell motility refer to the Akt-mediated JNK1/2 and ERK1/2 signaling pathways	[242]
In vivo & in vitro	Female athymic nude mice Metastatic and non-metastatic breast cancer cell lines (MDA-MB-231)	100 mg/kg/day 1 mM	Lowering the numbers of lung metastasis Decreasing ROCK-1 protein expression in metastatic foci Reducing cell viability and invasion/migration Decreasing ROCK-1 gene expression in metastatic cells and protein expression in non-metastatic cell line	[235]
			Therapy adjunct in tumor treatment
In vitro	Human non-small-cell lung cancer (NSCLC) cells lines H1299 and A549	1 mM	Enhancing the berberine-mediated growth inhibition of lung cancer cells through simultaneous modulation of caspase/cyt C, AP-2β/hTERT, NF-κB/COX-2, and Akt/ERK signaling pathways	[157]
In vitro	Breast cancer cells	1 nM	Mediating the sensitization to the ionizing radiation by decreasing around 50% the activity and expression of proteins involved in the synthesis of estrogens Reducing the amount of active estrogens at cancer cell level Inducing a 2-fold change in p53 expression compared to radiation alone	[243]
In vivo	Female patients	Melatonin-containing cream for twice daily use	Significantly lowering the occurrence of grade 1/2 acute radiation dermatitis in patients with breast-conserving surgery for stage 0–2 breast cancer	[244]
In vivo	Male Wistar rats	10 mg/kg/week	Mitigating PVB-induced testicular dysfunction	[245]
In vivo & in vitro	Female athymic nude mice Human colon cancer cell lines SW620	25 mg/kg 1 mmol/L	Exerting synergistic anti-tumor effect by inhibiting the AKT and iNOS pathway Enhancing the 5-FU-mediated inhibition of cell proliferation, colony formation, cell migration and invasion Synergizing with 5-FU to promote the activation of the caspase/PARP-dependent apoptosis pathway and induce cell cycle arrest Synergizing anti-tumor effect of 5-FU by targeting the PI3K/AKT and NF-κB/iNOS signaling	[70]
In vitro	Human colorectal cancer cells	N/A	MT2 mRNA expression levels increased The profile of melatonin receptors gene expression and genes associated with their activity in colorectal cancer	[236]
In vitro	Estrogen receptor-positive endometrial cancer cell line, Ishikawa	1 × 10−9 M	MT1 receptor expressing but not MT2 Attenuating ERα mRNA expression Enhancing anti-tumor effects of paclitaxel among anticancer drugs tested	[237]
Cardiovascular Protection
In vivo	Patients with confirmed nocturnal hypertension	2 mg 2 h before bedtime for 4 weeks	Reducing nocturnal systolic and diastolic BP significantly (p = 0.01)	[249]
In vivo	Spinal cord injury (SCI) mice model	5, 10, 25, 50, 100 mg/kg i.p.	50 mg/kg exhibiting significantly reduced blood spinal cord barrier permeability Restraining microvessel loss and attenuating edema Protecting the tight junction proteins, endothelial cells and pericytes Decreasing cell apoptosis and reducing MP3/AQP4/HIF-1α/VEGF/VEGFR2 expression	[251]
In vivo	Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR)	30 mg/kg/day for 4 weeks	Decreasing reflex chronotropic responses to phenylephrine and sodium nitroprusside Reducing mean arterial pressure and heart rate Improving bradycardic and tachycardic baroreflex responses without modifying catecholamine responses Increasing glutathione peroxidase activity in plasma and erythrocytes	[252]
In vivo	Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR)	30 mg/kg/day for 4 weeks	Decreasing mean arterial pressure (MAP) and heart rate Restoring the plasma noradrenaline concentrations, the chronotropic response to isoproterenol and the proportions of β1/β2-adrenoceptors in the heart in SHRs to the levels Decreasing the release of [3H] noradrenaline from isolated atria Improving the relaxation in the aorta	[253]
In vivo	Rats	50 mg/kg	Preventing vasculitis Decreasing elementary pathological lesions of radiation-induced heart disease (RIHD) like fibrosis and necrosis	[254]
In vitro	BM-MSCs	200, 20, and 2 µM(dose-dependent)	Reducing BM-MSC apoptotic death while increasing the levels of TGF-β, bFGF, VEGF, PDGF and Bcl-2, and decreasing Bax, p53 Upregulating modulator of apoptosis (PUMA) and caspase 3 Upregulating the phosphorylation of AMPK, which promotes ACC phosphorylation	[255]
In vivo & in vitro	Female C57BL/6a mice with MI Adipose-derived MSCs	20 mg/kg/day for 28 days 5 µM	Promoting functional survival of AD-MSCs in infarcted heart and provoking a synergetic effect with AD-MSCs to restore heart function associated with alleviated inflammation, apoptosis, and oxidative stress in infarcted heart Exerting cytoprotective effects against hypoxia/serum deprivation (H/SD) injury Attenuating inflammation, apoptosis, and oxidative stress Enhancing SIRT1 signaling, with the increased expression of anti-apoptotic protein Bcl-2, and decreased the expression of Ac-FoxO1, Ac-p53, Ac-NF-KappaB, and Bax.	[256]
In vitro	Perfused isolated rat hearts and cultured neonatal rat cardiomyocytes	5 µM	Improving postischemic cardiac function, decreasing infarct size, reducing apoptotic index, and diminishing lactate dehydrogenase release Upregulating the anti-apoptotic protein Bcl-2 and downregulating Bax Preserving mitochondrial redox potential and elevating SOD activity Decreasing formation of mitochondrial H2O2 and MDA	[257]
In vivo	Rats with sepsis	30 mg/kg	Improving survival rates and cardiac function, attenuating myocardial injury and apoptosis Decreasing the serum LDH, decreasing inflammatory cytokines TNF-α, IL-1β, and HMGB1 Increasing anti-oxidant enzyme activity and p-Akt and Bcl-2 levels	[258]
In vivo	Drosophila melanogaster	5 µM	Increasing the regularity of heartbeat, rescuing rhythmicity in flies bearing mutations, increasing cardiac regularity independent of alteration of heart rate, which is mediated via a specific G-Protein-coupled receptor encoded by the CG 4313 gene	[259]
In vivo	Patients with heart failure	N/A 1-year follow-up	As a predictors of left ventricular reverse remodeling (LVRR) and the adverse clinical events, increasing the area under of curve for the prediction LVRR	[260]
In vivo	Mice with Mst1 transgenic (Mst1 Tg) and Mst1 knockout (Mst1−/− )	20 mg/kg/d for 1 week	Alleviating postinfarction cardiac remodeling and dysfunction by upregulating autophagy, decreasing apoptosis, and modulating mitochondrial integrity and biogenesis via Mst1/Sirt1 signaling	[261]
Anti-diabetic Activities
In vivo	Albino Wistar rats	10 mg/kg b.w.	Increasing the inhibited activity of catalase in liver cells Restoring the dysfunctional mitochondria related to diabetes	[274]
In vivo	Rat	2.8, 14, 28, and 140 nM	Inhibiting hepatic gluconeogenesis Activating hypothalamic Akt via membrane receptors MT1 and MT2	[275]
In vivo	Rat	10 mg/kg/day	Increasing Ca2+ levels in lots of organs and tissues	[11]
In vitro & in vivo	H9C2 cell line Rat	0.1, 1, 10, 100, 1000 µM 20 mg/kg/day	Activating of SIRT1 signaling pathway (significant at 100 and 1000 µM) Inactivating PERK/eIF2α/ATF4 signaling pathway	[276]
In vitro	INS 832/13 cells	1–100 nM	Attenuating β-cell apoptosis, improving β-cell function, prolonging β-cell survival (particularly evident at 10 nM)	[277]
In vivo	Rat	10 mg/kg/day	Improving neurogenesis, synaptogenesis in hippocampi, increasing the receptors of melatonin and insulin, and restoring the downstream signaling pathway for insulin	[278]
In vivo	Rat	250 µg/animal/day/i.p.	Accelerating bone healing	[279]
In vivo	Rat	10 mg/kg/d, i.p.	Restoring the endothelial dysfunction and improving vascular responses	[271]
Anti-obese Activities
In vivo	Rat	10 mg/kg/day	Inducing white adipose tissue browning in rats with obesity-related type 2 diabetes	[282]
In vivo	Rat	20 mg/L	Benefiting homeostasis of renal glutathione	[283]
In vitro	Mouse Gsk3b knockout (Gsk3b−/−) and wild-type (Gsk3b+/+) MEF cells	10 nM	Inhibiting Akt activation Increasing GSK3B activity	[169]
In vivo	Mice	100 mg/kg/day	Ameliorating obesity-induced adipokine alteration	[285]
In vivo	Women	N/A	Melatonin was involved in the development of obesity	[288]
In vitro	Mice	20 mg/kg/day	Promoting circadian rhythm-mediated proliferation in adipose tissue	[206]
In vivo	Rat	4 mg/kg/day	Decreasing myocardial infarct sizes and insulin resistant Increasing serum PKB/Akt, ERK42/44, GSK-3β and STAT3	[289]
In vivo	Mice	100 mg/kg/day	Increasing mitofusin-2 expression	[290]
In vivo	Mice	10 mg/kg/day	Modulating the MAPK-JNK/p38 signaling pathway	[291]
Neuroprotection
In vivo	Mice	10 mg/kg	Increasing the activity of antioxidant enzymes Mediating the Nrf2-ARE pathway	[293]
In vivo	C57BL/6J mice	10 mg/kg given twice	Reducing IR-induced mitochondrial dysfunction Activating SIRT1 signaling	[294]
In vivo	Rat	150 mg/kg	Suppressing cortical expressions of proinflammatory cytokines	[295]
In vivo	Mice	5 mg/kg	Reducing oxidative damage by scavenging radicals	[296]
In vivo	Rat	10 mg/kg	Reversing the increased plasma TNF-α, IL-1β levels Decreasing BDNF, S100B and IL-10 values	[297]
In vivo	Rat	10 mg/kg and 50 mg/kg	Preventing the decrease of the number and the diameter of sciatic nerve axons	[298]
In vivo	Rat	20 mg	Preventing the decrease in VEPs and PLR Inhibiting microglial reactivity, astrocytosis, demyelination, and axon and retinal ganglion cell loss Preserving anterograde transport of cholera toxin β-subunit	[299]
In vivo	Mice	10 mg/kg	Restoring mRNA and protein levels of BACE1 and PS1	[305]
In vitro & in vivo	Rat hippocampal neurons Rat	50 μM 500 mg/kg b.w.	Improving the soluble Abeta1–42-induced impairment of spatial learning and memory, synaptic plasticity and astrogliosis	[301]
In vivo	Rat	10 mg/kg	Improving motor activity and muscular strength	[306]
In vitro	Mouse neuroblastoma cells	1 μM	Activating transcription factor EB-dependent autophagy-lysosome	[136]
In vivo	Rat	100 mg/kg	Inhibiting caspase-3	[307]
In vivo	Rat	50 mg/kg/day	Protecting the cell against neuronal damage in the hippocampus	[308]
Other Bioactivities
In vivo	Rat	10 mg/kg/day	Improving the microstructure and biomechanical properties of aged bones	[311]
In vivo	Patients	10 mg/day, 60 mg/day	Reducing the hyperoxidative and inflammatory process	[150]
In vivo	Mice	30 mg/kg/day	Decreasing plasma creatine kinase activity, increasing total glutathione content Lowering the oxidized/reduced glutathione ratio	[312]
In vitro	NCI-H292 cells	50, 100, 200, and 400 μM (dose-dependent)	Inhibiting mucin 5AC production	[313]
In vivo	Rat	4 mg/kg, i.p 10 mg/kg, i.p	Exhibits renoprotective effects against ischemia reperfusion induced AKI due to antioxidant properties and the involvement of progesterone receptors	[314]
In vivo	Rat	10 mg/kg/day	Scavenging free radicals	[315]
In vivo	Rat	N/A	Activating SIRT1 signaling	[316]
In vitro	Human ASCs	100 μM for 3 h	Enhancing human ASCs’ survival and their therapeutic effectiveness on injured tissue	[317]
In vivo	Rat	10 mg/body	Interacting with other hormones	[319]
In vivo	Rat	10 mg/kg/day	Decreasing the increased myeloperoxidase activities and osteoclast and neutrophil densities	[322]
In vivo	Rat	10 mg/kg/day	Decreasing serum cyclophosphamide levels and increasing ALP levels	[323]