Safety considerations for dietary supplement manufacturers in the United States.

Due to significant dietary supplement use in the US, product manufacturers must understand the importance of implementing a robust approach to establishing safety for all ingredients, including dietary ingredients, components, and finished dietary supplement products. Different regulatory pathways exist by which the safety of dietary ingredients can be established, and thus allowed to be marketed in a dietary supplement. For individual dietary ingredients, safety information may come from a variety of sources including history of safe use, presence of the ingredient in foods, and/or non-clinical and clinical data. On occasion safety data gaps are identified for a specific ingredient, particularly those of botanical origin. Modern toxicological methods and models can prove helpful in satisfying data gaps and are presented in this review. For finished dietary supplement products, issues potentially impacting safety to consider include claims, product labeling, overages, contaminants, residual solvents, heavy metals, packaging, and product stability. In addition, a safety assessment does not end once a product is marketed. It is important that manufacturers actively monitor and record the occurrence of adverse events reported in association with the use of their products, in accordance with the law. Herein, we provide a comprehensive overview of considerations for assessing dietary supplement safety.

Clinical pharmacokinetics of thalidomide

Thalidomide is a racemic glutamic acid derivative approved in the US for erythema nodosum leprosum, a complication of leprosy. In addition, its use in various inflammatory and oncologic conditions in being investigated. Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (Cmax) of 1-2mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUCoo) of 18mg - h/L, apparent elimination half-life of 6 hours and apparent systemic clearence of 10 L/H. Thalidomide pharmacokinetics are best described by a one-comportment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacolinetics (the 'flip-flop' phenomenon), with its elimination rate being faster than in absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The 'true' apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state Cmax (Cssmax) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accululation, with Css of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400mg. Because of the low solubility of thalidomide Cmax is less than proportional to dose, and tmax is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokonetics are not expected to change in patients with impaired liver...

A 90-day oral gavage toxicity study of d-methylphenidate and d,l-methylphenidate in beagle dogs.

d-Methylphenidate (d-MPH) was approved as a treatment for attention deficit hyperactivity disorder (ADHD) in children. The repeated-dose toxicity of the d enantiomer of d,l-methylphenidate (d,l-MPH) was assessed in male and female Beagle dogs. Dogs were orally dosed twice a day in equally divided doses 6 hours apart for total daily doses of 1, 3, and 10 mg/kg/day d-MPH or 20 mg/kg/day d,l-MPH for 90 days, followed by a 30-day recovery period. The top d-MPH dose of 10 mg/kg was equimolar to 20 mg/kg d,l-MPH in d-MPH content. The 10-mg/kg d-MPH and d,l-MPH doses were at least 13 times the maximum therapeutic dose giving rise to systemic exposures that were equivalent to or at least 2 times greater than those at the maximum therapeutic doses in children. The 10-mg/kg d-MPH and 20-mg/kg d,l-MPH doses had systemic exposures that were equivalent to or two to five times greater than the maximum therapeutic plasma levels in children respectively. There was no treatment-related mortality in all doses tested. Reversible salivation, hyperactivity, and diarrhea were seen in the high-dose d-MPH and d,l-MPH groups. Significant body weight loss and reduction in food consumption were observed in males for both high-dose groups with weights comparable to control values by the end of the recovery period. There were no abnormal clinical pathology or macroscopic or microscopic findings. Based on body weight changes, the no-observed-adverse-effect level (NOAEL) of d-MPH in beagle dogs was 3 mg/kg/day.

Neurobehavioral effects of racemic threo-methylphenidate and its D and L enantiomers in rats.

D,L-methylphenidate (Ritalin) is used to treat attention deficit hyperactivity disorder (ADHD) in children. The therapeutic effect is predominantly due to the d enantiomer. Dexmethylphenidate (D-MPH; Focalin) was therefore developed for its better therapeutic index. The present study determined and compared the acute behavioral toxicity of D,L-MPH, D-MPH and L-MPH in rats after oral dosing. Comprehensive functional observational battery (FOB) evaluations and rota-rod tests were performed 30, 60 and 120 min after dosing. Ten rats/sex/dose were administered a single dose of vehicle, 2, 20, 100 mg/kg D,L-MPH and 1, 10, 50 mg/kg D-MPH or 1, 100, 500 mg/kg L-MPH. There was no mortality. Certain FOB evaluations were statistically significant from vehicle control at any of the time points with most occurring at 60 and 120 min in the high D,L-MPH dose. These included increases in rearing, difficulty in removal from box, arousal, click, tail-pinch and decreases in hind-limb splay distance, hind-limb grip strength and handling reactivity. Behavioral responses were also present at the mid-dose D,L-MPH and high dose D- and L-MPH. Responses in female were significantly different from males in D,L- and L-MPH groups suggesting a sex difference in sensitivity. In the rota-rod test, mean latency to remain on the rod was significantly less for males compared to control given high dose D-MPH and D,L-MPH. In females, latency times were significantly less for high doses of all three compounds. In summary, fewer significant FOBs were seen with D- and L-MPH compared to equimolar doses of D,L-MPH. L-MPH was the least potent in producing FOBs. These results were supported by rota-rod studies.