Quote from ZJ on February 7, 2019, 4:14 pm

This looks very promising!

https://patents.google.com/patent/US4649040A/en

 

The present invention discloses a pharmaceutical composition and a method of treating retinoid induced pathogenesis. The pathological effect of retinoid is ameliorated by a suitable dose of a rescuing agent selected from the group consisting of choline chloride, methionine, betaine, biotin and inositol, the rescuing agent having the property of preventing formation of fatty liver.

In accordance with the present invention any agent or compound which prevents the formation of fatty liver can be used to ameliorate the pathological or toxic effects of retinoids.

In the experiments described hereunder mice (C57 BL/6J-males) were used. A toxic dose of 13-trans retinoic acid, 500 mg/kg, was administered by an intraperitoneal injection of the suspension of the acid in physiological saline. This one time dose has several pathological effects in mice as described by Bolag, supra, and results in death of nearly all of the animals. Mice injected with retinoic acid were thereafter divided into the following groups: (a) control animals which received tap water to drink; (b) treated groups which, in place of tap water, were supplied with solutions of various rescuing agents in tap water.

The progress of the development of pathological changes were followed daily. Results of three independent experiments are shown in FIGS. 1 and 2. These results are representative of other similar tests. Experiments were also conducted which established the non-toxicity of the rescuing agents mentioned herein.

Results in FIG. 1 show that the administration of 1% (weight by volume) choline chloride or 0.02% biotin or 1% betaine in drinking water rescued about 40% of mice from death caused by retinoic acid. In the same experiment a supersaturated solution of biotin (0.06%) was also used. This led to the rescue of about 50% of the mice. The most potent substance of the group was L-methionine, which at 1% concentration led to the rescue of 70% of the mice.

FIG. 2 shows the results of addition of 0.2% of myoinositol (inositol) to drinking water which rescued about 30% of the mice from death induced by retinoic acid. The percentage of rescue increased to 50% when myoinositol was supplemented by 0.1% of choline chloride. FIG. 2 also shows the results of another experiment wherein the mixture of myoinositol and choline chloride was further supplemented with biotin (0.02%). The results clearly demonstrate that an increased rescue (about 80%) can be achieved by such a supplementation.

The experimental evidence presented herein clearly establishes that a group of agents known to prevent formation of fatty liver, when administered in sufficient doses ameliorates the pathological changes induced by retinoids. Without being bound to any theory, it is suggested that these agents presumably accelerate metabolism and excretion of retinoids thereby reducing their toxic or pathological effects. These rescuing agents are minor components of certain foods and are non-toxic. They are easily assimilable and show immediate and efficacious utility.