The invention relates to vaginal composition comprising a combination of estrogen and vitamin D or a vitamin D analog at a daily dosage delivery of (i) estrogen ranging from 1 μg to 100 μg estrogen of estradiol equivalent and (ii) vitamin D or analog ranging from 7.5 μg to 100 μg of vitamin D equivalent.

The invention relates to vaginal composition comprising a combination of estrogen and vitamin D or a vitamin D analog at a daily dosage delivery of (i) estrogen ranging from 1 μg to 100 μg estrogen of estradiol equivalent and (ii) vitamin D or analog ranging from 7.5 μg to 100 μg of vitamin D equivalent.

A composition for reducing damage associated with oxidative phosphorylation. The composition comprises an upregulating compound mixture configured to upregulate an endogenous antioxidant system, an exogenous antioxidant mixture configured to inhibit oxidation of biomolecules by reactive oxygen species, and a mineral mixture configured to provide one or more cofactors to a endogenous antioxidant enzyme. The endogenous antioxidant system includes a Nrf2 transcription factors that promotes transcription of antioxidant genes.

A composition for reducing damage associated with oxidative phosphorylation. The composition comprises an upregulating compound mixture configured to upregulate an endogenous antioxidant system, an exogenous antioxidant mixture configured to inhibit oxidation of biomolecules by reactive oxygen species, and a mineral mixture configured to provide one or more cofactors to a endogenous antioxidant enzyme. The endogenous antioxidant system includes a Nrf2 transcription factors that promotes transcription of antioxidant genes.

The invention provides compounds of formula (I), their pharmaceutically acceptable salts and prodrugs thereof for use in preventing, inhibiting or treating a disease caused by a mutation in the gene coding for hydroxymethylbilane synthase, in particular for preventing, inhibiting or treating acute intermittent porphyria: (I) wherein: A is selected from N and CR.sup.10 (wherein R.sup.10 is H, —NO.sub.2, C.sub.1-6 haloalkyl or —C(O)R.sup.17 in which R.sup.17 is H or C.sub.1-6 alkyl); Z is selected from N and CR.sup.9 (wherein R.sup.9 is H, halogen (e.g. F, Cl, Br or I) or —OR.sup.16 in which R.sup.16 is H, C.sub.1-6 haloalkyl, or optionally substituted C.sub.1-6 alkyl); L is selected from —CH.sub.2—, —C(O)—, —CH(OH)—, —C(O)—NR′—, and —NR′—C(O)— (wherein R′ is H or C.sub.1-3 alkyl, e.g. —CH.sub.3); R.sup.1 is H; R.sup.2 is selected from H, halogen (e.g. F, Cl, Br or I), —NR.sup.11R.sup.12 (wherein R.sup.11 and R.sup.12 are independently selected from H and C.sub.1-6 alkyl or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated ring), and —OR13 (wherein R.sup.13 is H or C.sub.1-6 alkyl); R.sup.3 is selected from H, —CH.sup.2OH and —C(O)R.sup.14 (wherein R.sup.14 is H or C.sub.1-6 alkyl); R.sup.4 is selected from H, halogen (e.g. F, Cl, Br or I) and —OR.sup.15 (where R.sup.15 is H or C.sub.1-6 alkyl); R.sup.5 is selected from H and C.sub.1-6 alkyl; R.sup.6 is selected from H, —NO.sub.2 and halogen (e.g. F, Cl, Br or I); R.sup.7 is H; and R.sup.8 is selected from H, C.sub.1-6 alkyl, and halogen (e.g. F, Cl, Br or I); or wherein: R.sup.7 and R.sup.8 together with the intervening ring carbon atoms form an unsaturated ring, preferably an aryl ring.

##STR00001##

The invention provides compounds of formula (I), their pharmaceutically acceptable salts and prodrugs thereof for use in preventing, inhibiting or treating a disease caused by a mutation in the gene coding for hydroxymethylbilane synthase, in particular for preventing, inhibiting or treating acute intermittent porphyria: (I) wherein: A is selected from N and CR.sup.10 (wherein R.sup.10 is H, —NO.sub.2, C.sub.1-6 haloalkyl or —C(O)R.sup.17 in which R.sup.17 is H or C.sub.1-6 alkyl); Z is selected from N and CR.sup.9 (wherein R.sup.9 is H, halogen (e.g. F, Cl, Br or I) or —OR.sup.16 in which R.sup.16 is H, C.sub.1-6 haloalkyl, or optionally substituted C.sub.1-6 alkyl); L is selected from —CH.sub.2—, —C(O)—, —CH(OH)—, —C(O)—NR′—, and —NR′—C(O)— (wherein R′ is H or C.sub.1-3 alkyl, e.g. —CH.sub.3); R.sup.1 is H; R.sup.2 is selected from H, halogen (e.g. F, Cl, Br or I), —NR.sup.11R.sup.12 (wherein R.sup.11 and R.sup.12 are independently selected from H and C.sub.1-6 alkyl or, together with the nitrogen atom to which they are attached, form a 5- or 6-membered saturated ring), and —OR13 (wherein R.sup.13 is H or C.sub.1-6 alkyl); R.sup.3 is selected from H, —CH.sup.2OH and —C(O)R.sup.14 (wherein R.sup.14 is H or C.sub.1-6 alkyl); R.sup.4 is selected from H, halogen (e.g. F, Cl, Br or I) and —OR.sup.15 (where R.sup.15 is H or C.sub.1-6 alkyl); R.sup.5 is selected from H and C.sub.1-6 alkyl; R.sup.6 is selected from H, —NO.sub.2 and halogen (e.g. F, Cl, Br or I); R.sup.7 is H; and R.sup.8 is selected from H, C.sub.1-6 alkyl, and halogen (e.g. F, Cl, Br or I); or wherein: R.sup.7 and R.sup.8 together with the intervening ring carbon atoms form an unsaturated ring, preferably an aryl ring.

##STR00001##

The present application is concerned with methods for increasing the bioavailability and/or activity of agents and in particular allows selective targeting of an agent to, or via, the liver or allows the liver to be bypassed. By selecting which of saturated fatty acids (SFA), short chain fatty acids (SCFA), medium chain fatty acids (MCFA), polyunsaturated fatty acids (PUFA), monounsaturated fatty acids (MUFAs) and long chain fatty acids (LCFA) are present in a composition and which predominates it is possible to substantially boost bioavailability and also to selectively target whether an agent is delivered to, or via, the liver or alternatively bypasses the liver. The approach is a versatile platform technology which may be applied to agents in general helping achieve better and more efficient delivery. In one preferred embodiment particular carotenoids are employed to further influence whether delivery is to, or via, the liver, or bypasses the liver.

The present application is concerned with methods for increasing the bioavailability and/or activity of agents and in particular allows selective targeting of an agent to, or via, the liver or allows the liver to be bypassed. By selecting which of saturated fatty acids (SFA), short chain fatty acids (SCFA), medium chain fatty acids (MCFA), polyunsaturated fatty acids (PUFA), monounsaturated fatty acids (MUFAs) and long chain fatty acids (LCFA) are present in a composition and which predominates it is possible to substantially boost bioavailability and also to selectively target whether an agent is delivered to, or via, the liver or alternatively bypasses the liver. The approach is a versatile platform technology which may be applied to agents in general helping achieve better and more efficient delivery. In one preferred embodiment particular carotenoids are employed to further influence whether delivery is to, or via, the liver, or bypasses the liver.

The invention relates to a carotenoid for use in the treatment or prevention of stress induced conditions, and in particular it relates to the treatment or prevention of a disease mediated by glucocorticoid receptor activity. The invention also relates to a cosmetic method for preventing premature-aging of skin in a subject which comprises administering a carotenoid to said subject. Finally, the invention relates to a method for modulating the activity of a glucocorticoid receptor comprising contacting the receptor with a carotenoid.

The invention relates to a carotenoid for use in the treatment or prevention of stress induced conditions, and in particular it relates to the treatment or prevention of a disease mediated by glucocorticoid receptor activity. The invention also relates to a cosmetic method for preventing premature-aging of skin in a subject which comprises administering a carotenoid to said subject. Finally, the invention relates to a method for modulating the activity of a glucocorticoid receptor comprising contacting the receptor with a carotenoid.