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Co-Director, The Ohio State University College of Medicine

As a biomarker, breast milk retinol concentrations may reflect recent dietary intake and not necessarily be a reflection of vitamin A status, as shown in rats (22) and swine (23). A comparison between vitamin A indicators suggests that casual breast milk retinol may perform better when corrected for fat content (24). Quantitative biochemical indicators Indirect semi-quantitative and quantitative methods include dose response and isotope dilution tests. Dose response tests have utility from deficiency through to the adequate range of vitamin A liver reserves. However, they probably do not quantitatively reflect status above the adequate range. Isotope dilution tests give a quantitative estimate of liver reserves from deficiency through to toxic vitamin A status (Figure A2. The test was refined by establishing standard doses of the test dose dependent on the age group and suggesting a range of response times to obtain the blood sample (31). Endogenous concentrations of 3, 4didehydroretinol are low in humans and therefore a baseline blood sample is not needed. A distinguishing response between depleted and sufficient liver reserves can be measured in as little as 4 hours and has been validated in animals against liver vitamin A reserves (26­28, 32). One of the first comparisons was done in two groups of Indonesian preschool-age children (12). Serum retinol concentrations did not differ between those who had received the supplement and those who had not, and nor did the serum retinol concentrations respond to treatment. Furthermore, in an urban group of Ghanaian lactating women, the baseline serum retinol concentration was 1. After use of an intervention with indigenous African green leaves, serum retinol concentrations did not change or differ during the study 48 A2. Serum carotenoid concentrations were analysed in these low-income women and children and in some cases -carotene was not detectable, indicating that vegetable consumption was likely very low (34, 35). When data from several piglet studies were combined (32, 36­38), liver reserves <17 g/g liver (0. From these data and those obtained in rats where down-regulation of lecithin:retinol acyltransferase, which is responsible for retinol esterification, occurred at the same liver concentration (39), the author proposes that 0. If liver reserves elicit a biological response to a vitamin A challenge dose, vitamin A status is not in equilibrium and the individual should be considered at risk for vitamin A deficiency. These are only applicable when individuals are free of infection and other confounders such as protein-energy undernutrition or zinc deficiency. A positive response means the indicator classifies the individual as vitamin A deficient while a negative response means the indicator classifies the individual as vitamin A adequate. Retinol isotope dilution the most sensitive method of evaluation of vitamin A status to liver reserves of vitamin A is isotope dilution testing (40­42), which uses either deuterated or 13C-labelled retinyl acetate as the tracer. All methods that calculate total body stores of vitamin A use the same fundamental massbalance equation with various adaptations to reflect the unique metabolism of vitamin A (46): (Fa Ч a) + (Fb Ч b) = (Fc Ч c) Where: a refers to the amount of dose absorbed and stored (determined experimentally to be 0. Examples of this include estimating relative vitamin A equivalency factors (49), assessing the effect of different intake levels of vitamin A on calculations of total body reserves (50) and effects of supplementation on liver stores (44). Vitamin A supplementation and abrupt changes in dietary intake may result in the exaggeration of liver reserves or affect value estimates with the test (44, 50). The 13C-retinol dilution test has been validated in rats with a depleted and adequate vitamin A status (17) and in rhesus monkeys known to have hypervitaminosis A against liver reserves (51). Although isotope dilution testing is usually too expensive to consider as a means to evaluate a programme, a sugar-fortification programme was evaluated in a small group of Nicaraguan children (52). One year after sugar fortification was implemented, liver reserve concentrations increased to an average of 1. Because many foods are now being considered for fortification, this sensitive methodology may have to be used, as no other method except liver biopsy is able to diagnose hypervitaminosis A. Considering the validation in monkeys and these results in children, isotope methodology can be useful in defining the hypervitaminotic range of liver reserves.

Perhaps more important is the stability of the enolate: the more stable the starting enolate, the easier it is to reverse both reactions and this favours the more stable conjugate addition product. You will recall that the carbonyl carbon is a relatively hard centre, whereas the carbon of an enone is soft. As the nucleophilic enolate becomes more stabilized with extra electron-withdrawing groups, it becomes increasingly soft and hence more likely to attack the carbon. The unsaturated component plays an important role н these factors are discussed in Chapters 10 and 23. The nature of the carbonyl group in the,-unsaturated electrophile is also important as the more electrophilic carbonyl groups give more direct addition and the less electrophilic carbonyl groups (esters, amides) give more conjugate addition. Aldehydes are unhindered and very reactive and thus very prone to direct addition but, if the enolate equivalent is carefully chosen, conjugate addition works well. Ketones are borderline and can be pushed towards either the aldol or conjugate addition pathways by choice of enolate equivalent as we shall see. Esters and amides are much less electrophilic at the carbonyl carbon and so are good substrates for conjugate addition. O EtO O O O diethyl malonate diethyl fumarate н Hydrolysis and decarboxylation and the choice of base were discussed in Chapter 26. Diethyl fumarate is an excellent Michael acceptor because two ester groups withdraw electrons from the alkene. The mechanism involves deprotonation of the malonate, conjugate addition, and reprotonation of the product enolate by ethanol solvent. In this reaction two ester groups stabilize the enolate and two more promote conjugate addition. This route is very general and could be used to make a range of anhydrides with different substituents simply by choosing an appropriate unsaturated ester. The key step in the dehydration reaction is the formation and cyclization of the mixed anhydride formed from the diacid and acetic anhydride. Both steps have the same mechanism, attack of an acid on an anhydride, but the second step is intramolecular. Like most cyclizations the reaction is entropically favoured as two molecules react to give three-the cyclic anhydride and two molecules of acetic acid. Lithium binds strongly to oxygen and so tends to prevent reversible aldol addition, which leads to loss of conjugate addition product. Potassium t-butoxide is the ideal base for this example as it is hindered and so will not attack the ester but is basic enough to deprotonate the ketone to a certain extent. Two enolates are possible but, under the equilibrating conditions, the more stable and more reactive enolate is the important intermediate leading to the more interesting product with a quaternary carbon atom. This unlikely outcome is favoured by hindered t-Bu nucleophiles and conjugated or hindered carbonyls. In these cases the lack of reversibility is not an issue as the aldol product is never formed. In this example the enolate of the t-butyl ketone is the hindered nucleophile and the conjugated ketone is rather unreactive. Conjugate addition can be catalytic in base As the penultimate product in a conjugate addition is an enolate anion, if the pKa of the nucleophile is appropriate, only a catalytic quantity of base is required to initiate the reaction. The enolate anion of the product is protonated by a molecule of starting material to give the neutral final product and another enolate anion of starting material. The reversible reaction sequence, including the unwanted aldol equilibrium, can be forced over towards the conjugate addition product. The balance of pKas is likely to be right for nucleophiles with two electron-withdrawing groups when adding to a double bond conjugated to a single carbonyl group. The cycle is started by an external base removing a proton from the most acidic species present in the reaction mixture at the start which is the nucleophile. This is an important condition for success of the catalytic method and the reason that all the reactants can be mixed together at the start of the reaction with no adverse effects. There is no need to form the nucleophilic enolate quantitatively; more is formed as the reaction proceeds. H product emerges here 753 Hydrogen fluoride is a weak acid in aqueous solution, pKa = 3. The main cycle rotates anticlockwise round the centre of the diagram with the starting materials entering top right and bottom left with the product emerging top left.

Therefore an interaction with propranolol based on this mechanism is unlikely to be clinically important. G Ginkgo + Phenobarbital the interaction between ginkgo and phenobarbital is based on experimental evidence only. Conversely, the phenobarbital-induced sleeping time was reduced markedly from about 8 hours to about 3 hours. However, the modest reduction in levels seen with high-dose ginkgo does not explain the marked reduction in sleeping time. Importance and management the evidence for this interaction is limited to an animal study and the doses used are far higher than those used in humans. If anything, it would appear that the interaction may be beneficial (reduced sedation), but this is far from established. Ginkgo + Protease inhibitors Ginkgo does not appear to affect the pharmacokinetics of lopinavir/ritonavir. Clinical evidence In a study in 14 healthy subjects, ginkgo 120 mg twice daily for 2 weeks had no significant effect on the pharmacokinetics of lopinavir/ritonavir 400 mg/100 mg twice daily (given for 2 weeks alone before adding the ginkgo). The ginkgo extract was assayed and contained 29% flavonol glycosides and 5% terpene lactones. Importance and management the study here shows that ginkgo does not alter the pharmacokinetics of lopinavir/ritonavir, and no special precautions are required on concurrent use. As regards protease inhibitors that are not boosted by ritonavir, the authors of this study recommend avoiding ginkgo. Ginkgo + Risperidone An isolated case describes priapism in a patient taking risperidone and ginkgo. Clinical evidence A 26-year-old paranoid schizophrenic who had been taking risperidone 3 mg daily for the past 3 years developed priapism that had lasted for 4 hours 2 weeks after starting ginkgo 160 mg daily for occasional tinnitus. Risperidone was then restarted and the patient reported no further episodes of priapism at follow-up 6 months later. Risperidone alone does rarely cause priapism, probably because of its alpha-adrenergic properties, and ginkgo might have vascular effects that could be additive. Importance and management the use of ginkgo is widespread and this appears to be the only report in the literature of an interaction with risperidone. G Clinical evidence In one study, 18 healthy Chinese subjects were given a single 40-mg dose of omeprazole before and after a 12-day course of a standardised extract of ginkgo 140 mg twice daily. Importance and management this appears to be the only study examining the effects of ginkgo on proton pump inhibitors. Pharmacogenetics and herb-drug interactions: experience with Ginkgo biloba and omeprazole. Ginkgo + Theophylline the interaction between ginkgo and theophylline is based on experimental evidence only. Importance and management the evidence for this interaction is limited to experimental data and the dose of ginkgo used is far higher than the most common clinical dose. Therefore an interaction with theophylline based on this mechanism is unlikely to be clinically important. Herb-drug interactions: Effect of Ginkgo biloba extract on the pharmacokinetics of theophylline in rats. Mechanism It was suggested that the flavonoids in the ginkgo had a subclinical direct effect on the benzodiazepine receptor. Importance and management Evidence for an interaction between ginkgo and trazodone appears to be limited to this isolated case, from which no general conclusions can be drawn. Bear this interaction in mind in case of an unexpected response to concurrent use. Ginkgo + Tolbutamide Gingko does not appear to have a clinically relevant effect on the metabolism or blood-glucose-lowering effects of tolbutamide. Clinical evidence In healthy subjects, ginkgo extract (Ginkgold) 120 mg twice daily for 7 days had no effect on the urinary metabolic ratio of tolbutamide. The ginkgo product used was Ginkgold, which contained 24% flavone glycosides and 6% terpene lactones. The pharmacodynamics of tolbutamide were not significantly altered although there was a tendency towards the attenuation of its hypoglycaemic effects by ginkgo (14% reduction).

Otherwise the single bond region is usually crowded with hundreds of absorptions from Table 3. Group Frequency, cm­1 Strength Among the hundreds of peaks in the fingerprint 1440­1470 medium region, there are some of a quite different kind. Bending of bonds, particularly C­H and N­H bonds, also leads to quite strong peaks. Bending a bond is easier than stretching it (which is easier, stretching or bending an iron bar? Consequently, bending absorptions need less energy and come at lower frequencies than stretching absorptions for the same bonds. These bands may not often be useful in identifying molecules, but you will notice them as they are often strong (they are usually stronger than C=C stretches for example) and may wonder what they are. Finally in this section, we summarize all the useful absorptions in the fingerprint region. Please be cautious in applying these as there are other reasons for bands in these positions. The first is an industrial emulsifier used to blend solids and liquids into smooth pastes. Its electron impact mass spectrum has peaks at 75 and 74 (each about 20%) and a base peak at 58. The two peaks at 75 and 74 cannot be isotopes of bromine as the separation is only one mass unit, nor can 75 be a 13C peak as it is far too strong. It looks as though 75 might be the molecular ion and 74 an unusual loss of a hydrogen atom. There is one signal for saturated carbon next to oxygen, and two for other saturated carbons, one more downfield than the other. Neither of these carbons can be duplicated (as there is only one O and only one N! There is no room for double bonds or rings because we need to fit in the eleven hydrogen atoms. The base peak in the mass spectrum was at 58 and this fits well with a fragmentation of one structure but not of the other: the wrong structure would give a fragment at 59 and not 58. Each time you make a ring or a double bond, you have to lose two more hydrogen atoms. So, for a compound containing C, H, and O only, take the actual number of hydrogen atoms away from (2n + 2) and divide by two. Every nitrogen adds one extra hydrogen atom because nitrogen can make three bonds. The formula becomes: subtract actual number of hydrogens from (2n + 2), add one for each nitrogen atom, and divide by two. The saturated nitro compound has (2n + 2) = 16 less 15 (the actual number of Hs) plus one (the number of nitrogen atoms) = 2. You would be wise to check that you can do these calculations without much trouble. You may prefer this method for all compounds as it has the advantage of finding one possible structure before you really start! High resolution reveals a formula of C5H9BrO2 and the five carbon atoms make it look as though the glycol has added in too. If we add everything together we find that the unknown compound is the result of the three reagents added together less one molecule of water. These have all disappeared in the product and for the five carbon atoms we are left with four signals, two saturated, one next to oxygen, and one at 102. We have established that chemical shifts are roughly additive so two oxygen atoms would just do. This would give us a fragment C­O­C­O­C accounting for three of the five carbon atoms. We could join the skeleton of the present molecule up in many rings of various sizes like this one in the margin. It is much more likely that the basic skeletons of the organic reagents are preserved, that is, that we have a two-carbon and a three-carbon fragment joined through oxygen atoms. Determining organic structures these are all quite reasonable, though we might prefer the third as it is easier to see how it derives from the reagents.