Polymorph , additive effect

Elevations of TCA levels may occur when combined with CYP2D6 inhibitors or from constitutional factors. About 7% of the Caucasian population in the USA has a CYP2D6 polymorphism that is associated with slow metabolism of TCAs and other 2D6 substrates. Combination of a known CYP2D6 inhibitor and a TCA in a patient who is a slow metabolizer may result in additive effects. Such an interaction has been implicated, though rarely, in cases of TCA toxicity. There may also be additive TCA effects such as anticholinergic or antihistamine effects when combined with other agents that share these properties such as benztropine or diphenhydramine. Similarly, antihypertensive drugs may exacerbate the orthostatic hypotension induced by TCAs. 

Nakano, K., Sada, K. and Miyata, M. (1996). Novel additive effect of inclusion crystals on polymorphs of cholic acid crystals having different hydrogen-bonded networks with the same organic guest. Chem. Commun., 989-90. [58]... 

In the crystallization of polymorphs influence with some special additives is observed(i-3). Such effect is due to the relative change of nucleation rate and growth rate of the polymorphs, the effect also contains the change in transformation rate(4,5). Furthermore, a morphological change occurs in many cases. On the other hand, a crystallographic approach has been applied to effect of various type of additives on crystal growth(6-fl). However, the effect of additives espeddly on the kinetic behavior of polymorphism has not usually been treated quantitatively and the mechanisms are not known. 

Polymer applications of DSC are numerous and concern the determination of Tm (ASTM E 794), Tg (ASTM E 1326-03, ISO/FDIS 11357-2), specific heat capacity of a material (ASTM E 1269, ASTM D 4816), crystallisation temperature upon cooling (ASTM E 794), transition temperatures (ASTM D 3418, ASTM D 4419, ASTM D 4591), purity of a material [79,80], contamination outgassing (ASTM E 1559), reaction rates, sample composition, reaction kinetic constants (ASTM E 698), reaction mechanisms, thermal stability (ASTM E 537), minimum processing temperatures, heat of fusion and crystallisation (ASTM D 3417), heat of crystallisation (ASTM E 793), additive effects on a material, quality control of raw materials [25], discrimination between materials, detection of polymorphism [81], characterisation of thermally and UV cured materials (cure state, degree of cure) (ASTM D 2471, ASTM D 5028), oxidative stability testing, QIT (ASTM D 3895, ASTM D 3012, ASTM E 1858-03), etc. 

In addition, / 2-adrenoceptor polymorphisms are associated with severity of asthma [23] and variability in antagonist responses used in treatment [24]. ACE polymorphisms are associated with both susceptibility to essential hypertension [25] and response to therapeutically effective ACE inhibitors [25]. 

In addition to the frequency considerations attendant to the examination of polymorphisms or haplotypes, one must also consider the impact of possible differences in the magnitude of effects of any putative loci. The magnitude of any effects is denoted as "scale" effects based on the notion from quantitative genetics that there will be a displacement from the overall population mean for a trait that is dependent on genotype. To illustrate the effects of scale and frequency, consider two well-known examples of genetic effects. These are the effect of the apolipoprotein E (apo E) polymorphism on cholesterol levels and the impact of the familial hypercholesterolemia polymorphism on cholesterol levels. 

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