Dimorphism matters

While I suspect most people working in drug discovery are aware of gender differences in the way drugs can behave in the clinic, dimorphism in cells is perhaps less well recognised. A Nature comment from Elizabeth Pollitzer highlights the importance of recording the gender of cells in experiments citing examples of differences in response of muscle derived stem cells from male and female subjects and responses of cells to stress. Dr Pollitzer also notes that ten prescription drugs were withdrawn between 1997 and 2001 due to gender differences in adverse events a figure which did surprise me a little. While hormonal differences can explain some differences in both exposure and efficacy/safety others have been attributed to differences in metabolic pathways.

Thinking within the context of a drug screening cascade at what stage should one be checking for dimorphism –Dr Pollitzer recommends ideally running separate cell based studies from both males and females which seems very reasonable. Perhaps (and admittedly much more demanding) does this need extending to the in vivo situation running male/female PK/PD, on late leads, at least where other evidence suggests this may be appropriate. From a metabolic perspective, one thing I am not clear about with microsomal studies – are pooled microsomes or hepatocytes pooled from both male and female or from single gender. Will we see drugs being developed which only achieve exposure/efficacy in one gender – clearly I am not considering treatments for more obviously gender specific diseases here?  Perhaps also we may see an improvement of reproducibility of experiments from the literature if (again as Dr Pollitzer urges) journal editors and referees insist on the reporting of the source gender of cells

Finally in similar vein reinforcing the importance of recognising and understanding gender differences two EU reports. The first on gendered innovations that considers where there may be opportunities for innovation based on gender biases in population analysis – eg in cardiovascular disease historically it has been mainly males that have been studied – is this information as relevant to the female as the male? The second I guess reinforces the first by emphasising that the absence of thought about dimorphism in running and reporting of experiments is a bigger concern than any funding or recruitment gender inequities.


Chronobiology, chronotoxicity, chronoefficacy!

Just picked up this article on Wee1 expression in the circadian rhythm dependent intestinal damage induced by docetaxel from Fujimura’s group which identifies increased expression of Wee1 (controlled by the clock gene complex clock/bmal), phosphorylated CDK1, and cleaved Caspase-3 and lower levels of survivin in animals dosed with docetaxel 14 hours after lights on (HALO) compared with those dosed 2 HALO. The 14 HALO group showed increased intestinal damage compared with the 2 HALO group although the mechanistic relationship of the changes in protein expression and intestinal damage is unclear. Drug exposures were the same from the two dosing protocols. It has previously been suggested that docetaxel is more efficacious when dosed during the light period time point while another recent report highlighted the circadian nature of toxicity and efficacy of oxaliplatin. The idea of chronotherapy is, of course, not new with various reviews written on the field . Finally chronotoxicity as determined by MTD and efficacy for celecoxib is discussed with respect to efficacy in a breast cancer mouse xenograft model I found the results quite impressive.

However, this did set me thinking a few thoughts. Do we as research scientists consider sufficiently the timing of drug dosing either for efficacy or for minimising side effects either preclinically or clinically? Is this a variable that needs tighter control in the preclinical setting? What are the consequences on drug efficacy for those who suffer from disrupted sleep patterns (be it due to ill health, life style or required work patterns)? Could co-administration (or with a 12hr off-set) of an appropriate hypnotic (and its not entirely clear what would be an appropriate hypnotic) or improved sleep hygiene improve efficacy of some therapeutics?