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In vitro pharmacological profiling is increasingly being used earlier in the drug discovery process to identify undesirable off-target activity profiles that could hinder or halt the development of candidate drugs or even lead to market withdrawal if discovered after a drug is approved. Here, for the first time, the rationale, strategies and methodologies for in vitro pharmacological profiling at four major pharmaceutical companies (AstraZeneca, GlaxoSmithKline, Novartis and Pfizer) are presented and illustrated with examples of their impact on the drug discovery process. We hope that this will enable other companies and academic institutions to benefit from this knowledge and consider joining us in our collaborative knowledge sharing. [ABSTRACT FROM AUTHOR]

1. Endothelium-derived relaxing factors (EDRF), including nitric oxide (NO), prostacyclin (PGI2) and an as yet uncharacterized endothelium-derived hyperpolarizing factor (EDHF), are now recognized to induce relaxation of vascular smooth muscle, in part via the activation of K+ channels. 2. Experiments using selective K+ channel blockers, including iberiotoxin (IbTX), glibenclamide, apamin and 4-aminopyridine (4-AP) to inhibit endothelium-induced relaxation suggest that more than one type of K+ channel may be involved, depending on the species and tissue, including: (i) large conductance Ca2+-activated (BKCa) channels; (ii) ATP-sensitive (KATP) channels; (iii) small conductance Ca2+-activated (SKCa) channels; and (iv) voltage-gated (Kv) K+ channels. 3. Recent observations suggest a role for Kv channels in some vessels based on a sensitivity of NO- and PGI2-mediated relaxations to 4-AP, as well as a complete suppression of EDHF- dependent relaxation by a combination of charybdotoxin (ChTX) and apamin but not IbTX and apamin. 4. The molecular identity of the K+ channels affected by EDRF is not well characterized. Recently, findings indicate that the pore-forming α-subunit tetramers of vascular smooth muscle BKCa channels are due to the expression of the so-called Slo channel gene. The identities of the KATP, SKCa and Kv channels involved in endothelium-dependent vasodilation are not known. 5. The component of whole-cell Kv current affected by PGI2 may be due to slowly inactivating, 4-AP-sensitive, 15 pS delayed-rectifier K+ channels (KDR); the activity of these channels in vascular myocytes is increased by forskolin and protein kinase A (PKA) and rabbit portal vein Kv1.5 pore-forming α-subunits, which... [ABSTRACT FROM AUTHOR]

The interrelationships of 'blues' and later postpartum depression with a number of biochemical, medical, and psychosocial variables have been examined in 52 subjects. The two syndromes shared only an impressive association with a prior history of gynaecological problems. Puerperal 'blues' was characterised in addition by associations with primiparity, tearfulness during pregnancy, and reduced plasma total tryptophan in the early puerperium. Depressive symptomatology up to nine months postpartum was related to an excess of male births and to an altered pattern of decline of non-esterified fatty acids immediately postpartum. In each case, the 'risk' variables were statistically independent and combined linearly. Stepwise discriminant analysis successfully discriminated 'blues' and depression from their respective non-cases. 'Blues and postpartum depression were only weakly related and, apart from gynaecological history, each was associated with separate and independent causative factors. [ABSTRACT FROM AUTHOR]

Plasma cortisol, free and total tryptophan were determined in 71 subjects on 8 occasions between 36 weeks gestation and 6 weeks post-partum. Affect was measured by rating scales and clinical interview. Twenty-eight subjects were judged to have experienced post-partum 'blues'. Seasonal variation occurred in the incidence of 'blues' and in cortisol and free tryptophan levels. Puerperally-depressed mood was correlated with high cortisol at 38 weeks irrespective of season. Free tryptophan was reduced in 'blues' subjects but only at the time of year when free tryptophan was normally high. Total tryptophan was low antenatally; a rapid rise on days 1 and 2 post-partum was superimposed on a slower return to normal. This initial peak was clearly absent in 37 per cent of subjects. Its absence was significantly related to occurrence of post-partum 'blues' and of complaints of depression in the ensuing 6 months. This finding is discussed in relation to the possible occurrence of an occult disturbance of tryptophan handling in subjects susceptible to depression. [ABSTRACT FROM AUTHOR]

An addition to the flora of Canada, Pumpkin Ash (Fraxinus profunda),is reported from the southwestern counties of Essex, Kent, Elgin andHaldimand-Norfolk. This is a native tree species of swamp forests. The species is most readily distinguished from other ashes by its relatively large samaras 4--7.5 cm long. [ABSTRACT FROM AUTHOR]