Paradoxical pharmacology: turning our pharmacological models upside down

Paradoxical pharmacology is a term first suggested by Richard Bond to refer to intriguing observations that chronic use of some drug types can have the opposite biological effect(s) to those seen following acute administration of the same drug. A good example of 'paradoxical pharmacology' is the research Richard has pioneered showing that whereas acute administration of β-blockers is contraindicated in the treatment of asthma, chronic use of certain β-blockers can have therapeutic benefit. It would appear that those β-blockers that can act as inverse agonists at the β2 receptor particularly show this paradoxical effect and the findings of Richard's research not only challenge the dogma of the treatment of asthma but also challenge many of the pharmacological principles of ligand/receptor interactions established by Sir James Black and others. In this paper, I discuss Richard's efforts to evaluate the chronic effects of β-blockers in the airways and how this research caught the imagination of Sir James Black.     

Didemnidines A and B, indole spermidine alkaloids from the New Zealand ascidian Didemnum sp

Two new indole spermidine alkaloids, didemnidines A (1) and B (2), have been isolated from the New Zealand ascidian Didemnum sp. The structures of the metabolites, determined by analysis of 2D NMR spectra and confirmed via synthesis, embody an indole-3-glyoxylamide moiety linked to the N(1) position of spermidine, the latter motif being particularly rare among marine natural products. Didemnidine B and a synthetic precursor exhibited mild in vitro growth inhibition of Plasmodium falciparum with IC(50)'s of 15 and 8.4 μM, respectively.     

A multistage association study identifies a breast cancer genetic locus at NCOA7

Estrogen metabolism and growth factor signaling pathway genes play key roles in breast cancer development. We evaluated associations between breast cancer and tagging single-nucleotide polymorphisms (SNP) of 107 candidate genes of these pathways using single allele- and haplotype-based tests. We first sought concordance of associations between two study populations: the Nashville Breast Cohort (NBC; 510 cases, 988 controls), and the Cancer Genetic Markers of Susceptibility (CGEMS) breast cancer study (1,145 cases, 1,142 controls). Findings across the two study populations were concordant at tagging SNPs of six genes, and at previously published SNPs of FGFR2. We sought further replication of results for EGFR, NCOA7, and FGFR2 in the independent Collaborative Breast Cancer Study (CBCS; 1,552 cases, 1,185 controls). Associations at NCOA7 and FGFR2 replicated across all three studies. The association at NCOA7 on 6q22.32, detected by a haplotype spanning the initial protein-coding exon (5'-rs9375411, rs11967627, rs549438, rs529858, rs490361, rs17708107-3'), has not been previously reported. The haplotype had a significant inverse association with breast cancer in each study [OR(Het): 0.69 (NBC), 0.76 (CGEMS), 0.79 (CBCS)], and a meta-analysis OR(Het) of 0.75 (95% CI, 0.65-0.87, P = 1.4 × 10(-4)) in the combined study populations. The haplotype frequency was 0.07 among cases, and 0.09 among controls; homozygotes were infrequent and each OR(Hom) was not significant. NCOA7 encodes a nuclear receptor coactivator that interacts with estrogen receptor α to modulate its activity. These observations provide consistent evidence that genetic variants at the NCOA7 locus may confer a reduced risk of breast cancer.     

Patterns of physician follow-up among young cancer survivors: report of the Childhood, Adolescent, and Young Adult Cancer Survivors (CAYACS) research program

Objective

To describe the frequency and pattern of physician visits in 1998 to 2000 among childhood and adolescent cancer survivors in British Columbia (BC), to compare their use of physician services with use in the general population, and to examine the effects of clinical and sociodemographic factors on care.

Design

Retrospective, observational, population-based cohort study, with a comparison group. Cohort records from population registries were linked to physician claim data and oncology visit records for 1998 to 2000.

Setting

Outpatient physician care in BC.

Participants

All (N = 1157) survivors of cancer diagnosed before age 20 years in BC between 1970 and 1992 who survived at least 5 years after diagnosis, and an age-sex frequency–matched population sample of 11 570 individuals.

Main outcome measures

Probability of a physician visit and frequency of physician visits.

Results

Approximately 97% of survivors saw at least 1 physician in the 3-year period, compared with 50% of the general population sample. The probability of a GP visit was 96% higher (adjusted 95% confidence interval [CI] 1.8 to 2.1), and the likelihood of a specialist visit was 157% higher (adjusted 95% CI 2.4 to 2.8) than for the general population. Survivors were more than twice as likely to see GPs at least 10 times (adjusted relative risk 2.23, 95% CI 2.0 to 2.4) and had 49% more visits than the general population. Cancer diagnosis and treatment affected visit patterns, but socioeconomic status and rural residency did not significantly affect the probability of a visit.

Conclusion

Demand for physician care among childhood and adolescent cancer survivors is considerably greater than for the general population, and this need persists many years after diagnosis. Physicians need information on the unique health care requirements of this patient group in order to provide appropriate care.     

Diazine indole acetic acids as potent, selective, and orally bioavailable antagonists of chemoattractant receptor homologous molecule expressed on Th2 cells (CRTH2) for the treatment of allergic inflammatory diseases

New classes of CRTH2 antagonists, the pyridazine linker containing indole acetic acids, are described. The initial hit 1 had good potency but poor permeability, metabolic stability, and PK. Initial optimization led to compounds of type 2 with low oxidative metabolism but poor oral bioavailability. Poor permeability was identified as a liability for these compounds. Addition of a linker between the indole and diazine moieties afforded a series with good potency, low rates of metabolism, moderate permeability, and good oral bioavailability in rodents. 32 was identified as the development track candidate. It was potent in cell based, binding, and whole blood assays and exhibited good PK profile. It was efficacious in mouse models of contact hypersensitivity (1 mg/kg b.i.d.) and house dust (20 mg/kg q.d.) when dosed orally. In sheep asthma, administration at 1 mg/kg iv completely blocked the LAR and AHR and attenuated the EAR phase.     

Pharmacological modulation of the inflammatory actions of platelets

Patients with inflammatory diseases often exhibit a change in platelet function, with these alterations being clearly distinct from the well-characterized role of platelets in haemostasis and thrombosis. It has recently been revealed that platelets can behave as innate inflammatory cells in immune responses with roles in leukocyte recruitment, migration into tissues, release of cytotoxic mediators, and in tissue remodelling following injury.Platelets exhibit a wide range of receptors for mediators involved in the inflammatory pathway and the immune response (Fig. 1). These include purinergic receptors, selectins, integrins, toll-like receptors, immunoglobulins, and chemokine receptors, but the precise role platelets play in the inflammatory process is still under investigation. Nevertheless, given that many of these receptors are distinct from those involved in thrombosis and haemostasis, this raises the real possibility of targeting these receptors to regulate inflammatory diseases without compromising haemostasis.     

Recruitment difficulties in a primary care cluster randomised trial: investigating factors contributing to general practitioners' recruitment of patients

Background  

Recruitment of patients by health professionals is reported as one of the most challenging steps when undertaking studies in primary care settings. Numerous investigations of the barriers to patient recruitment in trials which recruit patients to receive an intervention have been published. However, we are not aware of any studies that have reported on the recruitment barriers as perceived by health professionals to recruiting patients into cluster randomised trials where patients do not directly receive an intervention. This particular subtype of cluster trial is commonly termed a professional-cluster trial. The aim of this study was to investigate factors that contributed to general practitioners recruitment of patients in a professional-cluster trial which evaluated the effectiveness of an intervention to increase general practitioners adherence to a clinical practice guideline for acute low-back pain.     

Clinical nursing leaders', team members' and service managers' experiences of implementing evidence at a local level

kitson a., silverston h., wiechula r., zeitz k., marcoionni d. & page t. (2011) Journal of Nursing Management 19 , 542–555
Clinical nursing leaders’, team members’ and service managers’ experiences of implementing evidence at a local level Aim To describe the experiences of 14 clinical nursing leaders introducing a knowledge translation (KT) project into one metropolitan acute care hospital in South Australia. The study also explored team members’ and service managers’ experiences. Background KT strategies assume that local (nursing) clinical leaders have the capacity and capability to champion innovation combining positional leadership roles (ward leader) with a project lead role. There is limited evidence to support these assumptions. Method Semi-structured interviews of clinical nursing leaders and managers were undertaken at month 4 and 12 of the project. Data were also collected from the interdisciplinary team members (n = 28). Results Clinical nursing leaders identified risks and anxieties associated with taking on an additional leadership role, whereas managers acknowledged the multiple pressures on the system and the need for local level innovation. Team members generally reported positive experiences. Conclusions With support, clinical nursing leaders can effectively embrace KT project leadership roles that complement their positional leadership roles. Clinical nursing leaders’ experiences differed from nursing and medical managers’ experiences. Implications for nursing management Managers need to be more attuned to the personal risks local leaders experience, providing support for leaders to experiment and innovate. Managers need to integrate local priorities with broader system wide agendas.