Is there a functional correlate of Kv1.5 in the ventricle of canine heart and what would it mean for the use of IKur blockers?

The cardiac ultrarapid outward current I(Kur), encoded by KCNA5, is of special pharmacological interest, because it is considered to be atrium-specific. I(Kur) has therefore become a target in the therapy of atrial tachyarrhythmias. However, the concept of atrium specificity is only valid if a functional I(Kur) current is in fact absent from the ventricle. However, new work has detected a I(Kur)-like current in canine ventricular myocytes, sensitive to 4-aminopyridine and suppressed by the I(Kur) blocker DPO-1, findings that support the existence of a functional ventricular I(Kur). These indications are, however, indirect and more effort is needed to clarify unequivocally the putative role of an expectedly small I(Kur) component in the ventricle.     

The epidermal growth factor receptor gene family as a target for therapeutic intervention in numerous cancers: what’s genetics got to do with it?

Over the past 30 years, a relatively simple growth factor and its cognate receptor have provided seminal insights into the understanding of the genetic basis of cancer, as well as growth factor signalling. The epidermal growth factor (EGF), its cognate receptor (EGFR) and related family members have been shown to be important in normal, as well as the malignant growth of many cell types including: glioblastomata, astrocytomas, medulloblastomata, non-small cell lung carcinoma (NSCLC) and breast cancer. This review summarises the history of the EGFR gene and the v-ErbB oncogene, as well as diverse approaches developed to inhibit EGFR activity. The two most advanced therapies use either small-molecule cell membrane permeable kinase inhibitors or antibodies which prevent receptor activation. Recent clinical trials indicate that certain NSCLC patients have mutations in the EGFR gene which makes them more responsive to kinase inhibitors. These mutations appear to enhance the ability of the ligand to activate EGFR activity and also prolong the binding of the EGFR inhibitor to the kinase domain. Evidence to date suggests that these EGFR mutations in NSCLC occur more frequently in Japan than in the western hemisphere. Although these mutations are correlated with enhanced efficacy to the inhibitors in NSCLC, they can not explain or predict the sensitivity of many other cancer patients to the beneficial effects of the EGFR kinase inhibitors or antibody mediated therapy. As with as other small-molecule kinase inhibitors and susceptible diseases (e.g., imatinib and chronic myeloid leukaemia), resistance to EGFR inhibitors has been reported recently, documenting the requirement for development of multi-pronged therapeutic approaches. EGFR kinase inhibitors are also being evaluated as adjuvants in hormonal therapy of breast cancer – especially those which overexpress EGFR. Genetically engineered antibodies specific for the EGFR family member ErbB2 have been developed which show efficacy in the treatment of primary, and prevent the relapse of, breast cancer. Clearly, the EGF/EGFR signalling cascade has, and continues to play, an important role in the development of novel anticancer targeted therapies.     

National and local guidance on services for drug misusers: do they influence current practice?— results of a survey of community pharmacists in South East England

Objective — To investigate levels of awareness of national and local guidance about services for drug misusers and their effect on pharmacy practice. Method — A postal survey in 1997 to collect data on current involvement in services for drug misusers, awareness of and receipt of key documents pertaining to drug misuse, effects of guidelines and protocols on practice, and influences on decisions to provide services. Setting — A random one in two sample (n=1,582) of community pharmacies in the South East of England (North and South Thames regions). Key findings — A 65.1 per cent response rate was achieved. Just over half (54.7 per cent) were dispensing Controlled Drugs for the management of dependence, 47.2 per cent were selling clean injecting equipment and 15.5 per cent were offering a needle exchange service. Most respondents were unaware of key government documents, with the exception of “Health of the nation,” and only a small minority had received copies. The most influential factors on current position on service provision were “personal experience,” “local need” and “Royal Pharmaceutical Society of Great Britain (RPSGB) policy.” New local guidelines and initiatives mainly related to supervised consumption of methadone in pharmacies and pharmacy needle exchange. Conclusion — Community pharmacies are substantially and increasingly involved in providing*** primary care services for drug misusers. However, there is a disturbing lack of awareness of key government initiatives, possibly due to the lack of dissemination of such documents. RPSGB policy as a key influencing factor points to an opportunity for the profession to take a more influential position.     

The epidermal growth factor receptor gene family as a target for therapeutic intervention in numerous cancers: what's genetics got to do with it?

Over the past 30 years, a relatively simple growth factor and its cognate receptor have provided seminal insights into the understanding of the genetic basis of cancer, as well as growth factor signalling. The epidermal growth factor (EGF), its cognate receptor (EGFR) and related family members have been shown to be important in normal, as well as the malignant growth of many cell types including: glioblastomata, astrocytomas, medulloblastomata, non-small cell lung carcinoma (NSCLC) and breast cancer. This review summarises the history of the EGFR gene and the v-ErbB oncogene, as well as diverse approaches developed to inhibit EGFR activity. The two most advanced therapies use either small-molecule cell membrane permeable kinase inhibitors or antibodies which prevent receptor activation. Recent clinical trials indicate that certain NSCLC patients have mutations in the EGFR gene which makes them more responsive to kinase inhibitors. These mutations appear to enhance the ability of the ligand to activate EGFR activity and also prolong the binding of the EGFR inhibitor to the kinase domain. Evidence to date suggests that these EGFR mutations in NSCLC occur more frequently in Japan than in the western hemisphere. Although these mutations are correlated with enhanced efficacy to the inhibitors in NSCLC, they can not explain or predict the sensitivity of many other cancer patients to the beneficial effects of the EGFR kinase inhibitors or antibody mediated therapy. As with as other small-molecule kinase inhibitors and susceptible diseases (e.g., imatinib and chronic myeloid leukaemia), resistance to EGFR inhibitors has been reported recently, documenting the requirement for development of multi-pronged therapeutic approaches. EGFR kinase inhibitors are also being evaluated as adjuvants in hormonal therapy of breast cancer - especially those which overexpress EGFR. Genetically engineered antibodies specific for the EGFR family member ErbB2 have been developed which show efficacy in the treatment of primary, and prevent the relapse of, breast cancer. Clearly, the EGF/EGFR signalling cascade has, and continues to play, an important role in the development of novel anticancer targeted therapies.     

What role do pharmaceuticals play in the treatment of Peyronie’s disease and is there a need for new emerging drugs?

Introduction: Finding novel medical treatment for Peyronie’s disease (PD) has suffered from similar limitations and difficulties as other fibrotic diseases.Areas covered: Underlying fibrosis, there is a vastly complex intertwining of several pathways. Focusing on a single target during antifibrotic drug development has not led to the development of many efficacious drugs, especially in PD. Inhibiting one cog in this large machinery usually leads to activation of compensatory mechanisms.Expert opinion: Novel strategies in drug discovery such as phenotypical drug screening and gene expression profiling technologies could provide a solution for this impasse.