The potential to use biomarkers for identifying patients that are more likely to benefit or experience an adverse reaction in response to a given therapy, and thereby better match patients with therapies, is anticipated to have a major effect on both clinical practice and the development of new drugs and diagnostics. In this article, we consider current and emerging examples in which therapies are matched with specific patient population characteristics using clinical biomarkers - which we call stratified medicine - and discuss the implications of this approach to future product development strategies and market structures.
The current drug R&D pipeline for most neglected diseases remains weak, and unlikely to support registration of novel drug classes that meet desired target product profiles in the short term. This calls for sustained investment as well as greater emphasis in the risky upstream drug discovery. Access to technologies, resources, and strong management as well as clear compound progression criteria are factors in the successful implementation of any collaborative drug discovery effort. We discuss how some of these factors have impacted drug discovery for tropical diseases within the past four decades, and highlight new opportunities and challenges through the virtual North–South drug discovery network as well as the rationale for greater participation of institutions in developing countries in product innovation. A set of criteria designed to facilitate compound progression from screening hits to drug candidate selection is presented to guide ongoing efforts.
In this paper, we examine the process of dynamic capability development in a large pharmaceutical firm. Using interviews with multiple managers at different organizational levels, we developed two narratives of the process of developing two separate dynamic capabilities in the same firm. We focus on three areas that prior research has shown to be critical in the early stages of the process of implementing new strategic initiatives: the cognitive orientations of key personnel, managerial action undertaken within the firm, and the firm's internal and external contexts. We provide evidence that managers undertake specific initiatives based on their own particular cognitive orientations, and that senior managers play a major role in the development of capabilities by imprinting the organization with their specific cognitive orientation and then orchestrating the multilevel organizational routines necessary for actualization of a capability. These replicable actions by senior management during the early stages of capability development can lead to the development of a capability that is not initially in the cognitive frames of lower level employees. Finally, we will show that internal and external contingencies have a profound impact on the decision to develop a capability, and to discontinue its development. Our findings thus suggest that the process of developing new capabilities shares common elements with other strategic initiatives.
Declining pharmaceutical industry productivity is well recognized by drug developers, regulatory authorities and patient groups. A key part of the problem is that clinical studies are increasingly expensive, driven by the rising costs of conducting Phase II and III trials. It is therefore crucial to ensure that these phases of drug development are conducted more efficiently and cost-effectively, and that attrition rates are reduced. In this article, we argue that moving from the traditional clinical development approach based on sequential, distinct phases towards a more integrated view that uses adaptive design tools to increase flexibility and maximize the use of accumulated knowledge could have an important role in achieving these goals. Applications and examples of the use of these tools--such as Bayesian methodologies--in early- and late-stage drug development are discussed, as well as the advantages, challenges and barriers to their more widespread implementation.
N-Methyldopamine (epinine), one of the few modifications of the dopamine (DA) molecule that retains agonist activity at the DA, receptor, was administered orally as the diisobutyric ester, ibopamine (100, 200, and 300 mg), to 15 patients with congestive heart failure. An increase in cardiac index and decline in systemic vascular resistance was observed with each dose, and these hemodynamic effects persisted for 3 to 6 hr. Small transient increments in right atrial and pulmonary capillary wedge pressures occurred 0.5 hr after ingestion of 200 and 300 mg of ibopamine, but these pressures returned to baseline or lower levels within 30 min. Heart rate and mean arterial pressure were unchanged. Plasma concentrations of epinine peaked 0.5 hr after administration of drug and then declined to minimal levels at 3 hr. Ten patients enrolled in a trial to evaluate the efficacy of long-term therapy with ibopamine; after 8 weeks of treatment, the initial hemodynamic responses to the drug were attenuated and no significant improvement in oxygen uptake at peak exercise was observed. A decline in plasma norepinephrine concentrations, which could be attributed to activation of a2-adrenoceptors and/or DA2 receptors on sympathetic nerves, was observed after initial administration of ibopamine and persisted after long-term drug ingestion; no long-term hemodynamic benefit could be ascribed to the reduction in sympathetic activity. Circulation 73, No. 4, 740-748, 1986. THE ADMINISTRATION of dopamine to patients with congestive heart failure may effect an improvement in the performance of the impaired myocardium, and thus an oral formulation of this drug would be desirable. 2 The beneficial actions of dopamine in patients with heart failure have been attributed not only to a positive inotropic effect that is mediated by activation of the 8,1-adrenoceptor, but also to its agonist activity at the dopamine vascular (DA1) receptor.3 Activation of the DA1 receptor in the renal vascular bed appears primarily responsible for the marked natriuresis produced by this drug. N-Methyldopamine (epinine) is one of the few modifications of the dopamine molecule that retains full agonist activity at the DA1 receptor.4 Ibopamine is the diisobutyric ester of epinine, and after ingestion, it is hydrolyzed by plasma esterases to yield epinine.5 Initial studies have demonstrated beneficial short-term hemodynamic responses to ibopamine in patients with heart failure.-9 This investigation was undertaken to evaluate the hemodynamic actions and bioavailability of ibopamine after short-and long-term administration to patients with chronic congestive heart failure, and to assess the role of the sympathetic nervous system in modulating the hemodynamic responses to the drug.
Three patients with rapidly progressive, disseminated malignant pheochromocytoma were treated with a combination chemotherapeutic regimen consisting of cyclophosphamide, vincristine, and dacarbazine in repeated 21- to 28-day cycles. All three patients had a marked decrease in blood pressure and an improvement in performance status within the first few cycles of treatment. At a follow-up of 6 to 13 months all patients continue to receive chemotherapy with further regression of tumor in two and stable disease in one. Their blood pressure is normal with minimal or no antiadrenergic therapy. Therapy has been well tolerated; moderate reversible granulocytopenia, neurotoxicity, and one episode of pneumonitis have been the major toxicities encountered. Thus, combination chemotherapy appears to be effective for symptomatic malignant pheochromocytoma.
Cartilage degeneration in osteoarthritis is initiated by a loss of proteoglycan. Intra-articular injection of papain causes a reversible loss of proteoglycan in rabbit knees. Rabbits were scanned with magnetic resonance imaging (MRI), using a 1.5T Signa superconducting magnet with 3 inch surface coil. Spin echo sequences were performed in the coronal and sagittal planes at 0, 24, 48, and 72 h after intra-articular injection of papain to obtain T1, proton density, and T2-weighted images. Cartilage proteoglycan content was measured biochemically and histochemically. Reduced articular cartilage thickness in the MR images of papain-treated knees corresponded to changes in cartilage proteoglycan content.
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