Pharmacological treatment of idiopathic pulmonary fibrosis: from the past to the future.

During the past decade important progress has been made regarding the pathogenesis of idiopathic pulmonary fibrosis (IPF), which is the most devastating form of idiopathic interstitial pneumonia with a median survival of 3 years. The knowledge gained has been used to design multicentre, randomised, placebo-controlled trials in order to investigate agents with different mechanisms of action. Encouraging results have led to licensing of the first IPF-specific drug, pirfenidone. However, the road to successful treatment is still long. The main aim for the future should be the careful design of clinical trials, by choosing the most clinically meaningful end-point and keeping in mind that combination of various agents may be more effective. This approach has been used in the treatment of lung cancer with which IPF presents many similarities.

Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor.

Apixaban (BMS-562247; 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide), a direct inhibitor of activated factor X (FXa), is in development for the prevention and treatment of various thromboembolic diseases. With an inhibitory constant of 0.08 nM for human FXa, apixaban has greater than 30,000-fold selectivity for FXa over other human coagulation proteases. It produces a rapid onset of inhibition of FXa with association rate constant of 20 µM⁻¹/s approximately and inhibits free as well as prothrombinase- and clot-bound FXa activity in vitro. Apixaban also inhibits FXa from rabbits, rats and dogs, an activity which parallels its antithrombotic potency in these species. Although apixaban has no direct effects on platelet aggregation, it indirectly inhibits this process by reducing thrombin generation. Pre-clinical studies of apixaban in animal models have demonstrated dose-dependent antithrombotic efficacy at doses that preserved hemostasis. Apixaban improves pre-clinical antithrombotic activity, without excessive increases in bleeding times, when added on top of aspirin or aspirin plus clopidogrel at their clinically relevant doses. Apixaban has good bioavailability, low clearance and a small volume of distribution in animals and humans, and a low potential for drug-drug interactions. Elimination pathways for apixaban include renal excretion, metabolism and biliary/intestinal excretion. Although a sulfate conjugate of Ο-demethyl apixaban (O-demethyl apixaban sulfate) has been identified as the major circulating metabolite of apixaban in humans, it is inactive against human FXa. Together, these non-clinical findings have established the favorable pharmacological profile of apixaban, and support the potential use of apixaban in the clinic for the prevention and treatment of various thromboembolic diseases.

Topical treatments for onychomycosis: a historical perspective.

Topical treatment of onychomycosis, in contrast to systemic oral therapy, allows the patient to apply medication directly to the affected area, thereby decreasing the potential for adverse events and drug interactions. Historically, several topical antifungal agents have been used in the treatment of onychomycosis; however, the evidence for their effectiveness is based on very limited data or anecdotal reports. Recently, the development of new, effective topical agents has renewed interest in this form of therapy. As clinical experience with newer topical agents expands, they may be found to be an effective option for the treatment of onychomycosis.

Ciclopirox nail lacquer and podiatric practice.

Ciclopirox 8% nail lacquer has recently been approved by the US Food and Drug Administration (FDA) for the management of mild-to-moderate dermatophytic onychomycosis not involving the lunula. Previously, the agents that were approved for the treatment of dermatophytic pedal onychomycosis--griseofulvin, itraconazole, and terbinafine--were administered orally. When ciclopirox nail lacquer is used, it is recommended that the infected nail undergo debridement by a health-care professional as frequently as monthly. It is important to be aware of the circumstances under which debridement of the mycotic nail may be considered medically necessary and therefore potentially eligible for reimbursement by third-party payers. For many nail presentations, nail debridement is an important component of a treatment protocol involving either the oral medications or the topical lacquer, as it serves to reduce the fungal load and ameliorate symptoms. With the availability of a new FDA-approved topical treatment alternative, it remains to be seen if podiatrists will embrace the definitive treatment of onychomycosis using the newer oral agents, the new nail lacquer, or both in combination with nail debridement to treat the disease.

Historical perspectives on inotropic agents.

Although early experiments in animals and humans suggested that digitalis glycosides increased cardiac output only in the failing heart, later studies showed that these cardiotonic agents increase intraventricular systolic pressure and decrease relaxation time in the normal animal. The controversy concerning the peripheral vascular or direct cardiac effects of digitalis was finally resolved when new methods were applied to the study of the effects of this drug on intraventricular pressures and cardiac contractile force. Other positive inotropic agents, such as the adrenergic agonists, have also been tested for the treatment of heart failure. However, during long-term oral or intravenous therapy, the effectiveness of these drugs appears to diminish. Clinical studies of glucagon, a polypeptide with positive inotropic and chronotropic effects, have revealed its potential for causing side effects and its reduced activity in patients with chronic heart failure. With the discovery of several new types of inotropic agents, i.e., the bipyridines and the imidazole and benzimidazole derivatives, interest in revising our therapeutic approach to congestive heart failure has increased. This review discusses recent developments in this area.