Is there a need for more precise definitions of bioavailability?

Summary After evaluation of the present definitions in a set of particular cases, it was agreed that there was no need for more precise definitions and that the current ones were adequate in the majority of cases. However, it was felt that the present definitions might be improved, in particular in view of the existence of non-systemically acting drugs and future targeted drugs. Thus, the FDA definition might be modified as follows: Bioavailability means the rate and extent to which the active drug ingredient or therapeutic moiety from a drug product becomes available at the site of drug action or in a biological medium believed to reflect accessibility to a site of action.     

Is there a role for therapeutic drug monitoring of new anticonvulsants?

Despite the fact that all new anticonvulsants have undergone extensive pharmacokinetic scrutiny prior to their introduction to the market, the opportunity to perform good prospective studies on their concentration-effect relationship has been largely missed, in some cases deliberately because therapeutic drug monitoring (TDM) is considered unfavourable for the marketing of a new drug. However, there are reasons to believe that TDM may play a useful role in maximising the therapeutic potential of new anticonvulsants. In fact, these drugs have a narrow therapeutic index, careful individualisation of dosage to optimise response is required, and inter- and intra-individual pharmacokinetic variability may translate into differences in dosage requirements. The wide interindividual variability in the serum concentrations at which therapeutic and toxic effects of these drugs are observed does not necessarily imply that TDM cannot be useful: indeed, a marked pharmacodynamic variability has also been reported for all the currently monitored older anticonvulsants. The new anticonvulsants which, based on their properties, are particularly attractive candidates for TDM include lamotrigine, topiramate, tiagabine, zonisamide and felbamate. However, in the absence on sound information on the target concentration ranges of these drugs, the routine concentration monitoring of these drugs cannot be recommended. Despite this, serial measurements of serum drug concentrations may be useful in selected patients, especially those suspected of poor compliance and those in whom pharmacokinetic changes caused by disease or administration of concomitant medication are anticipated. Even in the presence of marked interindividual pharmacodynamic variability, it is often possible to empirically determine the concentration at which each patient exhibits the best response, and apply that information in subsequent management. Prospective studies, using preferably a randomised concentration-controlled design, are necessary to better characterise concentration-effect relationships for these agents.     

Is there a need for emerging drugs for the acute respiratory distress syndrome?

The acute respiratory distress syndrome (ARDS) is a common and devastating syndrome of acute respiratory failure for which little effective pharmacotherapy exists. The authors describe some interventions that show promise as potential therapies for this condition, with particular reference to clinically relevant human models of ARDS. Aspirin, mesenchymal stromal (stem) cells, keratinocyte growth factor, IFN-β and oncostatin M inhibition are discussed.     

Is there a need for "professional psychotherapy" in methadone programs?

The role of "professional psychotherapy" in methadone programs has been unclear because of its expense as compared to counseling, shortage of trained, experienced personnel, and confusion in the literature as to its efficacy. This research capsule reviews some recent studies pertaining to this and some of the methodological difficulties in arriving at a clear answer. Psychotherapy so far appears most helpful for patients with a defined psychiatric diagnosis in addition to their drug diagnosis. In addition, benefits appear to be greater if patients are treated early in their treatment program.     

Is there a place for duloxetine?

Duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, is licensed in the UK under two brand names for a total of three different indications. It is available as Cymbalta (jointly promoted by Boehringer Ingelheim and Lilly) for the treatment of patients with major depression, or with diabetic peripheral neuropathic pain; and as Yentreve (Lilly) for the treatment of women with "moderate to severe" stress urinary incontinence. Here we consider whether duloxetine has a role in the treatment of patients with any of these conditions.     

Is there a future for renin inhibitors?

Pharmacological interruption of the renin-angiotensin system is possible at three major sites, the angiotensin-converting enzyme (ACE), the AT1 receptor and at the interaction of renin with its substrate, angiotensinogen. Skeggs and his associates in 1957 argued logically but without prognostic accuracy that 'since renin is the initial and rate-limiting substance in the renin-angiotensin system, it would seem that the renin inhibition approach would be the most likely to succeed'. In fact, the development of agents that act at all three levels has enjoyed substantial success, yet renin inhibition, which showed early progress in studies in humans, has languished. Our task in this essay is to review the reasons for the slow evolution of renin inhibition and to discuss the potential of such agents in modern pharmacotherapy. All of the structure-action relationships have involved variation on the original peptide structure. The possibility that alternative approaches based on x-ray crystallography and reconstruction of the structure of the active site would lead to novel agents, appears not to have been explored systematically. This opportunity is all the more attractive because renin is one of the few targets that is actually soluble and amenable to x-ray crystallographic studies. At the moment, it appears that all renin inhibitor development programs have been closed, although hints periodically reappear to indicate that one company or another is pursuing a novel agent. The decision to close programs seems to have reflected not the therapeutic potential of renin inhibitors, but rather the cost of their synthesis, continuing problems with bioavailability and the remarkable success of the competitor class--the AngII antagonists. We believe that the potential of renin inhibition in human therapy has been under estimated and still shows substantial promise.     

Is there a future for direct renin inhibitors?

Importance of the field: The renin-angiotensin-aldosterone system (RAAS) is a key regulator of blood pressure (BP), as well as volume and electrolytes, in both hypertensive and normotensive individuals. Inappropriate activation of the RAAS is important in hypertension-induced cardiovascular disease (CVD) and chronic kidney disease (CKD). Renin is the rate-limiting step in the RAAS cascade, which makes direct renin inhibitors (DRIs) an attractive target for RAAS suppression and treatment of hypertension. Current regimens using either angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) result in feedback upregulation of renin and aldosterone breakthrough, which contribute to incomplete suppression of the RAAS. Thereby, aliskiren – alone or in combination – might offer a novel therapeutic intervention to improve suppression of the RAAS, with potential to translate to improved CVD and CKD outcomes.

Areas covered in this review: Herein, we present the current state of knowledge of DRIs in the preclinical and clinical realm and their antihypertensive efficacy in relation to cardiovascular and renal risk. Recent clinical trials (2007 – 2009) support the efficacy of aliskiren, and studies suggest the potential for improved CVD and CKD outcomes.

What the reader will gain: An understanding of the mechanism of action of DRIs and a perspective of recent clinical trials.

Take home message: The DRI aliskiren is an effective antihypertensive agent that preliminary data suggests has a beneficial effect in CVD and CKD. Combination of aliskiren with an ACEi or ARB may be better tolerated than the ACEi–ARB combination. Future work is needed to further quantify aliskiren's impact on hard CVD and CKD end points.     

Is there a best strategy for drug discovery?

The Society for Medicines Research held a meeting on March 18, 2003, at the National Heart & Lung Institute in London, United Kingdom, to discuss strategies for drug discovery. The meeting began with a history of the origins of drug discovery. Discussions also covered the best strategies for drug discovery, including combinatorial chemistry and high-throughput screening, and ways to meet the challenge of the so-called "innovation gap," among other topics. Speakers included a Nobel Laureate and discoverer of two of the most significant drug classes of the 20th century, and the greatest drug generator of all time. Various companies and institutions were also represented in the talks.     

Acellular pertussis vaccines: new preparation. Better tolerated but less active?

(1) In France SmithKline Beecham market a three-component acellular pertussis vaccine in the form of a tetravalent vaccine and a pentavalent vaccine. Pasteur M/erieux MSD also market in France a two-component acellular pertussis vaccine in the form of a tetravalent vaccine and a pentavalent vaccine. (2) The two pentavalent vaccines are indicated for an early booster injection at age 16-18 months; the two tetravalent vaccines are indicated for a late booster injection at age 11-13 years. (3) The published assessment file on these vaccines is limited. (4) Immunological studies show that the acellular pertussis valency does not reduce the antigenicity of the valencies with which it is combined (diphtheria, tetanus and poliomyelitis), although there is some doubt regarding the Haemophilus influenzae tybe b valency. (5) In the absence of direct comparisons with the cellular pertussis vaccine available in France in tetravalent or pentavalent vaccines, indirect evidence and data from a trial comparing the acellular two-component vaccine with the cellular vaccine (Vaxicoq degrees ) marketed in France (combined with diphtheria and tetanus valencies) suggest that clinical protection is slightly lower after primary vaccination with the two acellular vaccines. (6) In children, acellular pertussis vaccines are globally better tolerated than the cellular pertussis vaccine. (7) In adolescents, a small study has shown that the three-antigen acellular pertussis vaccine is relatively well tolerated. But the acellular vaccine was released too recently onto the international market to know the precise incidence of rare and severe adverse effects. (8) The new French vaccination schedule for pertussis now includes a booster between 11 and 13 years. Only long-term epidemiological follow-up can show if routine vaccination of adolescents against pertussis will have an impact on the incidence of pertussis in infants and adults. (9) The incidence of Haemophilus b meningitis must continue to be monitored.