Phonophoresisis it a reality?

Phonophoresis - the application of ultrasound to enhance percutaneous drug delivery - has been administered by physiotherapists for over 30 years. However, since the treatment has been conducted on a highly subjective and non-quantitative basis, no clear consensus exists on the effectiveness of the technique nor on the nature of the phonophoretic mechanism. Ultrasonic energy can perturb mammalian tissue via its heating, radiation pressure, cavitation and acoustic microstreaming effects and each of these is discussed in turn in relation to topical drug delivery. Evidence from the literature is reviewed from the separate perspectives of in vitro research, animal studies and human volunteer trials. It may be concluded that phonophoresis is indeed a reality for certain molecules under certain conditions and that ultrasonic heating is its main though not exclusive mechanism of action. However, at present the therapeutic value of the technique is still under question.     

Transfollicular drug delivery--is it a reality?

Once regarded as merely evolutionary remnants, the hair follicles and sebaceous glands are increasingly recognised as potentially significant elements in the percutaneous drug delivery paradigm. Interest in pilosebaceous units has been directed towards their use as depots for localised therapy, particularly for the treatment of follicle-related disorders such as acne or the alopecias. Furthermore, considerable attention has also been focused on exploiting the follicles as transport shunts for systemic drug delivery. This paper reviews various key facets of this field including; relevant aspects of pilosebaceous anatomy and physiology, the design and efficacy of follicle-targeting formulations and the emergence of quantitative modeling systems. Several novel developments in this area promise to greatly expand our understanding of this field in the near future.     

Social functioning: should it become an endpoint in trials of antidepressants?

DSM-IV has recommended use of the Social and Occupational Functioning Scale (SOFAS) as a clinician-rated global assessment scale for measuring social functioning; this scale is analogous to the Clinical Global Impression (CGI) scale traditionally used as a secondary outcome measure in patients with depressive symptoms. However, we believe that health-related quality of life is the most appropriate indicator of social functioning when considering this dimension as an endpoint in clinical trials of antidepressants. As health-related quality of life is a purely subjective measure, patient-rated questionnaires have been found to be most important in this context. In this respect, the Sheehan Disability Scale has been recommended as the most relevant global self-reported assessment of social functioning in trials of antidepressants.A review of questionnaires found that the three most frequently used scales selectively directed at obtaining information about social functioning in trials of antidepressants are the Social Adjustment Scale - Self Report (SAS-SR), the Social Adaptation Self-Evaluation Scale (SASS) and the Short-Form Health Survey (SF-36). However, the number of placebo-controlled trials of antidepressants that have used these scales is still too limited to allow comparisons in terms of responsiveness.Health-related quality of life includes dimensions other than social functioning, e.g. physical health and mental health (including both cognitive and affective problems). The SF-36 includes subscales relating to physical and mental health, which, like the social functioning subscales, are measured in terms of degrees of well being. Another quality-of-life questionnaire, the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), covers social, mental and physical problems, in this case measured in terms of degrees of satisfaction. Recently, the Q-LES-Q has been reduced from a comprehensive scale including 60-92 items to a brief version including 15 items. An additional item measures overall life satisfaction. As most of the items in the brief Q-LES-Q include social functioning, the scale can be considered as an alternative to SF-36 or the Sheehan Disability Scale when the focus is on satisfaction with treatment. However, there are insufficient numbers of trials of antidepressants using these questionnaires to allow comparisons.The examples of trials of antidepressants with the SF-36 subscales discussed in this review have mostly involved SSRIs. These trials have demonstrated that although antidepressants improve social functioning compared with placebo over a 6-week treatment period, the endpoint scores are still significantly below the national norms at this point. Only after 12 weeks of therapy are the endpoint scores of the social functioning scales within the limits of the national norms. In relapse prevention trials or in maintenance trials to prevent recurrence of depression, comparisons of social functioning scores with national norms can be important supplementary indicators of the need for treatment.In conclusion, social functioning as part of the health-related concept of the patient-reported quality-of-life measure should constitute an endpoint in trials of antidepressants to help clarify the goals of treatment in patients with major depression. In medium- and long-term trials, SF-36 subscales should be used as a supplement to symptom-orientated scales. In trials of shorter (6-8 weeks) duration, use of other scales such as the SAS-SR, the Q-LES-Q or the Sheehan Disability Scale should be considered. These scales should be considered as supplementary to each other rather than alternatives; it may be necessary to use more than one of these scales in a trial.     

Lignin for pharmaceutical and biomedical applications – Could this become a reality?

Lignin is an aromatic biopolymer and a primary component of the cell walls in lignocellulosic biomass, where it constitutes between 15 and 40% of its dry mass. This percentage can vary, not only among plant species, but also among different cell types. Currently, the pulping and biorefinery industries worldwide extract large amounts of lignin, which is mostly combusted to generate the power needed to productively transform the lignocellulosic biomass. The specific composition and structure of this technical lignin depends on its botanical origin and on the extraction method applied. In general, however, lignin possesses antioxidant and antimicrobial properties, UV-absorbing capabilities, biocompatibility and low cytotoxicity. Moreover, lignin can increase the mechanical strength of numerous processed biomaterials. Accordingly, lignin is a promising aromatic raw material for the pharmaceutical and biomedical field. This work discusses the recent advances in the valorisation of lignin through the development of drug and gene delivery systems, wound dressings, tissue engineering or sunscreen actives. Finally, a brief overview on the current challenges and opportunities for making lignin-based products for pharmaceutical and medical applications a reality is also discussed.     

Neutral endopeptidase inhibition: could it have a role in the treatment of female sexual arousal disorder?

Female sexual arousal disorder (FSAD) is the inability to attain or maintain an adequate lubrication-swelling response of sexual excitement. The potentiation of vascular responses leading to increased blood flow in clitoris and vagina has represented the main focus in the pharmacological treatment of FSAD, including the evaluation of the type 5 phosphodiesterase (PDE5) inhibitors. However, due to a lack of clear efficacy, there is no approved pharmacotherapy for FSAD to date. In the present issue of the British Journal of Pharmacology, Wayman et al. show that the administration by intravenous or intravaginal routes of a novel neutral endopeptidase inhibitor, UK-414,445, results in enhanced genital blood flow responses to pelvic nerve stimulation in female rabbits, without significantly affecting blood pressure. Neutral endopeptidase inhibition, by preserving vasoactive peptides such as vasoactive intestinal polypeptide, raises the possibility of a new pharmacological approach to the treatment of FSAD.This article is a commentary on Wayman et al., pp. 51–59 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2010.00691.x     

The cost of asthma: can it be reduced?

Asthma is a major public health problem in developed countries, where it consumes a large and increasing share of scarce health resources. Ideally, medical management should be both optimal in terms of improving the patient's quality of life, and cost-effective for society. At present, there is very little information relating to costs and economic efficiency of current asthma management. Although the true total cost of asthma is unknown, current estimates suggest it is high. The main value of recent total cost estimates is that they identify the most expensive areas of asthma costs, and ideally, formal cost-effectiveness analyses should be concentrated on these areas. Asthma is still under- or inappropriately diagnosed, and undertreated. Several national and international consensus plans for the optimal management of asthma in children and adults have been published. If these inadequacies in asthma management were corrected, using current treatment recommendations, the overall cost of asthma from both the community and patient perspective should fall. The situation requires increased use of preventative medications {sodium cromoglycate (cromolyn sodium) or inhaled corticosteroids}, more widespread use of written crisis plans, more proactive medical consultations (rather than reactive or urgent consultations), further expansion of asthma education programmes, and further education of medical practitioners about the optimum management of both long term asthma and the acute exacerbation of asthma in the patient's home, the doctor's office, the hospital emergency room and the hospital inpatient setting. The increased costs associated with these measures would be more than offset by reduced expenditure on bronchodilator drugs, less widespread use of nebulisers at home and in hospitals, reduced antibiotic usage, reduced need for expensive emergency medical care and particularly reduced utilisation of hospital resources. To ensure that resources are being directed into the most cost-effective areas of asthma care, clinical trials of asthma should include utilisation of healthcare resources as an outcome measure, and estimates of the costs of the treatment under study. In addition, since the intangible cost (quality of life) is one of the most important effects of treatment from the patient's perspective, this should be more widely used as an outcome measure in clinical trials. Ultimately, prevention of asthma is the long term goal. If the hypothesis that sensitisation to house dust mite in early infancy is a major contributor to the subsequent development of asthma, then prevention may require drastic and expensive changes to current housing.     

The co-dependency concept: Does it offer a solution for the spouses of alcoholics?

The popularity of the co-dependency concept has grown rapidly in the alcoholism treatment field. At the same time, empirical findings gained through scientific research have raised questions concerning the validity of the concept. This paper discusses some of the problems that are created by the disease model of co-dependency and highlights some alternatives views that may be more appropriate. It is argued that the field's understanding of the alcoholic/spouse relationship and its ability to help the spouse are limited unless other conceptualizations are seriously considered.     

The Choice of Proton Pump Inhibitor: Does it matter?

Proton pump inhibitors are used at different dosages for the treatment of acid-related gastrointestinal disorders, such as gastro-oesophaeal reflux and peptic ulcer disease. Comparisons of four different proton pump inhibitors: lansoprazole, omeprazole, pantoprazole, and rabeprazole show that they all have similar potency and efficacy. Rabeprazole, however, displays a slightly more rapid onset of acid inhibition than the others; the clinical advantage of this seems limited. The S-isomer of omeprazole, esomeprazole, exhibits a somewhat higher potency than the other proton pump inhibitors. Reports supporting a clinical advantage of this property are not convincing. To conclude, all inhibitors seem comparable as regards inhibition of gastric acid secretion.     

Gene directed enzyme prodrug therapy for ovarian cancer: could GDEPT become a promising treatment against ovarian cancer?

Gene-directed enzyme prodrug therapy (GDEPT) involves the treatment concept of having maximal efficacy and minimal adverse effects. Several GDEPT strategies have been developed combining cytosine deaminase and 5-fluorocytosine, cytochrome P450 2B1 and cyclophosphamide, and carboxylesterase (CES) and irinotecan in experimental models. The active forms of these prodrugs, however, are not a frontline therapy for the treatment of ovarian cancer. It would be beneficial to develop a more effective prodrug-enzyme combination for the treatment of this disease. Paclitaxel (Taxol; TAX) is currently one of the most important anti-cancer drugs in chemotherapy of ovarian cancer. One of TAX prodrugs, 2'-ethylcarbonate-linked paclitaxel (TAX-2'-Et), was generated and examined regarding its pharmacological aspects. The prodrug of TAX-2'-Et converts into active form TAX by carboxylesterase (CES). TAX-2'-Et did not exhibit polarized transport in the Caco-2 cells expressing P-glycoprotein (P-gp) in the absence or presence of verapamil which is a inhibitor of P-gp, suggesting that TAX-2'-Et is not a target of P-gp like TAX and rhodamine123. Moreover, SKOV3/TAX60 cells which are overexpressing P-gp did not also exhibit any change in cellular uptake of TAX-2'-Et regardless of the absence or presence of verapamil. Consequently, the uptake of TAX-2'-Et into the TAX-resistant cells was quantitatively similar to that internalized in the parental SKOV3 cells which are P-gp-negative. In the CES-transfected SKOV3 cells, the EC50 value of TAX (10.6 nM) was approximately 4-fold higher than that of TAX-2'-Et (2.5 nM). We herein provide evidence that TAX-2'-Et could circumvent P-gp-associated cellular efflux of TAX, suggesting that this combination therapy is a potential GDEPT strategy for ovarian cancer in the future. Finally, this review focuses on the development, application and potential of various GDEPTs for treating ovarian cancer, and the scope and progress of new GDEPTs are discussed.     

Gene medicines: the end of the beginning?

First-generation gene medicines and genetic vaccines represent a promising new class of therapeutics that have the potential to prevent, correct, or modulate genetic or acquired diseases. The rational design of synthetic gene delivery and expression systems continues to be essential to enable the precise temporal and spatial control of transgene expression in vivo. With the tantalizing efficacy results and outstanding safety profile observed with nonviral, plasmid-based product candidates in early clinical trials, a multidisciplinary approach remains critical to further improve the effectiveness, reduce the manufacturing costs, and maintain the safety of gene therapeutics and vaccines for their successful development. This commentary provides an historical perspective on somatic gene therapy and briefly addresses the rate-limiting steps in effective gene transfer and expression. The importance of understanding plasmid pharmacokinetics after administration by conventional routes in animal models and in humans is emphasized. Pharmaceutical scientists have a pivotal role to play in deciphering the key biological parameters to effective gene transfer and designing gene delivery systems that will enable plasmid-based products to become an integral part of the future medical armamentarium.     

The Green Prescription: a field of dreams?

Increasing the physical activity of New Zealanders has assumed a higher priority with new primary healthcare strategies. Physical Educators, the professionals who research, teach and practise in the domain of physical activity and exercise, have raised concerns regarding the strategies employed. This essay details several misgivings with public health initiatives designed to increase physical activity, and makes a case for recognising the expertise of graduates specifically trained in this specialist field. A system of referral to accredited exercise professionals is suggested to be a more efficacious means of changing physical activity behaviours.     

The threat represented by toxins: myth or reality?

The reasons underlying our fear of the use of toxins as new weapons different from chemical agents are discussed together with the conditions required for their use on the battlefield. The undeniable scientific contribution of toxins as pharmacological tools for the study of neurosciences and disease genesis and their prophylaxis is emphasized. In conclusion, the threat for mankind constituted by proliferation of this novel class of agents is stressed.     

Superior efficacy of new medicines?

Purpose  

To provide an overview of and discuss newly authorised medicines with an improved efficacy.