A review of in vitro-in vivo investigations on dendrimers: the novel nanoscopic drug carriers

Dendrimers have emerged as one of the most interesting themes for researchers as a result of their unique architecture and macromolecular characteristics. Several groups are involved in exploring their potential as versatile carriers in drug delivery. The use of dendrimers in drug delivery has been reviewed extensively. The increasing relevance of the potential of dendrimers in drug delivery emphasizes the need to explore the routes by which they can be administered. The present review focuses on dendrimer-mediated drug delivery based on various routes of administration, a topic that has received little attention in the available literature. With this focus in mind, we present a comprehensive exploration of the recent advances in the investigational aspects of these nanoscopic polymeric devices. Also included are some in vitro studies that present data suggestive of their possible application in different routes of administration.     

Targeting opioid receptor heterodimers: Strategies for screening and drug development

G-protein-coupled receptors are a major target for the development of new marketable drugs. A growing number of studies have shown that these receptors could bind to their ligands, signal, and be internalized as dimers. Most of the evidence comes from in vitro studies, but recent studies using animal models support an important role for dimerization in vivo and in human pathologies. It is therefore becoming highly relevant to include dimerization in screening campaigns: the increased complexity reached by the ability to target 2 receptors should lead to the identification of more specific hits that could be developed into drugs with fewer side effects. In this review, we have summarized results from a series of studies characterizing the properties of G-protein-coupled receptor dimers using both in vitro and in vivo systems. Since opioid receptors exist as dimers and heterodimerization modulates their pharmacology, we have used them as a model system to develop strategies for the identification of compounds that will specifically bind and activate opioid receptor heterodimers: such compounds could represent the next generation of pain relievers with decreased side effects, including reduced drug abuse liability.     

Rationalization of physicochemical characters of 1,5-diarylpyrazole analogs as dual (COX-2/LOX-5) inhibitors: a QSAR approach

Arachidonic acid metabolizing enzymes cyclooxygenases and lipoxygenases lead to the formation of various eicosanoids involved in variety of human diseases, like inflammation, fever, pain, rheumatic and osteoarthritis, etc. Non-steroidal anti-inflammatory drugs are useful tools in the treatment of prostaglandin mediated complications. The development of dual inhibitors may prevent a drift of arachidonic acid metabolism towards the other pathway, leading to potential side effects. Hence emphasis was focused on quantification of structure-activity relationship, with a view to delineating the influence of key COX-2/LOX-5 activity, to explore structural insights to aid the designing of safer dual inhibitors. The quantification of the structural features of 1,5-diarylpyrazole analogs with various biological activities gave some important structural insights, i.e. Hy (hydrophilic factor) and Mor17v (3D molecular representation of structure based on electron diffraction code). These two physicochemical properties may be helpful in development of more selective dual COX-2/LOX-5 inhibitors.     

Topical amiloride ointment accelerates healing of mechanical skin ulcers in albino rabbits and patients

The present investigation was undertaken to explore the ulcer-healing property of 1% amiloride ointment on mechanically produced skin ulcers in albino rabbits and at donor site of patients requiring split skin graft. Four skin ulcers measuring 2 X 2 cm(2) (two on either side of the midline) were made 2 cm apart on the pre-shaved back of each anesthetized rabbit up to the depth of subcutaneous tissue. Ulcers on one side of the midline were treated with sterile soft paraffin and served as control, whereas those on the other side were treated with amiloride ointment. Each ulcer was observed for its size, slough formation, and any sign of irritation on alternate days, until healing was complete. Healing of ulcers was significantly (p<0.001) accelerated with amiloride ointment in terms of days required for complete healing, ulcer size, and area under the size-time curve. In each patient, the anterior thigh was used as donor site. Grafts were harvested from midline using Watson's modification of Humby's knife. Each site was divided into proximal and distal halves and was covered with either soft paraffin tulle serving as control or 1% amiloride tulle as test site and then dressed conventionally. Healing was evaluated visually on 10th postoperative day. Healing was significantly accelerated by amiloride tulle in terms of days required for complete healing (p<0.01), better quality of skin regenerated, leading to ease of removal of dressing with less of patient's discomfort, and hence more acceptability (p<0.01). No irritation or suppression of immunity was noticeable. Thus, topical amiloride may prove to be an inexpensive and better ulcer-healing agent with no apparent side effect. Inhibition of urokinase-type plasminogen activator and modulation of field strengths by amiloride seem to be responsible for this effect.     

Practical considerations for carbamazepine use in bipolar disorder

Carbamazepine (CBZ) has a long history of successful use in epilepsy and, therefore, has a safety profile that is well characterised. Additionally, an extended-release formulation of CBZ (CBZ-ERC; Equetro, Shire US) has recently been approved for use in bipolar disorder. The most frequent adverse events associated with CBZ are somnolence, fatigue, dizziness and headache. Rash and leukopoenia may occur in approximately 10% of patients, but are benign and transient in most cases. Rare serious adverse effects include agranulocytosis, aplastic anaemia, Stevens-Johnson syndrome and toxic epidermal necrolysis. Although changes in lipid profiles have been noted, hyperglycaemia does not occur with CBZ, and clinically significant weight gain is uncommon. Proper monitoring and careful titration of the extended-release formulation should allow for successful use of CBZ in psychiatric patients.     

The extent and severity of urinary incontinence amongst women in UK GP waiting rooms

INTRODUCTION: Few women seek help for urinary incontinence. Subsequently, there may be many women accessing primary care services who would benefit from treatment or advice. If high levels of unexpressed need are present in this population, a more proactive approach to continence management may be appropriate, but the feasibility of this depends on an accurate assessment of the level of unmet need in this population. AIM: To assess the prevalence of urinary incontinence in a female population attending primary care and the extent of treatment seeking in relation to level of need. METHODS: A cross-sectional survey of urinary incontinence of adult women attending primary care practices in West Yorkshire, London, Glasgow and Leicestershire during a 10- or 15-day period. RESULTS: Three thousand two hundred and seventy-three (54%) women responded. Twenty-one per cent reported stress urinary incontinence only, 3.5% reported urge incontinence only and 21% reported mixed stress and urge incontinence during the preceding month (9% had moderate or severe symptoms). Fifty-three per cent of these had not consulted a health care professional, which is equivalent to 1 in 20 of women in GP waiting rooms, most of whom have stress and urge incontinence (75%) or stress incontinence only (21%). CONCLUSIONS: Nearly half of female primary care attendees had experienced incontinence during the preceding month, but only a minority had sought help. Even amongst the nearly 1 in 10 women with moderate or severe incontinence only about half had sought help. There remains considerable health decrement due to urinary incontinence in those not receiving help in a population readily accessible to primary care services.     

Assessment of computer game as a psychological stressor

To simulate the effects of acute psychological stress, the effects of stressful computer game in young adult subjects were assessed by various physiological, psychological and biochemical parameters. The results showed a significant increase in the physiological and psychological markers of stress. It is concluded from these results that computer game can be used as an acute laboratory psychological stressor for future studies on physiological effects of stress.     

Isolation, structure elucidation and in vivo hepatoprotective potential of trans-tetracos-15-enoic acid from Indigofera tinctoria Linn

The bioassay guided fractionation of the dried aerial part of Indigofera tinctoria Linn. led to the identification of an active fraction labelled as indigotin. On further chemical analysis, a compound isolated from indigotin was identified and characterized as trans-tetracos-15-enoic acid (TCA). The chemical structure of this compound was established on the basis of physical properties and spectral data, including NMR. It afforded significant hepatoprotection against carbon tetrachloride and paracetamol induced hepatotoxicity in experimental models. Silymarin, a well known plant based hepatoprotective agent, and N-acetylcysteine, which has proven efficacy as a replenisher of sulfhydryls, were used for relative efficacy. TCA was found to reverse the altered hepatic parameters in experimental liver damage. In the safety evaluation study the oral LD50 was found to be more than 2000 mg/kg, with no signs of abnormalities or any mortality for the 15 day period of observation after administration of a single dose of drug in mice. The studies revealed significant and concentration dependent hepatoprotective potential of TCA as it reversed the majority of the altered hepatic parameters in experimental liver damage in rats and mice and may be useful in the management of liver disorders.     

Rational design of the microtubule-targeting anti-breast cancer drug EM015

We studied in silico docking of noscapine onto tubulin, combined with calculations of surface charge, pi-pi, van der Waals, and hydrogen bonding interactions, to rationally design a new compound, EM015. This tubulin-binding semisynthetic compound is a selective and potent anti-breast cancer agent and displays a 20-fold lower IC(50) against many tumor cells compared with our founding compound, (S)-6,7-dimethoxy-3-((R)-4-methoxy-6-methyl-5,6,7,8-tetrahydro[1,3]-dioxolo-[4,5-g]isoquinolin-5-yl)isobenzo-furan-1(3H)-one (noscapine). Furthermore, EM015 is also effective against a variety of drug-resistant cells. Surprisingly, the cell cycle profile of nontumorigenic normal cells is not affected. Many antimicrotubule cancer drugs in clinic today, particularly taxanes and Vincas, face challenges including frequent visits to the hospital for prolonged i.v. infusions, toxicities, and tumor recurrences due to drug resistance. EM015, on the other hand, is orally available, regresses breast tumor xenografts in nude mice models, and increases longevity. Furthermore, we have failed to observe any detectable toxicity in tissues, such as liver, kidney, spleen, lung, heart, and brain, as well as neurons, which are common targets of antimicrotubule drug therapy. Thus, EM015 has a great promise in the clinic.