Successful management of deep facial burns in a patient with extensive third-degree burns: the role of a nanocrystalline silver dressing in facilitating resurfacing

Full-thickness burns of the face are notoriously difficult to repair and their management poses a series of problems to the surgeon. We present the case of a 49-year-old man (only survivor of a catastrophic airport accident) with third-degree flame burns to >80% of total body surface area and extensive face damage who achieved a fully satisfactory outcome after a treatment plan based on gradual escharectomy followed by application of artificial dermis and, later, grafting with sheets of cultured keratinocytes. Re-epithelialisation was already visible at day 16 after admission and all facial wounds were closed by day 56, the treatment continuing on the scalp. Within 6 months of the accident, the patient had recovered functional and cosmetic features (including re-growth of skin appendages) that were beyond expectations. The use of nanocrystalline silver-coated dressings during the escharectomy and resurfacing phases was important, as part of a multifaceted strategy, in ensuring excellent antimicrobial control, thus avoiding the need for autologous grafting and contributing to a rapid healing and complete restoration of the face and head skin.     

Pharmacokinetics and distribution of clioquinol in golden hamsters

Clioquinol (5-chloro-7-iodo-8-quinolinol) is a zinc and copper chelator that can dissolve amyloid deposits and may be beneficial in Alzheimer's disease. Prion diseases are also degenerative CNS disorders characterised by amyloid deposits. The pharmacokinetics and tissue distribution of drugs active against prions may clarify their targets of action. We describe the pharmacokinetics of clioquinol in hamster plasma, spleen and brain after single and repeated oral or intraperitoneal administration (50 mg kg(-1)), as well as after administration with the diet. A single intraperitoneal administration led to peak plasma clioquinol concentrations after 15 min (Tmax), followed by a decay with an apparent half-life of 2.20 +/- 1.1 h. After oral administration, Tmax was reached after 30 min and was followed by a similar process of decay; the AUC(0-last) was 16% that recorded after intraperitoneal administration. The Cmax and AUC values in spleen after a single administration were about 65% (i.p.) and 25% (p.o.) those observed in blood; those in liver were 35% (p.o.) those observed in blood and those in brain were 20% (i.p.) and 10% (p.o.) those observed in plasma. After repeated oral doses, the plasma, brain and spleen concentrations were similar to those observed at the same times after a single dose. One hour after intraperitoneal dosing, clioquinol was also found in the ventricular CSF. Clioquinol was also given with the diet; its morning and afternoon concentrations were similar, and matched those after oral administration. No toxicity was found after chronic administration. Our results indicate that clioquinol, after oral administration with the diet, reaches concentrations in brain and peripheral tissues (particularly spleen) that can be considered effective in preventing prion accumulation, but are at least ten times lower than those likely to cause toxicity.     

NMR structural studies of the supramolecular adducts between a liver cytosolic bile acid binding protein and gadolinium(III)-chelates bearing bile acids residues: molecular determinants of the binding of a hepatospecific magnetic resonance imaging contrast agent

The binding affinities of a selected series of Gd(III) chelates bearing bile acid residues, potential hepatospecific MRI contrast agents, to a liver cytosolic bile acid transporter, have been determined through relaxivity measurements. The Ln(III) complexes of compound 1 were selected for further NMR structural analysis aimed at assessing the molecular determinants of binding. A number of NMR experiments have been carried out on the bile acid-like adduct, using both diamagnetic Y(III) and paramagnetic Gd(III) complexes, bound to a liver bile acid binding protein. The identified protein "hot spots" defined a single binding site located at the protein portal region. The presented findings will serve in a medicinal chemistry approach for the design of hepatocytes-selective gadolinium chelates for liver malignancies detection.     

Clinical pharmacokinetics of atypical antipsychotics: a critical review of the relationship between plasma concentrations and clinical response

In the past, the information about the dose-clinical effectiveness of typical antipsychotics was not complete and this led to the risk of extrapyramidal adverse effects. This, together with the intention of improving patients' quality of life and therapeutic compliance, resulted in the development of atypical or second-generation antipsychotics (SGAs). This review will concentrate on the pharmacokinetics and metabolism of clozapine, risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, aripiprazole and sertindole, and will discuss the main aspects of their pharmacodynamics. In psychopharmacology, therapeutic drug monitoring studies have generally concentrated on controlling compliance and avoiding adverse effects by keeping long-term exposure to the minimal effective blood concentration. The rationale for using therapeutic drug monitoring in relation to SGAs is still a matter of debate, but there is growing evidence that it can improve efficacy, especially when patients do not respond to therapeutic doses or when they develop adverse effects. Here, we review the literature concerning the relationships between plasma concentrations of SGAs and clinical responses by dividing the studies on the basis of the length of their observation periods. Studies with clozapine evidenced a positive relationship between plasma concentrations and clinical response, with a threshold of 350-420 ng/mL associated with good clinical response. The usefulness of therapeutic drug monitoring is well established because high plasma concentrations of clozapine can increase the risk of epileptic seizures. Plasma clozapine concentrations seem to be influenced by many factors such as altered cytochrome P450 1A4 activity, age, sex and smoking. The pharmacological effects of risperidone depend on the sum of the plasma concentrations of risperidone and its 9-hydroxyrisperidone metabolite, so monitoring the plasma concentrations of the parent compound alone can lead to erroneous interpretations. Despite a large variability in plasma drug concentrations, the lack of studies using fixed dosages, and discrepancies in the results, it seems that monitoring the plasma concentrations of the active moiety may be useful. However, no therapeutic plasma concentration range for risperidone has yet been clearly established. A plasma threshold concentration for parkinsonian side effects has been found to be 74 ng/mL. Moreover, therapeutic drug monitoring may be particularly useful in the switch between the oral and the long-acting injectable form. The reviewed studies on olanzapine strongly indicate a relationship between clinical outcomes and plasma concentrations. Olanzapine therapeutic drug monitoring can be considered very useful in assessing therapeutic efficacy and controlling adverse events. A therapeutic range of 20-50 ng/mL has been found. There is little evidence in favour of the existence of a relationship between plasma quetiapine concentrations and clinical responses, and an optimal therapeutic range has not been identified. Positron emission tomography studies of receptor blockade indicated a discrepancy between the time course of receptor occupancy and plasma quetiapine concentrations. The value of quetiapine plasma concentration monitoring in clinical practice is still controversial. Preliminary data suggested that a therapeutic plasma amisulpride concentration of 367 ng/mL was associated with clinical improvement. A therapeutic range of 100-400 ng/mL is proposed from non-systematic clinical experience. There is no direct evidence concerning optimal plasma concentration ranges of ziprasidone, aripiprazole or sertindole.     

Determining therapeutic approaches in the elderly with rectal cancer

BACKGROUND: To evaluate the toxicity and feasibility of pelvic radiotherapy (RT) and/or surgery in elderly patients with locally advanced low-lying rectal cancer. PATIENTS AND METHODS: From November 1999 to November 2005, 51 patients aged >or=70 years who underwent RT for locally advanced low-lying rectal cancer were retrospectively examined. Variables considered were age, co-morbidities (evaluated according to the Charlson score and the Cumulative Illness Rating Scale-Geriatric [CIRS-G] score) and surgery versus no surgery. RESULTS: The median age was 80 years (range 70-94 years) and the male : female ratio was 33 : 18. A total of 5.9% of patients were considered 'fit', 72.5% had one or more CIRS-G grade 1 or 2 co-morbidities and 21.6% had one or more CIRS-G grade 3 co-morbidities. 54.9% of patients underwent surgery and 45.1% underwent RT. Only 9 of 21 (42.8%) patients who underwent radical resection received the full course of adjuvant RT and only seven (50%) of all patients treated with RT alone received the full dose of therapy. Patients with one or more CIRS-G grade 3 co-morbidities reported similar numbers of grade 1-2 toxicities as patients with one or more CIRS-G grade 2 co-morbidities. CONCLUSION: Notwithstanding the small number of patients analysed, the findings of this study indicate that elderly patients with rectal cancer and mild co-morbidities could probably receive the same treatment as fit elderly patients, given that tolerability appeared to be similar in both categories of patients. Neither age nor co-morbidities should be considered reasons to deny the patient the possible benefits of receiving complete treatment. Moreover, Multidimensional Geriatric Assessment should always be undertaken to help clinicians make better decisions about treatment. Further prospective trials are needed to confirm these results.     

The use of escitalopram beyond major depression: pharmacological aspects, efficacy and tolerability in anxiety disorders

Escitalopram, the active (S)-enantiomer of citalopram, has been approved in many countries throughout the world for the treatment of depression and anxiety disorders. It is more potent and selective than citalopram in inhibiting serotonin re-uptake in the CNS, and less potent than various other selective serotonin re-uptake inhibitors in relation to other transporter proteins and receptors: in particular, it is six times less potent than citalopram in binding to the histamine H1 and muscarinic receptors. Escitalopram has favourable pharmacokinetics: it is rapidly absorbed, has a bioavailability of 80% and is not affected by food intake. It has little potential for drug interactions: it has low protein binding and, as it is metabolised by three CYP isozymes, any impairment in the activity of one is unlikely to have a significant effect on metabolic clearance. Caution is necessary only when it is coadministered with drugs metabolised by CYP2D6, such as metoprolol, or administered to the elderly or patients with severe hepatic or renal impairment. The multiple-dose pharmacokinetics of oral escitalopram are proportional at a range of doses including its therapeutic doses. Escitalopram is approved for the treatment of a number of anxiety disorders. It seems to be well tolerated and induces few or no discontinuation symptoms, and may be considered a first-line agent for the pharmacotherapy of obsessive-compulsive disorder, generalised anxiety disorder, panic disorder and social phobia. Further studies are needed to define its activity in impulse control disorders.     

Topical antiinflammatory activity of an innovative aqueous formulation of actichelated propolis vs two commercial propolis formulations

A novel aqueous commercial formulation of a new hydrophilic propolis product (Actichelated((R)) Propolis, contained in 'LeniGola PropolEffect Spray Senza Alcohol'; Pharbenia, Milan, Italy) was evaluated for its topical antiinflammatory activity in comparison with a hydroglyceric propolis spray solution ('Propoli LeniGola Spray Senza Alcool'; Pharbenia, Milan, Italy) and a hydroalcohol preparation ('Propoli LeniGola Spray Forte'; Pharbenia, Milan, Italy). Actichelated propolis (Actimex, Trieste, Italy) is a multicomposite material obtained with a patented technology, mechano-chemical activation, which application led to a new hydrosoluble form of propolis. Each propolis preparation provoked a dose-dependent inhibition of the croton oil-induced ear oedema in mice. Considering the administered doses of flavonoids, 'LeniGola PropolEffect Spray Senza Alcool' (ID(50) = 13.6 microL/cm(2), corresponding to 13.6 microg flavonoids/cm(2)) is slightly more active than the hydroglyceric formulation 'Propoli LeniGola Spray' (ID(50) = 13.7 microL/cm(2), corresponding to 20.6 microg flavonoids/cm(2)) and six times more active than the hydroalcohol preparation 'Propoli LeniGola Spray Forte' (ID(50) = 5.5 microL/cm(2), corresponding to 82.5 microg flavonoids/cm(2)). As a reference, 15 microL/cm(2) of the commercial sprays Tantum Verde and Froben, containing 37.5 or 45 microg of the non-steroidal antiinflammatory drugs benzidamine hydrochloride or flurbiprofen, induced 18% and 35% oedema inhibition, respectively.     

Analysis of therapeutic benefits of antivenin at different time intervals after experimental envenomation in rabbits by venom of the brown spider (Loxosceles intermedia)

Bites by the brown spider (Loxosceles spp.) are an important health problem in South America, where three species predominate (Loxosceles laeta, Loxosceles gaucho, Loxosceles intermedia). Brown spider bites (loxoscelism) induce a block of cutaneous necrosis and, less commonly, may cause fatal systemic poisoning. A variety of controversial protocols are used to treat loxoscelism, while treatment with antivenin is the only venom specific treatment.Here we studied the action of the venom as well as the response to the antivenin for Loxosceles through an experimental study that simulates bites of L. intermedia (bites of this species are the most common in Brazil). Beneficial effects are known for antivenin applied quickly (within 4 h) after envenomation. Here we wished to examine the temporal development of the brown spider bite as well as the temporal patterns of the action of the antivenin to determine the time limits for beneficial use of the antivenin after envenomation. This information is important since most patients only appear for treatment several hours after being bitten.New Zealand rabbits were experimentally exposed to the venom from brown spiders by the injection of venom from L. intermedia (2× minimum necrotic dose), followed at regular time intervals by antivenin. The use of the loxoscelic antivenin - CPPI (4 mL per animal) - minimized the effects of envenomation when applied for up to 12 h after the injection of the venom, as evaluated by cutaneous (erythrema, edema, ecchymosis and necrosis) and systemic (blood cell and platelet counts, hematimetrics and fibrinogen dosage) criteria. Also, antivenin reduced the size of the necrotic area when applied up to 48 h after envenomation. Thus, therapy with loxoscelic antivenin, CPPI, may provide beneficial results by interfering with envenomation well after the bite occurred and therefore may become an important tool for medical treatment of brown spider bites.