Polycarboxylates enhance beetle antifreeze protein activity

Antifreeze proteins (AFPs) lower the noncolligative freezing point of water in the presence of ice below the ice melting point. The temperature difference between the melting point and the noncolligative freezing point is termed thermal hysteresis (TH). The magnitude of the TH depends on the specific activity and the concentration of AFP, and the concentration of enhancers in the solution. Known enhancers are certain low molecular mass molecules and proteins. Here, we investigated a series of polycarboxylates that enhance the TH activity of an AFP from the beetle Dendroides canadensis (DAFP) using differential scanning calorimetry (DSC). Triethylenetetramine-N,N,N',N',N',N'-hexaacetate, the most efficient enhancer identified in this work, can increase the TH of DAFP by nearly 1.5 fold over than that of the published best enhancer, citrate. The Zn(2+) coordinated carboxylate results in loss of the enhancement ability of the carboxylate on antifreeze activity. There is not an additional increase in TH when a weaker enhancer is added to a stronger enhancer solution. These observations suggest that the more carboxylate groups per enhancer molecule the better the efficiency of the enhancer and that the freedom of motion of these molecules is necessary for them to serve as enhancers for AFP. The hydroxyl groups in the enhancer molecules can also positively affect their TH enhancement efficiency, though not as strongly as carboxylate groups. Mechanisms are discussed.     

Facilitation of AMPA receptor synaptic delivery as a molecular mechanism for cognitive enhancement

Cell adhesion molecules and downstream growth factor-dependent signaling are critical for brain development and synaptic plasticity, and they have been linked to cognitive function in adult animals. We have previously developed a mimetic peptide (FGL) from the neural cell adhesion molecule (NCAM) that enhances spatial learning and memory in rats. We have now investigated the cellular and molecular basis of this cognitive enhancement, using biochemical, morphological, electrophysiological, and behavioral analyses. We have found that FGL triggers a long-lasting enhancement of synaptic transmission in hippocampal CA1 neurons. This effect is mediated by a facilitated synaptic delivery of AMPA receptors, which is accompanied by enhanced NMDA receptor-dependent long-term potentiation (LTP). Both LTP and cognitive enhancement are mediated by an initial PKC activation, which is followed by persistent CaMKII activation. These results provide a mechanistic link between facilitation of AMPA receptor synaptic delivery and improved hippocampal-dependent learning, induced by a pharmacological cognitive enhancer.     

<Emphasis Type="Italic">In vitro</Emphasis> Enhancement of Lactate Esters on the Percutaneous Penetration of Drugs with Different Lipophilicity

Lactate esters are widely used as food additives, perfume materials, medicine additives, and personal care products. The objective of this work was to investigate the effect of a series of lactate esters as penetration enhancers on the in vitro skin permeation of four drugs with different physicochemical properties, including ibuprofen, salicylic acid, dexamethasone and 5-fluorouracil. The saturated donor solutions of the evaluated drugs in propylene glycol were used in order to keep a constant driving force with maximum thermodynamic activity. The permeability coefficient (K _p), skin concentration of drugs (SC), and lag time (T), as well as the enhancement ratios for K _p and SC were recorded. All results indicated that lactate esters can exert a significant influence on the transdermal delivery of the model drugs and there is a structure-activity relationship between the tested lactate esters and their enhancement effects. The results also suggested that the lactate esters with the chain length of fatty alcohol moieties of 10–12 are more effective enhancers. Furthermore, the enhancement effect of lactate esters increases with a decrease of the drug lipophilicity, which suggests that they may be more efficient at enhancing the penetration of hydrophilic drugs than lipophilic drugs. The influence of the concentration of lactate esters was evaluated and the optimal concentration is in the range of 5∼10 wt.%. In sum, lactate esters as a penetration enhancer for some drugs are of interest for transdermal administration when the safety of penetration enhancers is a prime consideration.     

The impact of neuroscience on society: cognitive enhancement in neuropsychiatric disorders and in healthy people

In addition to causing distress and disability to the individual, neuropsychiatric disorders are also extremely expensive to society and governments. These disorders are both common and debilitating and impact on cognition, functionality and wellbeing. Cognitive enhancing drugs, such as cholinesterase inhibitors and methylphenidate, are used to treat cognitive dysfunction in Alzheimer''s disease and attention deficit hyperactivity disorder, respectively. Other cognitive enhancers include specific computerized cognitive training and devices. An example of a novel form of cognitive enhancement using the technological advancement of a game on an iPad that also acts to increase motivation is presented. Cognitive enhancing drugs, such as methylphenidate and modafinil, which were developed as treatments, are increasingly being used by healthy people. Modafinil not only affects ‘cold’ cognition, but also improves ‘hot’ cognition, such as emotion recognition and task-related motivation. The lifestyle use of ‘smart drugs'' raises both safety concerns as well as ethical issues, including coercion and increasing disparity in society. As a society, we need to consider which forms of cognitive enhancement (e.g. pharmacological, exercise, lifelong learning) are acceptable and for which groups (e.g. military, doctors) under what conditions (e.g. war, shift work) and by what methods we would wish to improve and flourish.     

Transbuccal Delivery of 5-Fluorouracil: Permeation Enhancement and Pharmacokinetic Study

The purpose of this study was to determine the effect of permeation enhancers on the transbuccal delivery of 5-fluorouracil (FU). The effect of permeation enhancers on in vitro buccal permeability was assessed using sodium deoxycholate (SDC), sodium dodecyl sulphate (SDS), sodium tauroglycocholate (STGC), and oleic acid and their concentrations for absorption enhancement were optimized. STGC appeared to be most effective for enhancing the buccal permeation of FU than the other enhancers. These enhancements by STGC were statistically significant (p < 0.05) compared to control. The order of permeation enhancement was STGC > SDS > SDC > oleic acid. Histological investigations were performed on buccal mucosa and indicated no major morphological changes. The enhancing effect of STGC on the buccal absorption of FU was evaluated from the mucoadhesive gels in rabbits. The absolute bioavailability of FU from mucoadhesive gels containing STGC increased 1.6-fold as compared to the gels containing no permeation enhancer. The mean residence time and mean absorption time considerably increased following administration of gel containing penetration enhancer compared with the gel without penetration enhancer.     

Lipoplasty claims experience of U.S. insurance companies

An analysis of medical liability claims for lipoplasty (liposuction) from January of 1985 through June of 1998 compared the insurance industry experience of plastic surgeons with that of other physicians. The Data Sharing Project database of the Physician Insurers Association of America, a trade association of professional liability companies owned and operated by medical professionals that collectively insure approximately 60 percent of America's private practice physicians, was queried. Of the nearly 45,000 total entries in the database, 292 were claims for adverse events related to lipoplasty or liposuction. These raw data were stratified by physician specialty, severity of complication, practice location, patient gender, indemnity payment, and other insurance industry-relevant variables.To simplify interspecialty comparisons, we normalized the claims rate to incidents per 100 insured physicians. The indexed lipoplasty claims rate was 3.0 per 100 insured plastic surgeons and 4.1 for other surgeons; the indexed lipoplasty claims rate for nonsurgical specialists was 2.5 per 100 insured dermatologists and 2.3 for other nonsurgeons. The higher claims rate for surgeons most likely reflects the wider scope of full-service aesthetic surgery performed by surgical specialists. Nearly two-thirds of claims (65.4 percent) during the 13-year survey period were the result of hospital-based lipoplasty; 20.9 percent were office-based claims. The prevalence of hospital-based claims may be a consequence of both historical bias introduced by hospital-based specialty surgery in the early years and prudent patient safety considerations during performance of complex or prolonged procedures in more recent years.Two-thirds of the claims (67 percent) arose from informed-consent or breach-of-contract issues, far higher than the 26 percent aggregate claims norm. The mean indemnity payment was $94,534 per lipoplasty claim; claims paid against board-certified specialists averaged $83,350. Consistent with national lipoplasty demographics, 87 percent of claims were brought by women and 13 percent were brought by men. Seven fatalities (three women and four men) were noted; cause of death is not recorded in this type of database.     

Hormone replacement therapy: a survey of Ontario physicians' prescribing practices

BACKGROUND: Although much has been written about hormone replacement therapy (HRT), there are few clearcut recommendations on its use. The purpose of this study was to determine Ontario physicians'' patterns of and reasons for prescribing HRT, their use of pretreatment investigations and their surveillance of HRT users, and to determine whether physicians'' reported practice is consistent with existing recommendations. METHODS: A self-administered questionnaire was mailed to a nonproportional stratified sample of 327 Ontario physicians (23.9% gynecologists, 76.1% general practitioners/family physicians [GP/FPs]). Outcome measures were ranking of reasons for prescribing HRT, nature of preliminary testing, regimens prescribed, duration of HRT and frequency of follow-up. RESULTS: The response rate was 60.9% overall (70.9% of the gynecologists, 58.3% of the GP/FPs). Prevention of osteoporosis was reported by 97.4% as an important or very important reason for prescribing HRT; prevention of coronary artery disease was important or very important for 89.3%. When considering whether or not to prescribe HRT, 97.3% stated that breast cancer was an important or very important factor. When presented with hypothetical cases, 97.0% stated that they would prescribe combined estrogen-progestin for a symptomatic woman with an intact uterus; 13.6% stated that they would do so for a woman with no uterus. Most reported that they would prescribe HRT for 12 or more years (73.3%) and would follow up patients every 1 to 2 years (70.6%). INTERPRETATION: Despite controversy about HRT in the published literature, the Ontario physicians surveyed reported similar reasons and patterns of prescribing, pretreatment investigations, and surveillance of postmenopausal women using HRT. These results suggest that Ontario physicians'' knowledge about HRT is consistent with recommendations in the published literature.     

Role of the wheelchair in the management of the muscular dystrophy patient.

During the postambulatory period, patients with pseudohypertrophic muscular dystrophy depend entirely on their wheelchairs for comfort and spinal support. Without the comfort they are unable to enjoy and participate in every waking activity; without the spinal support they are destined to accept a bedbound life, not so much by the actual weakness as by the progression of spinal deformity. Present-day wheelchairs are not comfortable and they do not provide adequate spinal support. A novel spinal support system (brace) has been prescribed for 50 patients during the last 24 months. It consists of a contoured seat, mounted on a modified wheelchair frame, with integral armrests, footrests and headrest. All patients are clearly more comfortable and spend between 9 and 14 hours a day in their special wheelchairs, compared with 2 to 3 hours at a time in standard wheelchairs. Parents, teachers and therapists have reported a definite improvement in the attitudes of these patients. Although we have measured no progression in spinal deformity and have recorded regression in a few patients, we cannot yet assess the final value of this promising method of support in preventing spinal collapse.     

Synthetic ceramide analogues as skin permeation enhancers: structure-activity relationships

The study presents new information about the structure–activity relationships of the skin permeation enhancers. A series of ceramide analogues including eight different polar head groups and six different chain lengths was synthesised. The compounds were evaluated as permeation enhancers in vitro using porcine skin. The physico-chemical parameters of the tested compounds obtained by computer modelling were used to evaluate, by multiple linear regression, the enhancement ratios (ERs) of the compounds. The regression analysis suggests that the hydrogen bonding ability of the compounds is inversely related to the ER values and that the molecular size and lipophilicity must be well balanced. In the studied enhancers having the same chain length, the enhancement activity is dependent only on their permeability coefficients. This finding confirms the Warner's hypothesis that the polar head of an enhancer is responsible for the permeation and anchoring of the molecule into the stratum corneum lipids and that it does not influence the mechanism of action. For the specific action of enhancers, that is disordering of the intercellular lipid packing, the length of the hydrophobic chain(s) and not the lipophilicity is important. Furthermore, the examination of the FTIR spectra indicated that the most active substances possess the most ordered chains. The described relationships could bring more rational approaches in designing new potent enhancers for transdermal formulations.