'Flu' and structure-based drug design

The threat of a catastrophic outbreak of influenza is ever present. Vaccines are only partially effective and the two compounds, amantidine and rimantidine, used clinically against influenza A cause side-effects and rapid viral resistance. Recent advances bring hope that specific and potent drugs against influenza may soon be available in the clinic. These compounds were designed to inhibit influenza neuraminidase (NA), one of the viral coat glycoproteins, using the crystal structure of NA which was first published in 1983. In this review, the application of structure-based drug design approaches to the design of anti-influenza agents targeted at NA and haemagglutinin (HA), the other viral surface glycoprotein, is discussed.     

Displaced adolescents in Croatia: sources of stress and posttraumatic stress reaction

This study explored sources of stress and psychosocial reactions of adolescents displaced as a result of the war in the Republic of Croatia. The most frequent stressful events they faced were loss of home (80%), loss of personal belongings (66.7%), separation from family members (66.7%), damage to property (48.9%), exposure to enemy attacks (46.7%), and death of a family member or friend (37.8%). Among the most frequent posttraumatic stress reactions were intrusive images (48.9%), loss of interest (40.9%), restlessness (37.8%), appetite disturbances (33.3%), and increased irritability (31.1%). The exposure to a greater number of stressful events was related to increased depression. More posttraumatic stress reactions were evident in females, in adolescents who were exiled for longer periods, and in those whose parents were more anxious. Adolescents who manifested a higher number of stress reactions had poorer expectations regarding their future.     

Finite element stress analysis of a new design of synthetic leaflet heart valve

This paper presents a parametric finite element analysis of the stresses in the leaflets of a new design of polyurethane heart valve in the closed position. The alpharabola geometry of the valve has previously been reported by Leat and Fisher (1) and has been shown to demonstrate good opening characteristics. The effects of variations in leaflet offset parameter, g, length, h, and local thickening have been determined for a valve where the frame is assumed rigid. A spherical leaflet geometry has also been analysed for comparative purposes. Results have shown that the alpharabola leaflet geometry can reduce the maximum principal tensile stress to 60 per cent of that for a spherical valve of the same mesh density.     

Physiopathological study in 2 cases of Bartter's syndrome

Batter's syndrome is characterized by retardation in growth pitressin-resistant hypostenuria, hypokalemic alkalosis, high activity of the jux angiotensin-renine-aldosterone system with normal blood pressure; vascular insensibility to angiotensin and hypertrophy and hyperplasia of the juxtaglomerular apparatus. In both patients we studied, we found negative balance of sodium and potassium conditioned to a renal loss of them.     

Retrometabolic approaches for drug design and targeting

Retrometabolic drug design approaches incorporate targeting and metabolic considerations into the drug design process and represent a novel, systematic methodology for the design of safe, localized compounds. Two major design concepts aimed to increase the therapeutic index (the activity/toxicity ratio) of drugs were developed. Chemical delivery systems (CDS) are primarily used to allow targeting of the active biological molecules to specific target sites or organs based on predictable enzymatic activation. Brain-targeted delivery of different agents like estradiol or AZT was successfully achieved, and recent progresses include delivery of peptides using a complex strategy designated as molecular packaging. Sequential site- and stereospecific enzymatic activation of oxime/alkoxime precursors of beta-adrenergic antagonists allows their eye targeted delivery. Soft drug approaches are used to design new drugs by building in the molecule, in addition to the activity, the most desired way in which the molecule is to be deactivated and detoxified subsequent to exerting its biological effects. Many examples are available to illustrate soft drug design, e.g., soft anticholinergics, soft b-blockers, soft antiinflammatory steroids. Special computer programs were developed that starting from a lead compound generate complete libraries of possible soft analogs and then help ranking these candidates based on molecular size/shape, electronic properties, predicted solubility/partition properties, and atomic charge distributions. Recent developments in the field are presented in a supplement to this issue.     

Physiopathological basis of the treatment of heart failure

Therapeutic advances have changed the mode of presentation of cardiac failure over the last decades: the main cause, nowadays, is myocardial ischaemia. The modern treatment of cardiac failure is based on relatively simple physiopathological mechanisms which take into account the different aspects of cardiac physiology: a pump, a muscle, a coronary circulation supplying oxygen to the myocardium, an automatic contraction. The concept of vasodilatation and the blocking of vasoconstrictive systems introduced during the 70s is the basis of modern treatment of cardiac failure which involves angiotensin converting enzyme inhibitors and, increasingly, betablockers. In the near future, with earlier treatment of cardiac failure, the stimulation of vasodilator systems could become a new therapeutic strategy. Early detection of ischaemia and its complications with the aim of limiting the loss of cardiac myocytes is a priority for slowing the progression of cardiac failure. The prevention of cardiac failure also depends on educating cardiologists to treat rapidly the factors predisposing to or prolonging episodes of even mild cardiac failure.     

Measurement and analysis of unbound drug concentrations

The plasma protein binding of drugs has been shown to have significant effects on numerous aspects of clinical pharmacokinetics and pharmacodynamics. In many clinical situations, measurement of the total drug concentration does not provide the needed information concerning the unbound fraction of drug in plasma which is available for distribution, elimination, and pharmacodynamic action. Thus, accurate determination of unbound plasma drug concentrations is essential in the therapeutic monitoring of drugs. Many methodologies are available for determining the extent of plasma protein binding of drugs, however, in the clinical evaluation of drug therapy, equilibrium dialysis and ultrafiltration are the most routinely utilised methods. Both of these methods have been proven to be experimentally sound and to yield adequate protein binding data. Furthermore, the characterisation of the interactions between drug and protein molecules is essential for the assessment of the pharmacokinetic implications of drug-protein binding. Protein binding parameters which characterise the affinity of the drug-protein association, the number of classes of binding sites, the number of binding sites per class or protein and the binding capacity are useful for predicting unbound drug concentrations. Simple graphical methods have often been used to obtain protein binding parameters, but these methods have limitations and are not useful for drugs with more than 1 class of binding site. Therefore, the fitting of protein binding models which characterise the drug-protein binding interaction for experimental data is the preferred method of calculating binding parameters. Using the appropriate model, values for binding parameters are typically estimated by using nonlinear least-squares regression analysis.     

Individual differences in reaction to failure-induced stress.

"The McKinney Reporting Test and the MMPI were administered to samples of aviation cadets, aircraft commanders, copilots, and ROTC student officers. Two criterion groups representing the extremes in adjustment were selected within each of the military samples… . There was an overall-significant tendency among the low adjustment cases for those who shifted toward more accurate performance on the McKinney stress period to answer on the Hy scale… like Janet's psychasthenic type, and for those who became more inaccurate to answer like the hysteric. This tendency did not hold for high adjustment cases." (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Posttraumatic stress disorder and drug disorders: testing causal pathways

BACKGROUND: Although there is a high degree of comorbidity between posttraumatic stress disorder (PTSD) and drug use disorders, little is known about causal relationships between PTSD, exposure to traumatic events, and drug use disorders. METHODS: In a longitudinal study in southeast Michigan, 1007 adults aged 21 to 30 years were initially assessed in 1989 and were followed up 3 and 5 years later, in 1992 and 1994. Psychiatric disorders according to DSM-III-R criteria were measured by the National Institute of Mental Health Diagnostic Interview Schedule. To take into account temporal sequencing, the associations between PTSD, traumatic events, and drug use disorders were analyzed by using Cox proportional hazards models with time-dependent covariates. RESULTS: Posttraumatic stress disorder signaled an increased risk of drug abuse or dependence (hazards ratio, 4.5; 95% confidence interval, 2.6-7.6, adjusted for sex), whereas exposure to traumatic events in the absence of PTSD did not increase the risk of drug abuse or dependence. The risk for abuse or dependence was the highest for prescribed psychoactive drugs (hazards ratio, 13.0; 95% confidence interval, 5.3-32.0). There was no evidence that preexisting drug abuse or dependence increased the risk of subsequent exposure to traumatic events or the risk of PTSD after traumatic exposure. CONCLUSION: The results suggest that drug abuse or dependence in persons with PTSD might be the inadvertent result of efforts to medicate symptoms, although the possibility of shared vulnerability to PTSD and drug use disorders cannot be ruled out.     

A shape-based machine learning tool for drug design

Building predictive models for iterative drug design in the absence of a known target protein structure is an important challenge. We present a novel technique, Compass, that removes a major obstacle to accurate prediction by automatically selecting conformations and alignments of molecules without the benefit of a characterized active site. The technique combines explicit representation of molecular shape with neural network learning methods to produce highly predictive models, even across chemically distinct classes of molecules. We apply the method to predicting human perception of musk odor and show how the resulting models can provide graphical guidance for chemical modifications.     

Heuristic lipophilicity potential for computer-aided rational drug design

In this contribution we suggest a heuristic molecular lipophilicity potential (HMLP), which is a structure-based technique requiring no empirical indices of atomic lipophilicity. The input data used in this approach are molecular geometries and molecular surfaces. The HMLP is a modified electrostatic potential, combined with the averaged influences from the molecular environment. Quantum mechanics is used to calculate the electron density function rho(r) and the electrostatic potential V(r), and from this information a lipophilicity potential L(r) is generated. The HMLP is a unified lipophilicity and hydrophilicity potential. The interactions of dipole and multipole moments, hydrogen bonds, and charged atoms in a molecule are included in the hydrophilic interactions in this model. The HMLP is used to study hydrogen bonds and water-octanol partition coefficients in several examples. The calculated results show that the HMLP gives qualitatively and quantitatively correct, as well as chemically reasonable, results in cases where comparisons are available. These comparisons indicate that the HMLP has advantages over the empirical lipophilicity potential in many aspects. The HMLP is a three-dimensional and easily visualizable representation of molecular lipophilicity, suggested as a potential tool in computer-aided three-dimensional drug design.     

DNA methylation as a target for drug design

The mechanism of cell death induced by Actinobacillus actinomycetemcomitans leukotoxin (LTX) has been investigated with flow cytometry and patch electrode recording using cultured HL60 cells. The kinetics of propidium iodide (PI) positive staining of HL60 cells was measured as a function of LTX concentration at 37 degreesC. Results showed a concentration-dependent decrease in the tk times. Cell kill was slow at <1 microg/ml LTX concentrations with fewer than 50% of the cells killed after 1 h; at 1 microg/ml, the tk times ranged from approximately 15 to 30 min. At higher concentrations, the tk times decreased rapidly. The rate of cell kill was appreciably slowed at 20 degreesC. HL60 whole cell currents were recorded with patch electrodes. Immediately following exposure to high concentrations of LTX, large currents were recorded suggesting that the membrane potential of these cells had collapsed due to the large conductance increases. At low toxin concentrations, rapid conductance fluctuations were seen suggestive of a limited number of toxin-mediated events. Cells exposed to low concentrations of LTX exhibited these conductance fluctuations for up to 1 h, whereas toxin-insensitive cells were unaffected by long exposures to high concentrations of toxin. Our results are consistent with LTX-induced pores in susceptible cells which overwhelm the ability of the cell to maintain osmotic homeostasis causing cell death.     

Stage analysis of reaction time.

Stage analysis of reaction time includes the decomposition of reaction time into stages and the analysis of processing within those stages. This report reviews the analytic methodology employed in stage analysis and includes suggested improvements in this methodology. The major topics covered are the construction of models of the stage, the combination of stage models into a model of the complete reaction process, the use of process models in the decomposition of reaction time, and the use of stage models in the analysis of component stages. The methods of analysis presented are applicable to a wide range of reaction processes, including processes in which the execution of stages is not strictly serial, or in which the stage times are interdependent. (33 ref) (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

In vitro drug assays and statistical analysis

The development of in vitro drug tests to assess the efficacy of drugs against Pneumocystis carinii has been hindered by the lack of efficient methods for continuous cultivation of the microorganism. However, different short-term culture systems have been proposed by many teams. In the present contribution an in vitro microplate drug assay and two statistical programs allowing the analysis of results are presented.