Busulfan and cycosporin in bone graft children

Most drugs exhibit both inter- and intra-individual pharmacokinetic and pharmacodynamic variability. This variability explains the different responses observed in patients exposed to standard doses and must be taken into consideration when the therapeutic window is narrow. Population pharmacokinetics provides mean (or median) values of pharmacokinetic parameters as well as the distribution pattern and the statistical relationship with covariables in a group of individuals presenting common characteristics. Among the different methods developed for population pharmacokinetics, the data pool method, as well as the two-step and one-step methods (NONMEM and NPEM) are attractive. Population models can then be developed using bayesian logistics to obtain an estimation of the pharmacokinetic parameters of a given patient and predict the most adapted dose in light of the therapeutic target (residual serum concentration, mean concentration.). Busulfan is an alkylizing agent used instead of radiotherapy for pre-graft preparation before bone marrow grafts in children. This compound requires dose monitoring because of its narrow therapeutic window: under-dosing raises the risk of graft rejection; inversely over-dosing can cause potentially fatal complications such as occlusive venous disease. Interindividual variability is characteristic of busulfan kinetics. Several factors can explain part of this variability: age, underlying disease, changes in liver function, drug bioavailability, chronobiology. The short treatments used (most protocols have 16 doses given in four days) require rapid monitoring to propose effective adjustments. In this context, use of bayesian logistics to estimate the patient's pharmokinetic parameters is very useful for correct dosing. This type of monitoring could also be used for other compounds such as cyclosporine, with a narrow therapeutic window.     

The pharmaceutical industry and the adverse effects of the drugs

New drug development is a long, expensive and hazardous process especially regarding the final outcome. During the first non-clinical steps, molecules identified as potential candidates are screened for their toxicological profile, which allows to eliminate some but also to identify possible "target" organs. Then clinical trials are conducted, where tolerance profile knowledge is increased through the development with the detection of the most frequent adverse effects (between 1% and 1 per thousand). At marketing authorization, because of the limited number and of the selectivity of patients enrolled in clinical trials, the drug safety profile is based on the more frequent adverse effects. In Europe, since November 2005, a new regulation - the Risk Management system - has been added to Pharmacovigilance. These are designed to better anticipate and even minimize important identified or potential risks or to better inform on populations not studied during the clinical trials. This concept is based on risk reduction throughout drug's life cycle with specific strategic actions in addition to the product information, in order to optimise the drug benefit/risk ratio. Pharmaceutical companies will therefore invest significantly in post-marketing, allowing proper and safety use of their products. As they played a major role in the clinical development few years ago, they could from now on, be recognised as the key player towards this new paradigm defined as the post-approval development.     

Imaging mass spectrometry: a new tool for the analysis of skin biopsy. Application in Fabry's disease

The advent of innovative techniques in mass spectrometry, especially in the area of imaging, prompted us to evaluate two promising techniques: secondary ion mass spectrometry (SIMS) and matrix-assisted laser desorption/ionization (MALDI) mass spectrometry. For this purpose, sections of cutaneous biopsies from patients affected by Fabry's disease and control patients were analyzed. In the course of this disease, two physiological glycosphingolipids [globotriasylceramide (Gb3) and the galabiosylceramide (Ga2)] accumulate in certain tissues owing to a catabolism failure. The ability of these techniques to localize sites of accumulation in body tissues and their capacity to identify the accumulated lipid structures by mass spectra were evaluated. Results demonstrated that these two techniques provide complementary information:-secondary ion mass spectrometry enabled precise localization of areas of accumulation with lateral resolution in the micrometer range;-the signal obtained with matrix-assisted laser desorption/ionization mass spectrometry was high enough to identify these structures according to their molecular weight.     

Effects of cations and temperature on the binding of [3H]spiperone to sheep caudate nucleus

The specific [3H]spiperone binding by sheep caudate nucleus homogenate is increased by divalent cations. The effect of Ca2+ or Mn2+ (5 mM) is temperature-dependent, and it is optimal at about 37 degrees, but is relatively low below 15 degrees and above 50 degrees. In the absence of added Ca2+ or Mn2+, the maximal specific [3H]spiperone binding is observed at about 25 degrees, and the cations shift the optimum to about 37 degrees. Under the experimental conditions used, the KD is about 0.6 nM and is not influenced by Ca2+ or Mn2+, or by temperature (25 and 37 degrees). In addition to Ca2+ and Mn2+, Mg2+ and Zn2+ also increase the specific [3H]spiperone binding, but to a smaller extent. At the concentrations of Ca2+, Mn2+, Mg2+ and Zn2+ which produce a maximal increase in the [3H]spiperone binding, the membranes are nearly saturated with the cations which bind about 100 nmoles of Ca2+ or Mg2+/mg of protein, 170 nmoles Zn2+/mg of protein and at least 300 nmoles Mn2+/mg of protein. It is suggested that the cations increase the [3H]spiperone binding by either exposing more binding sites, by preventing denaturation or by increasing the solubility of [3H]spiperone in the membrane phase, or by a combination of these processes.     

氟喹诺酮类药物所致尖端扭转型室性心动过速

氟喹诺酮类常用药物中左氧氟沙星、环丙沙星、加替沙星和莫西沙星等可以引起尖端扭转型室性心动过速(TdP).TdP的临床表现为眩晕、昏厥甚至心搏停止,心电图可见QT间期延长及TdP.其发生机制尚不明确,可能与抑制心肌细胞K<'+>离子通道,使K<'+>外流受阻有关.氟喹诺酮类常用药物所致TdP的危险因素有女性、高龄、器质性心脏病(特别是充血性心力衰竭、QT间期延长、心动过缓)、肝肾功能损害、低钾低镁血症,以及合用可以引起QT间期延长的药物等.一旦患者出现QT间期延长及TdP应立即停药,补充钾和镁抑制早期后除极,也可采用人工临时心脏起搏或异丙肾上腺素提高基础心率.意识丧失和心室颤动者,可进行体外电复律.     

Melt granulation with glyceryl palmitostearate to obtain taste-masked acetaminophen

A melt granulation process designed to obtain a taste-masked acetaminophen using glyceryl palmitostearte (Precirol Ato 5) is described. Melting this lipid material in a high-smear mixer gives granules which can be directly compressed after blending with the required excipients. The phase diagram shows the absence of interaction between the phases of the two components and no effect on acetaminophen polymorphism. A water dispersible tablet formulation is proposed for oral administration of cristallized acetominophen (500 mg) devoid of bitterness of which 90% dissolves within 15 minutes.     

高分辨心电图鉴别室速与预激综合征逆向折返性心动过速

目的 :应用高分辨心电图鉴别室性心动过速 (室速 )与预激综合征逆向折返性心动过速。方法 :对17例室律整齐的室速和12例预激综合征逆向折返性心动过速患者进行心电信号叠加高频滤波分析 ,观测QRS波与P波的关系。结果 :在心电信号叠加高频滤波图上 ,17例室速中16例未见P波 ,12例预激综合征逆向折返性心动过速者全部见到P波 ,两组差异有统计学意义 (P<0.001)。结论 :应用心电信号叠加高频滤波分析显示P波的方法有助于室律整齐的室速与预激综合征逆向折返性心动过速的鉴别诊断     

Pharmacokinetics of cefotiam after i.v. administration to healthy volunteers

The inability to calculate a definitive value for apparent volume of distribution at steady state is discussed and a method presented whereby the possible minimum and maximum values for V_ss may be determined for a drug obeying linear kinetics whose disposition may be characterized by means of a tri-exponential equation.     

Effects of biogenic amines on the concentration of adnosine 3',5'-monophosphate in bovine superior cervical ganglion.

The accumulation of cyclic AMP elicited in bovine superior cervical ganglia by several biogenic amines in the presence of theophylline was investigated in vitro. The response to dopamine (10^?4M), after 6 min of incubation, was found to exceed that induced by equimolar concentrations of norepinephrine. Experiments with an inhibitor of dopamine-beta-oxidase showed that prior conversion of dopamine to norepinephrine was not necessary for the activation of ganglionic adenylate cyclase. The effect of norepinephrine could be prevented by pre-incubation with a combination of alpha- and beta-adrenergic antagonists; the cyclic AMP increase caused by epinephrine was predominantly beta-sensitive. Tyramine, 5-hydroxytryptamine and histamine caused a moderate increase in the concentration of cyclic AMP. The effect of histamine, which could be reduced by pre-incubation with an antihistamine, burimamide, was found to be additive to that of dopamine and norepinephrine.     

Quality control in coprology

Quality control in medical laboratories was defined in guidelines for good execution of laboratory analyses issued by the French health authorities in 1994. Application of these guidelines is difficult in coprology because the sample is a complex heterogeneous matrix which varies with disease, surgery, food intake, and treatment. In addition, commercial quality control kits are not available for stool biochemical analyses and a national quality control program has not been established. We thus developed our own fecal quality control technique using pooling lyophylized stool samples. Manual or partially automated methods are used in coprology, leading to a long pre-analysis phase which is not always taken into account in quality control. This implies the need for complementary tools to insure the quality of coprology analyses. For example, semi-quantitative microscopic lipid analysis can be used as an internal standard for a given specimen. Quality assurance also involves a post-analytical phase where results obtained for a given specimen are compared with other available data and interpreted in light of the patient's clinical and therapeutic status. This quality assurance strategy enables accurate reliable results useful for long-term patient management.     

De novo design of a pentameric coiled‐coil: decoding the motif for tetramer versus pentamer formation in water‐soluble phospholamban*

Abstract: Water‐soluble phospholamban (WSPLB) is a designed, water‐soluble analogue of the pentameric membrane protein phospholamban (PLB), which contains the same core and interhelical residues as PLB, with only the solvent‐exposed positions mutated. WSPLB contains the same secondary and quaternary structure as PLB. The hydrophobic cores of PLB and WSPLB contain Leu and Ile at the a ‐ and d ‐positions of a heptad repeat ( abcdefg ) from residues 31–52, while residues 21–30 are rich in polar amino acids at these positions. While the full‐length WSPLB forms pentamers in solution, truncated peptides lacking residues 21–30 are largely tetrameric. Thus, truncation of residues 1–20 promotes a switch from pentamer to tetramer formation. Here, the motifs for WSPLB pentamerization were elucidated by characterizing a series of peptides, which were progressively truncated in this polar ‘switch’ region. When fully present, the ‘switch’ region promotes pentamer formation in WSPLB, by destabilizing a more stable tetrameric species which exists in its absence. We find that the burial of hydrogen bonding residues from 21 to 30 drives WSPLB from a tetramer to a pentamer, with direct implications for coiled‐coil design.     

浅述他克莫司在皮肤科的临床应用

他克莫司是一种新型的皮肤外用免疫抑制剂.本文简要介绍它在皮肤科中的一些临床用途,而且它在临床应用过程中确实取得了满意的疗效.通过本文的介绍,希望它能在皮肤病的治疗中不断应用和推广,并能发现它有更多的临床用途.     

Prolongation of the QT interval and cardiac arrhythmias associated with cisapride: limitations of the pharmacoepidemiological studies conducted and proposals for the future

Not all hazards can be identified from clinical studies prior to marketing of medicinal products. Pre-marketing large-scale trials for cisapride did not report any serious cardiac arrhythmias. After a long period of availability in several countries it was withdrawn in 2000 because of reports of serious, and in many cases fatal, cardiac events. Whilst spontaneous reporting systems for adverse drug reactions (ADRs) have limitations such as under-reporting, they are an effective system for signal generation, particularly of rare ADRs. Pharmacoepidemiological studies aim to identify and calculate the incidence of adverse reactions, with increased sensitivity to less common ADRs compared to randomised controlled trials, yet cohort sizes may be insufficient to detect very rare ADRs such as drug-induced Torsade de Pointes, with an estimated incidence of the order of 1 per 12,000 to 1 per 120,000 patients. Several pharmacoepidemiological studies investigated adverse events associated with cisapride, one of which specifically examined the association between serious cardiac arrhythmias and cisapride. These observational studies were conducted using large population databases, but each failed to identify sufficient cases to establish a causal relationship. Explanations include that the cohort sample sizes were too small, and either under-, or mis-reporting of events of interest may have occurred. To estimate the risk of very rare adverse events, pharmacoepidemiological studies require very large numbers. Furthermore, the events in question need to be clinically recognisable by doctors and adequately documented in patients' notes, computer records, or on study questionnaires. The establishment of a national registry for drug-induced QT prolongation to identify cases and correlate clinical information may help to better identify these rare ADRs earlier. Such proactive surveillance could avoid unnecessary delays for other drugs where QT prolongation and serious cardiac arrhythmias may be an issue.     

The lipophilicity of deuterium atoms. A comparison of shake-flask and HPLC methods

Isotopic effects are demonstrated in the lipophilicity, measured by shake-flask and HPLC methods, of a series of deuterated aromatic compounds. The results indicate that deuterated compounds are less lipophilic than their protium isomers by about ?0.006 per deuterium atom on the log P_oct scale. This isotopic effect is satisfactorily accounted for by differences in molar volumes of isotopomers. The partition coefficient of benzene and toluene is critically evaluated in view of the volatility of these compounds.