Dose dependent pharmacokinetics of nitroglycerin after multiple intravenous infusions in healthy volunteers

Evaluation of the pharmacokinetics of nitroglycerin has been hindered in the past by the lack of specific and sensitive analytical procedures, and the unavailability of parenteral nitroglycerin and infusion sets which did not adsorb nitroglycerin. The purpose for this present study was to determine the pharmacokinetic parameters of nitroglycerin and the dinitrate metabolites after multiple intravenous infusions of nitroglycerin in healthy volunteers. Six volunteers received variable infusion rates of nitroglycerin. Generally, at 0, 40, 80, and 120 min, the infusion rates were adjusted to 10, 20, 40, and 10 g/min, respectively. Plasma samples were drawn and analyzed for nitroglycerin and its 1,2-and 1,3-dinitraie metabolites using capillary GC. Steady-state nitroglycerin plasma concentrations attained at 10, 20, 40, and 10g/min were 0.44±0.31, 1.32±0.71, 4.23±1.50 and 1.04±0.43 ng/ml, respectively. As the infusion rate was increased, the steady-state concentrations increased disproportionately. When the dose was decreased from 40 to 10g/min, the steady-state nitroglycerin concentrations were always higher than those at the initial low infusion rate. Thus, in the majority of subjects, a hysteretic type of response was present. The hysteresis observed in the dose versus steady-state concentration curve may be explained by either end-product inhibition or saturable binding of nitroglycerin to blood vessels. The clearance values (5.5 to 71 l/min) were very high and far exceed the maximum possible hepatic clearance suggesting that nitroglycerin is metabolized by organs other than liver. Clearance was not directly related to plasma concentrations but was found to decrease to a constant value (approximately 11±6 l/min< as nitroglycerin concentrations initially increased.Supported in part by NIH Grant HL 32243 and by a grant from Key Pharmaceuticals, Inc., Miami, Florida. During the course of the work, PKN received support as an AFPE James F. Hoge Memorial Fellow.     

Cutaneous Pharmacodynamics of Transdermally Delivered Isosorbide Dinitrate

Laser doppler velocimetry (LDV) has been used to assess the cutaneous pharmacodynamics of isosorbide dinitrate (ISDN) following transdermal delivery of the drug from prototypal patches. The delivery systems, which were saturated with ISDN, (a) produced various degrees of skin occlusion and (b) spanned a six-fold range of adhesiveness. The patches were applied to the ventral forearm skin of 10 healthy volunteers and the local ISDN-induced increase in local skin blood flow was determined using LDV by locating the probe in a central hole in the delivery system. Measurements were made for 1.5 hr and the pharmacodynamics were quantified by (i) the maximum LDV response and (ii) the area under the LDV response versus time curve. These parameters were not sensitive to patch occlusivity. They were significantly (P < 0.01) dependent on patch adhesiveness, though, and decreased with increasing adhesion. Although this observation suggested that ISDN diffusion through the adhesive could determine, at least in part, the rate of drug delivery, it was subsequently demonstrated that ISDN release (in vitro, into a perfect "sink) was unaffected by the level of cross-linking in the adhesive polymer. Because the drug was present in all systems at unit thermodynamic activity, these results cannot be explained on the basis of altered ISDN partitioning at the device–stratum coraeum interface. We speculate that the in vivo-in vitro discrepancy may be due to the efficiency of skin contact achieved by different adhesives: that is, the more adhesive, less flexible systems make poorer contact with the skin surface, thereby decreasing the effective surface area of drug delivery. These results indicate that the noninvasive procedure of LDV contributes to the screening of transdermal formulations.     

前列地尔脂微球载体制剂治疗不稳定性心绞痛的临床评价

目的 :评价前列地尔脂微球载体 (LipoPGE1)注射液对不稳定性心绞痛 (UAP)的疗效。方法 :将5 4例UPA患者随机分成两组 ,对照组 2 6例加用单硝酸异山梨醇治疗 ,治疗组 2 8例加用LipoPGE1,进行临床和血液流变学对比研究。结果 :两组临床症状总有效率和心电图改善率相比无显著差异 (P >0 .0 5 ) ,但停药 2wk后 ,心绞痛的复发率治疗组明显低于对照组 (P <0 .0 5 ) ;血液流变学综合指标改善 ,治疗组亦优于对照组 (P <0 .0 5或P <0 .0 1)。结论 :LipoPGE1制剂治疗UPA效果可靠。     

硝酸异山梨酯对大鼠心肌后期预适应的诱导作用

目的：探讨硝酸异山梨酯（ISDN）能否诱导大鼠后期预适应及其可能机制。方法：采用大鼠在体缺血再灌注（I／R）模型，将动物随机分为生理盐水组、ISDN给药组、假手术组、后期缺血预适应组、生理盐水＋I，R组、ISDN＋I，R组、生理盐水＋格列苯脲＋I／R组、ISDN＋格列苯脲＋I／R组。前两组于给药24h后，测定心肌组织中的SOD和诱导型一氧化氮合成酶的含量，含I／R组于给药24h后进行缺血40min再灌注1．5h后测心肌梗死范围、心肌组织及血清学指标。结果：ISDN组心肌组织中诱导型一氧化氮合成酶浓度昵显比生理盐水组高（P〈0．01）；后期缺血预适应组和ISDN＋I／R组与生理盐水＋I/R组相比，心肌梗死面积、血清肌酸激酶和乳酸脱氢酶含量明显减少（前两者P〈0．05，后者P〈0．01），心肌组织中NO和锰-SOD显著增加，丙二醛显著下降（P〈0．05）。结论：ISDN能诱导心肌后期预适应，其机制与NO和诱导型一氧化氮合成酶的升高以及机体的抗氧化能力增强有关。     

Towards Investigating the Effect of Ammonium Nitrate on the Characteristics and Thermal Decomposition Behavior of Energetic Double Base NC/DEGDN Composite

This research work aimed to elaborate on a new modified double-base propellant containing nitrocellulose (NC), ammonium nitrate (AN), and diethylene glycol dinitrate (DEGDN). The developed AN/NC-DEGDN formulation was successfully obtained through a casting process and fully characterized in terms of its chemical structure, morphological features, and thermal behavior. Beforehand, theoretical calculation by the CEA-NASA program was applied to select the optimal composition of the formulation. Experimental findings demonstrated the homogenous dispersion of AN oxidizer in the NC-DEGDN matrix without alteration of their molecular structures. The catalytic influence of AN on the thermal decomposition behavior of NC-DEGDN film was also elucidated by thermal analyses. When AN was incorporated into the formulation, the decomposition peak temperatures for the different decomposition processes were shifted toward lower temperatures, while the total enthalpy of decomposition increased by around 1272.24 J/g. In addition, the kinetics of the thermal decomposition of the developed modified double base propellant were investigated using DSC results coupled with model kinetic approaches. It was found that the addition of AN decreases the activation energy of nitrate esters from 134.5 kJ/mol to 118.84 kJ/mol, providing evidence for its excellent catalytic effect. Overall, this investigation could serve as a reference for developing future generation of modified double-base propellants.     

The Alkylating Properties of Organophosphates

1. A brief introduction to the concept of alkylation is given, which discusses reaction mechanisms and reactivity, and includes an assessment of the susceptibility to alkylation of biologically-important molecules.

2. A semi-quantitative colour test for alkylating agents, with 4-(p-nitrobenzyl) pyridine (NBP), has been modified to give a quantitative method for the determination of second-order rate constants, k₂, for reaction at 37.5. These constants have been determined for dichlorvos, several other organophosphorus insecticides, and, for comparison, some known biological alkylating agents.

3. These results are discussed in relation to the extensive literature data pertaining to the chemical and biological reactivity of these compounds, and an assessment of the biological importance of the alkylating properties of dichlorvos and related organophosphorus insecticides has been made.

4. Since dichlorvos is rapidly metabolized in mammals by esterases present at high activity in the liver and moderate activity in lung, spleen, kidney and blood plasma, the chances of its manifesting spontaneous deleterious biological alkylating activity are very low, and may even be zero. Structure/activity correlations suggest that this will also apply to other organophosphate insecticides, but not necessarily to simple alkyl phosphates such as trimethyl phosphate.     

Development of nitrate tolerance and usefulness of pulse therapy in a patient with vasospastic angina.

In a 58-year-old man with vasospastic angina, we investigated the relationship between the antianginal effects of isosorbide dinitrate (ISDN) and plasma ISDN concentration. Despite adequate plasma ISDN levels, sustained therapy using ISDN tapes and oral ISDN (transcutaneously 160 mg and orally 100 mg ISDN day-1) failed to exhibit antianginal effects. However, pulse therapy using sublingual short-acting ISDN prevented anginal episodes, although the plasma ISDN levels were less than those of sustained therapy. Nitrate tolerance of the antianginal effects was avoided by creating an abrupt plasma ISDN concentration gradient using sublingual ISDN.     

Preparation and control-release kinetics of isosorbide dinitrate microspheres

Microcapsules for sustained release of poorly soluble isosorbide dinitrate (ISDN) were prepared based on ethylcellulose (EC) and/or blended with appropriate amounts of relatively hydrophilic hydroxypropyl cellulose (HPC) as matrix materials using the oil-in-oil emulsion evaporation method. The microspheres studied had three-mode sizes (100–150, 250–300 and 400–450?µm) and four polymer compositions (1, 0.833, 0.67 and 0.5 weight fraction EC). The microspheres were observed to contain essentially no drug crystalline domain and were of a porous morphology. The cumulative amounts of ISDN releasing from the microspheres as functions of mode fractions size and polymer compositions were measured in vitro. It was observed that the microspheres’ size influenced the release behaviour of drug more obviously than the polymer composition. The smaller size and the higher hydrophilic HPC content show the faster release rate of drug and the smaller amount of drug residue. The kinetics of drug release depends on the size and polymer composition. The microspheres with 100–150?µm, of all polymer compositions, present one-stage diffusion kinetic with a lag period for drug release. On the other hand, the microspheres with the other two sizes exhibit two-stage diffusion kinetic with a lag period. According to the kinetic model, the microspheres obtained are surmised to have a core-shell like drug concentration distribution and/or a core-shell morphology.     

联合用药治疗肺心病难治性心力衰竭疗效观察

目的探讨治疗肺心病难治性心力衰竭更为有效的方法。方法将患者60例,按入院治疗的先后顺序随机分为观察组36例和对照组24例。两组均采用常规治疗,包括持续低流量吸氧、控制感染、祛痰平喘、强心利尿等综合治疗。观察组在常规治疗的基础上,同时将小剂量肝素50mg、硫酸镁注射液2．5g、消心痛注射液20mg分别加入液体中静脉点滴,1次/d,10d为1个疗程。结果经χ^2检验,提示观察组疗效明显优于对照组,具有显著性差异（P〈0．05）。结论肺心病难治性心力衰竭在常规治疗无效时加用小剂量肝素和硫酸镁以及消心痛可减轻心衰的临床症状,改善心功能。