Synthesis and biological activity of organosilicontitanium glycerohydrogels

A series of organosilicontitanium (OST) glycerohydrogels with the general formula 2Si(C₃H₇O₃)₄ ⋅ Ti(C₃H₇O₃)₄ ⋅ xC₃H₈O₃ ⋅ yH₂O (where 9 ≤ x ≤ 30 and 60 ≤ y ≤ 120) were synthesized and some of their pharmacological properties were studied. High percutaneous activity of the compounds was revealed by measuring the diffusion of sodium diclofenac through intact skin membranes in vitro. It was established that all of the synthesized substances are nontoxic. The wound-healing and antioxidant properties of the glycerohydrogels were studied. The experimental results show that OST glycerohydrogels can be recommended for further testing as effective percutaneous vehicles of medicines with wound-healing, burn-healing, and antioxidant action. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 43, No. 2, pp. 26–32, February, 2009.     

Absorption rate of methylxanthines following capsules,cola and chocolate

Objective: To compare caffeine and theobromine absorption after oral administration of capsules, cola beverage and chocolate candy. Methods: Three males and four females who abstained from methylxanthines received five methylxanthine-containing treatments: caffeine in capsules (72 mg), administered twice; theobromine in capsules (370 mg); cola beverage (72 mg caffeine) and chocolate candy (72 mg caffeine and 370 mg theobromine). Plasma methylxanthine levels were assayed from samples collected before and 0.25, 0.50, 0.75, 1.0, 1.5, 2.0, and 3.0 h after caffeine capsule and cola treatments and, additionally, at 4.0 and 6.0 h after theobromine capsule and chocolate treatments. Results: Caffeine plasma concentrations increased rapidly and peaked at approximately 30 min following both capsule treatments 1 (C_max: 1.93 μg ⋅ ml⁻¹); and 2 (C_max: 2.05 μg ⋅ ml⁻¹). Relative to capsules, caffeine absorption from cola and chocolate was delayed and produced lower maximum caffeine plasma concentrations which peaked 1.5–2.0 h after treatment (For cola, C_max: 1.57 μg ⋅ ml⁻¹); and for chocolate, C_max: 1.50 μg ⋅ ml⁻¹. Theobromine plasma concentrations peaked approximately 3 h after capsule administration (C_max: 6.72 μg ⋅ ml⁻¹). Relative to capsules, theobromine absorption from chocolate was more rapid and produced higher maximum theobromine plasma concentrations which peaked approximately 2 h after treatment (C_max: 8.05 μg ⋅ ml⁻¹). Conclusions: The results suggest that a usual dietary portion of the cola or chocolate used in this study would produce behaviorally discriminable plasma levels of caffeine in most subjects and of theobromine in at least one subject. Received: 6 December 1995/Accepted in revised form: 6 July 1996     

中国乌头的研究——Ⅹ.关白附子中的新生物碱

从关白附子(Aconitum koreanum R.Raymund)中共分得六种生物碱。其中一种是已知生物碱,卽次乌头碱,另五种为新生物碱,暂称为关附甲素C₂₄H₃₁O₆N、乙素C₂₂H₂₉O₅N、丙素C₂₂H₃₃O₂N、丁素C₂₄H₃₅O₃N及戊素C₂₉H_(43)O₇N。关附甲素是关附乙素的一乙酸酮。关附甲素、乙素、丙素的示性式分别定为:C₁₉H₂₀(OH)₂(CH₃COO)₂(CH₃)(∶N·),C₁₉H₂₀(OH)₃(CH₃COO)(CH₃)(∶N·),C₁₉H₂₃(OH)₂(CH₃)(N—C₂H₅)。后二种生物碱因量少尚待研究。     

中国乌头的研究 Ⅷ.黄草乌根中的生物碱

从云南黄草乌根中分得三种生物碱,其中两种暂称为黄草乌碱甲及乙.甲碱C₃₃H₄₇O₉N,熔点为182-184℃;乙碱C₂₁H₃₃O₄N,熔点为184-185℃;和另一微量生物碱,熔点151-152℃.其中甲碱为主要成分,经官能团测定后,定其示性式为C₁₉H₂₁(OH)₂(OCH₃)₄-(CH₃OC₆H₄COO)(N-C₂H₅).     

Plasma concentrations and pharmacokinetics of idebenone and its metabolites following single and repeated doses in young patients with mitochondrial encephalomyopathy

Objective: The pharmacokinetics and tolerance of idebenone after single or repeated doses have been studied in young patients with mitochondrial encephalomyopathy. Results: No significant adverse effects were noted. In 3 out of 7 patients idebenone induced overall stimulation and improvement in arousal. Plasma concentrations of idebenone and its main metabolites were determined and the pharmacokinetic parameters of idebenone after single and repeated doses were estimated. During the single dose study, the mean plasma concentrations of idebenone and its main metabolites and mean pharmacokinetic parameters were comparable to published results (C_max = 452.2 ng ⋅ ml⁻¹, t_max = 2.3 h, AUC = 26 μg ⋅ ml⁻¹⋅ h, t_1/2β = 16.5 h). During the repeated doses study, no significant difference was found between mean residual plasma concentrations of idebenone on Day 2 (47 ng ⋅ ml⁻¹) and Day 5 (70.6 ng ⋅ ml⁻¹), and mean t_1/2β of idebenone after the single and after repeated dose studies, i.e., there was no evidence of accumulation. Although idebenone did not appear to accumulate during this study, the coadministration of anticonvulsants, often prescribed during mitochondrial encephalomyopathy, can affect its pharmacokinetics. Received: 2 January 1995/Accepted in revised form: 1 April 1996     

Parallel and antiparallel aggregation of α-helices

An apolar helical decapeptide with different end groups, Boc- or Ac-, crystallizes in a completely parallel fashion for the Boc-analog and in an antiparallel fashion for the Ac-analog. In both crystals, the packing motif consists of rows of parallel molecules. In the Boc-crystals, adjacent rows assemble with the helix axes pointed in the same direction. In the Ac-crystals, adjacent rows assemble with the helix axes pointed in opposite directions. The conformations of the molecules in both crystals are quite similar, predominantly α-helical, except for the tryptophanyl side chain where χ¹? 60° in the Boc- analog and ? 180° in the Ac-analog. As a result, there is one lateral hydrogen bond between helices, N(lε)…O(7), in the Ac-analog. The structures do not provide a ready rationalization of packing preference in terms of side-chain interactions and do not support a major role for helix dipole interactions in determining helix orientation in crystals. The crystal parameters are as follow. Boc-analog: C₃H₇,N₁₁O₁₃ C₃H₇OH, space group P1 with a = 10.250(3) Å, b = 12.451(4) Å, c = 15.077(6) Å, x= 96.55(3)°, β= 92.31(3)°, y= 106.37(3)°, Z = 1, R = 5.5% for 5581 data (|F| > 3.0a(F)), resolution 0.89 Å. Ac-analog: C₅₇,H₉₁,N₁₁,O₁₂, space group P2₁, with a = 9.965(1) Å, b = 19.707(3) Å, c = 16.648(3) Å, β= 94.08(1), Z = 2, R = 7.2% for 2530 data (|F| > 3.0σ(F)), resolution 1.00 Å.     

中国延胡索的研究 Ⅱ.江苏元胡中的生物碱

从江苏野生的延胡索(Corydalis humasa Migo)的块茎中,分得五种生物碱,其中三种巳鉴定为普鲁托品(protopine)、左旋四氢黄连碱和毕扣扣灵(bicuculline);其他二种为未知成分,暂命名为苏元胡碱甲和乙。苏元胡碱甲的实验式为C₂₃H₂₃O₇N,熔点205℃;苏元胡碱乙的实验式为C₁₈H₁₉O₆N,熔点191—192℃。     

Effect of diprafenone on the pharmacokinetics of digoxin

This study was conducted to investigate the effect of diprafenone on the steady-state pharmacokinetics of digoxin. Twelve healthy men, all rapid hydroxylators of debrisoquine, received digoxin (0.5 mg per day over 7 days with a loading dose of 2 × 1 mg) or digoxin and diprafenone (3 × 100 mg per day) in three different phases, without a wash-out period (phase 1, digoxin alone; phase 2, digoxin + diprafenone; phase 3, digoxin alone). Blood and urine samples were collected for pharmacokinetic analyses. Diprafenone caused a statistically significant increase in digoxin trough concentrations [1.4 (SD 0.2) vs 1.6 (0.3) ng ⋅ml⁻¹], AUC_0–24 values [41 (7) vs 48 (9) ng⋅h⋅ml⁻¹ and C_ss-max [3.9 (0.6) vs 5.5 (0.9) ng⋅ml⁻¹]. In all volunteers the parameters tended to return to the original values after administration of diprafenone was discontinued [1.4 (0.3) ng⋅ml⁻¹, 39 (11) ng⋅h⋅ml⁻¹, and 3.9 (1.1) ng⋅ml⁻¹ for trough concentration, AUC_0–24 and C_max respectively]. The mean relative magnitude of the increase in AUC_0–24 and trough concentration values corresponded to the mean relative decrease in the renal clearance of digoxin (in both cases approximately 20%). This suggests that the increase in AUC and C_ss was caused by reduced renal clearance of digoxin. Received: 10 July 1995 /Accepted in revised form: 5 October 1995     

Isolation and identification of a flavone (quercetin) from <Emphasis Type="Italic">Butea frondosa</Emphasis> bark

A flavone was isolated from the stem bark of Butea frondosa (Leguminosae). It was given a working name of BF-1 and characterized by m.p., 309–311°C and an empirical formula of C₁₅H₁₀O₇. On the basis of chemical and spectral evidence and upon comparison with the literature data, the isolated compound is identified for the first time as quercetin. Published in Khimiko-Farmatsevticheskii Zhurnal, Vol. 41, No. 5, pp. 37–39, May, 2007. The first two authors contributed equally to this work     

左氧氟沙星的单晶制备及其结构表征

目的培养左氧氟沙星单晶,进行结构表征。方法用乙腈–水体系培养单晶,并用单晶X射线衍射仪(SXRD)检测分析。结果制备得到左氧氟沙星无色片状晶体,该晶胞属于单斜晶系,空间群为P21,分子式为C18H20FN3O4·H2O,相对分子质量为379.38,晶体密度为1.469 mg/mm3,绝对构型为S构型。结论实验证明了左氧氟沙星的立体构型,培养的晶体晶型为一水合物。     

Enantioselective pharmacokinetics of tramadol in CYP2D6 extensive and poor metabolizers

Objective To describe in detail the intravenous, single oral and multiple oral dose enantioselective pharmacokinetics of tramadol in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs).Methods Eight EMs and eight PMs conducted three phases as an open-label cross-over trial with different formulations; 150 mg single oral tramadol hydrochloride, 50 mg single oral tramadol hydrochloride every 8 h for 48 h (steady state), 100 mg intravenous tramadol hydrochloride. Urine and plasma concentrations of (+/−)-tramadol and (+/−)-M1 were determined for 48 h after administration.Results In all three phases, there were significant differences between EMs and PMs in AUC and t_1/2 of (+)-tramadol (P≤0.0015), (−)-tramadol (P≤0.0062), (+)-M1 (P≤0.0198) and (−)-M1 (P≤0.0370), and significant differences in C_max of (+)-M1 (P<0.0001) and (−)-M1 (P≤0.0010). In Phase A and C, significant differences in t_max were seen for (+)-M1 (P≤0.0200). There were no statistical differences between the absolute bioavailability of tramadol in EMs and PMs. The urinary recoveries of (+)-tramadol, (−)-tramadol, (+)-M1 and (−)-M1 were statistically significantly different in EMs and PMs (P<0.05). Median antimodes of the urinary metabolic ratios of (+)-tramadol / (+)-M1 and (−)-M1 were 5.0 and 1.5, respectively, hereby clearly separating EMs and PMs in all three phases.Conclusion The impact of CYP2D6 phenotype on tramadol pharmacokinetics was similar after single oral, multiple oral and intravenous administration displaying significant pharmacokinetic differences between EMs and PMs of (+)-tramadol, (−)-tramadol, -(+)-M1 and (−)-M1. The O-demethylation of tramadol was catalysed stereospecific by CYP2D6 in the way that very little (+)-M1 was produced in PMs.     

滇产植物的皂素成分研究 Ⅰ.滇吉祥草的甾体成分(1)

从滇吉祥草(Reineckea yunnanensis W.W.Smith)中分得两个甾体皂甙元,其一为薯蓣皂甙元(diosgenin),另一皂甙元暂名为滇吉祥草皂甙元(yunnanogenin),熔点275—277℃,[α]_D^17°—64.1(CHCl₃,c=0.156),制成双乙酰化物,熔点181—182℃,双苯甲酰化物,熔点236—239℃,23-溴代双乙酰化物,熔点196—199℃。由上述数据及红外吸收光谱数据,推测为一正系饱和的双羟基皂甙元。     

Pharmacokinetics of flosequinan in patients with heart failure

Objective: The pharmacokinetics of flosequinan were studied in a group of 18 patients with chronic cardiac failure. Results: After a single dose of 100 mg, C_max of the parent compound (2.52 mg ⋅ l⁻¹) was recorded at 1.4 h, and of the sulphone metabolite flosequinoxan at 21.7 h. The plasma elimination half lives of the parent compound (6.4 h) and of the metabolite (54.3 h) were prolonged compared to previous studies in normal volunteers. After repeated dose administration for 36 days, the kinetics of the parent compound and metabolite remained essentially unchanged with an expected significant accumulation of metabolite (C_max 8.4 vs 3.21 mg ⋅ l⁻¹). No adverse effects were observed. Conclusion: It is possible that altered drug kinetics in patients with heart failure, probably related to altered hepatic blood flow, could contribute to drug toxicity. Received: 16 January 1995/Accepted in revised form: 30 October 1995     

Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers

Objective: The present study was conducted with the aim of investigating the absolute bioavailability of fluphenazine in healthy volunteers after administration of immediate and slow release oral formulations. Methods: The oral dose was 12 mg fluphenazine hydrochloride. The intravenous bolus dose was 2.5 mg. Fourteen healthy volunteers of both sexes were enrolled in this randomised, crossover trial. Twelve volunteers completed the trial according to protocol. Results: The concentration maxima after administration of the slow release formulation were approximately half those measured after the immediate release formulation and were recorded later by a factor of 2 (immediate release: C_max = 2.3 ng⋅ml⁻¹, t_max = 2.8 h; slow release: C_max = 1.2 ng⋅ml⁻¹, t_max = 4.6 h). The concentrations measured 10 min after intravenous bolus administration of 2.5 mg fluphenazine hydrochloride were approximately 100 times higher (261 ng⋅ml⁻¹). The geometric means for the absolute bioavailability of fluphenazine were 2.7% for the immediate release formulation and 3.4% for the slow release formulation. The absolute bioavailability of fluphenazine is thus much lower than previously generally accepted. Received: 14 December 1995/Accepted in revised form: 26 March 1996     

The crystal and molecular structure of 1-(Hexahydro-1H-azepin-1-yl)-3-(p-tolylsulfonyl) Urea: Tolazamide (C14H21N3O3S)

Crystals of tolazamide, C₁₄H₂₁N₃O₃S, are triclinic, space group PĪ, with cell dimensions ofa=6.355(2),b=9.223(2),c=13.510(3) A, α=101.04(8), β=92.80(5), γ=85.72(6)° and Z=2. Intensities were collected on an automated four-circle diffractometer using graphite-monochromated Cu K α radiations. The structure was solved by direct method and refined by full-matrix least-squares to an R factor of 0.058 for 1184 observed reflections. The molecules are dimerized by the N-H···O hydrogen bonds. There are only van der Waals interactions between these molecular dimers.     

Cyclophosphamide analogues: synthesis, spectroscopic study, and antitumor activity of diazaphosphorinanes

Some diazaphosphorinanes were synthesized and characterized by ¹H, ¹³C, ³¹P NMR and IR spectroscopy and elemental analysis. The antitumor activity of cyclophosphamide (CP) and its nine analogoues with formula , R = OC₆H₅CH₃-4 (1), NHC₆H₄S(O)₂NH₂-4 (2), NHC(O)NHC₆H₄-CH₃-2 (3), NHC(O)NHC₆H₄-NO₂-2 (4), NHC(O)NHC₆H₄-NO₂-3 (5), NHC(O)NHC₆H₄-NO₂-4 (6), NHC(O)C₆H₄-NO₂-2 (7), NHC(O)C₆H₄-NO₂-3 (8), and NHC(O)C₆H₄-NO₂-4 (9) were evaluated by cell culture on K562 cell line using MTT cell proliferation assay. The IC₅₀ values for CP and the compounds 1–9 were in the range of 0.140 (for 3) to 58.250 μM (for 2). It was found that compounds 3–6 are the best candidates for antitumor activity close to CP. Compound 2 containing aminosulfonamide substituent is very much less toxic among these compounds.     

The effect of hypoxaemia on drug disposition in chronic respiratory failure

Objective: The influence of hypoxaemia on the disposition of two common drugs has been examined in ten adults with stable chronic respiratory failure. Methods: There were two experimental periods in this cross-over study: during these periods supplemental oxygen was either withheld or administered to impose clinical hypoxaemia or maintain normoxaemia, respectively. Each participant received either oral (40 mg) or intravenous (20 mg) frusemide combined with oral paracetamol (500 mg) on consecutive days of the two experimental periods. Results: The total (bound plus unbound) plasma clearance of frusemide during hypoxaemia (arterial oxygen tension, PaO₂ ≤ 50 Torr) was not significantly different from the value during normoxaemia (PaO₂ ≥ 60 Torr) [76.9 and 62.4 ml ⋅ min⁻¹]. The volume of distribution was not affected by acute hypoxaemia (121 ml ⋅ kg⁻¹ without and 109 ml ⋅ kg⁻¹ with oxygen; P > 0.05). Renal and non-renal clearances of frusemide were similar during the period of hypoxaemia (31 and 38 ml ⋅ min⁻¹, respectively) compared to respective values during supplemental oxygen delivery (29 and 32 ml ⋅ min⁻¹). The absolute bioavailability of frusemide during hypoxaemia (0.62) was not different to that obtained during normoxaemia (0.56). The combined sodium and potassium excretion rate (expressed as a function of the frusemide excretion rate) was not altered by changing the oxygen tension. The pharmacokinetics of paracetamol were unaffected by hypoxaemia.     

中国乌头的研究——Ⅸ.川乌、附子中的生物碱

作者对中药川乌的生物碱进行研究,从其中共分得六种结晶性的生物碱,并证明四种是已知物,卽次乌头碱(hypaconitine)、乌头碱(aconitine)、新乌头碱(mesaconitine)和塔拉地萨敏(talatisamine).另二种为新生物碱,暂称为川乌碱甲和川乌碱乙.川岛碱甲,熔点111℃,实验式为C₂₃H₃₇NO₆;川乌碱乙,熔点185℃,实验式为C₂₂H₃₅NO₄。另在附子中亦分得新马头碱及次乌头碱.     

A single dose of ursodiol does not affect cyclosporine absorption in liver transplant patients

Objective: To study the possible influence of ursodiol (ursodeoxycholic acid), a hydrophilic bile acid, on cyclosporine (CsA) bioavailability. Methods: Seven adult liver transplant recipients participated in a randomised cross-over pharmacokinetic study comparing ursodiol (600 mg) with placebo in single doses. Blood concentrations of CsA were measured by HPLC. Results: There was no significant effect of ursodiol on CsA absorption: AUC was 5011 vs 5486 ng⋅h⋅ml^–1, C_max was 832 vs 871 ng⋅ml^–1 and t_max was 2 vs 2 h, after ursodiol and placebo, respectively. Conclusion: Although a significant period effect was observed, we conclude that a single dose of ursodiol has little effect on CsA absorption in liver transplant patients and that an interaction in the intestinal lumen between these two drugs is unlikely. Received: 19 October 1995/Accepted in revised form: 8 January 1996     

Interindividual variability in catalytic activity and immunoreactivity of three major human liver cytochrome P450 isozymes

Objective: Interindividual variations in immunoreactivity and function of three major human drug metabolising P450 monooxygenases has been investigated in liver microsomes from 42 Caucasians (kidney donors or liver biopsies). Methods: Diclofenac 4′-hydroxylation, dextromethorphan O-demethylation and midazolam 1′-hydroxylation, measured by HPLC in incubates, were used as probes to determine CYP2C9, CYP2D6 and CYP3A4 function kinetics, respectively. Immunoquantification of the three isoforms was achieved by Western blotting, using rabbit polyclonal antibodies raised against human CYP2C9 and human CYP3A4, and mouse monoclonal antibody raised against human CYP2D6. Results: Diclofenac 4′-hydroxylation exhibited Michaelis-Menten kinetics with k_M= 3.4 μmol ⋅l⁻¹ and V_max = 45 nmole ⋅mg⁻¹P ⋅h⁻¹. Relative immunoreactivity of CYP2C9 was correlated with V_max and CL_int. Dextromethorphan O-demethylation in EM (extensive metabolisers) liver microsomes also showed Michaelis-Menten kinetics, with k_M = 4.4 μmol ⋅l⁻¹ and V_max = 5.0 nmol ⋅mg⁻¹P ⋅h⁻¹. Relative immunoreactivity of CYP2D6 was correlated with V_max and CL_int. Midazolam 1′-hydroxylation also exhibited Michaelis-Menten kinetics with k_M = 3.3 μmol ⋅l⁻¹ and V_max = 35 nmol ⋅mg⁻¹P ⋅h⁻¹. Relative immunoreactivity of CYP3A4 was correlated with V_max and CL_int. Immunoreactivity and function were correlated for each isozyme, but there was no cross correlation between isozymes. Conclusion: The velocity of metabolite formation (V_max) by the three major human drug metabolising P450 monooxygenases is correlated with their immunoreactivity in liver microsomes. Interindividual variation was much larger for V_max than k_M. Interindividual variability was more pronounced for CYP2D6, probably due to the presence of several different functional alleles in the population of extensive metabolisers. Received: 27 December 1995/Accepted in revised form: 29 March 1996