89SrCl2治疗恶性肿瘤骨转移的影响因素分析

目的 探讨⁸⁹SrCl₂治疗恶性肿瘤骨转移的疗效影响因素。方法 选择南充市川北医学院附属医院2013年2月至2016年9月行⁸⁹SrCl₂治疗的恶性肿瘤骨转移患者99例,分析患者的年龄、性别、肿瘤病理类型、⁸⁹SrCl₂治疗次数、手术切除原发灶、放疗、化疗、肿瘤骨转移的病灶数量、联合止痛药状况以及碱性磷酸酶（ALP）是否会影响⁸⁹SrCl₂的治疗效果。结果 ⁸⁹SrCl₂治疗的总有效率为63.6%。单因素分析结果显示不同肿瘤病理类型、不同治疗次数、是否联合放射治疗、是否手术切除原发灶、不同肿瘤骨转移病灶数量及是否联合止痛药患者的治疗效果进行比较,差异具有统计学意义（P<0.05）。logistics回归分析显示,患者的肿瘤病理类型、⁸⁹SrCl₂治疗次数、手术切除原发灶、肿瘤骨转移的病灶数量及联合止痛药是影响⁸⁹SrCl₂疗效的独立因素（P<0.05）。结论 肿瘤病理类型、⁸⁹SrCl₂治疗次数、手术切除原发灶、肿瘤骨转移病灶数量以及联合止痛药能影响⁸⁹SrCl₂治疗恶性肿瘤骨转移的疗效。     

Evaluation of antidiarrheal and in vitro antiprotozoal activities of extracts of leaves of Alocasia indica

Context: Alocasia indica Schott (Araceae) is used in several regions of India, especially in rural communities, by traditional medicine practitioners to treat diarrhea. However, no scientific data are available to justify the traditional potentials of the plant species in gastrointestinal disorders.

Objective: To evaluate the antidiarrheal and in vitro antiprotozoal activities of extracts of leaves of Alocasia indica using various pharmacological models.

Materials and methods: In vitro antidiarrheal activity of aqueous and ethanol extracts of Alocasia indica was evaluated against Escherichia coli, Salmonella typhimurium, Shigella flexneri and Staphylococcus aureus by agar well diffusion method. In vivo antidiarrheal activity of the extracts was studied against recinolic acid-induced diarrhea and magnesium sulfate-induced diarrhea. The effect of the extracts on normal intestinal transit, recinolic acid-induced intestinal transit, recinolic acid-induced intestinal fluid accumulation (enteropooling) and gastric emptying was assessed. In vitro antiprotozoal activity of aqueous and ethanol extracts of Alocasia indica was studied against Entamoeba histolytica and Giardia intestinalis.

Results: The aqueous and ethanol extracts exhibited significant in vitro antidiarrheal activity compared to the standard drug ciprofloxacine (10 µg/mL). The plant extracts showed significant (P <0.05) and dose-dependent antidiarrheal activity comparable to that of the reference drug, loperamide (10?mg/kg). The plant extracts exhibited significant in vitro antiprotozoal activity against both protozoa compared to the standard amebicidal and giardicidal drugs, metronidazole and emetine.

Discussion and conclusion: The results showed that the extracts of Alocasia indica have significant antidiarrheal and in vitro antiprotozoal activities which support its use in traditional herbal medicine practice.     

Evaluation of anti-inflammatory activity and standardisation of hydro-methanol extract of underground tuber of Dioscorea alata

Context The underground edible tuber of Dioscorea alata L. (Dioscoreaceae) is a functional food with high nutritive value and therapeutic potential. The tuber is known to possess anti-inflammatory properties in traditional medicine.

Objective The present study explores the anti-inflammatory activity and standardisation of D. alata tuber hydromethanol extract.

Materials and methods Hydromethanol extract (70%) of D. alata tuber was chemically characterised using HPLC and GC-MS techniques. Murine lymphocytes were cultured for 48?h with six different concentrations (0–80?μg/mL) of the extract. The expression of nitric oxide (NO), TNF-α, COX-1, COX-2, and PGE₂ were evaluated using colorimetric and ELISA methods.

Results Dioscorea alata extract inhibited the expression of NO and TNF-α with an IC₅₀ value of 134.51?±?6.75 and 113.30?±?7.44?μg/mL, respectively. The IC₅₀ values for inhibition of total COX, COX-1, COX-2 activities and PGE₂ level were 41.96?±?3.07, 141.41?±?8.99, 32.50?±?1.69, and 186.34?±?15.36?μg/mL, respectively. Inhibition of PGE₂ level and COX-2 activity was positively correlated (R²?=?0.9393). Gallic acid (GA), 4-hydroxy benzoic acid (4HBA), syringic acid (SYA), p-coumaric acid (PCA), and myricetin (MY) were identified and quantified using HPLC. GC-MS analysis revealed the presence of 13 different phytocompounds such as hexadecanoic acid, methyl stearate, cinnamyl cinnamate, and squalene.

Conclusion The D. alata extract significantly down-regulated the pro-inflammatory signals in a gradual manner compared with control (0?μg/mL). Different bioactive phytocompounds individually possessing anti-inflammatory activities contributed to the overall bioactivity of the D. alata tuber extract.     

Bioavailability of intranasal formulations of dihydroergotamine

Objective: A comparison of the pharmacokinetic properties of two novel intranasal preparations of dihydroergotamine mesilate (DHEM) with a commercially available intranasal preparation. Methods: Two intranasal formulations of DHEM in combination with randomly methylated β-cyclodextrin (RAMEB) were prepared. Subsequently, in an open, randomised, crossover study in nine healthy volunteers, the following medication was administered: 2 mg DHEM/2% RAMEB nasal spray ( =two puffs of 100 μl); 2 mg DHEM/4 mg RAMEB nasal powder; 2 mg Diergo nasal spray ( =four puffs of 125 μl); 0.5 mg DHEM i.m., and 2 mg DHEM solution p.o. Results: No statistically significant differences were found in maximum plasma concentration (C_max), time to reach C_max (t_max), area under plasma concentration–time curve (AUC_0–8 h), Frel_(t=8 h) and C_max/ AUC_(t=8 h) for the three intranasal preparations. The relative bioavailabilities of the DHEM/RAMEB nasal spray, the DHEM/RAMEB nasal powder and the commercially available DHEM nasal spray were 25%, 19% and 21%, respectively, in comparison with i.m. administration. The relative bioavailability after oral administration was 8%. Conclusion: The pharmacokinetic properties of the novel intranasal preparations are not significantly different from the commercially available nasal spray. Advantages of the DHEM/RAMEB nasal spray are (1) less complicated handling, (2) reduction of the number of puffs and (3) a preference by the volunteers. Received: 12 February 1999 / Accepted in revised form: 23 August 1999     

Anticholinergic effects of cis- and trans-isomers of two metabolites of propiverine

The muscarinic receptor antagonist propiverine used for therapy of overactive bladder undergoes first pass metabolism, leading to several active metabolites, which affect muscarinic receptors and L-type Ca²⁺ channels with different potencies. M-5, the major metabolite in blood, and M-6 can be synthesized as cis- and trans-isomers. We systematically investigated the pharmacodynamic profiles of the isomers on detrusor contractile function. In murine and porcine detrusor, the effects of the derivatives were examined on contractions induced by electric field stimulation (EFS), cumulatively increasing concentrations of carbachol or high KCl concentration. EFS contractions were concentration-dependently reduced by the M-5 and M-6 isomers although to a different extent. M-5 _cis was slightly more potent than M-5 _trans , but the differences did not reach statistical significance. M-6 _cis was significantly more potent than M-6 _trans . Responses to carbachol were antagonized by all compounds due to rightward shifts of the concentration–response curves, but only M-5 _trans also significantly reduced the maximum response. pK _B values obtained with Schild plot analysis indicated slightly higher potency for M-6 _cis than M-6 _trans . Ca²⁺ influx-dependent contractions elicited by K⁺ depolarization were less impaired by low concentrations of the M-6 isomers, but strongly suppressed by 100 µM of the M-5 isomers, suggesting an additional effect of the two M-5 isomers on Ca²⁺ influx. All investigated isomers of M-5 and M-6 are biologically active in reducing detrusor contraction in animal tissue. While M-5 _cis, M-6 _cis , and M-6 _trans possess surmountable or partially surmountable antagonistic properties at muscarinic receptors, M-5 _trans is a strong non-competitive antagonist. However, at higher concentration ranges, all four compounds seem to have additional effects on Ca²⁺ influx.     

Evaluation of Some Pharmacological Activities of ethanol extracts of seeds, pericarp and leaves of Eugenia Jamolana in Rats

The present study investigated the effect of ethanol extracts of seeds, pericarp and leaves of Eugenia Jamolana (E. Jamolana) on inflammation, gastric ulcer, anti-oxidants and hepatoprotective in rats. The acute inflammation was induced by intra-plantar injection of carrageenan (100 μl of 1 %) in the rat hind paw. Gastric ulcer was evoked by indomethacin (25 mg/kg) oral administration. Liver damage was induced by given CCL₄ (2.5 ml/kg) orally. The median lethal (LD₅₀) of the ethanol extract of both seeds and pericarp were determined and revealed that the investigated extracts of seeds and pericarp were non toxic up to 5g/kg. The anti-inflammatory results showed that the oral administration of ethanol extract of E. Jamolana seeds (250,500 mg/kg) showed significant inhibition of oedema formation in dose-dependent manner by −27.86, −41.23, −44.73, −51.78 % and by −63.16, −37.77, −47.04, −55.36 % at 1, 2, 3 and 4 h at 1, 2, 3 and 4 h, respectively. While the pericarp given at dose (500 mg/kg) exhibited significant inhibition of the oedema formation by −34.64, −21,8, 19.23 and −33.47 % at 1, 2, 3 and 4 h, respectively post carrageenan injection as compared with saline control group. E. Jamolana leaves fraction 1 given orally at dose of 25 mg/kg, induced non significant change on oedema, while the oedema response was significantly inhibited by −25.14, −33.4, −20.57 and −26.46 % at 1, 2, 3 and 4 h, respectively in group of rats that received leaves fraction 2 at the same dose. Rats were given leaves fraction 3 extract showed inhibition of oedema formation by −4.48 % at 1^st h post- carrageenan injection, while at 2^nd, 3^rd and 4^th h showed non significant change on oedema formation. The acute gastric mucosal lesions was significantly reduced by given ethanol extract of E. Jamolana seeds, pericarp (250, 500 mg/kg) and leaves fractions 1, 2 and 3 (25 mg/kg) respectively in dose dependent manner, as compared with indomethacin treated group (control group). All tested extracts showed significant reduction in elevated serum ALT, AST and ALP levels as compared with CCl ₄ treated group. The ethanol extract of E. Jamolana seeds, pericarp and leaves fractions 1, 2, 3 showed significant elevation of blood GSH level and significant reduction in elevated plasma lipid peroxides (MDA) as compared with CCl₄ treated group. In conclusion we can see that the ethanol extracts of E. Jamolana of seeds, pericarp and leaves fractions showed anti-inflammatory, anti-ulcer, hepatoprotective and anti-oxidants activity. Received 15 June 2008; accepted 11 November 2008     

Epidemiology of Acinetobacter baumannii of animal origin

Acinetobacter baumannii is an opportunistic pathogen responsible for nosocomial infections, however the origins of these bacteria remain unclear. Sixteen A. baumannii strains collected from animals slaughtered for human consumption were investigated for their susceptibility profiles, resistance islands (RIs), class 1 integrons, insertion sequence ISAba1, and bla_OXA-51-like and bla_AmpC genes. Polymerase chain reaction (PCR) and sequencing approaches were used to identify and type the isolates using the intrinsic gene bla_OXA-51-like genes. Genotyping was also performed by pulsed-field gel electrophoresis (PFGE) to establish whether there was a genetic relationship between animal isolates and the main human isolates of European clones I, II and III (ECI, ECII and ECIII) known to cause major hospital outbreaks. All 16 isolates (100%) were sensitive to carbapenems, gentamicin, ciprofloxacin and piperacillin/tazobactam but were resistant to amoxicillin, cefradine, trimethoprim and chloramphenicol. Moreover, all isolates had a baseline resistance to ceftazidime, with a minimum inhibitory concentration of 4 mg/L. All isolates lacked RIs, ISAba1 and class 1 integrons but harboured bla_OXA-51-like and bla_AmpC genes. In addition, this study reports for the first time three new bla_OXA-51-like genes (bla_OXA-148, bla_OXA-149 and bla_OXA-150) isolated from bacteria in cattle, which have not been found previously in human isolates. However, all isolates recovered from pig faecal samples harboured one type of bla_OXA-51-like (bla_OXA-51 itself), which has already been reported in human clinical isolates. From sequencing of the bla_OXA-51-like genes from animal isolates, it was possible to identify four different clusters similar to those identified by PFGE, which in turn also distinguished these four groups from the human ECI, ECII and ECIII strains.     

Models of estimation of the content of secondary metabolites in some Hypericum species

In the present study, models for estimation of the content of main secondary metabolites, namely hypericin, pseudohypericin, and hyperforin, were developed for Hypericum origanifolium Willd. (Guttiferae), Hypericum perfoliatum L., and Hypericum montbretii Spach., growing in Northern Turkey. Wild growing plants were harvested at vegetative, floral budding, full flowering, fresh fruiting, and mature fruiting stages and dissected into stem, leaf, and reproductive tissues. Actual secondary metabolite contents of plant materials were measured by a high performance liquid chromatography method. Multiple regression analysis using the Excel 2003 computer package was performed for each species and chemical separately to develop multiple regression models. The equation produced for predicting the content of secondary metabolites in different tissues of the species was formulized as: SMC?=?[a + (b₁?×?S) + (b₂?×?L) + (b₃?×?RP) + (b₄?×?S²) + (b₅?×?(1/RP))], where SMC is the secondary metabolite content of the whole plant, S is the secondary metabolite content of the stem, L is the secondary metabolite content of the leaf, RP is the secondary metabolite content of the reproductive parts, and a, b₁, b₂, b₃, b₄, and b₅ are coefficients. The R² coefficient values between predicted and observed contents of secondary metabolites were determined as 0.99 for H. origanifolium, 0.95–0.98 for H. perfoliatum, and 0.90–0.99 for H. montbretii. All R² values and standard errors were found to be significant at the p?<?0.05 level.     

Involvement of Thromboxane A2 in the Modulation of Pacemaker Activity of Interstitial Cells of Cajal of Mouse Intestine

Although many studies show that thromboxane A₂ (TXA₂) has the action of gastrointestinal (GI) motility using GI muscle cells and tissue, there are no reports on the effects of TXA₂ on interstitial cells of Cajal (ICC) that function as pacemaker cells in GI tract. So, we studied the modulation of pacemaker activities by TXA₂ in ICC with whole cell patch-clamp technique. Externally applied TXA₂ (5µM) produced membrane depolarization in current-clamp mode and increased tonic inward pacemaker currents in voltage-clamp mode. The tonic inward currents by TXA₂ were inhibited by intracellular application of GDP-β-S. The pretreatment of ICC with Ca²⁺ free solution and thapsigargin, a Ca²⁺-ATPase inhibitor in endoplasmic reticulum, abolished the generation of pacemaker currents and suppressed the TXA₂-induced tonic inward currents. However, chelerythrine or calphostin C, protein kinase C inhibitors, did not block the TXA₂-induced effects on pacemaker currents. These results suggest that TXA₂ can regulate intestinal motility through the modulation of ICC pacemaker activities. This modulation of pacemaker activities by TXA₂ may occur by the activation of G protein and PKC independent pathway via extra and intracellular Ca²⁺ modulation.     

Characterization of the prostanoid receptors mediating inhibition of PAF-induced aggregation of guinea-pig eosinophils

1. Prostanoids induce a wide range of biological actions which are mediated by specific membrane-bound receptors. We have recently shown that the E-type prostaglandins, PGE₁ and PGE₂, effectively inhibit eosinophil aggregation induced by platelet-activating factor (PAF). In an attempt to determine which prostanoid receptor(s) were involved, we investigated the effects of a range of selective prostanoid agonists and antagonists on eosinophil homotypic aggregation induced by PAF.
2. Both PGE₁ and PGE₂ (10⁻¹⁰ to 10⁻⁶ M) induced a concentration-related inhibition of the aggregation response induced by PAF. PGE₁ was more effective than PGE₂ but PGE₂ was slightly more potent than PGE₁ (approximate IC₅₀ values for PGE₁ and PGE₂ of 1.5×10⁻⁸ M and 5×10⁻⁹ M, respectively).
3. The EP₂-selective agonists, 11-deoxy-PGE₁, butaprost and AH13205, and the EP₂/EP₃-selective agonist, misoprostol, also inhibited PAF-induced aggregation. The rank order of potency for EP₂-selective agonists was 11-deoxy-PGE₁ > misoprostol > butaprost = AH13205. The protein kinase A inhibitor, KT5720 (10⁻⁶ M), reversed the inhibitory effects of 11-deoxy-PGE₁ (10⁻⁶ M) and AH13205 (10⁻⁵ M).
4. The EP₁/EP₃-selective agonist, sulprostone, and the EP₁-selective agonist, 17-phenyl-ω-trinor PGE₂, had no significant inhibitory activity when tested at concentrations up to 10⁻⁶ M. The EP₄-receptor antagonist, AH23848B, had no effect on PAF-induced aggregation and did affect the inhibitory activity of PGE₁.
5. The IP-selective agonist, cicaprost (up to 10⁻⁶ M), and the IP/EP₁-receptor agonist, iloprost (up to 10⁻⁵ M), had no significant effect on PAF-induced eosinophil aggregation. However, iloprost significantly augmented the inhibitory effects of a maximally inhibitory concentration of PGE₂.
6. PGD₂ (10⁻⁵ M) had no effect on eosinophil aggregation and the inhibitory activity of PGE₁ on PAF-induced eosinophil aggregation was not altered by the DP-selective receptor antagonist, BWA868C.
7. The results presented here suggest that the inhibition of PAF-induced eosinophil aggregation by prostanoids is mediated by the occupation of EP₂-receptors. It is important to note that the effects of naturally occuring prostanoids, such as PGE₂, on eosinophil aggregation occur at low concentrations highlighting a potential role for EP₂ receptors in regulating eosinophil function in vivo.

     

Binding of Memantine to Melanin: Influence of Type of Melanin and Characteristics

Purpose. The objectives of this study were to characterize sepia, synthetic, and bovine melanin and to determine their binding characteristics to the drug memantine. Methods. Physical methods were used to characterize sepia, synthetic, and bovine melanin. Their binding properties toward memantine were determined in deionized water and phosphate-buffered saline (PBS) at 37°C. Melanin-memantine binding was measured indirectly by determining the unbound fraction of memantine. Curve fitting according to the Langmuir binding isotherm for one binding site was used for the determination of binding capacity (B _Lmax ) and dissociation constant (K _D ). Results. Synthetic and sepia melanin had comparable Gaussian particle size distributions, whereas bovine melanin showed a heterogeneous distribution profile. The suspension medium had a small effect on the particle size distribution of synthetic and bovine melanin. There were characteristic differences in the infrared spectra of the melanins. The rank order for B _Lmax in deionized water was sepia > bovine > synthetic melanin. However, when the melanins were suspended in PBS, the B _Lmax values were lower, and the rank order was bovine > sepia > synthetic. Whereas the K _D values for sepia and synthetic melanin remained largely the same in deionized water and PBS, the K _D value for bovine melanin in PBS was more than twice than in deionized water. Conclusions. This study showed that the physical characteristics of the melanins investigated differ markedly. The binding of memantine to melanin is thought to be determined by the different chemistries of the melanins, particle size, and buffer electrolytes.     

Estimation of Surface Polarity of Silicas by Absorption Spectroscopy of Glycerin Suspensions of Adsorbed 6-Nitrobenzoindolinopyran

The title compound (6-NO₂-BIPS) is adsorptiochromic, becoming colored upon adsorption to a polar surface. Powders of 6-NO₂-BIPS adsorbed to silica gel or silicic acid are suspended in glycerin, and the absorption spectrum of the adsorbate is recorded by conventional absorption spectroscopy. The wave number of maximum absorption is related to the effective surface polarity by v*/cm^–1 = 90.85 Z + 11,571, where Z is the Kosower polarity measure. Silica surface polarity corresponds to Z = 86–89.     

大鼠盆总神经节腺苷三磷酸释放的调节

用荧光素-荧光素酶方法测定大鼠盆总神经节腺苷三磷酸(ATP)释放. 钠通道阻断剂河豚毒素(1 μmol·L^-1)抑制电刺激诱发的盆总神经节ATP的释放. 灌流液中去除Ca^2＋并加入EGTA(1 mmol·L^-1)后消除ATP的释放. 腺苷(100 μmol·L^-1)，A₁腺苷受体激动剂环戊腺苷 (0.1 μmol·L^-1)，毒蕈碱性受体激动剂氧化震颤素(1 μmol·L^-1)和5-羟色胺(100 μmol·L^-1)减少ATP的释放. A₁腺苷受体拮抗剂8-环戊基-1，3-二丙基黄嘌呤(10 nmol·L^-1)，α₂肾上腺素受体拮抗剂育亨宾(3 μmol·L^-1)，D₂多巴胺受体拮抗剂舒必利(20 μmol·L^-1)和组胺(100 μmol·L^-1)增加ATP的释放.　结果提示， 在大鼠盆总神经节存在着作为神经递质参与突触传递的ATP释放. A₁腺苷受体，毒蕈碱性受体，α₂肾上腺素受体，D₂多巴胺受体，5-羟色胺受体及H₁组胺受体激动剂或拮抗剂可以通过节前机制影响ATP的释放.     

罗布麻提取物对STZ糖尿病大鼠肾损害的防护作用

本文探讨了罗布麻提取物 (AV) 对STZ大鼠糖尿病肾脏损害的防护作用及部分作用机制。采用链脲佐菌素 (STZ) 诱导大鼠糖尿病模型方法, 观察8周时大鼠血糖、肾功能、氧化应激等指标以及经AV治疗后的变化。结果显示, 糖尿病大鼠的血糖、血尿素氮、24 h尿蛋白含量、尿量、肾脏肥大指数、肾皮质MDA含量显著升高; 肾皮质SOD、GSH活性显著降低。AV干预治疗组的上述指标得到改善, 具有显著性差异。实验结果表明, AV对STZ大鼠糖尿病肾功能有明显的防护作用, 其作用可能与抑制肾脏氧化应激作用有关。     

The contribution of absorption of integral nanocrystals to enhancement of oral bioavailability of quercetin

In this study, self-discriminating hybrid nanocrystals was utilized to explore the biological fate of quercetin hybrid nanocrystals (QT-HNCs) with diameter around 280 nm (QT-HNCs-280) and 550 nm (QT-HNCs-550) following oral and intravenous administration and the contribution of integral nanocrystals to oral bioavailability enhancement of QT was estimated by comparing the absolute exposure of integral QT-HNCs and total QT in the liver. Results showed that QT-HNCs could reside in vivo as intact nanocrystals for as long as 48 h following oral and intravenous administration. A higher accumulation of integral QT-HNCs in liver and lung was observed for both oral and intravenous administration of QT-HNCs. The particle size affects the absorption and biodistribution of integral QT-HNCs and total QT. As compared to QT-HNCs-550, QT-HNCs-280 with smaller particle size is more easily absorbed, but dissolves faster in vivo, leading to higher distribution of QT (146.90 vs. 117.91 h·μg/mL) but lower accumulation of integral nanocrystals (6.8 2e10 vs. 15.27e10 h·[p/s]/[µW/cm²]) in liver following oral administration. Due to its slower dissolution and enhanced recognition by RES, QT-HNCs-550 with larger diameter shows higher liver distribution for both of QT (1015.80 h·μg/mL) and integral nanocrystals (259.63e10 h·[p/s]/[µW/cm²]) than those of QT-HNCs-280 (673.82 & 77.66e10 h·[p/s]/[µW/cm²]) following intravenous administration. The absolute exposure of integral QT-HNCs in liver following oral administration of QT-HNCs are 8.78% for QT-HNCs-280 and 5.88% for QT-HNCs-550, while the absolute exposure of total QT for QT-HNCs-280 and QT-HNCs-550 are 21.80% and 11.61%, respectively. Owing to imprecise quantification method, a surprisingly high contribution of integral QT-HNCs to oral bioavailability enhancement of QT (40.27% for QT-HNCs-280 and 50.65% for QT-HNCs-550) was obtained. These results revealed significant difference in absorption and biodistrbution between integral nanocrystals and overall drugs following oral and intravenous administration of QT-HNCs, and provided a meaningful reference for the contribution of integral nanocrystals to overall bioavailability enhancement.     

Synthesis of two nitro analogs of tranylcypromine: Relations of aromatic substitution of nitro groups to MAO-Inhibitory activity

Two new nitro analogs of tranylcypromine, (E)-2-(p-nitrophenyl)cyclopropylamine ((E)-p-NTCP) and (E)-2-(m-nitrophenyl)cyclopropylamine ((E)-m-NTCP) were synthesized in order to examine the effect of aromatic nitro substitution on the MAO-inhibitory activity of 2-phenylcyclopropylamines. The compounds were obtained by treatingt-butyl (E)-2-(p-nitrophenyl) cyclopropanecarbamate andt-butyl (E)-2-(m-nitrophenyl)cyclopropanecarbamate withp-toluenesulfonic acid in CH₃CN. Inhibitions of rat brain mitochondrial MAO-A and B by the compounds were examined using serotonin and benzylamine as the substrate at bothin vitro andex vivo levels. It was found fromin vitro measurements that(E)-p-NTCP at 6.0×10^?5M elicited merely 22.5% inhibition against MAO-B without any effect on MAO-A. In contrast,(E)-m-NTCP showed fair degrees of inhibitions of MAO-A and B with IC₅₀ values, 2.5×10^?7M and 1.4×10^?6M, respectively. It was also noted from(E)-m-NTCP thatm-nitro substitution caused a shift of selectivity of the inhibition toward MAO-A. According toex vivo measurements at 1.5, 3, 6, and 12 hr following the administration of a dose of 0.015 mmol/kg, i.p. to the rats, the inhibition percents of MAO-A by(E)-m-NTCP were 58.6, 63.7 63.6, and 46.6%, slightly lower than those observed by tranylcypromine. Whereas,(E)-p-NTCP at the same dose level did not show significant inhibitions against both MAO-A and MAO-B. Possible reasons for the difference in potencies between(E)-m-NTCP and(E)-p-NTCP were sought in relation to differing electron withdrawing effects ofm-andp-substituents which will influence electron density of the side chain amino functions and the partitions.     

Evaluation of the use of partition coefficients and molecular surface properties as predictors of drug absorption: a provisional biopharmaceutical classification of the list of national essential medicines of Pakistan

Background and the purpose of the study

Partition coefficients (log D and log P) and molecular surface area (PSA) are potential predictors of the intestinal permeability of drugs. The aim of this investigation was to evaluate and compare these intestinal permeability indicators.

Methods

Aqueous solubility data were obtained from literature or calculated using ACD/Labs and ALOGPS. Permeability data were predicted based on log P, log D at pH 6.0 (log D_6.0), and PSA.

Results

Metoprolol''s log P, log D_6.0, and a PSA of <65 Å correctly predicted 55.9%, 50.8% and 54.2% of permeability classes, respectively. Labetalol''s log P, log D_6.0 and PSA correctly predicted 54.2%, 64.4% and 61% of permeability classes, respectively. Log D_6.0 correlated well (81%) with Caco-2 permeability (P_app). Of the list of national essential medicines, 135 orally administered drugs were classified into biopharmaceutical classification system (BCS). Of these, 57 (42.2%), 28 (20.7%), 44 (32.6%), and 6 (4.4%) were class I, II, III and IV respectively.

Conclusion

Log D_6.0 showed better prediction capability than log P. Metoprolol as permeability internal standard was more conservative than labetalol.     

卡贝缩宫素对比缩宫素预防剖宫产后出血有效性及安全性的Meta-分析

目的 系统评价卡贝缩宫素对比缩宫素预防产后出血的临床疗效和安全性。方法 计算机检索EMbase、PubMed、中国期刊全文数据库（CNKI）、维普中文科技期刊全文数据库（VIP）、中国生物医学文献数据库（CBM）和万方数据库,收集卡贝缩宫素对比缩宫素用于预防产后出血的随机对照研究（RCT）,检索时限均从2000年1月至2017年12月。由2位研究者筛选文献、提取资料,采用Rev Man 5.1软件进行Meta-分析。结果 共纳入14个RCTs,3 052例患者。Meta-分析结果显示相对于缩宫素,卡贝缩宫素能显著降低产后出血率[OR=0.48,95% CI（0.36~0.63）,P<0.001],术中出血量[MD=-67.31,95% CI（-86.34~-48.28）,P<0.001]、术后2 h出血量[MD=-50.43,95% CI（-71.32~-29.55）,P<0.001]和术后24 h出血量[MD=-62.87,95% CI（-85.59~-40.16）,P<0.001];血红蛋白减少[MD=-4.24,95% CI（-6.16~-2.31）,P<0.001]和不良反应发生率[OR=0.52,95% CI（0.41~0.65）,P<0.001]。结论 本研究结果显示卡贝缩宫素预防产后出血的临床疗效和安全性优于缩宫素,值得临床推广。     

Hepatic Failure Leads of Lethality of Chlordecone-Amplified Hepatotoxicity of Carbon Tetrachloride

Hepatic Failure Leads to Lethality of Chlordecone-AmplifiedHepatotoxicity of Carbon Tetrachloride. SONI, M. G., AND MEHENDALE,H. M. (1993). Fundam. Appl. Toxicol. 21, 442–450. Chlordecone (Kepone) amplification of CCl₄ toxicity occurs atsmall, nontoxic levels of chlordecone and CC1₄ and results inhighly increased irreversible hepatotoxicity culminating inlethality. Although it is generally assumed that CCl₄ lethalityis due to hepatic failure, no definitive studies are availablein the literature bridging massive liver failure and death.The present studies were designed to evaluate whether hepaticfailure is the cause of the lethality during chlordecone-amplifiedCCl₄ toxicity. Male Sprague-Dawley rats were maintained on controlor a chlordecone (10 ppm) diet for 15 days and injected withCCl₄ (100 µl/kg, ip) on Day 16. Rats were killed at 0,6, 12, 24, 36, and 48 hr after CCl₄ challenge. Hepatic failurewas evaluated by measuring plasma glucose, ammonia, bilirubin,aspartate trans-aminase (AST), alanine transaminase (ALT), sorbitoldehydrogenase (SDH), hepatic ATP, glycogen, and by histologicaland histomorphometric analyses. Plasma creatinine, urea, andkidney histopathology were also assessed for possible renalinjury. As expected CCl₄ administration to chlordecone-pretreatedrats resulted in 20% lethality by 36 hr, which progressed withtime, and all rats died within 72 hr. A significant and progressivehypoglycemia was observed with a 60% reduction in plasma glucoseat 48 hr. Hepatic glycogen content dropped precipitously. Similarly,hepatic ATP levels remained suppressed (80% of control) at allthe time points studied. Plasma ammonia levels were significantlyelevated, and by 48 hr, a threefold increase was observed. PlasmaALT, AST, SDH, and bilirubin increased progressively until thedeath of rats receiving the chlordecone + CCl₄ combination.Histopathologically, the liver sections revealed a progressiveand irreversible damage evidenced by vacuolation, accumulationof fat, and increase in hepatocellular necrosis resulting indisrupted hepatolobular structure. Administration of the samedose of CCl₄ to rats maintained on a normal diet resulted inonly marginal changes in plasma enzymes, no increase in serumbilirubin, and no significant injury in liver sections at 24hr. CCl₄ administration to chlordecone-pretreated rats resultedin a marginal increase in plasma creatinine and urea only atlater time points. Histopathological examination of sectionsof kidneys from rats receiving either chlordecone + CCl₄ combinationor the same dose of CCl₄ alone did not reveal any evidence ofsignificant renal injury. The clinical end points of hepaticfunction measured in the present study are consistent with thesequel of hepatic failure and hepatic encephalopathy leadingto animal death in chlordecone-amplified CCl₄ toxicity.     

An exploration of the autonomic effects of phenothiazines

Summary To summarize, seven male chronic schizophrenic patients who were tested when under placebo and again under active phenothiazine medication were compared with eleven male patients tested both times under active phenothiazines. Phenothiazines produced no appreciable change in autonomic balance but instead, in replication of Sherry's earlier findings, brought about a change in autonomic pattern in which an increase in heart rate, a decrease in skin conductance, and possibly an increase in finger temperature predominated. There was an indication that heart rate reactivity is reduced by phenothiazines. A more desirable psychological status in terms of behavior ratings tends to be associated with a more parasympathetic autonomic balance. Other studies have shown that the use of phenothiazines is associated with improvement in behavioral ratings, but the present study suggests that phenothiazines do not produce an autonomic balance shift in the parasympathetic direction. In the discussion of this apparent contradiction, it was suggested that those who improve most from phenothiazine treatment may be those in whom a particular autonomic pattern induced by such drugs is less pronounced.

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Résumé Quelques tests physiologiques ont été appliqués chez sept mâles schizophrènes chroniques d'abord sous d'traitement de placebo et ensuite sous le traitement avec des phénothiazines. Ce groupe était comparé avec un autre groupe se composant d'onze malades indentiques auxquels les même tests les deux fois pendant ont été appliqués le traitement avec les phénothiazines. Les phénothiazines ont produit très peu de modification de la balance autonomie mais plutôt, comme dans l'expérience de Sherry, une modification du modèle autonomie y comprenant un rythme cardiaque plus rapide, une diminution de la conduction de la peau, et, peut-être, une augmentation de la température des doigts. Il y avait quelque indication que la réactivité du rythme cardiaque est réduit par les phénothiazines. Un meilleur état psychologique concernant l'évaluation du comportement apparaît s'associer avec une balance autonomie plutôt parasympathique. D'autres études ont démonstré que l'emploi des phénothiazines s'associet avec une amélioration de l'évaluations du comportement, mais la présente étude suggère que les phénothiazines ne produisent pas un changement de la balance autonomie dans la direction parasympathique. En discutant cette contradiction apparente l'auteur propose que les individus qui s'améliorent le plus par le traitement des phénothiazines sont ceux chez lesquels le modèle autonomie particulier induit par les drogues susdites est moins prononcé.

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A slightly different version was presented at the Eighth Annual Veterans Administration Conference on Cooperative Studies in Psychiatry, Kansas City, 1963.