Effect of a Bis(Benzyl)Polyamine Analogue, and DL-α-difluoromethylornithine on Parasite Suppression and Cellular Polyamine Levels in Golden Hamster During Leishmania Donovani Infection

We examined the antileishmanial activity of DL-α-difluoromethylornithine (DFMO) and a bis(benzyl)polyamine analogue (MDL 27695; N,N′-bis{3[(phenyl-methyl)amino] propyl} 1,7-diaminoheptane) in L. donovani infected golden hamsters. DFMO, an enzyme activated irreversible inhibitor of ornithine decarboxylase, the rate limiting enzyme in polyamine biosynthesis, has potent antileishmanial activity. When given as a 2% solution in drinking water 2 days after infection and continued for 4 days, it suppressed liver parasites by 90% and spleen parasites by 99%. Liver parasites were suppressed by 50% and spleen parasites by 77% in L. donovani infected hamsters when treated three times per day for 4 days with a total dose of 60 mg kg^-1 body weight of MDL 27695. The polyamine content of the liver and spleen of hamsters was determined after 8 days of L. donovani infection and also after treatment with these drugs. Putrescine and spermidine levels increased significantly in both liver and spleen after Leishmania infection of golden hamsters. Treatment with drugs that inhibit the growth of Leishmania amstigotes in the liver and spleen of golden hamsters also reduced polyamine levels of previously infected golden hamsters. There is a close correlation between the therapeutic activity of the drugs and the polyamine content.     

Effects of the phosphodiesterase 4 inhibitors SB 207499 and AWD 12-281 on the inflammatory reaction in a model of allergic dermatitis

The inhibitors of the phosphodiesterase 4, SB 207499 (cilomilast, c-4-cyano-4-(3-cyclopentyloxy-4-methoxy-phenyl)-r-L-cyclohexane carboxylic acid) and AWD 12-281 (N-(3,5-dichloropyrid-4-yl)-[1-(4-fluorobenzyl)-5-hydroxy-indole-3-yl]-glyoxylic acid amide) were tested in a model of allergic dermatitis in mice. To obtain an allergic dermatitis, BALB/c mice were sensitized to toluene-2,4-diisocyanate. The allergic reaction was challenged by topical administration of toluene-2,4-diisocyanate onto the mice ears. Before challenge, two groups of mice were treated topically (ear skin) with SB 207499 or AWD 12-281. There was a significant ear swelling in toluene-2,4-diisocyanate-challenged mice ears 4, 8, 16, 24 and 48 h after challenge. SB 207499 and AWD 12-281 inhibited this swelling significantly 8, 16, 24 and 48 h after the challenge. For biochemical parameters and histology, ears were sampled from mice sacrificed 4, 8 and 16 h after the challenge. In homogenized tissue, SB 207499 and AWD 12-281 inhibited significantly the secretion of interleukin 1beta induced by toluene-2,4-diisocyanate 4 and 8 h after challenge. The cell influx (granulocytes) observed in the toluene-2,4-diisocyanate-challenged mice 8 and 16 h after challenge was nearly abolished by AWD 12-281 and SB 204799.     

吡喹酮对日本血吸虫皮层损害的扫描电镜观察

给感染血吸虫病的小鼠一次灌胃吡喹酮300 mg/kg后10分钟至48小时,自鼠肝内取虫作体表皮层扫描电镜观察。结果表明,干给小鼠药后10分钟,两性血吸虫皮层即有变化,1～2小时后已十分明显,主要变化为水肿,皮层褶嵴紧密连接、融合,形成大量球状物或小泡,感觉器肿大、破溃,以及皮层糜烂、剥落和白细胞附着于皮层损害处等。     

叙利亚地鼠作为狂犬病暴露后免疫动物模型的研究

目的  对叙利亚地鼠（地鼠）作为狂犬病暴露后疫苗免疫效果动物模型的可行性进行研究。方法 将狂犬病病毒CVS株和CTN-1V株分别肌内感染不同周龄的地鼠和小鼠,观察动物对不同毒株的敏感性。用直接免疫荧光法检测CVS株进入地鼠脑组织的情况;用快速荧光灶抑制试验检测血清中和抗体。以不同病毒量CVS株感染8周龄雌性地鼠,确定暴露时病毒的最佳感染剂量。对暴露后地鼠用疫苗进行免疫,观察疫苗的保护效果。结果  地鼠感染后7 d左右出现狂犬病临床症状,同一病毒株对地鼠的致病力比小鼠强〔6.4～8.0 lg半数致死量（LD₅₀）/ml对3.4~6.5 lgLD₅₀/ml〕;3周龄和8周龄地鼠对病毒的敏感性无差异。感染后5~6 d病毒进入地鼠脑组织。以3.8～4.0 lg小鼠脑内半数致死量（MICLD₅₀）/ml的CVS株感染后6～7 d,地鼠血清中检出中和抗体。暴露后疫苗免疫结果显示,不同疫苗具有不同程度的保护效果。结论  地鼠对狂犬病病毒神经外途径感染敏感,临床症状典型,潜伏期恒定,感染后免疫血清抗体应答出现早,具备作为暴露后疫苗免疫动物模型的条件。     

Synthesis of 2,4-disubstituted 6-methoxy-8-aminoquinoline analogues as potential antiparasitics

A series of 2,4-disubstituted 8-aminoquinoline analogues were synthesized and evaluated against Plasmodium berghei in mice and Leishmania donovani in hamsters. 8-[[6-(Diethylamino)hexyl]amino]-2-ethyl-6-methoxy-4-methylquinoline (8a) possessed significant activity against L. donovani. 2-Ethyl-4-methylprimaquine (7a) was evaluated against Plasmodium cynomolgi in rhesus monkey and found to have activity equal to that of primaquine.     

Primaquine analogues: derivatives of 4-amino-2-methoxyacridine.

Based on the antimalarial activity of primaquine (1a) and its 4-methyl analogue 1b, 4-aminoacridinyl analogues, 4-[(4-amino-1-methylbutyl)amino]-2-methoxyacridine (2a) and 4-[(4-amino-1-methylbutyl)amino]-2-methoxy-9-methylacridine (2b), were prepared and evaluated as potential tissue schizonticidal agents. These compounds were found to be substantially less active than primaquine against Plasmodium cynomolgi in the rhesus monkey. The antileishmanial activity in hamsters of 4-[[6-(diethylamino)hexyl]amino]-2-methoxy-9-methylacridine (2d) was found to be considerably less than that of 8-[[6-(diethylamino)hexyl]amino]-6-methoxy-4-methylquinoline (1c).     

A double-blind, placebo controlled, cross-over comparison of the analgesic effect of ibuprofen 400 mg and 800 mg on laser-induced pain.

1. The analgesic efficacy of single oral doses (400 mg, 800 mg) of ibuprofen on argon laser-induced pain was studied in a double-blind, placebo controlled, three way cross-over comparison. Ten healthy volunteers participated. 2. Pain thresholds and plasma concentrations of the S- and R-enantiomers of ibuprofen were measured every hour up to 8 h after medication. 3. Ibuprofen (400 mg) produced an analgesic effect significantly superior (P less than 0.05) to placebo 1-4 h after medication. Ibuprofen (800 mg) was significantly superior to placebo 2-4 h after administration. No differences were found between 400 mg and 800 mg, when hourly threshold differences were compared. 4. Comparing total analgesic effect (area under effect curve), both active medications were superior to placebo (P less than 0.01-0.05), and 400 mg was superior to 800 mg (P less than 0.05). 5. Peak plasma concentrations of S- and R-ibuprofen occurred between 1.2 and 1.5 h. Concentrations after the 800 mg dose were higher than those after the 400 mg dose at all times.     

他莫昔芬对高血压脑出血模型大鼠早期脑损伤的神经保护作用研究

目的:研究他莫昔芬对高血压脑出血模型大鼠早期脑损伤的神经保护作用。方法:取大鼠随机分为假手术组、模型组和高、中、低剂量实验(他莫昔芬10、5、2.5 mg/kg)组,每组48只,除假手术组外其余各组大鼠建立高血压脑出血模型,建模后分别腹腔注射相应药物,每24 h给药1次。考察给药后4、8、12、24、72 h和7 d时各组大鼠血肿周围脑组织中Fas相关死亡域蛋白(FADD)的阳性细胞数、凋亡细胞数、脑水肿情况以及脑组织形态学变化情况。结果:与假手术组比较,其余各组大鼠不同时间的脑组织中FADD阳性细胞数、凋亡细胞数、脑水肿比例均明显增加(P<0.05);与模型组比较,低剂量实验组大鼠的FADD阳性细胞数(给药后24、72 h)、凋亡细胞数(给药后24、72 h和7 d)和脑组织含水量(给药后72 h)均明显减少(P<0.05),中、高剂量实验组大鼠的FADD阳性细胞数(给药后8、12、24、72 h)、凋亡细胞数(给药后12、24、72 h和7 d)和脑组织含水量(给药后12、24、72 h和7 d)均明显减少(P<0.05),各剂量实验组大鼠血肿周围组织水肿范围变小、程度减轻,炎症细胞的浸润减轻,固缩细胞减少,肿胀细胞增多,细胞周围间隙变小,且均呈剂量依赖性。结论:他莫昔芬能够呈剂量依赖性地抑制高血压脑出血模型大鼠的FADD阳性细胞表达,减少脑组织细胞的凋亡,同时减轻脑出血后的脑水肿,发挥显著的神经保护作用。     

Treatment of spatial memory impairment in hamsters infected with West Nile virus using a humanized monoclonal antibody MGAWN1

In addition to functional disorders of paresis, paralysis, and cardiopulmonary complications, subsets of West Nile virus (WNV) patients may also experience neurocognitive deficits and memory disturbances. A previous hamster study has also demonstrated spatial memory impairment using the Morris water maze (MWM) paradigm. The discovery of an efficacious therapeutic antibody MGAWN1 from pre-clinical rodent studies raises the possibility of preventing or treating WNV-induced memory deficits. In the current study, hamsters were treated intraperitoneally (i.p.) with 32 mg/kg of MGAWN1 at 4.5 days after subcutaneously (s.c.) challenging with WNV. As expected, MGAWN1 prevented mortality, weight loss, and improved food consumption of WNV-infected hamsters. The criteria for entry of surviving hamsters into the study were that they needed to have normal motor function (forelimb grip strength, beam walking) and normal spatial reference memory in the MWM probe task. Twenty-eight days after the acute phase of the disease had passed, MGAWN1- and saline-treated infected hamsters were again trained in the MWM. Spatial memory was evaluated 48 h after this training in which the hamsters searched for the location where a submerged escape platform had been positioned. Only 56% of infected hamsters treated with saline spent more time in the correct quadrant than the other three quadrants, as compared to 92% of MGAWN1-treated hamsters (P ? 0.05). Overall these studies support the possibility that WNV can cause spatial memory impairment and that therapeutic intervention may be considered.     

吡喹酮对21-d日本血吸虫童虫皮层损害的扫描电镜观察(英文)

目的:观察吡喹酮对21-d童虫皮层的作用.方法:小鼠于感染日本血吸虫尾蚴达21 d时,ig1剂吡喹酮,并在治疗后1-48 h的不同时间内剖杀取虫,作扫描电镜观察.结果:吡喹酮的剂量为300 mg·kg~(-1)时,宿主体内的21-d童虫示有轻度或中度的皮层褶嵴肿胀、融合、糜烂或破溃,且以盘状感觉器的肿胀为特征.用吡喹酮的较高剂量500 mg·kg~(-1)治疗,虫的体表亦有相似的变化,但较广泛和严重.若每d ig吡喹酮500 mg·kg~(-1),连给3 d,则虫的皮层严重肿、糜烂和剥落,并伴有宿主的白细胞附着.结论:结果表明,吡喹酮对21-d童虫有直接杀死作用.     

人尿液三苯双脒代谢物浓度测定及其排泄动力学研究

目的建立人尿液三苯双脒代谢物对-(1-二甲氨基乙亚氨基)苯胺(简称氨脒)浓度测定的HPLC法,并进行其排泄动力学研究。方法16名志愿者随机分为3组,分别空腹口服200、400和600 mg三苯双脒肠溶片,收集服药前及服药后0～2 h,～4 h,～6 h,～8 h,～12 h和～24 h尿液,稀释,以米氮平为内标,乙腈-甲醇-水-三乙胺(35:35:30:0.2,V:V:V:V)为流动相,采用Agilent Extend-C_(18)柱(4.6 mm×250 mm,5μm)分离,检测波长249 nm,流速0.7 mL·min~(-1)。结果氨脒在5～500 mg·L~(-1)浓度范围内线性关系良好,回归方程Y=4.283 X+0.001(r=0.999 4),最低定量限5 mg·L~(-1),低、中、高3个浓度样品相对回收率分别为(99.8±s 2.5)、(99.3±2.2)和(97.0±1.1)%,批内、批间变异RSD均小于5%,-20℃冷冻24 h及7 d稳定,反复冻融稳定。健康志愿者口服低、中、高3个剂量三苯双脒肠溶片后,约有35%～53%的氨脒于服药24 h后经尿液排出,采用DAS 2.0软件计算氨脒t_(1/2)分别为(4.4±1.9)、(4.5±2.3)和(3.8±0.9)h,Ke分别为(0.19±0.10)、(0.19±0.10)和(0.19±0.04)·h~(-1)。结论本方法简单、快速、灵敏、重现性好,能用于健康志愿者口服三苯双脒肠溶片后氨脒尿液浓度的测定,氨脒经肾脏排泄呈现明显的剂量依赖性特征。     

T-477, a novel Ca(2+)- and Na(+) channel blocker, prevents veratridine-induced neuronal injury

To evaluate the effect of (R)-(+)-2-(4-chlorophenyl)-2, 3-dihydro-4-diethyl aminoacetyl-4H-1,4-benzothiazine hydrochloride (T-477), a novel Na(+)- and Ca(2+) channel blocker, on neuronal injury in vitro, we studied veratridine-induced injury in cultured rat hippocampal neurons. Neurons swelled extensively 10 min after the addition of veratridine, and returned to their initial size within 2 h. Intracellular Na(+) and Ca(2+) concentrations and amino acid release from the cells, in particular, that of glutamate, increased after the treatment with veratridine. Approximately 70% of neurons died within 24 h. T-477 inhibited both veratridine-induced swelling and death in a concentration-dependent manner. Moreover, T-477 concentration dependently reduced the increases in Na(+) and Ca(2+) influx and amino acid release. These results suggest that T-477 prevented the veratridine-induced influx of Na(+) and, thereby, reduced neuronal swelling. This, combined with the effects of T-477 on the inhibition of Ca(2+) influx and glutamate release, possibly by the blockade of Na(+) channels, may be the mechanism by which T-477 protects neurons from death induced by veratridine.     

Swelling,Erosion, and Release Behavior of PEO/Primaquine Matrix Tablets

Extended-release primaquine tablets were developed using polyethylene oxide (PEO) as a hydrophilic swellable polymer with different amounts and molecular weights (4 × 10⁶ and 8 × 10⁶). Investigations were carried out in order to verify the matrix performance. The evaluated parameters were weight, hardness, thickness, friability, and drug content. The swelling and erosion matrices as well as drug release profile were analyzed under dissolution conditions. The statistical model ANOVA and Tukey-Kramer HSD were considered. The results showed that all formulations provided adequate physical characteristics and a time release about eight hours following a non-Fickian diffusion model. The kinetics of drug delivery was directly related to the synchronization of swelling and erosion matrices. The formulations prepared with high PEO concentrations showed a lower rate of erosion, a slower drug release, and faster rate of swelling, as compared with matrices containing lower PEO concentration.     

Hypolipidemic and antioxidant activity of the novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor KY-455 in rabbits and hamsters

The hypolipidemic and antioxidant effects of N-(4,6-dimethyl-1-pentylindolin-7-yl)-2,2-dimethylpropanamide (CAS 178469-71-1, KY-455), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, were examined in hyperlipidemic rabbits and normolipidemic hamsters. KY-455 inhibited rabbit intestinal, hepatic, macrophage and adrenal ACAT with IC50 values of 0.4, 0.9, 2.9 and 4.1 micromol/l, respectively. KY-455 also inhibited rabbit plasma and LDL-peroxidation (IC50: 0.4 and 1.7 micromol/l, respectively). In rabbits fed a high-cholesterol diet, treatment with KY-455 (30 mg/kg/day) for 8 days markedly lowered serum esterified, free, low-density lipoprotein (LDL)-cholesterol, and hepatic esterified cholesterol levels. KY-455 tended to inhibit ex vivo hepatic ACAT activity 5 h after the final administration. KY-455 also inhibited ex vivo peroxidation of plasma lipids 1 and 5 h after the final administration in rabbits. In normolipidemic hamsters fed a regular diet, treatment with KY-455 (30 mg/kg, twice a day) for 4 days significantly reduced serum esterified, free and LDL-cholesterol, and hepatic esterified and free cholesterol levels. A single administration of KY-455 (30 mg/kg) significantly inhibited ex vivo hepatic ACAT activity in hamsters. In conclusion, KY-455 showed in vitro inhibitory effects on LDL-peroxidation and macrophage ACAT activity at similar concentrations, and in vivo hypolipidemic and ex vivo antioxidative effects at the same dose. Long-term administration of KY-455 is expected to prevent the progress of atherosclerosis by lowering plasma lipid levels, inhibiting both LDL-oxidation and accumulation of cholesterol in macrophages.     

Comparative metabolism of polychlorinated biphenyls and tissue distribution of persistent metabolites in rats, hamsters, and Guinea pigs.

The present study was performed to compare the metabolite profiles of polychlorinated biphenyls (PCBs) in the liver and serum of rats, hamsters, and guinea pigs after exposure to a PCB mixture, Kanechlor 500 (100 mg/kg, i.p.). The percentage of contribution of major PCB residues in the liver 5 days after exposure indicated that nonplanar PCBs with 2,4- or 2,3,4-chlorine substitution were more abundant in the liver in the order rats (43% of total PCBs) > hamsters (20%) > guinea pigs (11%), whereas coplanar PCBs with 4-, 3,4-, or 3,4,5-chlorine substitution were predominant in guinea pigs (61%), followed by hamsters and rats (both 26%). The hepatic concentrations of methylsulfonyl metabolites (MeSO(2)-CBs) were higher in the order guinea pigs > rats > hamsters. Whereas hamsters formed minute amounts of MeSO(2)-CBs from 2,5-dichloro-substituted PCBs, guinea pigs formed higher levels of meta-MeSO(2)-CBs derived from 2,3,6-trichloro-substituted PCBs. In contrast, the serum concentrations of phenolic PCBs were higher in the order hamsters > rats > guinea pigs. Metabolites were predominated by 4-OH-2,3,5,3',4'-pentaCB (89% contribution) for rats, 3-OH-2,4,5,2',4'-pentaCB (56%) for guinea pigs, and dihydroxylated metabolites (39%) for hamsters. The reduced elimination of coplanar PCBs and the specific distribution of MeSO(2)- and phenolic PCBs may have implications for the differences in sensitivity to PCB toxicity among rats, guinea pigs, and hamsters.     

Effects of prenatal diazepam treatment on Mycobacterium bovis-induced infection in hamsters.

In utero exposure of rats to low dosages of diazepam has been found to result in depression of cellular and humoral immune responses during adulthood, with marked changes in macrophage spreading and phagocytosis. The present experiment was undertaken to investigate the resistance of adult hamsters to Mycobacterium bovis after prenatal exposure to diazepam. Time-pregnant hamsters were exposed to diazepam (1.0 or 1.5 mg kg(-1) day(-1) subcutaneously) or vehicle from gestational day 9 to 15. A total of 36 different litters (12 of them control and 12 for each experimental group) born after a 16/17-day gestation were used. One male from each litter was infected twice with identical inoculum concentrations of M. bovis at 75 and 107 days of age. This infection model involves the participation of macrophages and T and B cell populations. The animals prenatally exposed to the higher (1.5 mg/kg) dose of diazepam exhibited: (1) increased weight loss, (2) increased mortality, (3) increased granuloma areas measured in the liver, lung and spleen, (4) increased spleen weight, and (5) increased scores of M. bovis colony forming units (CFU) isolated from liver, lung and spleen. These effects were dose-dependent, and were not detected or were less severe in animals treated with the lower (1.0 mg/kg) dose of diazepam as well as in those of the control group. The present data demonstrate an impaired defence against M. bovis in adult hamsters after in utero exposure to a dosage of 1.5 mg/kg of diazepam.     

Role of the sarcoplasmic reticulum in altered action potential and contraction of myopathic human and hamster ventricle

1. The present experiments were performed in order to study the role of the sarcoplasmic reticulum (SR) in the altered action potential and contraction of ventricular myocardium obtained from myopathic Syrian hamster and explanted human hearts (n = 8). The hamsters included age-matched healthy hamsters (F1B; n = 18), young myopathic hamsters (Bio 14.6; n = 8; aged 17-27 weeks) and older myopathic hamsters (n = 10; aged 39-43 weeks). 2. Action potentials were recorded by means of a microelectrode technique and force was recorded using a transducer. Post-rest potentiation of contraction (PRPC), a measure of the SR Ca2+-pumping activity, was determined after different rest intervals (2-60 s). Furthermore, cyclopiazonic acid (10 micro mol/L), a specific blocker of SR Ca2+-ATPase, was used to unmask abnormalities in the function of the SR. 3. The relationship between PRPC and rest interval was similar in younger healthy and myopathic hamsters, but the curve of the older myopathic muscle was obviously shifted downwards. Cyclopiazonic acid decreased predominantly the ascending part of the curve in both the healthy and myopathic hamster myocardium and could induce spontaneous action potentials during drug exposure or after washout. 4. In human myopathic myocardium, the curve of the PRPC-rest interval peaked at longer intervals (40-60 s) compared with that of the hamsters (10-20 s). Cyclopiazonic acid markedly depressed the relationship and increased the diastolic force (contracture) at high driving frequency, but did not induce action potentials during the rest interval. 5. We conclude that an impaired function of the SR contributes to the progressive deterioration of ventricular function in dilated cardiomyopathy and that the electromechanical behaviour of the ventricular myocardium of patients affected by dilated cardiomyopathy shows similarity and differences with the myopathic Syrian hamster model.     

海藻酸钙凝胶微丸作为口服缓释给药载体的研究

将海藻酸钠溶液滴入胶凝剂氯化钙溶液中制备了海藻酸钙凝胶微丸。以胶凝过程中凝胶微丸重量变化 (失水量 )研究了胶凝速率及不同浓度海藻酸钠溶液 ( 1 %～ 4 % )与氯化钙溶液 ( 0 0 5～0 2 0mol/L)对胶凝速率的影响 ,结果是 6h前胶凝速率快 ,随后减慢 ,约 70h胶凝完全 ,氯化钙溶液的浓度≥ 0 1mol/L对胶凝速率无明显影响。干燥的凝胶微丸在不同水性介质中溶胀试验结果表明 :在温度约 37℃时 ,微丸在蒸馏水和 0 1mol/L盐酸 ( pH1 0 )中几乎不溶胀 ,而在磷酸盐缓冲溶液( pH6 8)中1h溶胀 ,溶胀后的微丸直径是干燥前湿微丸直径的 1 80 %。海藻酸钙凝胶微丸这种溶胀的 pH敏感性 ,使它能成为口服药物缓释制剂的载体。以硝苯地平为模型药物制备的海藻酸钙凝胶微丸 ,其体外释放试验结果 ,2h累积释放量为 2 0 %～ 30 % ,6h为 6 0 %～ 80 % ,1 2h时大于85 %。药物从微丸中的释放是以扩散和骨架溶蚀相结合的方式。由此可见 ,硝苯地平的海藻酸钙凝胶微丸具有缓释作用     

The Release of 5-Fluorouracil from a Swellable Matrix of a Triblock Copolymer of ε-Caprolactone and Ethylene Oxide

Purpose. The purpose of this study was to investigate the influence of hydration characteristics on the in vitro release of 5-fluorouracil from a swellable matrix prepared using a novel triblock copolymer of poly(-caprolactone) and poly(oxyethylene). Methods. Matrices were prepared by dry compression of mixtures of the drug and copolymer using low compressional forces. Release studies were performed using a custom made rotating basket dissolution apparatus. The positions of the eroding and swelling fronts within the matrices during hydration were monitored using freeze fracture scanning electron microscopy. Results. Analysis of the release data revealed a predominantly diffusion controlled mechanism. Observations of the swelling characteristics of the copolymer matrices on immersion in Sørensen's buffer at pH 7.4 revealed gel formation and preferential swelling in the radial direction with visible erosion of the matrix after 4h. During hydration, a gradual increase in gel layer thickness was noted prior to the erosion and eventual dissolution of the matrix. Conclusions. This study demonstrates a means of differentiating the relative importance of the swelling characteristics in determining the release mechanism and subsequent release rate from swellable matrices.     

Formulation and evaluation of delayed-onset extended-release tablets of metoprolol tartrate using hydrophilic-swellable polymers

In view of the circadian rhythm of cardiovascular diseases, a delayed-onset extended-release (DOER) formulation of metoprolol tartrate (MT) was prepared. This was achieved through dissolution-guided optimization of the proportion of Methocel K4M and Methocel K15M. Core erosion ratio was greater than 50 %, thereby showing steady release of the drug after the lag time until complete dissolution. Optimized formulation produced a lag phase of 6 h followed by complete release of 98.7 ± 2.1 % in 24 h. Water uptake study revealed that Methocel K15M has lower water uptake (30 ± 1 %) than Methocel K4M (40 ± 2 %) after 24 h. Axial swelling of polymers was higher than swelling in the radial direction. Drug-polymer interaction study precludes any interaction between drug and polymer. Such a drug delivery system may provide a viable alternative for effective management of hypertension and other related disorders. This work also proposes an approach to attain DOER for a hydrophilic drug by using a hydrophilic swellable polymer in press coat.