Metabolic fate of exogenous chondroitin sulfate in the experimental animal

After the administration of tritiated chondroitin sulfate (CS) by oral and intramuscular route, the distribution of radioactivity was investigated in two opportunist omnivorous animals, namely the rat and the dog. More than 70% of the orally administered radioactivity was absorbed. Independently of the administration route, radioactivity was mainly excreted through the urine. Plasma levels showed a rapid increase after oral administration, followed by a large plateau with a maximum at the 14th and 28th h in the rat and in the dog, respectively. A tropism of the radioactivity was observed towards glycosaminoglycan-rich tissues, such as joint cartilage. The analysis of the molecular weight of the radioactive material showed that compounds with a molecular weight corresponding to those of CS, poly-, oligo- and monosaccharides as well as of tritiated water, were present in the plasma, urine, synovial fluid and cartilage. The level of radioactive low molecular weight material, derived from the metabolism of CS and from the exchange reaction, increased with the time after administration. The high molecular weight fraction represented at least 10% of the orally administered CS.     

Metabolic fate of partially depolymerized chondroitin sulfate administered to the rat

Partially depolymerized chondroitin sulfate (dCS) was tritiated and given to rats. With both the intramuscular and oral routes of administration the main route of excretion is urine. More than 40% of the radioactivity is present in tissues 24 h after administration. After intramuscular injection, radioactivity plasma levels rapidly increase with a peak at 0.6 h. The separation of the radioactive material on a Biogel P-4 column shows that the radioactivity in the first hour after injection is mainly constituted of dCS with molecular weight higher than 4000 daltons (dCS greater than 4000). The composition of the radioactive material changes with time; after 24 h the dCS greater than 4000 is a few percent of the total radioactivity. A large amount of tritiated water due to exchange and metabolization of dCS is found. Mono-, oligo- and polysaccharides resulting from the breakdown of dCS are also present. After oral administration, plasma radioactivity rapidly increases, with a shoulder and a small peak after 1 h and a large peak after 11 h. A tropism of the radioactivity towards glycosaminoglycan-rich tissues is observed. The presence of dCS greater than 4000 in plasma, synovia and cartilage after oral and intramuscular administrations of dCS may explain the chondroprotective effect of exogenous dCS. In fact, desulfated and sulfated oligo- and polysaccharides have regulatory effects on the synthesis and breakdown of hyaluronate-proteoglycan complexes of cartilage.     

Metabolic fate of mescaline in man

Summary Human subjects given C¹⁴-mescaline by mouth excrete an average of 87% of the dose during the first 24 hours and an average of 92% during the first 48 hours. Average half-life of mescaline in six hours.The composition of the urine in respect to the various metabolites of mescaline from hour to hour has been determined. The concentration of mescaline and its metabolites in the plasma and the cerebrospinal fluid at the various times has also been determined.Mescaline, 3,4,5-trimethoxyphenylacetic acid, N-acetyl--(3,4-dimethoxy-5-hydroxyphenyl) ethylamine and N-acetyl-mescaline have been identified in human urine after mescaline administration in the following amounts: mescaline 55–60%, 3,4,5-trimethoxyphenylacetic acid 27–30%, N-acetyl--(3,4,dimethoxy-5-hydroxyphenyl) ethylamine 5% and N-acetylmescaline less than 0.1%. Five other metabolites have been partially characterized.Chromatographic evidence is presented for the presence of mescaline, 3,4,5-trimethoxyphenylacetic acid, N-acetylmescaline and N-acetyl--(3,4-dimethoxy-5-hydroxyphenyl) ethylamine in the cerebrospinal fluid in man after oral mescaline administration.This investigation was supported in part by Public Health Service Research Grant, MH-10777, from the National Institute of Mental Health.     

Metabolic fate of fenetylline in rat and man

1. Metabolic fate of 7-[2-(α-methylphenylethylamino)ethyl]theophylline hydrochloride (fenetylline) was investigated in male Sprague-Dawley rats and three male volunteers.

2. Six metabolites were identified in the rat urine as amphetamine(AP), p-hydroxy-AP, acetylaminoethyl-theophylline(TP), aminoethyl-TP, hydroxyethyl-TP and carboxymethyl-TP by comparison of their spectral properties and h.p.l.c. and g.l.c. characteristics with those of authentic samples. All these metabolites was also detected in the urine of humans receiving fenetylline.

3. Quantification of these metabolites using h.p.l.c. and g.l.c. showed that carboxymethyl-TP, p-hydroxy-AP and acetylaminoethyl-TP were the major metabolites in 0-24h rat urine at 13.7%, 11.2% and 9.3% of dose, respectively. In men, carboxymethyl-TP(39–43% dose) and AP(23–33% dose) were the major metabolites in 0–48 h urine.

4. These results suggest that fenetylline metabolism proceeds via oxidative cleavage at two different sites to produce aminoethyl-TP and AP, respectively. The pathway producing AP predominates, in both man and rat, but is more predominant in the former.     

Metabolic fate of fenetylline in rat and man

1. Metabolic fate of 7-[2-(alpha-methylphenylethylamino)ethyl]theophylline hydrochloride (fenetylline) was investigated in male Sprague-Dawley rats and three male volunteers. 2. Six metabolites were identified in the rat urine as amphetamine(AP), p-hydroxy-AP, acetylaminoethyl-theophylline(TP), aminoethyl-TP, hydroxyethyl-TP and carboxymethyl-TP by comparison of their spectral properties and h.p.l.c. and g.l.c. characteristics with those of authentic samples. All these metabolites was also detected in the urine of humans receiving fenetylline. 3. Quantification of these metabolites using h.p.l.c. and g.l.c. showed that carboxymethyl-TP, p-hydroxy-AP and acetylaminoethyl-TP were the major metabolites in 0-24 h rat urine at 13.7%, 11.2% and 9.3% of dose, respectively. In men, carboxymethyl-TP(39-43% dose) and AP(23-33% dose) were the major metabolites in 0-48 h urine. 4. These results suggest that fenetylline metabolism proceeds via oxidative cleavage at two different sites to produce aminoethyl-TP and AP, respectively. The pathway producing AP predominates, in both man and rat, but is more predominant in the former.     

含玻璃酸钠的复方硫酸软骨素滴眼液中硫酸软骨素的含量测定

目的建立含玻璃酸钠(SH)的复方硫酸软骨素滴眼液中硫酸软骨素(CS)的含量测定方法。方法通过醋酸钠调节样品的酸碱度和离子强度,氯化十六烷基吡啶(CPC)可选择性地沉淀CS,采用咔唑法测定CS的含量,而不受SH的影响。结果优化的样品预处理条件为:醋酸钠的浓度为16%,CPC的浓度为0.8%,充分搅拌后,静置2 h,20μm滤膜过滤;滤饼经8%氯化钠溶液超声解离后,用于CS的含量测定,回收率为100.2%,RSD为1.17%。结论此法简便,快速,结果准确,可作为含SH的复方硫酸软骨素滴眼液中CS的含量测定方法。     

高效液相色谱法测定复方盐酸氨基葡糖硫酸软骨素片中硫酸软骨素的含量

目的 建立高效液相色谱法测定复方盐酸氨基葡萄糖硫酸软骨素片中硫酸软骨素的含量.方法 采用nucleosil 100-5SB（强阴离子交换硅胶,（5 μm 4.6 mm×250 mm）柱分离,以pH 3.5的水为流动相A,以pH 3.5的2 mol·L-1氯化钠溶液为流动相B,进行梯度洗脱.检测波长232 nm流速为1.0 mL·min-1,进样量为20 mL.结果 硫酸软骨素B、硫酸软骨素C和硫酸软骨素A的相邻之间分离度分别为24.32和2.37,线性范围为2.5125～20.1 g·L-1 （r=0.999 5,A=712.59C＋137.64）;平均回收率为103.06%,RSD为2.71%.结论 该方法简便,重复性好,结果可靠,可做为复方盐酸氨基硫酸软骨素片质量控制方法之一.     

Metabolic fate of zetidoline,a new neuroleptic agent,in man

Summary Healthy volunteers administered orally a single dose (20 mg) of [2-¹⁴C]zetidoline, a new dopamine antagonist, exhibited rapid absorption of radioactivity with peak plasma levels of 250–300 ng/ml achieved in 1 h. The compound underwent intensive metabolic first-pass so that plasma radioactivity was represented mostly by two products, metabolite B endowed with neuroleptic activity, and metabolite D inactive, while unchanged zetidoline was not detected. Disappearance of radioactivity from plasma was rapid with a half-life of 1.78±0.20 h.The simultaneous assay of plasma prolactin showed increased levels of the hormone (+464% at the peak time) up to the 6th h after dosing, with plasma concentration profile which mimic those of metabolite B.The radioactive test-dose was eliminated mainly via the kidneys with an average urinary recovery of 84.7±1.7% in 4 days (73.4±1.1% within 8 h). The main urinary metabolite (metabolite G) and two minor ones (metabolites B and D) were purified and their structures assigned by IR, MS and NMR spectroscopy, they are: 1-(3-chloro-4-hydroxyphenyl)-3[2-(3,3-dimethyl-1-azetidinyl)ethyl]imidazolidin-2-one, metabolite B; 1-[2-(3,3-dimethyl-1-azetidinyl)ethyl]imidazolidin-2-one, metabolite D and the 4-O-sulphate ester of metabolite B, metabolite G.The metabolic fate of zetidoline in man follows the same phase I reactions demonstrated in rats and dogs, while the phase II reaction is sulphoconjugation instead of the glucuronidation observed in animals.     

微波萃取法提取复方硫酸软骨素片中硫酸软骨素C的研究

目的从复方硫酸软骨素片中提取硫酸软骨素C(Chs-C)。方法采用微波萃取法提取复方硫酸软骨素片中的Chs-C,以Chs-C的提取率为考察指标,在单因素试验基础上进行正交试验,确定微波萃取最佳条件。结果微波萃取最佳条件为:萃取功率为595W,浸提时间90s,固液比为1∶75。在此条件下,提取率可达4.1%。结论对照传统乙醇沉淀法,微波法具有省时,操作简单,提高效率等优势。     

比色法测定复方硫酸软骨素片中硫酸软骨素含量

目的建立比色法测定复方硫酸软骨素片中硫酸软骨素含量 (以氨基已糖计 ) ,提高该制剂含量测定方法的专属性。方法硫酸软骨素经酸水解后生成氨基葡萄糖 ,用Elson Morgan法 ,在碱性条件下先与乙酰丙酮反应 ,再与对二甲氨基苯甲醛反应生成红色进行测定。结果此法干扰小 ,专属性强 ,平均回收率为 98.1 % ,RSD为 2 .1 %(n =6)。结论此法提高了该制剂含量测定的专属性 ,可用于复方硫酸软骨素片的含量测定     

Chondroprotection with chondroitin sulfate

The remarkable insights into the pathogenesis of osteo-arthrosis (OA) have also affected the therapeutic field. Efforts have been made to find drugs which would somehow block or slow down the evolution of this disease. In this connection, a major contribution has been made by the investigations on glycosaminoglycans (GAGs), which play a crucial role in the physiology of joint cartilage. It was thus suggested that proper supplementation with GAGs might enable chondrocytes to replace the proteoglycans (PG). Galactosaminoglucuronoglycan sulfate (GAGGS) has been used for this purpose. In preliminary clinical trials, GAGGS exhibited a remarkable tolerability and good therapeutic efficacy. GAGs are generally able to inhibit certain enzymes present in the synovial fluid which may damage joint cartilage (elastase, hyaluronidase). Moreover, GAGGS has also been shown to act as an anti-inflammatory drug since it has an inhibitory effect over the complement. All these data supply evidence that, in theory, GAGGS may have a chondroprotective effect in patients with OA. In addition to the positive results of preliminary clinical trials, the use of GAGGS in OA therapy is based on the fact that this drug is absorbed by the body, is concentrated in the cartilages and produces no toxic or teratogenic effects. In the clinical studies performed so far, although of the open type, GAGGS has always yielded clinical improvement both of painful symptoms and of limited function thanks to its proven anti-inflammatory activity. Thus once the results from other ongoing trials (double blind) are available, hopefully GAGGS will in fact become a basic drug for OA therapy.     

HPLC法同时测定复方硫酸软骨素片中硫酸软骨素和甘草酸含量的研究

目的:建立高效液相色谱梯度洗脱-波长切换法同时测定复方硫酸软骨素片中硫酸软骨素和甘草酸含量的方法。方法:采用InertSustain C₁₈色谱柱(4.6 mm×250 mm, 5μm),以5 mmol·L^-1庚烷磺酸钠溶液为流动相A,乙腈为流动相B,梯度洗脱,柱温为35℃,检测波长为199 nm(0～8 min时,检测硫酸软骨素)、251 nm(8～30 min时,检测甘草酸)。结果:硫酸软骨素钠和甘草酸分别在0.150 2～3.004 9 mg·mL^-1和0.012 67～0.316 8 mg·mL^-1范围内与峰面积呈良好的线性关系,且该检测方法专属性、精密度、回收率等良好。4批样品中,硫酸软骨素和甘草酸的含量分别为72.196 3～73.801 4和1.498 8～1.548 0 mg·片^-1。结论:该方法操作简单,结果准确,可用于复方硫酸软骨素片的质量控制。     

硫酸软骨素在骨关节炎防治中的作用

综合国内外相关文献,介绍硫酸软骨素在骨关节炎防治中的作用。     

Metabolic fate of delmopinol in man after mouth rinsing and after oral administration

1. The metabolism of delmopinol, an inhibitor of plaque formation and gingivitis. has been studied after mouth rinsing or an oral dose of 14C-delmopinol to healthy male volunteers. The metabolite pattern was studied in urine and plasma samples (unhydrolysed or hydrolysed with conjugate cleaving enzymes) by liquid chromatography (LC) with radio detection. Metabolite identifications were carried out by gas chromatography-electron-impact mass spectrometry (GC-MS) and by liquid chromatography-thermospray mass spectrometry (LC-MS). 2. The metabolic clearance of delmopinol was high, and < 0.2% of the dose was excreted as intact delmopinol in the urine. The main metabolites were, for both administration routes, glucuronide conjugates of delmopinol and of (omega-1-hydroxy) delmopinol. These metabolites were predominant and accounted for nearly the entire urinary radioactivity and most of the plasma radioactivity. After mouth rinsing, parent delmopinol was also one of the main compounds in plasma. 3. Several other products of oxidation of the aliphatic side-chain were present in minor amounts in urine. These metabolites also appeared to be excreted as glucuronic acid conjugates. 4. Glucuronidated (omega-1-hydroxy) delmopinol separated into three peaks by the LC system used. This could be due to different chromatographic properties of conjugate isomers, positional or optical.     

Metabolic fate of delmopinol in man after mouth rinsing and after oral administration

1. The metabolism of delmopinol, an inhibitor of plaque formation and gingivitis, has been studied after mouth rinsing or an oral dose of ¹⁴C-delmopinol to healthy male volunteers. The metabolite pattern was studied in urine and plasma samples (unhydrolysed or hydrolysed with conjugate cleaving enzymes) by liquid chromatography (LC) with radio detection. Metabolite identifications were carried out by gas chromatography-electron-impact mass spectrometry (GC-MS) and by liquid chromatography-thermospray mass spectrometry (LC-MS). 2. The metabolic clearance of delmopinol was high, and &lt; 0.2% of the dose was excreted as intact delmopinol in the urine. The main metabolites were, for both administration routes, glucuronide conjugates of delmopinol and of (ω-1-hydroxy) delmopinol. These metabolites were predominant and accounted for nearly the entire urinary radioactivity and most of the plasma radioactivity. After mouth rinsing, parent delmopinol was also one of the main compounds in plasma. 3. Several other products of oxidation of the aliphatic side-chain were present in minor amounts in urine. These metabolites also appeared to be excreted as glucuronic acid conjugates. 4. Glucuronidated (ω-1-hydroxy) delmopinol separated into three peaks by the LC system used. This could be due to different chromatographic properties of conjugate isomers, positional or optical.     

Sensitization studies on chondroitin sulfate

Results of several tests in guinea pigs performed in order to check the hypersensitivity hazard of chondroitin sulfate are reported. As per theoretical expectations, no immuno-enhancing effect leading to hypersensitivity was recorded.     

Classification of chondroitin sulfate A, chondroitin sulfate C, glucosamine hydrochloride and glucosamine 6 sulfate using chemometric techniques

Chondroitin sulfate A, chondroitin sulfate C, glucosamine hydrochloride and glucosamine sulfate are natural products that are becoming increasingly popular in the treatment of arthritis. They belong to a class of compounds known as glycosaminoglycans (GAGs). They are available over the counter as nutritional supplements. However, increasing use has led to increasing scrutiny of the quality of products on the market. There is also interest in the pharmacological properties of these compounds. To facilitate this, there is a need for better qualitative and quantitative methods of analysis. This paper describes methods for achieving the qualitative identification of chondroitin sulfate A, chondroitin sulfate C, glucosamine hydrochloride or glucosamine sulfate. Fourier transform infrared spectroscopy coupled with a variety of chemometric methods successfully classified these compounds. Using soft independent modeling of class analogies (SIMCA), hierarchical cluster analysis (HCA) and principal components analysis (PCA) samples were classified as either chondroitin sulfate A, chondroitin sulfate C, glucosamine hydrochloride or glucosamine sulfate. This work also examined the discriminating ability of different sections of the spectrum. It was found that for the classification of these compounds that using the finger print region of the spectrum (below 2000 cm(-1)) gave the best discrimination.     

硫酸软骨素二糖重复片段的合成

目的 设计一种新的方法合成硫酸软骨素二糖骨架.方法 以2位三氯乙氧羰基、4,6位苯亚甲基保护的氨基半乳糖苯硫苷为供体,以2位苯甲酰基、3位烯丙基、6位对溴苄基保护的对甲氧基苯基葡萄糖苷为受体,在NIS、TfOH催化下得到了二糖Ⅰ,并用1 HNMR、13CNMR和1H-1HCOSY、HMBC、HMQC、HRMS(ESI)...