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Introducción: El hidrocloruro de amantadina (I) es conocido como un medicamento antiviral utilizado para prevenir y tratar las infecciones por influenza A. También se utiliza para aliviar los síntomas de la enfermedad de Parkinson en el período inicial. Se han informado varios métodos para la preparación de (I). Estos procedimientos comienzan con adamantano (II) en cuatro o tres pasos de reacción, para producir hidrocloruro de amantadina con rendimientos globales que van del 45 por ciento al 58 por ciento. Objetivo: Mejorar el método para la síntesis de hidrocloruro de amantadina, que puede introducirse a escala industrial. Métodos: La optimización paso a paso para reducir el uso de reactivos, disolventes, así como las condiciones de cada paso, se seleccionaron para ser menos agresivas y más amigables con el medio ambiente. Resultados: Todos los factores relacionados con el rendimiento de la reacción para sintetizar los compuestos intermedios y finales se seleccionaron para obtener el mayor rendimiento de cada etapa. Finalmente, se estableció un procedimiento de dos pasos para la síntesis de (I) a partir de (II), a través de N- (1-adamantil) formamida (III), con un rendimiento global mejorado del 78 por ciento y una pureza del 99,2 por ciento. Se confirmó la estructura del producto por 1H-NMR, 13C-NMR, IR y MS. La síntesis de N- (1-adamantil) formamida (VI) a partir de (II) también se logró con éxito en un solo paso. Este método evita el uso de bromo líquido o ácido sulfúrico gaseoso como reactivos. La conversión posterior de (VI) a (I) se llevó a cabo bajo condiciones de reacción, más suaves sin usar solventes peligrosos. Conclusiones: Se logró la síntesis mejorada del clorhidrato de amantadina (I). Este resultado puede utilizarse en una producción industrialmente conveniente. Las materias primas y reactivos utilizados en esta investigación son baratas y están disponibles. El tiempo total de preparación se redujo significativamente, con ahorro de energía y mano de obra(AU)
Introduction: Amantadine hydrochloride (I) was well-known as an antiviral drug used to prevent and treat influenza A infections. Besides, it also was used to relieve the symptoms of Parkinson's disease in the early period. Several methods for the preparation of I have been reported. These procedures started with adamantane (II) in four or three reaction steps to produce amantadine hydrochloride with overall yields ranging from 45 percent to 58 percent. Objectives: Improving method for synthesis of amantadine hydrochloride could introduce to industrial scale. Methods: Step-by-step optimization to reduce the use of reagents, solvents, as well as the conditions of each step were screened to be milder and more environment-friendly. Results: All factors related to the yield of reaction to synthesize the intermediate and final compounds were screened to give the highest yield of each step. Finally, a two-step procedure for the synthesis of (I) from (II) via N-(1-adamantyl) formamide (III) with improving overall yield of 78 percent and a purity of 99.2 percent was established, and the structure of the product was confirmed by 1H-NMR,13C-NMR, IR and MS. The synthesis of N-(1-adamantyl) formamide (VI) from (II) also was successfully accomplished within only one step. This method avoided the use of liquid bromine or fuming sulfuric acid as reactants. The subsequent conversion of (VI) to (I) was carried out under milder reaction conditions without using hazardous solvents. Conclusions: An improved synthesis for amantadine hydrochloride (I) have been provided. This research can be an industrially convenient production of amantadine hydrochloride. Because the raw materials and reagents used in this research are cheap and available which also were screened to save their use. Moreover, the total preparation time was significantly reduced to save energy as well as labor(AU)
Subject(s)
Humans , Male , Female , Research , Adamantane , Pharmaceutical Preparations , Magnetic Resonance Spectroscopy , Amantadine , Indicators and ReagentsABSTRACT
Objective To study the dose-time-toxicity relationship of hepatotoxicity in mice with multiple administration of Paracetamol Tablets (PT),Compound Paracetamol and Amantadine Hydrochloride Tablets (CPAH),Compound Dextromethorphan Hydrobromide Tablets (CDH),and Chaiqin Qingning capsules (CQC).Methods Mice were randomly divided into control,PT,CPAH,CDH,and CQC high,medium,and low dose groups.The acetaminophen contents of high,medium,and low doses were 266.24,425.98,and 681.57 mg/kg in PT,CPAH,and CDH groups,and the doses of CQC group were 1437.70,2300.31,and 3 680.50 mg/kg,ig administration,once daily for 5 d.General state and toxicity of mice were observed.The changes of ALT,AST,AKP,TBIL,and ALB levels in serum and organ indexes of liver,spleen,thymus,and kidney were tested on day 1,3,7,11,and 14 after multiple administration.Results CQC with the dosage range of 1 437.70-3 680.50 mg/kg to mice within 14 d,has not yet induced the increase of AST,ALT,AKP,TBIL,and ALB levels and changes of organ indexes of liver,thymus spleen,and kidney compared with normal control (P ＞ 0.05).PT,CPAH,and CDH with repeated dose of 425.98-681.57 mg/kg could induce significant increase of the levels ofALT,AST,AKP,and TBIL which reached the peak on day 1 (P ＜ 0.05),and then gradually decreased on day 3-14.The level of ALB significant decreased on day 1-11 (P ＜ 0.05),and then gradually recovered on day 11-14.The liver index significant increased on day 1-3 (P ＜ 0.05),and recovered on day 7-14.Conclusion Multiple administration of CQC could not induce liver injury in mice within 14 d,while multiple administration ofPT,CPAH,and CDH could induce hepatotocixity in mice with a certain dose,and show an obvious dose-time-toxicity relationship.
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Objective To study the time-toxicity and dose-toxicity relationship of hepatotoxicity induced by Paracetamol Tablets (PT),Compound Paracetamol and Amantadine Hydrochloride Tablets (CPAH),Compound Dextromethorphan Hydrobromide Tablets (CDH),and Chaiqin Qingning Capsules (CQC) with single dose in mice.Methods In the Time-Toxicity relationship study,Kunming mice were randomly divided into control,PT,CPAH,CDH,and CQC group,and mice of.each drug administration group were randomly divided into nine subgroups according to the time (1,2,4,8,12,24,48,72 and 96 h after administration) of blood collection.The acetaminophen contents in PT,CPAH,and CDH groups were 425.98 mg/kg,and the dose of CQC group was 3 680.50 mg/kg.In the Dosage-Time relationship study,mice were randomly divided into control,PT,CPAH,CDH,and CQC high,medium and low dose group.The acetaminophen contents of high,medium,and low dose were 266.24,425.98,and 681.57 mg/kg in PT,CPAH,and CDH group,and the dose of CQC group was 1437.70,2300.31,and 3680.50 mg/kg,10 mice in each group,sex in half.Blood was collected 12 h after administration.Animal behavior was observed every day,blood and organs were collected at the corresponding time points,serum alanine aminotransferase (ALT),aspartate aminotransferase (AST),and alkaline phosphatase (ALP) level were detected,and the organs index of spleen and thymus,liver were calculated.Results There were no significant changes of ALT,AST,ALP,and organs index after once ig administration of CQC at dosage of 1437.70 mg/kg to 3680.50 mg/kg in mice.The study on time-toxicity relationship indicated that,after once administration of PT,CPAH,and CDH at 425.98 mg/kg,mice showed toxic symptom such as hypokinesia,dry hair and so on,12 h was the most obvious,24 ～ 72 h disappeared.The level of ALT,AST,and ALP in serum increased and reached to the peak at 12 h and then restored near normality after 72,24,and 24 h in PT,CPAH,and CDH group.Their organ index of liver,spleen and thymus all had no significant changes.The study on the dosage-toxicity relationship indicated that,there were no significant changes of animal behavior,ALT,AST,ALP,and organs index after once ig administration of PT,CPAH,and CDH at 266.24 mg/kg.Obvious liver injury can be induced by the three drugs with dosage of 425.98 to 681.57 mg/kg and the level of ALT,AST,and ALP increased significantly with the increase of dosage.Their liver index increased significantly with dosage of 681.57 mg/kg,but the organs index of spleen,thymus had no significant changes.Conclusion There was no hepatotoxicity after once ig administration of CQC with dosage of 3680.50 mg/kg in mice.Mice were once ig administration ofPT,CPAH,and CDH with a large dose,may induce acute liver injury and show obvious time-toxicity and dose-toxicity relationships.
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Objective To study the antipyretic effect of Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets,and Chaiqin Qingning Capsules on the fever model induced by LPS and dry yeast in rats.Methods Fever was induced by ip injecting LPS (100 μg/kg) or sc injecting dry yeast (20％) in rats.We observed the changes of temperature of the rats after administration of Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets (the acetaminophen contents were 205.67,102.83,and 51.42 mg/kg)and Chaiqin Qingning Capsules (1110.60,555.30,and 277.65 mg/kg).Maximum temperature rise height (△T) and temperature response index (TRI) were calculated,and the curve of average rise in temperature was drawn.Results Each dose group of Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets,and Chaiqin Qingning Capsules had obvious antipyretic effect on the fever model induced by LPS and dry yeast in rats,and there was a certain dose-effect relationship.Conclusion Paracetamol Tablets,Compound Paracetamol and Amantadine Hydrochloride Tablets,Compound Dextromethorphan Hydrobromide Tablets,and Chaiqin Qingning Capsules has certain antipyretic effect on LPS and dry yeast fever model in rats,and on the whole,the Western medicine acts rapid but continue for a short time,while the traditional Chinese medicine acts slow but continues for a long time.
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OBJECTIVE:To establish a method for the simultaneous determination of paracetamol,amantadine hydrochloride, caffeine,chlorphenamine maleate in Compound paracetamol and amantadine hydrochloride tablet. METHODS:GC was performed on the column of HP-5 sillica capillary,temperature programmed,detector was FID detector,with the temperature of 300 ℃,car-rier gas was nitrogen gas,the flow rate is 1.5 mL/min,the split ratio was 20:1 and injection volume was 1μL. RESULTS:The lin-ear range was 156.0-4990.4 μg/mL for paracetamol,125.7-4023.2 μg/mL for amantadine hydrochloride,19.14-612.4 μg/mL for caffeine and 2.515-80.48 μg/mL for chlorphenamine maleate(all r=0.9999);the limits of quantification were 1.4,0.5,1.1,0.9 ng,limits of detection were 0.4,0.2,0.3,0.3 ng;RSDs of precision,stability and reproducibility tests were lower than 2.0%;re-coveries were 99.59%-101.77%(RSD=0.8%,n=9),99.56%-101.80%(RSD=0.7%,n=9),98.44%-100.83%(RSD=0.7%,n=9) and 100.05%-101.91%(RSD=0.6%,n=9),respectively. CONCLUSIONS:This method is simple,rapid,accurate and reli-able,and suitable for the simultaneous determination of paracetamol,amantadine hydrochloride,caffeine,chlorphenamine maleate in Compound paracetamol and amantadine hydrochloride tablet.
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Objective: To establish a method for the determination of amidozon and amantadine hydrochloride in compound amantadine hydrochloride tablets by HPLC-ELSD.Methods: The analytical column was an Agilent Eclipse Plus C18 column (250 mm×4.6 mm, 5 μm).The mobile phase consisted of 0.1% trifluoroacetic acid solution-acetonitrile (85∶15) and the flow rate was 0.7 ml · min-1.The column temperature was room temperature.Both evaporation temperature and atomization temperature were 40 ℃.The flow rate of carrier gas (nitrogen) was 1.8 L · min-1 and the injection volume was 10 μl.Results: The peak area and logarithm of injection volume of ampicrine showed a good linear relationship within the range of 606.72-3 033.60 μg · ml-1 (r=0.999 7), and that of amantadine hydrochloride showed a good linear relationship within the range of 400.96-2 004.80 μg·ml-1 (r=0.999 4).The average recovery was 99.5% and 99.3%, and RSDs was 0.35% and 0.40%(n=9), respectively.Conclusion: The method is simple, rapid, accurate and reproducible, and suitable for the determination of aminopyrine and amantadine hydrochloride in compound amantadine aminopyrine tablets.
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Objective:To establish an HPLC method for the determination of P-aminophenol in pediatric paracetamol and amanta-dine hydrochloride granules. Methods: The column was Phenomenex Luna C8 (150 mm × 4. 6 mm, 5 μm), the mobile phase was phosphate buffer solution-methanol (93∶7), the flow rate was 0. 8 ml·min-1, the detection wavelength was 275nm, the column tem-perature was 30℃, and the injection volume was 10μl . Results: P-aminophenol showed good linearity within the range of 0. 528-42. 240 μg·ml-1(r=0. 999 9). The average recovery was 100. 03%(RSD=0. 9%, n=9). Conclusion:The method is simple with high accuracy and reproducibility, which can be used in the determination of P-aminophenol in pediatric paracetamol and amantadine hydrochloride granules.
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Objective:To establish a GC method for determining the content of amantadine hydrochloride in pediatric paracetamol and amanatadine hydrochloride granules. Methods:The ingredients were separated on an Agilent DB-5 quartz capillary column (30 m ×0.25 mm, 0.25 μm), the carrier gas was N2,and the flow rate was 1 ml·min-1. The column temperature was maintained at 130℃, the injection temperature was 250℃,the detection temperature was 280℃ with an FID as the detector , the injection volume was 2 μl, and the split ratio was 20∶1. Results:A good linear relationship was obtained between the peak area and the concentration of amantadine hydrochloride within the range from 0.103 2 to 6.456 0 mg·ml-1(r =0.999 9). The average recovery was 100.18%(RSD=0. 11%, n=6). Conclusion:The method is specific, accurate, reliable and reproducible, which can be used in the quality control of pediatric paracetamol and amanatadine hydrochloride granules.
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Background: Pegylated interferon (peg-IFN) alpha in combination with weight-based doses of ribavirin is currently recommended as a standard-of-care treatment for chronic hepatitis C virus (HCV) infection. However, the low response rate with interferon as well as the high occurrence of side effects has prompted investigators to search for other drugs which may be efficacious in the treatment of hepatitis C. Objectives: To evaluate the efficacy of amantadine hydrochloride versus amantadine sulphate monotherapy when administered to naïve Egyptian patients with chronic hepatitis C. Patients and Methods: Fifty Egyptian patients with chronic HCV were randomized to receive amantadine hydrochloride (100mg) two times daily or amantadine sulphate (100mg) two times daily for sixty days. Results: Patients treated with amantadine hydrochloride and amantadine sulphate showed highly significant reduction in serum AST and ALT levels but there was non significant reduction in HCV RNA viral load. Patients tolerate therapy well with no drop out. Conclusion: Amantadine oral therapy appears to have activity for treating hepatitis C.
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Aim: The aim of the present investigation was to perform the precolumn derivatization of Amantadine Hydrochloride (AMT) with phenylisothiocyanate and to develop a RP-HPLCPDA method for the quantification of Amantadine Hydrochloride-phenylisothiocyanate (AMT-PITC) complex in bulk and dosage forms which is rapid, sensitive and economical. Study Design: Method development and Validation study. Methodology: A Phenomenex C18 RP column of 250 x 4.6mm dimensions and 5μm particle size with mobile phase containing water and acetonitrile (40:60% v/v) was used at isocratic mode binary pump and eluent was monitored at 273nm. Results & Discussion: The retention time of AMT-PITC complex was 6.3 min. The developed method showed a good linearity in the concentration range of 10-50μg/mL with a correlation coefficient >0.998. The recoveries ranged between 95-105% with a Relative Standard Deviation of (RSD) < 2%. Conclusion: The developed method was validated as per ICH guidelines and successfully used for quantification of AMT by derivatization with PITC. The method was found to be rapid, specific and accurate.
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OBJECTIVE: To develop an HPLC-MS method for qualitative and quantitative analysis of nine antiviral agents illegally adulterated in traditional Chinese medicines. METHODS: The samples were separated on a CAPCELL PAK CR 1:4 column (2.0 mm × 150 mm, 5 μm) by gradient elution with 0.1% formic acid solution(adjusted to pH 3.5 with ammonium hydroxide) as the mobile phase A and acetonitrile as the mobile phase B. The gradient elution program was as follows: 0-12 min (90% A→48% A), 12-15 min (48% A→20% A), 15-19 min (20% A→15% A), 19-20 min (90% A). The flow rate was 0.2 mL·min-1 and the injection volume was 5 μL. After being separated by HPLC, the test solution was analyzed by mass spectrometer operated in positive ion mode and in product mode and SRM mode. RESULTS: The calibration curves of the nine antiviral agents showed good linearity and the correlation coefficients were more than 0.998. The recoveries at 3 spiked levels were in the range of 80.6%-117.7%. The limits of quantification were in the range of 0.1-1 μg·g-1. The fragmentation pattern of the nine antiviral agents was summarized. CONCLUSION: The method is sensitive, specific, accurate and applicable to detect the nine antiviral agents in traditional Chinese medicines.