Prediction of the Stability of Imipenem in Intravenous Mixtures

Yoshida, Miyako; Takasu, Yuko; Shimizu, Kaori; Asahara, Keiichi; Uchida, Takahiro

doi:10.1248/cpb.c12-00427

Cited by 9 publications

(7 citation statements)

References 23 publications

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“…These polyoxygenated tetranortriterpenoids are derived from tirucallane (20S) or euphane (20R) with a β-substituted furanyl ring at C-17α [ 21 , 23 , 24 ]. Previously, the havanensin-type limonoids TS1, TS2, TS3 [ 25 ], trichirubines A and B [ 26 ] and rubescins A, B and C [ 27 ] have been isolated from T . rubescens .…”

Section: Introductionmentioning

confidence: 99%

“…rubescens . Some of these substances have been shown to increase chloride conductance in epithelial cells [ 25 ], and to exhibit anti-plasmodial [ 26 ], and antioxidant [ 27 ] activities.…”

Section: Introductionmentioning

confidence: 99%

“…Here we analyzed the anti-cancer activity of 6 limonoids isolated from organic extracts of the roots and stem bark of T . rubescens [ 25 , 27 , 28 ]. Our results show that 2 of these limonoids, TR4 (TS3) and TR9 (Rubescin E), interfered with human hepatoma cell viability at lower TC50s than Sorafenib, and support its anti-cancer activity.…”

Section: Introductionmentioning

confidence: 99%

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The Limonoids TS3 and Rubescin E Induce Apoptosis in Human Hepatoma Cell Lines and Interfere with NF-κB Signaling

et al. 2016

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Hepatocellular carcinoma (HCC) is extremely resistant towards pharmacological therapy. To date, the multi-kinase inhibitor Sorafenib is the only available therapeutic agent with the potential to prolong patient survival. Using the human hepatoma cell lines HepG2 and Huh7, we analyzed anti-cancer activities of 6 purified havanensin type limonoids isolated from the traditional African medicinal plant Trichilia rubescens Oliv. Our results show that two of the compounds, TR4 (TS3) and TR9 (Rubescin E) reduced hepatoma cell viability, but not primary hepatocyte viability, at TC50s of 5 to 10 μM. These were significantly lower than the TC50s for Sorafenib, the histone deacetylase inhibitor SAHA or 5-Fluoruracil. In comparison, TR3 (Rubescin D), a limonoid isolated in parallel and structurally highly similar to TR4 and TR9, did not interfere with hepatoma cell viability. Both, TR4 and TR9, but not TR3, induced apoptosis in hepatoma cells and interfered with NF-κB activation. TR4 as well as TR9 significantly supported anti-cancer activities of Sorafenib. In summary, the limonoids TR4 and TR9 exhibit anti-cancer activities and support Sorafenib effects in vitro, having the potential to support future HCC therapy.

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Section: Introductionmentioning

confidence: 99%

“…rubescens . Some of these substances have been shown to increase chloride conductance in epithelial cells [ 25 ], and to exhibit anti-plasmodial [ 26 ], and antioxidant [ 27 ] activities.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The Limonoids TS3 and Rubescin E Induce Apoptosis in Human Hepatoma Cell Lines and Interfere with NF-κB Signaling

et al. 2016

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“…16) Both the k SBS and k cys of meropenem were smaller than those of imipenem. This means that meropenem is more stable than imipenem after mixing with an infusion containing SBS and L-cysteine, probably because hydrolysis of the β-lactam ring of imipenem occurs more easily than that of meropenem, due to its chemical structure.…”

Section: Resultsmentioning

confidence: 92%

Prediction of the Stability of Meropenem in Intravenous Mixtures

Takasu

Yoshida

Tange

et al. 2015

CHEMICAL & PHARMACEUTICAL BULLETIN

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The purpose of this study was to predict the stability of meropenem in a mixed infusion. The hydrolysis of meropenem in aqueous solution was found to be accelerated by pH, and by increasing concentrations of sodium bisulfite (SBS) and L-cysteine. Equations were derived for the degradation rate constants (k obs ) of pH, SBS and L-cysteine, and fractional rate constants were estimated by the nonlinear least-squares method (quasi-Newton method using the solver in Microsoft Excel) at 25°C. The activation energy (E a ) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the characteristic pH curve. From these results, an equation was derived giving the residual ratio (%) of meropenem at any time after mixing an infusion containing SBS and/or L-cysteine at any temperature, and in the pH range 4.0-10.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).Key words stability prediction; meropenem; pH; sodium bisulfite (SBS); L-cysteine; degradation rate constant Carbapenems are the most potent β-lactam antibiotics and were first developed in the 1980s to enhance resistance to β-lactamases. The early carbapenems were not very hydrolytically stable, however, limiting drug administration to controlled intravenous infusions. In the search for a more stable compound with better toxicity profile, the basic nuclear structure was maintained and a dimethyl carbamoyl-pyrrolidinylthio group was added as a weakly basic C-2 side-chain. This resulted in a reduction of central toxicity and nephrotoxicity, while maintaining anti-pseudomonal activity. In addition, the improvement of stability (DHP-I stability) in vivo and the improvement of activity against Haemophilus influenzae, etc., were achieved by introducing 1-β-methyl group into the carbapenem frame, resulting in the creation of meropenem. The improvement in nephrotoxicity was the key advance in allowing the global development of meropenem as a single agent. 1)Meropenem is a broad-spectrum carbapenem, active against several clinically relevant Gram-positive and Gram-negative aerobes, anaerobic bacteria and Pseudomonas aeruginosa. The bactericidal activity of meropenem results from the inhibition of cell wall synthesis through the inactivation of penicillin-binding proteins.Sodium and fluorouracil. 8) However, there are no reports of detailed kinetic studies on the degradation of meropenem in the presence of SBS.The prediction of the stability of a drug in an intravenous admixture (mixed infusion) is important for accurate and safe drug administration. Generally, the stability of a drug in a mixed infusion can be predicted from the pH profile and Arrhenius equation of the degradation rate constants, if the temperature and pH of the test solution are known. Although meropenem is generally administered as an infusion in saline, in some cases it may be mixed with other substances, such as amino acids. 9)A method for predicting the pH of mixed infusions was developed in orde...

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“…Sodium bisulfite (SBS), which is used as a stabilizer in injectable preparations, is known to degrade various drugs, including thiamine, 9) epinephrine, 10) gabexate mesilate, 11) nafamostat mesilate, 12) urokinase, 13) morphine, 14) fluorouracil 15) and imipenem. 16) However, there are no reports of detailed kinetic studies on the degradation of octreotide in the presence of SBS.…”

Section: Octreotide Acetate Chemical Formula D-phenylalanyl-l-cysteimentioning

confidence: 99%

Prediction of the Stability of Octreotide in a Mixed Infusion

Takasu

Yoshida

Shimizu

et al. 2014

CHEMICAL & PHARMACEUTICAL BULLETIN

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The purpose of this study was to predict the stability of octreotide in a mixed infusion containing sodium bisulfite (SBS). In aqueous solution the hydrolysis of octreotide was found to be accelerated by pH, and by increasing concentrations of SBS. Equations for the degradation rate constants (k obs ) of pH and SBS were derived. The fractional rate constants were estimated by the nonlinear least-squares method (quasiNewton method using the solver in Microsoft Excel) at 25°C. The activation energy (Ea) and frequency factor (A) were calculated using the Arrhenius equation. The pH of the mixed infusion was estimated using the pH characteristic (PHC) curve. From these results, an equation was derived giving the residual ratio (%) of octreotide at any time after mixing an infusion containing SBS at any temperature in the pH range 4.0-7.0. A high correlation was shown to exist between the estimated and determined residual ratios (%).Key words stability prediction; octreotide; pH; sodium bisulfite (SBS); pH characteristic (PHC) curve; degradation rate constant, is a long-acting octapeptide with pharmacologic actions mimicking those of the natural hormone somatostatin.1-3) The cyclic structure of octreotide ( Fig. 1) seems to play an important role in determining its unique pharmacological activity.Octreotide is increasingly used to treat symptoms of sickness and vomiting in terminal care patients suffering from gastrointestinal ileus. It is also used, in combination with standard therapies, in the symptom management of inoperable bowel obstructions in terminal cancer patients. [4][5][6] In Japan, octreotide is usually administered subcutaneously, but in the U.S. it is more often administered by deep subcutaneous (intrafat) or intravenous injection.3) The pharmacokinetics of octreotide are similar to those of many other agents administered continuously via intravenous or subcutaneous infusion, 7) and similar changes in pharmacokinetics would be expected if octreotide were to be administered by continuous intravenous administration instead of sustained subcutaneous administration, i.e., without the need for special equipment (e.g., miniature pump).We have been unable to find any reports describing the time-dependent stability of octreotide in amino acid infusions under different pH, temperature and ingredient such as sodium bisulfite. Especially, we have been unable to find reports evaluating such time-dependent stability of octreotide in amino acid infusions quantitatively.Hanamura et al. 8) report on the stability of octreotide in glucose and saline infusions, but its stability in amino acid infusion fluids was not investigated in detail. We have been unable to find any reports describing the stability of octreotide in amino acid infusions. Sodium bisulfite (SBS), which is used as a stabilizer in injectable preparations, is known to degrade various drugs, including thiamine, 9) epinephrine, 10) gabexate mesilate, 11) nafamostat mesilate, 12) urokinase, 13) morphine, 14)fluorouracil 15) and imipenem. 16) However, there ...

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Prediction of the Stability of Imipenem in Intravenous Mixtures

Cited by 9 publications

References 23 publications

The Limonoids TS3 and Rubescin E Induce Apoptosis in Human Hepatoma Cell Lines and Interfere with NF-κB Signaling

The Limonoids TS3 and Rubescin E Induce Apoptosis in Human Hepatoma Cell Lines and Interfere with NF-κB Signaling

Prediction of the Stability of Meropenem in Intravenous Mixtures

Prediction of the Stability of Octreotide in a Mixed Infusion

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