Effect of Preservatives on IgG Aggregation, Complement-activating Effect and Hypotensive Activity of Horse Polyvalent Antivenom Used in Snakebite Envenomation

Garcı́a, Mildred; Monge, María del Pilar Durán; León, Guillermo; Lizano, Sergio; Segura, Eduardo; Solano, Gabriela; Rojas, Gustavo; Gutiérrez, José Marı́a

doi:10.1006/biol.2002.0329

Cited by 55 publications

(49 citation statements)

References 22 publications

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“…This situation gave a good chance for formulators to employ different amounts of the same preservative, sometimes even to a level that may harm the patient. This discrepancy in concentration is clearly observed in most antivenom preparations (9,10,12,26).In this study, both polyvalent snake and scorpion antivenoms -containing m-cresol in a concentration of 0.15 g% and more -completely prevented the growth and proliferation of tested microorganisms. This result observes the requirements for the antimicrobial activity stated by the British Pharmacopoeia 2002, which states that the preservative properties of the preparation are adequate if, in the test conditions, there is a significant drop or no increase in the number of microorganisms in the preparation after the evaluation period in adequate conditions.…”

supporting

confidence: 46%

Section: Discussionmentioning

confidence: 94%

“…Turbidity in equine antivenoms depends, at least, in one way, on the interaction between initial protein concentration in the serum, and addition of phenol during fractionation of serum (10). Protein aggregation -besides loss of activity and safety of antivenom -is another important indicator of product instability caused by phenols, which are hydrophobic substances that may induce an increase in protein denaturation (3,12,21). García et al (12) found differences in the augmentation of aggregate levels and dimmers among antivenoms stored for three years that were devoid of phenol and contained different preservatives, meaning that these substances could accelerate the normal denaturation process.…”

Section: Introductionmentioning

confidence: 99%

“…Usually, phenol concentrations in antivenoms range from 0.15 to 0.5 g% (7)(8)(9)(10). Combinations of phenol and thimerosal in different ratios have also been effectively used in some antivenom preparations (11,12). M-cresol, a phenol derivative, is frequently utilized as preservative in numerous antivenom preparations in concentrations that range between 0.15 and 0.35 g% (4,7,13).…”

Section: Introductionmentioning

confidence: 99%

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What is the optimum concentration of m-cresol in antivenoms?

Abd-Elsalam¹,

Abdoon²,

Al-Ahaidib³

2011

J. Venom. Anim. Toxins incl. Trop. Dis

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Antivenoms against snake and scorpion envenomations are usually equine in nature and composed mostly of F(ab`)2; additionally, phenol and m-cresol are mainly employed for their preservation. Although there is no study on this subject, m-cresol is utilized by most manufacturers in a concentration that ranges from 0.15 to 0.35 g%. Decreasing the concentration of m-cresol to its minimal effective level may protect victims from its toxic effects and keep the antivenom stable during its shelf life without forming any aggregates. In the present work, different concentrations of m-cresol, ranging from 0.1 to 0.35 g%, were used with some selected batches of snake and scorpion antivenoms. A low concentration of 0.15 g% showed an acceptable preserving result that complies perfectly with antimicrobial specifications stated by the British Pharmacopoeia. Tested antivenoms (in 12 batches), when kept in a cold room for 39 months (more than their shelf life), retained their physical, chemical and microbiological activities according to the specifications of pharmacopeias. The present data demonstrated that reduction of m-cresol concentration to 0.15 g% in case of equine F(ab`)2 antivenoms will improve safety of such preparations and preserve their stability during their shelf life.Key words: antivenoms, preservative, m-cresol, stability. Original PaPer The Journal of Venomous Animals and Toxins including Tropical Diseases ISSN 1678-9199 | 2011 | volume 17 | issue 1 | pages 12-22 INTRODUCTIONAntivenoms are refined and concentrated preparations of equine serum globulins -mostly F(ab`)2 -obtained by fractionating blood from healthy horses that were previously immunized with different type of venoms (1, 2). For more than a century, antivenoms have been used effectively as the only treatment for snakebites and envenomations caused by other poisonous animals including spiders and scorpions (3). Most antivenoms are produced in liquid form to lower their cost and ease their use. Currently, there are eight antimicrobial preservatives commonly used in licensed parenteral products of which m-cresol and phenol are habitually employed by manufacturers as preservatives in antivenom formulations (4-6). Usually, phenol concentrations in antivenoms range from 0.15 to 0.5 g% (7-10). Combinations of phenol and thimerosal in different ratios have also been effectively used in some antivenom preparations (11,12). M-cresol, a phenol derivative, is frequently utilized as preservative in numerous antivenom preparations in concentrations that range between 0.15 and 0.35 g% (4,7,13).Despite their efficacy as additive, the use of these agents involves the possibility of some adverse effects. It is well known that phenol and cresol are toxic to humans in certain amounts (5,(14)(15)(16)(17)(18)(19). Repeated exposure may cause harmful effects on the liver and kidney. Additionally, potential development of multiple organ failure with persistence of organ dysfunction associated with the overdose of injectable phenol was already reported (20). Turbi...

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supporting

confidence: 46%

Section: Discussionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

What is the optimum concentration of m-cresol in antivenoms?

Abd-Elsalam¹,

Abdoon²,

Al-Ahaidib³

2011

J. Venom. Anim. Toxins incl. Trop. Dis

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“…16 The addition of thimerosal and/or phenol to IgG antivenoms increased the formation of dimeric and polymeric IgGs and induced higher complement activation compared with antivenoms formulated without preservatives. 17 All of these data indicate the lack of consensus in the literature regarding which types of antivenom induce fewer EARs and in particular, which mechanisms are involved in the genesis of these reactions, including the role of the complement system.…”

Section: Introductionmentioning

confidence: 99%

Anticomplementary Activity of Horse IgG and F(ab')2 Antivenoms

Squaiella-Baptistão¹,

Marcelino²,

Cunha³

et al. 2014

The American Society of Tropical Medicine and Hygiene

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Purification of equine IgG using membrane based enhanced hybrid bioseparation technique: A potential method for manufacturing hyperimmune antibody

Wang

Sun

Ghosh

2007

Biotech & Bioengineering

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Hyperimmune equine IgG is widely used as antivenom and anti-rabies agents. This article discusses a membrane based enhanced hybrid bioseparation technique for efficient and scalable purification of equine immunoglobulin G (IgG) from horse serum. This technique is an improved version of a standard hybrid bioseparation technique developed within our group earlier for fractionation of human plasma proteins (Ghosh. 2004. J Membr Sci 237: 109-117). In the presence of a high antichaotropic salt concentration, equine IgG is selectively and reversibly captured within a stirred cell membrane module from horse serum, partly due to precipitation and microfiltration, and partly due to hydrophobic interaction based membrane adsorption, while the impurities are washed out from the device. The reversibly sequestered IgG is then released by lowering the salt concentration which favor both dissolution of the precipitated IgG and desorption of the membrane bound IgG. The enhanced hybrid bioseparation technique improves the IgG recovery from the membrane module by switching from a stirring to non-stirring mode during the IgG release phase. It also reduces membrane fouling by an appropriate pH switch. The effects of operating conditions on equine IgG capture were first systematically studied. The enhanced hybrid bioseparation technique was followed by an ultrafiltration step to remove ammonium sulfate and low molecular weight impurities. The equine IgG purity obtained under optimized conditions was 88% and its recovery was over 90%, both being significantly higher than corresponding values obtained using currently used purification techniques.

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Effect of Preservatives on IgG Aggregation, Complement-activating Effect and Hypotensive Activity of Horse Polyvalent Antivenom Used in Snakebite Envenomation

Cited by 55 publications

References 22 publications

What is the optimum concentration of m-cresol in antivenoms?

What is the optimum concentration of m-cresol in antivenoms?

Anticomplementary Activity of Horse IgG and F(ab')2 Antivenoms

Purification of equine IgG using membrane based enhanced hybrid bioseparation technique: A potential method for manufacturing hyperimmune antibody

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