Reduction of primary postoperative adhesion formation under calcium channel blockade in the rabbit

doi:10.1016/0022-4804(90)90143-P

Journal of Surgical Research

Volume 48, Issue 1, January 1990, Pages 42-45

https://doi.org/10.1016/0022-4804(90)90143-P Get rights and content

Abstract

Preliminary studies in a hamster model have demonstrated calcium channel blocking agents to be potent inhibitors of primary post-traumatic peritoneal adhesion formation. The present investigation was designed to extend these observations to an extensively studied model, the rabbit, and to evaluate the optimal route of administration of these drugs for intraabdominal surgery. Rabbits were subjected to a standardized traumatic lesion of the left uterine horn. Subsequently, animals were divided into the following treatment groups: subcutaneous vehicle control (n = 7), intraperitoneal (ip) vehicle control (n = 8), subcutaneous verapamil treatment (n = 6), low-dose (2.5 μg/kg/hr) ip verapamil treatment (n = 10), and high-dose ip (25 μg/kg/hr) verapamil treatment (n = 6). All animals were reexplored at 1 week postop for evaluation of adhesion formation (scale: 0 to 4+). Calcium channel blockade-treated animals formed significantly fewer adhesions (0.45) than controls (3.93) (P < 0.01). There was no significant difference between animals treated with sc with verapamil sc and those treated with low- or high-dose verapamil ip (0.33 vs 0.20 vs 1.0). These data confirm our preliminary results, suggesting that calcium channel blockade potently modulates peritoneal healing and regeneration. Furthermore, intraperitoneal delivery and systemic administration appear equipotent in this model. Further study of these agents as potential adjuvants for intraperitoneal surgery is indicated.

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Rabbits are known to be prone to the formation of adhesions after surgical procedures.9 Medications that have been studied to decrease adhesion formation include verapamil, hyaluronic acid solutions, sodium carboxymethyl cellulose, and chondroitin sulfate.12,13 Since the patient in this report already had an identified adhesion, reducing postoperative adhesions was considered to be a necessity.
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As the initial response to injury involves the inflammatory cascade, corticosteroids [11] and non-steroidal anti-inflammatory drugs (NSAIDs) were among the earliest agents examined [12], as were anticoagulants such as heparin [13], and fibrinolytics such as streptokinase [14]. Recently the list of potential therapeutic agents has increased considerably, fueled by new insights into the biochemistry of adhesion formation, and has included growth factor inhibitors and modulators [15], tissue plasminogen activator [16], aromatase inhibitors [17], statins [18], angiotensin converting enzyme-inhibitors [19], extracellular matrix remodelers [20], antibiotics [21], platelet activating factor antagonists [22], hormones and hormone agonists [23, 24], calcium channel blockers [25], oxygen free radical inhibitors [26], and antiproliferative agents [27, 28]. Although some of these drugs demonstrated initial efficacy in a limited number of animal models, none has shown adhesion-reduction benefits in the clinical setting, and many have exhibited deleterious side effects.
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Fucoidan loaded films reduced adhesion scores by approximately 90% compared with control films (P < 0.05). A total of 50% to 100% of animals were adhesion free at fucoidan film loadings of 0.33% to 33% w/w compared with all control film animals having adhesions. No adverse effects were observed from 33% w/w fucoidan films equivalent to approximately 30 mg fucoidan/kg body weight.
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Aloe Vera gel [78] has considerably decreased postoperative adhesions. Experimental animal studies with colchicine [79], medroxyprogesterone acetate [80], calcium channel blockers [81], phosphatidylcholine [82], vitamin E [83], d-penicillamine [84], methylene blue [85], pentoxifylline [86], statins [87], and epidermal growth factor [88], show reduction in adhesion formation. Their efficacy in humans remains to be seen with further research.
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^☆: Supported by grants from the medical research committee of Valley Medical Center of Fresno and by Fresno Community Hospital, Fresno, California.

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Reduction of primary postoperative adhesion formation under calcium channel blockade in the rabbit☆

Abstract

Fertil. Steril.

Fertil. Steril.

Biochem. Pharmacol.

Amer. J. Med. Sci.

Biochem. Pharmacol.

Prevention and management of peritoneal adhesions

Fertil. Steril.

The use of diltiazem for prevention of postoperative adhesion formation

J. Reprod. Med.

Reduction of adhesion formation with perioperative verapamil treatment