REVIEW

The Role of Trypsin:Chymotrypsin in Tissue Repair

Dilip Shah . Kushal Mital

Received: October 25, 2017 / Published online: December 5, 2017� The Author(s) 2017. This article is an open access publication

ABSTRACT

Tissue damage of all types, such as surgical oraccidental injuries, fractures, and burns, stimu-lates a well-orchestrated, physiological processof healing, which ultimately leads to structuraland functional restoration of the damaged tis-sues. The tissue repair process can be broadlydivided into four continuous and overlappingphases—hemostasis and coagulation, inflam-mation, proliferation, and remodeling. If theprocess is interrupted or halted during anystage, it leads to impaired healing and forma-tion of a chronic wound. Chronic wounds areassociated with significant morbidity, mortality,and poor quality of life. Therefore, prompt andeffective management of acute tissue injury isnecessary to prevent it from progressing to achronic wound. Proteolytic enzymes have beenused to facilitate tissue repair since ancienttimes. Trypsin:chymotrypsin is an oral

proteolytic enzyme preparation which has beenin clinical use since the 1960s. It provides betterresolution of inflammatory symptoms and pro-motes speedier recovery of acute tissue injurythan several of the other existing enzymepreparations. This review article revisits the roleand clinical utility of trypsin:chymotrypsincombination in tissue repair.

Funding: Torrent Pharmaceuticals Limited.

Keywords: Accidental injuries; Burn; Healing;Proteolytic enzymes; Orthopedic injuries;Sciatica; Surgical injuries; Tissue injury; Tissuerepair; Trypsin:chymotrypsin

INTRODUCTION

Impaired tissue repair is a common medicalproblem, affecting millions of people worldwide[1]. Chronic wounds thus formed are a source ofsignificant morbidity, mortality, and poorquality of life. They also incur substantialhealthcare-related financial burden [1–3].Hence, prompt and effective management ofacute tissue injury is necessary to prevent itfrom progressing to a chronic wound [4].

Proteolytic enzymes have been used tofacilitate tissue repair since ancient times.Trypsin:chymotrypsin is an oral proteolyticenzyme preparation which has been in clinicaluse since the 1960s. It provides better resolution

Enhanced content To view enhanced content for thisarticle go to http://www.medengine.com/Redeem/67FCF0604A425994.

D. Shah (&)Saifee Hospital, Mumbai, Indiae-mail: drdilipdshah@gmail.com

D. ShahNanavati Hospital, Mumbai, India

K. MitalMedicare Hospital, Mumbai, India

Adv Ther (2018) 35:31–42

https://doi.org/10.1007/s12325-017-0648-y

of inflammatory symptoms and promotesspeedier recovery of acute tissue injury thanseveral of the other existing enzyme prepara-tions [4]. This paper revisits the role and clinicalutility of trypsin:chymotrypsin combination intissue repair.

This article is based on previously conductedstudies and does not involve any new studies ofhuman or animal subjects performed by any ofthe authors.

HEALING AND TISSUE REPAIR:INSIGHTS

Tissue damage of all types, such as surgical oraccidental injuries, fractures, and burns, stimu-lates a well-orchestrated, physiological processof healing, which ultimately leads to structuraland functional restoration of the damaged tis-sues. The repair process can be broadly dividedinto four continuous and overlapping phases—hemostasis and coagulation, inflammation,proliferation, and remodeling [1, 5, 6]. Thesephases are briefly described below (Fig. 1).

Phase I: Hemostasis and Coagulation

During the phase of hemostasis and coagulation,the damaged blood vessels constrict, platelets getactivated, the coagulation cascade is initiated, fib-rin clot is formed, and various substances arereleased from the platelets and damaged cells.These substances cause secondary vasodilation,increase vascular permeability, and act as chemo-tactic stimuli for different cells which facilitatesubsequent repair processes [7]. The provisionalfibrin matrix is ultimately invaded and degradedby plasmin—a serine protease which is formedfrom plasminogen by plasminogen activators,leading to reestablishment of circulation [4, 8].

Phase II: Inflammation

Inflammation starts within 24 h of the injuryand lasts for 2 weeks or more. It begins with therelease of growth factors and inflammatorycytokines from the activated platelets and thedamaged cells, which attract inflammatory cells

from circulation—the leukocytes—to the site ofinjury [9].

Neutrophils are the first leukocytes to reach theinjury site where they attach to the vascularendothelial cells and subsequently pass out to theextravascular space [9]. They secrete proteases,including elastase, which degrade and removecellular debris and hence help in the cleaning upprocess; a-1 protease inhibitor secreted by mac-rophages regulates the activity of elastase. Pro-teases also facilitate migration of neutrophils intothe extracellular space where they prevent con-tamination and infection from local bacterialflora by performing phagocytosis [7, 9, 10]. Addi-tionally, neutrophils release reactive oxygen spe-cies (ROSs) which possess anti-infective properties[11, 12]. Also, the proinflammatory cytokinessecreted by neutrophils facilitate recruitment offibroblasts and epithelial cells at the site of injury;these cells are involved in repair and remodelingof the damaged tissue [9].

Blood monocytes begin infiltrating the woundwithin 2 days of injury [7, 8, 13]. Their entrycoincides with decline in neutrophil infiltration.Upon entering the wound, they differentiate intomacrophages, which besides participating inphagocytosis of bacteria and muscular debris alsoperform a very important role of controlling thewound repair process [7, 11]. The latter effect isachieved by numerous cytokines, growth factors,and free radicals secreted by macrophages whichregulate recruitment of fibroblasts, endothelialcells, and keratinocytes to the injury site, forma-tion of extracellular matrix (ECM), angiogenesis,and fibrosis [9, 11, 12].

Apoptosis of inflammatory cells, the mecha-nisms of which remain predominantlyunknown, marks the resolution of the inflam-matory phase [1, 12].

Phase III: Proliferation

Resolution of the inflammatory phase marksthe beginning of the proliferative phase [1].During this phase, re-epithelialization, angio-genesis, and degradation and remodeling ofECM by proteases (especially matrix metallo-proteinases) and their inhibitors occur. Thisleads to wound closure [5, 11, 12].

32 Adv Ther (2018) 35:31–42

Phase IV: Remodeling

Following wound closure, the remodeling phasebegins which leads to formation of a collage-nous scar whose tensile strength is approxi-mately 80% of the normal, non-injured tissue[8, 9, 12].

ROLE OF PROTEASES IN TISSUEREPAIR

As discussed in the preceding sections, repair ofdamaged tissues is a well-coordinated, system-atic event which consists of four overlappingyet functionally distinct phases, namely

Fig. 1 Normal physiologic process of tissue repair [5, 8–13]

Adv Ther (2018) 35:31–42 33

hemostasis and coagulation, inflammation,proliferation, and remodeling [5, 12]. If theprocess is interrupted or halted during anystage, it leads to impaired healing and forma-tion of a chronic wound. Usually, chronicwounds are formed as a result of arrest of therepair process during the inflammatory stage[12, 14]. The excessive inflammation thus gen-erated increases the level of proteases relative totheir inhibitors. This imbalance disrupts thedelicate equilibrium between ECM depositionand degradation that is vital for effective tissuerepair, resulting in uncontrolled ECM destruc-tion and formation of a chronic wound [5, 14].Chronic wounds therefore contain increasedlevels of inflammatory cells and proteases thatdo not allow them to heal [12].

Role of Trypsin:Chymotrypsin in TissueRepair

Trypsin:chymotrypsin is a widely used oralproteolytic enzyme combination to hastenrepair of traumatic, surgical, and orthopedicinjuries. It shows high bioavailability withoutlosing its biological activities as an anti-inflam-matory, anti-edematous, fibrinolytic, antioxi-dant, and anti-infective agent. These propertieshelp in resolving signs and symptoms ofinflammation due to tissue injury and facilitatethe repair process. It also demonstrates anal-gesic effects and reduces the pain associatedwith healing [4, 15, 16].

Mechanisms of Beneficial Effectsof Trypsin:Chymotrypsin in Tissue Repair

Despite extensive evaluation, the mechanismsof beneficial effects associated withtrypsin:chymotrypsin combination remainincompletely understood [4]. The postulatedmechanisms are briefly discussed below.

Following an acute injury, there is a sharp risein the levels of the protease inhibitors a1-antit-rypsin and a2-macroglobulin. These acute phasereactants inhibit several proteolytic enzymes,which if uncontrolled can lead to unregulatedinflammation and impair healing. The order ofaffinity of a1-antitrypsin with proteolytic

enzymes is as follows: elastase[chy-motrypsin[cathepsin G[trypsin[plasmin.Similarly, a2-macroglobulin shows greatestaffinity with cathepsin G. At this point, it mustbe reiterated that plasmin causes fibrinolysis andits inhibition prevents fibrinolysis. Therefore, asteep rise in a1-antitrypsin and a2-macroglobu-lin following acute injury leads to a period offibrinolytic shutdown, with consequent mainte-nance of inflammatory response and edema anddelay in repair. Oral combination oftrypsin:chymotrypsin targets this early stage ofinflammation. Since a1-antitrypsin showsgreater affinity for trypsin and chymotrypsincompared to plasmin, oral supplementation ofthe enzyme complex ensures that plasminremains available for fibrinolysis and the periodof fibrinolytic shutdown is shortened. As a result,local microcirculation is restored, inflammatoryedema is cleared, and tissue repair is facilitated[4, 17].

Another mechanism which contributes toimproved healing with trypsin:chymotrypsincombination is that it helps in maintaininghigh levels of a1-antitrypsin for a long duration.Consequently, the activity of proteolyticenzymes and their degradative effects arecountered, leading to reduction in inflamma-tory milieu, ROS and oxidative stress, and fasterhealing. Additionally, the enzyme preparationalso increases enzymatic and non-enzymaticantioxidant levels, which further augments itsantioxidant and anti-inflammatory efficacy[17–20]. The anti-infective property of theenzyme complex may be explained byenhanced phagocytic activity of natural killercells and macrophages due to trypsin [4]. It isalso interesting to note that the combinationhas been shown to reduce the constant loss ofalbumin and pre-albumin after surgical proce-dures. Consequently, it may prevent many ofthe life-threatening postoperative complica-tions, such as shock [20]. Overall, the use oftrypsin:chymotrypsin in patients with acuteinjury reduces inflammatory edema and tissuedestruction, which in turn facilitates rapidhealing [17–19]. Figure 2 provides a compre-hensive overview of postulated mechanisms ofbeneficial effects of trypsin:chymotrypsin intissue repair [4, 17–20].

34 Adv Ther (2018) 35:31–42

Efficacy and Safetyof Trypsin:Chymotrypsin in VariousClinical Indications

Numerous clinical trials have attested the effi-cacy and safety of trypsin:chymotrypsin com-bination in resolving inflammation and edemasecondary to tissue damage of different types,such as accidental injuries, surgical and ortho-pedic injuries, burns, and sciatica [4, 15, 21, 22].

Trypsin:Chymotrypsin in Accidental, Surgical,and Orthopedic Injuries—Clinical AppraisalGoel and Sengupta [15] studied the efficacy oftrypsin:chymotrypsin (Chymoral) in accidentalsoft tissue injuries. They included 156 patients(age between 14 and 45 years) presenting in thecasualty department with bruises, lacerations,hematomas, and sprains and strains. The patientswere randomized into two groups: the Chymoralgroup (n = 79), which received trypsin:chy-motrypsin therapy along with standard emer-gency treatment, and the control group (n = 77),which received emergency treatment only. Therecommended dosage of Chymoral wasemployed, i.e., 2 tablets 4 times a day 9 7 days,30 min before a meal. The patients were followedeither once weekly or twice weekly and theirprogress was documented. Trypsin:chymotrypsin

use resolves bruises within 8–12 days, whichotherwise cleared in 10–15 days. In patients withlacerations, it improved the appearance of scar-ring due to stitches. Also, hematomas of theforehead and knees, which usually take 2–3 weeksto clear, resolved within 10–12 days in the Chy-moral group. Ankle sprains normally take 2–3 weeks to recover. However, speedy recovery wasdocumented with trypsin:chymotrypsin use,clearing as quickly as within 7–12 days. Addi-tional benefits associated with the use of theenzyme preparation included relief in pain andlower incidence of infection. It was concludedthat trypsin:chymotrypsin treatment in patientswith accidental soft tissue injuries hastens thehealing process and significantly reduces therecovery time. Table 1 shows majorfindings of thestudy.

Further validating the above findings, Brak-enbury and Kotowski [21] also demonstratedthat trypsin:chymotrypsin treatment improvedthe recovery rate in patients with ankle sprains.They conducted a double-blind randomizedcontrolled trial involving 252 patients withsprains of the medial/lateral ligaments of theankle that were immobilized using eitherbelow-the-knee plaster cast or an elastic ban-dage applied from the toes to below the knee.The patients were randomized to receive either

Fig. 2 Mechanisms of beneficial effects of trypsin:chymotrypsin in tissue repair [4, 17–20]

Adv Ther (2018) 35:31–42 35

trypsin:chymotrypsin (Chymoral Forte) or pla-cebo. Chymoral Forte contains 100,000 Armourunits of proteolytic activity and was given halfan hour before meal, 4 times a day 9 5 days. Intotal, four groups were formed: group 1,trypsin:chymotrypsin and plaster cast; group 2,placebo and plaster cast; group 3, trypsin:chy-motrypsin and elastic bandage; and group 4,placebo and elastic bandage. The patients wereexamined and evaluated for bruising andedema, power of dorsiflexion, and range ofmovement at baseline and at day 7 and day 14.The extent of bruising and edema was assessedon a scale of 0–3 as absent, mild, moderate, andsevere. A hand-held Hammersmith myometerwas used to measure power of dorsiflexion andrange of movement was recorded by goniome-ter. The following results were noteworthy:• Among patients with a plaster cast, the rate

of resolution of bruising was better in thosewho received trypsin:chymotrypsin treat-ment than in placebo on both day 7 andday 14 (Fig. 3a).

• Among placebo group patients, the use of anelastic bandage produced faster resolution ofbruising and edema than plaster cast on bothday 7 and day 14.

• Improvement in power of dorsiflexion wasfastest in those treated with an elastic ban-dage and trypsin:chymotrypsin.

• The complete global response rate at day 14was better in those who received trypsin:chy-motrypsin treatment than placebo (Fig. 3b).These findings suggest that trypsin:chy-

motrypsin treatment hastens the recovery ofaccidental soft tissue injuries.

Besides accidental injuries, the reparativerole of trypsin:chymotrypsin has also beenappreciated in surgical injuries. A multicentricIndian study [17] investigated the efficacy andsafety of trypsin:chymotrypsin (ChymoralForte) in patients with traumatic injuries fromaccidents, surgeries, burns, and others. A totalof 230 patients were recruited from 28 districtsacross India; 208 patients completed the studyand the remaining were lost to follow-up. These

Table 1 Comparative recovery time with and without trypsin:chymotrypsin (Chymoral) in patients with accidental softtissue injuries [15]

Type of injuries Chymoral (trypsin:chymotrypsin) group Control group

No. of cases Recovery time No. of cases Recovery time

Painful bruises

Facial and forehead bruises 6 8–12 days 6 10–15 days

Facial bruises and injury to nose 10 8 days 10 15 days

Facial bruises and black eyes 2 10–12 days 2 20 days

Soft tissue crush injury of thigh,

with arm bruises and toe wounds

2 12 days 2 4 weeks

Hematomas

Forehead hematoma, without skull fracture 10 10 days 10 15–20 days

Knee hematoma 5 12 days 5 3 weeks

Ankle sprain with bruises but without fracture

Lateral side bruises 20 10–12 days 20 2–3 weeks

Medial side bruises 10 8–10 days 12 2–3 weeks

Foot bruises 4 10–12 days 0 –

p B 0.02

36 Adv Ther (2018) 35:31–42

patients received 1 tablet of Chymoral Forte 4times a day 9 5–10 days. The levels of swelling,pain, and inflammation were measured on day0, 2, 4, 6, 8, and 10. Also, improvement inhematoma, healing of wound, and mobility wasevaluated. At the end of the study, the overallefficacy of the treatment was measured on a3-point scale as excellent (no signs and symp-toms of inflammation), good (swelling reduced,and no pain or other symptoms), and fair (somedegree of pain, swelling, and other symptoms).Statistically significant improvement in pain,swelling, and inflammation was noted from the6th day onwards; p\0.05 (Table 2). Likewise,improvement in hematoma, healing of wound,and mobility was noted by 6th day, which

further increased significantly by 10th day;p\0.05. At the end of the study, the overallefficacy of the treatment was determined to beexcellent in 48.2% patients, good in 44.7%patients, and fair in 7.0% patients (Fig. 4). Nocase of therapy discontinuation due to drug-re-lated adverse events attested the acceptable tol-erability of trypsin:chymotrypsin. On the basisof these findings, it was suggested thattrypsin:chymotrypsin treatment in patientswith surgical injuries, accidental injuries, andburns effectively resolves inflammation andimproves healing.

56

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Plaster cast + Placebo

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Trypsin:chymotrypsintreatment

Placebo

(a)

(b)

Fig. 3 a Resolution of bruising with trypsin:chymotrypsintreatment vs placebo in patients with ankle sprain who hada plaster cast [21]. b Global response at day 14 withtrypsin:chymotrypsin treatment vs placebo in patients withankle sprain who had either a plaster cast or elastic bandage[21]

Table 2 Improvement in swelling, pain, and inflammationwith trypsin:chymotrypsin (Chymoral Forte) treatment inpatients with traumatic injuries [17]

Meanswellingscore(p < 0.05)

Mean painscore(p < 0.05)

Meaninflammationscore (p < 0.05)

Baseline 2.46 ± 0.8 2.46 ± 0.8 2.29 ± 0.86

Day 6 0.99 ± 0.76 0.74 ± 0.71 0.81 ± 0.7

Day 8 0.51 ± 0.62 0.38 ± 0.56 0.41 ± 0.55

Day 10 0.22 ± 0.46 0.16 ± 0.41 0.1 ± 0.32

48.244.7

7

0

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Excellent efficacy Good efficacy Fair efficacy

Rate

(%)

Note: Excellent efficacy = no symptoms or signs of inflamma�on; good efficacy = swelling reduced, and no pain or other symptoms; fair efficacy = some degree of pain, swelling, and other symptoms

Fig. 4 Overall efficacy of trypsin:chymotrypsin (ChymoralForte) treatment in resolving signs of inflammation inpatients with traumatic injuries [17]

Adv Ther (2018) 35:31–42 37

Usefulness of trypsin:chymotrypsin treat-ment has also been recognized in orthopedicinjuries and surgeries. Pages [23] conducted aclinical trial to investigate efficacy, safety andtolerability of trypsin:chymotrypsin (ChymoralMauchant) treatment to resolve edema andhemorrhagic infiltration due to tissue trauma inorthopedic surgery patients. Chymoral Mau-chant contains 50,000 Armour units of trypsinand chymotrypsin, and in an adult of averagebody weight, 6–8 tablets daily were given. Goodand rapid absorption of edema and hemor-rhagic infiltration was interpreted as an ‘‘excel-lent result’’ and good but delayed resolution ofedema as a ‘‘good result’’ [23]. In 15 adultpatients who were treated therapeutically withtrypsin:chymotrypsin for the indications ofmaxillofacial injury, fractures, knee sprain,traumatic hematoma of the leg and thighs,hemarthrosis of the knee, and burns, excellentresults were produced in 46.67% patients, goodresults in 40% patients, average results in 6.67%patients, and no improvement in 6.67%patients. Its prophylactic use in 15 adultpatients for the indications of meniscectomy,fractures, skin grafting, digit amputation, repairof nerves and tendons, and repair of unsightlyharelip open scar yielded excellent results in86.67% patients, good results in 6.67% patients,and average results in 6.67% patients. Theobservation that none of the patients reportedany side effects established its good safety andtolerability profile. It was concluded that inorthopedic surgery patients, therapeutic use oftrypsin:chymotrypsin reduces edema and hem-orrhagic infiltration. Furthermore, it can beused prophylactically as well to prevent edemaand hematoma formation and reduce postop-erative complications.

Further direct evidence of the valuable role oftrypsin:chymotrypsin in orthopedic settings canbe gleaned from another study [4], whichdemonstrated its use to promote healing inpatients with orthopedic surgical injuries. Thisrandomized controlled study involved a total of75patientswho had undergone openreduction offractures. These patients were randomized toreceive trypsin:chymotrypsin (Chymoral Forte),serratiopeptidase (S) 5 mg oral tablets, or an oral

enzyme combination of trypsin 48 mg, bromelain90 mg, and rutoside 100 mg (TBR). The medica-tions were started 24 h after the surgery, 3 times aday for 7–10 days. Improvement in erythema,local irritation, wound discharge, edema, indura-tion, tenderness, and pain were documented onfollow-up visits on days 3, 5, 7 and if required onday 10. Global response was assessed at the end ofthe therapy (day 7 or day 10) using the 5-pointPatient Global Assessment ofResponse toTherapy(PGART) scale; 1 = excellent response, 2 = goodresponse, 3 = average response, 4 = no response,5 = poor response. Similarly, tolerability of treat-ment was assessed at the end of the therapy usingthe 5-point Patient Global Assessment of Tolera-bility to Therapy (PGATT) scale; 1 = excellenttolerability, 2 = good tolerability, 3 = averagetolerability, 4 = poor tolerability, 5 = very poortolerability. Trypsin:chymotrypsin treatmentproduced significantly greater improvement inerythema, local irritation, wound discharge,edema, induration, tenderness, and pain thanserratiopeptidase and trypsin:bromelain:rutosidetreatments. The overall efficacy and tolerability oftrypsin:chymotrypsin was also significantlysuperior to other treatments (Figs. 5, 6).

It was concluded that trypsin:chymotrypsintreatment is significantly better tolerated andmore effective than other enzyme preparationsin resolving symptoms of inflammation afterorthopedic surgeries and therefore promotesbetter healing [4].

Trypsin:Chymotrypsin in Burn Injuries—Clinical AppraisalBurn injuries are the most severe injuries sus-tained by the human body [6]. The phases ofhealing are similar to those that occur in anyother type of tissue injury. However, in contrastto other traumatic injuries, burn injuries causegeneralized increase in vascular permeability,which leads to localized and generalized edemaand hypovolemic shock [24]. Shock, in turn, isassociated with enhanced generation of freeradicals, which cause lipid peroxidation andsubsequent further damage to tissues andorgans [19].

Trypsin:chymotrypsin treatment in patientswith burn injuries reduces edema,

38 Adv Ther (2018) 35:31–42

inflammation, and oxidative stress which inturn attenuates tissue destruction and hastensthe repair process [6, 19].

Latha et al. [6] investigated the effects oftrypsin:chymotrypsin treatment on acute phaseproteins [C-reactive protein (CRP), a1-antit-rypsin, and a2-macroglobulin] in 30 patientswith 20–30% deep second-degree burns. These

patients were grouped into two groups: theenzyme-treated group, which receivedtrypsin:chymotrypsin (Chymoral Forte DS hav-ing enzymatic activity of 200,000 Armour units)4 times a day for 10 days, and the control group,which did not receive the enzyme treatment.An initial increase in the levels of acute phaseproteins(CRP, a1-antitrypsin, and a2-mi-croglobulin) was recorded in both groups. Theanti-inflammatory efficacy of trypsin:chy-motrypsin was reflected by a decline in CRPlevels by day 7 in the enzyme-treated group,which otherwise remained high in the controlgroup; note: CRP is an indicator of inflamma-tion. Other notable findings were significantdifferences in the levels of a1-antitrypsin anda2-macroglobulin between the two groups.While a1-antitrypsin levels started graduallydeclining from the 3rd day onwards in thecontrol group, in the enzyme-treated groupthey continued to rise, reaching a maximum onthe 5th day, and thereafter remained at thehigher levels for a longer duration. Trypsininhibitory capacity (TIC) was consequentlyhigher in the treated group than the controlgroup. The increase in a2-macroglobulin levelswas also greater in the treated group than thecontrol group. It was suggested that apart fromits anti-inflammatory, anti-edematous, and fib-rinolytic actions in burn injuries, the enzymecomplex minimizes protease-induced tissuedegradation by maintaining higher levels ofproteolytic inhibitors (a1-antitrypsin and a2-macroglobulin) for longer durations. Thus, itfacilitates healing of burn injuries by reducinginflammation, edema, and tissue destruction.

The investigators of the aforementionedstudy also evaluated the antioxidant efficacy oftrypsin:chymotrypsin in the same cohort ofburn patients. The lipid peroxidation products,which increased initially in both the treated andthe control groups, started to decrease in thetreated group from the 7th day onwards. Also,enzymatic and non-enzymatic antioxidantlevels were higher in the treated group than thecontrol group and remained at high levels forlonger durations. These findings support theaforementioned observations that trypsin:chy-motrypsin reduces tissue degradation, which inturn leads to decreased formation of free

88

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Fig. 5 Patient Global Assessment of Response to Therapy(PGART) for efficacy in patients with orthopedic surgicalinjuries who received either trypsin:chymotrypsin (Chy-moral Forte), serratiopeptidase, or trypsin:bromelain:ru-toside [4]

92

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lera

bilit

y

Fig. 6 Patient Global Assessment of Tolerability toTherapy (PGATT) for tolerability in patients withorthopedic surgical injuries who received eithertrypsin:chymotrypsin (Chymoral Forte), serratiopeptidase,or trypsin:bromelain:rutoside [4]

Adv Ther (2018) 35:31–42 39

radicals and hence maintenance of higherantioxidant levels for longer durations [19].

Trypsin:Chymotrypsin in Sciatica—ClinicalAppraisalSciatica is a painful condition characterized bypain radiating from the lower back to the leg. Inthe majority of cases, it is caused by interverte-bral disc herniation, resulting in spinal nerveroot compression and inflammation [25]. Theanti-inflammatory efficacy of trypsin:chy-motrypsin could therefore be utilized in thesepatients to reduce inflammation and improvesymptoms [22].

Gaspardy et al. [22] evaluated the effective-ness of trypsin:chymotrypsin (Chymoraltablets) treatment to improve symptoms of sci-atica due to intervertebral disc herniation. Theyconducted a double-blind cross-over trialinvolving 30 patients (age between 23 and70 years) with sciatica, who had previouslyfailed analgesics, physiotherapy, and injectionsof local anesthetics. The participants were ran-domly assigned into two groups. Group 1 firstreceived trypsin:chymotrypsin treatment and

subsequently placebo treatment, and group 2first received placebo treatment and subse-quently trypsin:chymotrypsin treatment. Thedosage of trypsin:chymotrypsin and placebowas 2 tablets 4 times a day for 3 days followedby 1 tablet 4 times a day for 4 days. In additionto the study treatments, all patients receivedbed rest, electrotherapy, analgesics, etc.Patients’ condition was assessed at baseline andat 7-day intervals. Symptom severity was gradedon a scale of 0–4 and straight leg raising test wasmeasured in degrees. At 1 week, group 1patients who first received trypsin:chy-motrypsin treatment showed considerabledecrease in symptoms compared with group 2patients who first received placebo. At 2 weeks,group 1 patients did not document any furtherdecrease in symptoms, whereas group 2 patientswitnessed a marked reduction in symptoms(Table 3).

It was suggested that trypsin:chymotrypsintreatment in patients with sciatica secondary tointervertebral disc protrusion significantlyimproves symptoms by decreasing inflamma-tory edema in the nerve roots [22].

Table 3 Impact of trypsin:chymotrypsin treatment on sciatica symptoms [22]

Symptoms Rate (%) of improvement in group 1 Rate (%) of improvement in group 2

Week 1(trypsin:chymotrypsintreatment)

Week 2 (placebotreatment)

Week 1(placebotreatment)

Week 2(trypsin:chymotrypsintreatment)

Spontaneous low back

pain

60 60 20 53.3

Spontaneous leg pain 46.7 46.7 33.3 46.7

Lumbar muscle spasm 54.5 72.7 33.3 53.3

Lumbar rigidity 73.3 73.3 33.3 60.0

Scoliosis 62.5 62.5 30.0 70.0

Sensitivity to pressure in

paravertebral region

53.3 53.3 6.7 80.0

Straight leg raise test 53.3 53.5 13.3 53.3

40 Adv Ther (2018) 35:31–42

CONCLUSIONS

Owing to anti-inflammatory, anti-edematous,fibrinolytic, anti-infective, and analgesic effects,trypsin:chymotrypsin oral combination hasemerged as a promising treatment to facilitatehealing of traumatic injuries. It promotesspeedier recovery and better resolution ofinflammatory signs and symptoms due to tissueinjury than several of the other existing enzymepreparations. It also demonstrates analgesiceffects and reduces pain associated with heal-ing. The efficacy and safety of trypsin:chy-motrypsin in accidental injuries, surgical andorthopedic injuries, burns, and sciatica has beencorroborated by a substantial and largely con-sistent body of evidence from clinical trials.

ACKNOWLEDGEMENTS

Funding. Article publication charges were fun-ded by Torrent Pharmaceuticals Limited.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship of thismanuscript, take responsibility for the integrityof the work as a whole, and have given finalapproval for the version to be published.

Medical Writing, Editorial, and OtherAssistance. The medical writing support hasbeen provided by Springer India Pvt Ltd and wasfunded by Torrent Pharmaceuticals Ltd.

Contributorship. The authors would alsolike to acknowledge Ms. Surbhi Sarvaiya for hercontribution towards the execution of thisproject.

Disclosures. Dilip Shah and Kushal Mitalhave nothing to disclose.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not involve any new studies of humanor animal subjects performed by any of theauthors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommer-cial use, distribution, and reproduction in anymedium, provided you give appropriate creditto the original author(s) and the source, providea link to the Creative Commons license, andindicate if changes were made.

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