A Randomized, Clinical Trial to Evaluate Efficacy and Tolerability of Trypsin:Chymotrypsin as Compared to Serratiopeptidase and Trypsin:Bromelain:Rutoside in Wound Management.

INTRODUCTION: Systemic enzyme therapy can play an important role in maintaining normal inflammatory processes within the body and thereby helps support and speed up healing. In the course of the anti-inflammatory action, enzymes degrade damaged cells and necrotic material and, through the inactivation of mediators and toxic products, they restrict the edema and pain. METHOD: The study conducted at Grant Medical College, Mumbai, India was a clinical trial comparing the efficacy and tolerability of three oral enzyme treatment groups-oral tablets containing trypsin:chymotrypsin (TC) (Chymoral Forte®), serratiopeptidase (S) 5 mg oral tablets, and oral enzyme tablets containing trypsin 48 mg, bromelain 90 mg, and rutoside 100 mg (TBR)-to evaluate their healing potential in surgical wounds after orthopedic surgery. RESULTS: A total of 75 patients were screened, randomized, and divided into three groups in 1:1:1 ratio receiving either of the three treatments. In the TC group, erythema was significantly reduced from 3.44 on day 3 to 1.16 on day 10 (p < 0.01). There was significantly better reduction in erythema scores in the TC group as compared to S and TBR groups (p < 0.05) at each follow-up visit. Similarly reduction in the local irritation, wound discharge, edema, induration, and tenderness score with TC treatment at the end of the study was significantly higher than that observed in the other two groups. In addition TC showed significant reduction in pain on the VAS scale (p < 0.01). Global assessment of response to therapy for efficacy and tolerability was reported to be good to excellent in 88% and 92% of the patients on TC as compared to 12% and 8% with S and 12% and 8% with TBR. CONCLUSION: TC provides a better resolution of symptoms of inflammation after orthopedic surgery as compared to S and TBR, thus facilitating better wound healing. Further studies are warranted to confirm the findings. TRIAL REGISTRATION: Clinical Trial Registry of India (Reg. No. CTRI/2011/07/001920).

[Effects of proteolytic enzyme therapy with Wobe Mugos against chemotherapy-induced toxicity in breast cancer patients - results of a pilot study]. / Proteolytische enzymtherapie mit wobe mugos gegen chemotherapie-bedingte toxizitäten bei brustkrebs-patientinnen - ergebnisse einer pilotstudie.

BACKGROUND: Wobe Mugos(®) is an enzyme preparation containing the proteases trypsin and papain from the pancreatic calf and commonly used in complementary medicine. From non-randomized studies, its multiple favorable effects including the reduction of adverse events from radiotherapy and chemotherapy in oncology patients have been reported. METHODS: Patients with invasive breast cancer receiving adjuvant or palliative chemotherapy between 2005 and 2006 and who were scheduled for at least two further cycles of this specific chemotherapy were included in this pilot study. A specific toxicity of at least grade 2 using the NCI common toxicity criteria which occurred during the preceeding cycle and was relevant to the patient was recorded. This specific toxicity, e.g. grade 2 emesis, was again evaluated after two analogously administered further chemotherapy cycles in which Wobe Mugos(®) had been coadministered. The hypothesis was that specific toxicites of individual patients will be reduced by this enzyme therapy. The majority of the 57 consecutive patients received palliative chemotherapy. Peroral enzyme therapy was coadministered with two uncracked coated tablets three times daily on all days of a chemotherapy cycle except on the day of chemotherapy administration. RESULTS: Tolerability was good. Positive and neutral effects on toxicity parameters were observed in 11 and 42 patients, respectively, and a negative influence in 4 women. CONCLUSION: We observed only a marginal influence of Wobe Mugos(®) in patients with breast cancer who had experienced at least a grade 2 toxicity in the preceding cycle and who received two further identical cycles of this chemotherapy in conjunction with the enzyme preparation. Randomized studies on homogenous patient populations are necessary.

Changes on venous diameter and leg perimeter with different clinical treatments for moderate chronic venous disease: evaluation using Duplex scanning and perimeter measurements.

AIM: To evaluate changes on venous diameter and perimeter of lower limbs in chronic venous disorder (CVD) patients after different clinical treatments for four weeks. METHODS: Fifty-two female patients classified as C2,s or C2,3,s (CEAP classification) were allocated consecutively in three groups: Cirkan (40 mg of the root extract of Ruscus aculeatus + 100 mg of flavonoid hesperidine methylchalcone + 200 mg of vitamin C per pill); elastic compression stockings (ECS) and no treatment (NT). Diameters were determined by duplex ultrasound and perimeter with Leg-O-Meter. RESULTS: After treatment, Cirkan significantly decreased popliteal vein and great saphenous vein (GSV) diameters bilaterally and ECS decreased popliteal vein diameter bilaterally and GSV and varices only on the left limb. Perimeters changed only with ECS. Clinical scores changed between Cirkan x NT and ECS x Cirkan. Disability score varied for ECS x NT and Cirkan x NT. chi2 test detected different distribution frequency for C3 and C2 classes according to treatment: ECS (both limbs) and Cirkan (only left limb). Varices and anatomical scores did not change. CONCLUSIONS: ECS emerges as the most effective clinical treatment tested but improvements with Cirkan on vein diameter and CEAP class were also observed. Clinical scores improved due to pain relief and edema reduction (ECS). These findings point to a positive effect of Cirkan, suggesting that venotonic drugs should be taken into account in the treatment of CVD.

Retrolective cohort study of an additive therapy with an oral enzyme preparation in patients with multiple myeloma.

PURPOSE: To evaluate the impact of an additive therapy with an oral enzyme (OE) preparation given for more than 6 months additionally to standard combination chemotherapy (vincristine/melphalan/cyclophosphamide/prednisone (VMCP)- or methylprednisolone/ vincristine/CCNU/cyclophosphamide/melphalan (MOCCA)-regimen) in the primary treatment of patients with multiple myeloma stages I-III. METHODS: A cohort of 265 patients with multiple myeloma stages I-III was consecutively treated at our institution in two parallel groups (control group (n = 99): chemotherapy +/-OE for less than 6 months; OE-group (n = 166): chemotherapy + OE for more than 6 months). The median follow-up time in the stages I, II, and III for the OE-group was 61, 37, and 46.5 months, respectively; for the control group the respective values were 33, 51.5, and 31.5 months. The primary endpoint of the study was disease-specific survival. Secondary endpoints were response to therapy, duration of first response and side effects. The chosen method for evaluation was the technique of a retrolective cohort analysis with a concurrent control group. Survival analysis was performed by the Kaplan-Meier method and multivariate analysis was done with the Cox proportional hazards model. RESULTS: Significantly higher overall response rates and longer duration of remissions were observed in the OE-group. Primary responders showed a longer mean survival time than non-responders. Additive therapy with OE given for more than 6 months decreased the hazard of death for patients at all stages of disease by approximately 60%. Observation time was not long enough to estimate the median survival for patients at stages I and II; for stage III patients it was 47 months in the control group versus 83 months for the patients treated with OE (P = 0.0014) which means a 3-year gain of survival time. Significant prognostic factors for survival, in the Cox regression analysis, were stage of disease and therapy with OE. The OE-therapy was generally well tolerated (3.6% of patients with mild to moderate gastrointestinal symptoms). CONCLUSION: OEs represent a promising new additive therapy in multiple myeloma which will be further evaluated in a randomized phase III trial in the USA.

Impact of complementary oral enzyme application on the postoperative treatment results of breast cancer patients--results of an epidemiological multicentre retrolective cohort study.

PURPOSE: [corrected] To evaluate the impact of postoperative treatment with an oral enzyme (OE) preparation given complementary to an antineoplastic therapy in patients with breast cancer. METHODS: The design of this epidemiological study was a retrolective cohort analysis with parallel groups. Design and conduct of the study were performed to current standards for prospective, controlled clinical trials. A cohort of 2,339 breast cancer patients undergoing surgical intervention and radio-, chemo- or hormonal therapy were studied in 216 centres. Of the 2,339 patients, 1,283 received complementary treatment with OE and 1,056 did not receive OE. Patients with other complementary medications were excluded and the final analysis was performed with the data from 649 patients, of whom 239 (37%) were additionally treated with OE (test group) and 410 (63%) without OE (control group). The median follow-up time for the test group was 485 days and for the control group 213 days. The primary endpoint of the study was to determine whether complementary treatment with OE can reduce typical disease- or therapy-associated signs and symptoms (gastrointestinal symptoms, mental symptoms, dyspnoea, headache, tumour pain, cachexia, skin disorders, infections, and side effects associated with the antineoplastic therapy) in patients with breast cancer. Imbalances for causal effects (covariates) were adjusted for by means of the propensity score. Outcome analysis was performed by estimating the linear regression between change in symptom score and propensity score with all data and using this regression line to calculate the change in symptom score which would be expected for each patient. Tumour-associated events (recurrence, metastasis, and death) were evaluated in terms of the number of events observed and time to event. The safety of treatment with OE was analysed in terms of the number and severity of adverse events, their duration, treatment and outcome. RESULTS: For all symptoms except tumour pain, the adjusted mean improvement in symptom scores was larger in the test group than in the control group. The adjusted difference was statistically significant for all symptoms, except tumour pain and infections. The results show that the typical disease- and therapy-associated signs and symptoms in patients on complementary therapy with OE during postoperative treatment were significantly less. For 75% of the test group and 55% of the control group the physician recorded "no signs and symptoms". A clear reduction in the side effects of radiotherapy and chemotherapy was documented in 74% of the test group and 55% of the control group. Analysis of survival, recurrence, and metastasis demonstrated a reduced number of events in the test group. There was evidence of a beneficial influence of OE on time to event, although the median observation time was too short in these breast cancer patients to draw definite conclusions. The safety component was judged in 98% of the test group and 76% of the control group as "very good" or "good". In the total sample of 2,339 patients, the rate of OE-associated adverse reactions was 3.2%. All side effects were mild to moderate gastrointestinal symptoms. CONCLUSION: Complementary treatment of breast cancer patients with OE improves the quality of life by reducing signs and symptoms of the disease and the side effects of adjuvant antineoplastic therapies. This epidemiological retrolective cohort analysis provides evidence that the patients may also gain benefit by a prolongation of the time to event for cancer recurrence, metastasis and survival. OE was generally well tolerated.

The effect of pneumoperitoneum on intraocular pressure in rabbits with alpha-chymotrypsin-induced glaucoma.

UNLABELLED: Increased intraperitoneal pressure is associated with physiological changes including alterations of intraocular pressure (IOP). We have previously shown that IOP is not adversely affected by increased intraperitoneal pressure up to 15 mm Hg in women with no preexisting eye disease. The aim of this study was to measure IOP changes associated with increased intraperitoneal pressure (up to 15 mm Hg) of 2 h duration in 12 rabbits with alpha-chymotrypsin-induced glaucoma. A reliable model of glaucoma was created by injecting alpha-chymotrypsin into the posterior chamber of the right eye in 12 rabbits. Thereafter, 5 of the 12 rabbits with glaucomatous eyes were treated with topical timolol. The left eye was used as a control. During pentobarbital general anesthesia, increased intraperitoneal pressure up to 15 mm Hg was created by intraperitoneal CO2 insufflation. Body temperature and expired CO2 were kept constant throughout the study. IOP measurements were made using an electronic pneumotonometer. IOP, mean arterial pressure, heart rate, and central venous pressure were recorded in head-up and head-down positions before, during, and after increased intraperitoneal pressure. The IOP of both eyes, in both treated and untreated rabbits, increased significantly from baseline only when increased intraperitoneal pressure associated with the head-down position resulted in a significant increase in central venous pressure. However, the IOP increase remained within the diurnal range. The major finding of this study is that, in a reliable model of glaucoma, CO2 pneumoperitoneum was associated with an increase in IOP when a head-down position was combined with pneumoperitoneum. IMPLICATIONS: In rabbits with alpha-chymotrypsin-induced glaucoma, increased intraperitoneal pressure (up to 15 mm Hg) resulted in a significant intraocular pressure increase when pneumoperitoneum was associated with the head-down position. However, the intraocular pressure increase remained within the diurnal range.

Pentoxifylline attenuates edema formation in proteolytic enzyme-induced lung injury.

Ex vivo canine lung lobes were exposed to a pancreatic proteolytic enzyme (chymotrypsin) alone or chymotrypsin after pretreatment with a continuous infusion with pentoxifylline. The lobes exposed to chymotrypsin gained 133 g, while the pentoxifylline-treated lobes gained only 65 g (p less than .05) over the 3-h experimental period. These results suggest that pentoxifylline significantly attenuates the lung weight gain associated with chymotrypsin.

Corneal and scleral penetration studies of 6-hydroxyethoxy-2-benzothiazole sulfonamide: a topical carbonic anhydrase inhibitor.

A newly synthesized topical carbonic anhydrase inhibitor, 6-hydroxyethoxy-2-benzothiazole sulfonamide (6-HS), was used as a model drug to determine its corneal and scleral permeabilities in rabbit eyes. The corneal permeability coefficient of 6-HS for short duration glaucoma and normal rabbit eye was not significantly different (its mean value was around 2.9 x 10(-6) cm/sec), while the corneal permeability coefficient for long duration glaucoma rabbit eye was 1.8 times greater than that for the normal eye. The sclera was found to have a higher permeability than the cornea in that after four hours perfusion the amount of drug which passed through the sclera was 11 times greater than that of the cornea. In addition, it was also noted that after topical instillation of 50 microL of 3% 6-HS gel the aqueous humor concentrations of 6-HS in short duration glaucoma eye and normal eye were not statistically different.

R-enantiomer of timolol: a potential selective ocular antihypertensive agent.

Various studies were conducted to evaluate the effects of timolol, an S-enantiomer, relative to its R-enantiomer upon intraocular pressure and related ocular systems in the rabbit. The R-enantiomer was about one-third as potent as timolol in displacing 3H-dihydroalprenolol binding to iris-ciliary body tissue, reducing aqueous humor formation, and lowering intraocular pressure of alpha-chymotrypsin hypertensive eyes. In contrast, the R-enantiomer was 50 to 90 times less potent than timolol in antagonizing the effects of isoproterenol on pulmonary and atrial beta-adrenergic receptors. The data indicate that the R-enantiomer may lower intraocular pressure in man at concentrations less likely than timolol to block extraocular beta-adrenergic receptors. Finally, to account for the differential effect of the R-enantiomer upon ocular as opposed to extraocular beta-adrenergic receptors, it is tentatively suggested that this agent may also act upon a population of ocular beta-adrenergic receptors showing relatively poor stereoselectively.

Effects of alpha chymotrypsin on the canine eye.

Injection of 150, 500, or 750 U of alpha chymotrypsin into the posterior chamber of clinically normal Beagles resulted in changes in intraocular pressure and iridocyclitis. In the 6 eyes treated with 500 or 750 U, lens subluxation occurred in 4 eyes, retinal detachment in 1 eye, retinal degeneration in 1 eye, and optic nerve degeneration in 6 eyes. Scanning electron microscopic changes included dose-related zonulolysis and zonulary remnants within the aqueous humor outflow pathways. Ultrastructural changes by transmission microscopy of the optic nerve degeneration revealed loss of axoplasm and organelles and disruption of the myelin sheaths. Retinal and optic nerve changes may represent the direct toxic effects of alpha chymotrypsin and/or the indirect effects of increased intraocular pressure.

Cataract and pseudoexfoliation. A clinicopathological study.

100 lenses from 98 consecutive patients with senile cataract were investigated histologically for pseudoexfoliation. The patients came from an area known for its high incidence of pseudoexfoliation. The examiner was not aware of the clinical examination at the time of histopathological study. Pseudoexfoliation was observed in 33 lenses. There seemed to be an increasing incidence of pseudoexfoliation with increasing age of the patients. Only 16 of the cases of pseudoexfoliation had been recorded preoperatively, but routine pupillary dilatation had not been carried out. The use of alpha-chymotrypsin at cataract extraction did not preclude histological diagnosis of pseudoexfoliation.

[Enzymatic ocular hypertension: a statistical study (author's transl)]. / Hypertension enzymatique: etude statistique.

The authors have carried out a statistical study on two large groups of patients operated on for cataract and in whom the enzyme alph-chymotrypsin has been used, and the occurrence of ocular hypertension has been examined. One group, which contained 1,003 operations most of which were under the microscope using a firm closure technique, was compared with another group of 324 cases operated under the same conditions but without using the enzyme. In all cases the intraocular pressure was measured 24-48 hours after the operation. The rise in pressure, the rapidity of its development were studied together with its duration and the concentration of the enzyme. In addition these findings were compared with another group of 2,334 eyes operated on several years previously with standard techniques using a less hermetic wound suture, without a microscope, with alpha-chymotrypsin, but whose tensions were controlled from the third week. The results show conclusively that there is a greater frequency of the occurrence of raised intra-ocular pressure when the enzyme is used (40,3%) than when it is not used (25,3%). This ocular hypertension persists in all cases to the end of three weeks. The time of the appearance of the hypertension, the numbers affected and the duration of the intraocular pressure were not significantly meaningful in the statistical analysis.

Studies on the sensitizing activity of alpha-chymotrypsin in man.

The sensitizing effect of alpha-chymotrypsin was followed up in a group of 116 women to whom parenteral treatment with this drug was associated to antibiotic therapy for various chronic inflammatory gynecopathies. The mean antibody titre to alpha-chymotrypsin, assayed by a passive hemagglutination technique, and the mean intensity of the intradermal tests with this drug were found significantly higher in 15 patients previously treated with alpha-chymotrypsin by comparison with 16 non-treated controls. A significant direct correlation was found between the titre of anti-alpha-chymotrypsin antibodies and the intensity of the intradermal tests. In 12 patients who had not previously been treated with alpha-chymotrypsin the antibody titre and the intensity of the intradermal tests rose significantly after a series of 10 injections with this drug. Eight of 116 patients (approximately 7%) treated with alpha-chymotrypsin developed overt symptoms of sensitization to the drug. The symptoms announcing the sensitization, the relation with the amount of the drug administered and the diagnostic value of intradermal tests are analysed. No relation was found between the presence of atopy and the sensitization to other drugs, on the one hand, and the sensitization to alpha-chymotrypsin, on the other hand.

[In vitro studies on the effect of alpha-chymotrypsin on hemostasis]. / In vitro-Untersuchungen zur Beeinflussung der Hämostase durch alpha-Chymotrypsin

Postoperative bleeding was observed in 2 patients for whom alpha-chymotrypsin had been prescribed to prevent haematoma or oedema formation. In vitro experiments with citrated blood added with alpha-chymotrypsin evidenced (thrombelastogram, hirudin tolerance test, euglobulin-lysis time) an action on haemostasis. As compared to blanks, the application of an alpha-chymotrypsin dose which was 100-fold higher than those currently used in therapy resulted in a significant shortening of the r-time (thrombelastogram), delayed blood clotting (hirudin tolerance test) and a shortening of the euglobulin-lysis time. In vivo experiments are needed for further elucidation.