Pelvic inflammatory disease (adnexitis) is an acute, subacute, recurrent or chronic infection of the oviducts (salpingitis) and ovaries with adjacent tissue involvement.

It is most commonly caused by sexually transmitted diseases, including Chlamydia and Gonorrhea that have ascended into the uterus, fallopian tubes, or ovaries.

Adnexitis may be either symptomatic (fever, abdominal pain; foul-smelling vaginal discharge) or asymptomatic.
Untreated Pelvic inflammatory disease can lead to serious consequences including infertility, ectopic pregnancy, abscess formation, and chronic pelvic pain.
Each year in the United States, more than 1 million women experience an episode of acute Pelvic inflammatory disease. More than 100,000 women become infertile each year as a result of Pelvic inflammatory disease, and a large proportion of the ectopic pregnancies occurring every year are due to the consequences of Pelvic inflammatory disease (adnexitis).

Enzyme therapy is as good as Diclofenac but with practically no side effects.

6 clinical studies with Enzyme-Therapy including 304 patients.

The expression of transforming growth factor-beta 1 (TGF-beta 1) in the liver of irradiated rats was increased in a dose-dependent fashion 9 months after irradiation. Expression of TGF-beta 1 was confined primarily to hepatocytes in the pericentral region of the liver, and the percentage of hepatocytes strongly positive for TGF-beta 1 was significantly correlated with the extent of fibrosis. We further showed that a localized injection of TGF-beta 1 into normal rat liver elicited a strong fibrotic reaction at the injection site. These results suggest that the increased hepatic concentration of TGF-beta 1 in response to radiation injury may be important in the pathogenesis of radiation hepatitis. TGF-beta 1 was also found to be present at a significantly higher concentration in unirradiated human hepatocytes than in normal rat hepatocytes, implying that the propensity for humans to develop radiation hepatitis may result in part from the elevated levels of TGF-beta 1 normally found in human liver

M. S. Anscher, L. B. Marks, T. D. Shafman, R. Clough, H. Huang, A. Tisch, M. Munley, J. E. Herndon, J. Garst, J. Crawford, and R. L. Jirtle. Risk of long-term complications after TFG-beta1-guided very-high-dose thoracic radiotherapy. Int J Radiat Oncol Biol Phys 56 (4):988-995, 2003.

PURPOSE: To report the incidence of late complications in long-term survivors of very-high-dose thoracic radiotherapy (RT) treated on a prospective clinical trial. METHODS AND MATERIALS: Patients with locally advanced or medically inoperable non-small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved lymph nodes to a dose of 73.6 Gy at 1.6 Gy twice daily. If the plasma transforming growth factor-beta1 (TGF-beta1) level was normal after 73.6 Gy, additional twice-daily RT was delivered to successively higher total doses until the maximal tolerated dose was reached. Patients within a given dose level were followed for 6 months before escalation to the next dose level was permitted. Late complications were defined according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS: Thirty-eight patients were enrolled between 1996 and 1999. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGF-beta1 levels. Fourteen patients received dose escalation (80 Gy in 8; 86.4 Gy in 6). Grade 3 or greater late complications occurred in 4 of 24, 1 of 8, and 2 of 6 patients treated to 73.6, 80, and 86.4 Gy, respectively. The corresponding patient numbers with late Grade 4-5 toxicity were 3 of 24, 0 of 6, and 0 of 8. Overall, 7 (18%) of the 38 patients developed Grade 3-5 late toxicity. Nonpulmonary complications predominated (4 of 7). Five (71%) of seven serious complications developed within 11 months after RT; however, the remaining two complications (29%) occurred very late (at 43 and 62 months). The 5-year actuarial risk of late Grade 3-5 complications was 33%. CONCLUSION: Long-term survivors of very-high-dose RT for non-small-cell lung cancer have a significant risk of severe treatment-related complications. At these high dose levels, the predominant toxicity may no longer be pulmonary. All Grade 4-5 complications occurred in patients whose dose was limited to 73.6 Gy because of a persistently elevated TGF-beta1. Thus, persistently elevated plasma TGF-beta1 levels toward the end of RT may identify patients at greatest risk of severe complications

Barcellos-Hoff. Latency and activation in the control of TGF-beta. J Mammary Gland Biol Neoplasia 1 (4):353-363, 1996.

The biological activity of the transforming growth factor-beta’s (TGF-beta) is tightly controlled by their persistance in the extracellular compartment as latent complexes. Each of the three mammalian isoform genes encodes a product that is cleaved intracellularly to form two polypeptides, each of which dimerizes. Mature TGF-beta, a 24 kD homodimer, is noncovalently associated with the 80 kD latency-associated peptide (LAP). LAP is a fundamental component of TGF-beta that is required for its efficient secretion, prevents it from binding to ubiquitous cell surface receptors, and maintains its availability in a large extracellular reservoir that is readily accessed by activation. This latent TGF-beta complex (LTGF-beta) is secreted by all cells and is abundant both in circulating forms and bound to the extracellular matrix. Activation describes the collective events leading to the release of TGF-beta. Despite the importance of TGF-beta regulation of growth and differentiation in physiological and malignant tissue processes, remarkably little is known about the mechanisms of activation in situ. Recent studies of irradiated mammary gland reveal certain features of TGF-beta 1 activation that may shed light on its regulation and potential roles in the normal and neoplastic mammary gland

F. Beaufort Reduction of radiation side-effects by hydrolytic enzymes Therapeutikon, 4 (10), 1990, 577-580

fifty-seven patients who underwent radiatio for abdominal cancer were taken into a randomized prospective clinical trial. Twenty-five of these patients received concomitantly to radiatio a preparation of hydrolytic enzymes and thymus. Thirty-seven patients without enzyme therapy served as control group.

In spite of randomization the two groups showed differences: the mean duration of hospitalization was 5.7 weeks in the control group and 6.6 weeks in the enzyme group, respectively. The patients in the control group got a cumulative radiatio dose of on average 46.7 Gy, in the enzyme group of 53.4 Gy. Nevertheless, the side effects due to radiatio – mainly gastrointestinal and genito-urinary complaints were comparable in both groups as for frequency and severity. The duration of the side effects, however, showed a statistically significant advantage in favour of the enzyme group: on average, the side effects lasted 24.6 days in the control group and only 13.8 days in the enzyme group. Thus, the duration of the side effects was shortened by the enzyme therapy to an extent of 43.9%. Relevant laboratory parameters showed no or only slight changes during therapy. Double blind trials have just been started to verify these results.

Dale-PS; Tamhankar-CP; George-D; Daftary-GV Co-medication with hydrolytic enzymes in radiation therapy of uterine cervix: Evidence of the reduction of acute side effects. Cancer-Chemotherapy-and-Pharmacology,-Supplement. 2001; 47(7): S29-S34

AB: Purpose: The use of additional therapy with an oral enzyme preparation containing trypsin, chymotrypsin and papain has been suggested for the reduction of toxicity due to radiation therapy. This study was conducted to rest the efficacy and tolerability of this enzyme combination in preventing or reducing the acute side effects of radiation therapy in patients with locally advanced cervical cancer. Methods: A prospective, randomised, open, clinical trial was carried out on 120 patients (aged 24-85 years) with locally advanced, biopsy-proven carcinomas of the uterine cervix (stages IIa, IIb or IIIb). Patients received 50 Gy of external radiation therapy over a period of 5 weeks, followed by intra-cavitary brachytherapy (20-30 Gy). Patients assigned to the test group (60 patients) received additional treatment with enzymes. Patients were evaluated at weekly intervals for acute radiation therapy-related side effects, according to the RTOG/EORTC grading criteria, and then alter the end of radiation therapy for another 8 weeks. Occurrence of adverse events, if any, was also recorded. Results: The study revealed that the maximum extent of acute radiation side effects was reduced in the enzyme group: skin reactions (mean: 0.97 vs 1.68 in the control group, P < 0.001), vaginal mucosal reactions (0.55 vs 0.85, P = 0.10), genitourinary symptoms (0.93 vs 1.38, P < 0.001) and gastrointestinal reactions (1.12 vs 1.30, P = 0.12). The sum-scores during treatment, expressed as area under the curve, were significantly less in the enzyme treated patients. In the follow-up visits all observed side effects of radiation therapy were of lower intensity in the enzyme group than in the control group. Conclusions: In patients with locally advanced cancer of the uterine cervix, oral enzyme therapy was found to be effective in significantly reducing radiation therapy-related side effects such as genitourinary symptoms, subcutaneous changes and reactions of the vaginal mucosa.

A. Derveniece, I. Hartmane, I. Mikazhans, I. Chema. Local Treatment Of Skin Injuries Caused By Radiation Therapy Of Oncological Patients. Enzīmterapija (Enzymtherapie) in Lettische Sprache Nr. 2, 2000, 10-13.

Poorly healing burned wounds and atrophy of skin is not rare outcomes of radiation therapy.

Investigation of clinical efficacy of different means for topical treatment such as ointments of WOBE-MUGOS, Wobenzym N, Diaethonum, Iruxol, and also Panthenol-Spray, Fucidine crĆØme and Solcoseryl gel were performed on 39 patients treated with radiation therapy in Oncological Center, Riga, Latvia. All patients besides of radiation therapy received one from mentioned means. Total doses of radiation for each patients was between 50-60 Gy, given as daily doses of 1,8 Gy. Efficacy of each mean was estimated measuring time of radio dermatitis, expressiveness of local edema.

After the treatment, during time of radiation therapy and 6 months observations period we obtained satisfactory efficacy in case of treatment with all testified means. We observed faster healing of erosive defects in skin using combination of Solcoseryl gel and Iruxol ointment. Also antibacterial and anti-oedematous effects of Fucidin H crĆØme were obtained. In patients used ointment of WOBE-MUGOSĀ® E we obtained less expressed signs of skin atrophy, typical for post-radiation lesions. In accordance to our point of view, ointment of WOBE-MUGOSĀ® E is acceptable for prevention and treatment of skin damage in oncological patients due to adequate efficacy and price.

Gujral M.S. Patnaik P.M. Kaul R., Daftary G.V., Parikh H.K., Tamhankar C.P., Schiess W. Oral enzymes preventing side effects of radiation therapy in patients with head and neck cancers The European Journal of Cancer 1999; 35(4): No. 634, 168.

Based on in vitro data and on clinical evidence of a protective action against acute side effects of radiotherapy, a prospective randomised study was undertaken to determine the safety and efficacy of an oral enzyme combination in patients with head and neck cancer receiving conventional fractionated radiotherapy (Wobe-MugosĀ® E, MUCOS Pharma, Geretsried, Germany) (OE). Two study centres included 100 patients with locally advanced head and neck cancer into this open study. Radiation was delivered with telecobalt machines using standard daily radiation dose of 150-200cGy in 30-35 fractions over a period of 6 weeks. Two lateral parallel opposing fields were used with the portal area generally being 4×6 inches. Patients were randomly allocated to two groups: Patients in the test group were given OE orally three times daily starting 3 days prior to radiotherapy and continuing up to 5 days after completing radiotherapy. Patients in the control arm were not given any drug. The control group and the test group were comparable with respect to presenting features. In the test group the maximum severity and duration of mucositis, skin reaction, and dysphagia were significantly less as compared to the control group. The duration of these side effects as well as the sum scores of toxicity was also significantly less in the OE group. In summary the use of OE with conventional fractionated radiotherapy was feasible without significant safety problems. There was a clinically relevant protection against acute side effects of radiotherapy in the OE group. Not only was the severity of acute side effects less, but the duration was shorter and the time to onset was also delayed.

Heinz, R. Wobe-Mugos als adjuvante Therapie bei Patienten unter Chemo- oder Strahlentherapie. Arzt & Praxis, 757: 828-834, 1996

Wobe-Mugos ist in Österreich zur unterstützenden Therapie bei malignen Tumoren bzw. als Zusatzbehandlung während und nach einer Strahlen- oder Chemotherapie zugelassen. Im Rahmen einer Anwendungsbeobachtung an 262 Patienten mit Karzinomen bescheinigten die Ärzte der adjuvanten Therapie mit Wobe-Mugos bei 77 % der Patienten eine sehr gute oder gute Wirksamkeit. Nebenwirkungen traten nur selten auf und betrafen überwiegend den gastrointestinalen Bereich.

Kan ID, Zverev MP, Dvorkina SI. [Prevention and treatment of early radiation reactions of the urinary bladder in patients with cancer of the cervix and corpus uteri]. Vopr Onkol 1988;34(6):713-7

The report discusses early-onset radiation injuries in the urinary bladder of more than 1000 patients with cancer of the cervix and corpus uteri. Clinical symptoms of such injuries were observed in 487 patients (44.3%). In 47 (10%), the lesions were pronounced. The degree of radiation-induced cystitis was evaluated on a 6-point scale used by WHO classification (1982). Said lesions mainly occurred at stage III of tumor and predominantly in cases of cancer of the corpus uteri. Complications development was stimulated by vascular lesions, diabetes mellitus and inflammatory processes in pelvic organs. Radiation injuries were treated by standard procedures as well as with immobilised trypsin administered in a cellulose powder vehicle. This method proved the most effective. Since patients suffering early-onset radiation-induced destructive injuries are at high risk of further exacerbation at later stages, they should be followed-up closely.

R. Kaul, B. K. Mishra, P. Sutradar, V. Choudhary, and M. S. Gujral. The role of Wobe-Mugos in reducing acute sequele of radiation in head and neck cancers–a clinical phase-III randomized trial. Indian J Cancer 36 (2-4):141-148, 1999.

Oral enzymes act as a potent antiinflammatory, antiedematous agents thereby decreasing acute toxigenic effect of radiation and increasing compliance, quality of life of our patients. Fifty patients were randomized 25 allocated in enzyme and radiotherapy arm, 25 in radiotherapy alone. Pre RT and post RT biopsies were taken from both arms. In our study it was found that there was clinical, histopathological as well as statistical significant difference in both arms. The enzyme arm patients had mucostis of grade I in 76%, grade II in 12%, grade III in 8% while as 8% had grade I, 68% grade II, 24% had grade III in RT arm alone. In enzyme patients skin reactions of grade I in 72%, 20% had grade II, 8% had grade III. In control arm 12% had grade I, 76% had grade II, 8% had grade III skin reaction

F. M. Kong, M. K. Washington, R. L. Jirtle, and M. S. Anscher. Plasma transforming growth factor-beta 1 reflects disease status in patients with lung cancer after radiotherapy: a possible tumor marker. Lung Cancer 16 (1):47-59, 1996.

PURPOSE: To determine the frequency with which elevated plasma transforming growth factor-beta 1 (TGF beta 1) concentrations occur in lung cancer patients, to determine the kinetics of TGF beta 1 expression during and after radiotherapy and to correlate plasma TGF beta 1 levels with disease status after treatment. MATERIALS AND METHODS: Plasma samples were obtained before, during and after radiotherapy in 54 patients with lung cancer and 20 normal controls. Plasma TGF beta 1 levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Baseline TGF beta 1 levels in lung cancer patients and normal controls were 13.0 +/- 2.5 and 4.4 +/- 0.3 ng/ml, respectively. Elevated TGF beta 1 were found in 50% (27/54) of lung cancer patients. During radiation therapy plasma TGF beta 1 levels declined, however, by the completion of treatment the mean TGF beta 1 level had not normalized in patients with lung cancer. The TGF beta 1 level at last follow-up correlated with disease status in those patients with an increased pretreatment plasma level. Three of four patients with no evidence of cancer had normal follow-up TGF beta 1 levels, compared to 2/16 patients with residual or recurrent tumor (P = 0.02). CONCLUSIONS: Elevated plasma TGF beta 1 levels occur frequently in patients with lung cancer. In those patients with an elevated plasma TGF beta 1 level at diagnosis, monitoring this level may be useful in detecting both disease persistence and recurrence after therapy.

Lukas-J; Betka-J; Klozar-J; Taudy-M; Honzikova-M., Systemic enzyme therapy in prevention of postirradiation complications Otorinolaryngologie-a-Foniatrie. 1999; 48/1 (14-17)

The authors present their initial experience with the preparation Wobenzym as a radioprotective agent. Systemic enzyme therapy was administered to 10 patients with squamous-cell carcinoma of the oropharynx after buccopharyngotomy with mandibulotomy and osteosynthesis with subsequent postoperative radiotherapy. Before the beginning of the prospective investigation Wobenzym was administered to three patients after buccopharyngotomy and mandibulotomy with osteosynthesis and postirradiation osteoradionecrosis, together with Dalacin. In patients with postirradiation necrosis also laboratory examinations of urine were made to detect pyridinium cross bonds as a marker of impaired bone metabolism. Postirradiation mucosal and osseous changes were evaluated according to the WHO scale. In none of the patients radiotherapy had to be discontinued on account of severe mucositis or dermatitis. In none of the patients of the group late postirradiation changes were detected such as osteoradionecrosis. Administration of systemic enzyme therapy as a radioprotective procedure is evaluated favourably by the authors.

T. Martin, K. Uhder, R. Kurek, S. Roeddiger, L. Schneider, H. G. Vogt, R. Heyd, and N. Zamboglou. Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of adjuvant pelvic irradiation? Results of a double-blind randomized trial. Radiother Oncol 65 (1):17-22, 2002

PURPOSE: Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of adjuvant pelvic radiotherapy? MATERIAL AND METHODS: Fifty-six patients with an indication for adjuvant pelvic irradiation after curative surgery were double-blind randomized. All patients took 3 x 4 capsules study medication daily during radiotherapy. Twenty-eight patients in the enzyme group (EG) received capsules containing papain, trypsin and chymotrypsin, 28 in the placebo group (PG) received placebo capsules. All patients were irradiated with 5 x 1.8 Gy weekly to 50.4 Gy using four-field-box technique after CT-based planning. Primary objective was the grade of diarrhea, nausea, vomiting, fatigue and epitheliolysis during radiotherapy. Secondary objectives were the number of supportive medications and treatment interruptions due to acute toxicity. RESULTS: None/mild diarrhea: 43% EG, 64% PG. Moderate/severe diarrhea: 57% EG, 36% PG (P = 0.11). Mean duration: 11 days in EG, 10 days in PG. None/mild nausea: 93% EG, 93% PG. Moderate/severe nausea: 7% EG, 7% PG. None/mild vomiting: 100% EG, 97% PG. None/mild fatigue: 82% EG, 93% PG. Moderate/severe fatigue: 18% EG, 7% PG (P = 0.23). None/mild epitheliolysis: 75% EG, 93% PG. Moderate/severe epitheliolysis: 25% EG, 7% PG (P = 0.16). Treatment interruption (mean days): 2.44 in EG, 1.46 in PG. Number of supportive medication: 29 in EG, 19 in PG. CONCLUSIONS: The prophylactic use of proteolytic enzymes does not reduce acute toxicities, treatment interruptions and number of supportive medication and therefore does not improve tolerance of adjuvant pelvic radiotherapy

Osterreicher-J; Skopek-J; Navratil-L; Knizek-J; Sebkova-V; Macela-A Enteral administration of proteinase mixture inhibits development of radiation pneumonitis and lung fibrosis in rats. International-Journal-of-Immunotherapy. 2000; 16(3-4): 45-51

AB: Wistar rats underwent a sublethal whole-thorax irradiation. One group of animals received a mixture of proteinases (60 mg/kg/day) by rectum every 12 h from day 1 following irradiation to the end of the experiment. Saline-treated animals were used as a control. The animals were observed for 8 and 42 weeks following irradiation. Transforming growth factor-< beta > (TGF-< beta >) 1-, 2- and 3-positive cells, alveolar septal thickness, neutrophil granulocyte number and connective tissue content in the lung tissue of the rats were measured. During the onset of the inflammatory phase, a significantly lower neutrophil number was found in the enzyme-treated rats in comparison to the saline-treated control animals. Furthermore, mixture of proteinases inhibited TGF-< beta >1 and 2 expression. During the onset of the fibrotic phase, significantly lower alveolar septal thickness, TGF-< beta >2 and 3 expression and connective tissue content were found in the group of enzyme-treated rats as compared to control rats. Based on the obtained results we suggest that specific mixtures of proteinases show both antiinflammatory and antifibrotic effects.

M. S. Pluzhnikov, M.A. Ryabova, S.A. KarpiscenkoThe effect of systemic enzyme therapy (Phlogenzym) in the treatment of radiomucositis in patients with laryngeal cancer. Folia Otorhinolaryngologica (1999): 5 (1-2), 73 ā€“ 75.

Healthy tissue surrounding oncologic lesion is regularly intervened in the course of radiotherapy, too. Three degrees of skin reaction are distinguished : 1. ā€“ erythema caused by the total doses of 30 ā€“ 35 Gy, 2. ā€“ dry dermatitis (hyperemia, edema, epidermal separation, sudoriferous and salivary gland functional impairment; skin is dry, pigmented) caused by total doses of 40 Gy, 3. ā€“ wet dermatitis, caused by the doses of 50 Gy and more. Mucosa seems to be more radio-sensitive than skin. As the basal layer gets damaged, cicatrization develops under white fibrinous deposit. The soreness makes swallowing very difficult. Xerostomia is detected as a consequence of progressive radiomucositis with impairment of salivary gland cells.

As the patients lose appetite, they mostly insist on discontinuation of radiotherapy. In order to prevent radiomucositis, a non-irritating diet is recommended as well as absence of alcohol and smoking. Postradiation disease is treated by antibiotics, analgesics, alkaline throat wash, vitamins etc.

Clinical effect of Phlogenzym on radiation-induced epitheliitis was studied at the Clinic of Otorhinolaryngology I.P.Pavlova in 15 patients suffering from laryngeal cancer. 9 patients underwent endoscopic resection of larynx, 2 patients underwent extirpation of larynx, 3 were treated by radiation only, and one patient was subject to pharyngotomy and resection of palate tonsil and tongue root. 15 patients suffering from laryngeal cancer and treated by radiation without administration of Phlogenzym served as a control group.

Xerostomia, swallowing difficulties, hyperemia, fibrinous deposits, and crusts on mucosa were recorded in the control group. In spite of the fact, that conventional palliative therapy was administered (antibiotics, NSAID, anesthetics), it was necessary to discontinue the treatment in 4 patients who refused to eat. Radiation side-effects persisted for 3 weeks up to 3 months, resulting in food intake reduction and necessary medication.

In the group of 15 patients receiving 2×3 tablets of Phlogenzym for 10 days, no case of radiomucositis of II degree was recorded, as well as the occurrence of fibrinous deposits and crusts.

The course of radiotherapy was not discontinued in any patient. Mean weight loss in the enzyme-treated patients was 5 %, while in the control group it was 10 %. Blood leukocyte count was 5 x 109 / l, while in the control group it was 3 x 109 / l. The symptoms of epitheliitis disappeared within one week after treatment. Administration of enzyme therapy alleviated the consequences of radiation-induced epitheliitis and Phlogenzym was well tolerated without any side effects.

Smolanka I.I. and Ganul V.L. Preliminary results of the combined treatment for patients with lung cancer and malignant thymomas using Wobe-Mugos. Poster at 2nd International Congress of Thorax Surgery, June 1998, Bologna, Italy, 1998.

Purpose

In order to increase effectiveness of pre- and postoperative gamma-therapy in the combined treatment of patients with locally advanced non-small cell lung cancer (NSCLC) stage IIIA and malignant thymomas we used enzyme therapy by Wobe-Mugos (Mucos Pharma).

Methods

The preoperative tumor irradiation (9 patients with NSCLC and 11-malignant thymomas) was performed daily using a “Rokus” instalation at a single dose of 5 Gy. The total focal dose reached 20 Gy. Surgery was performed after2 weeks. Irradiation was repeated on days 10-15 following surgery (30 Gy, 2,5-3,0 Gy daily). During treatment (2 month) the patients received Wobe-Mugos (6 tbl. daily).

Conclusions

Preliminary results indicate that this approach to the combined treatment is well tolerated. Wobe-Mugos in the combined treatment did not complicate the surgical procedure and the postoperative period; allowed to increase the effectiveness of gamma-therapy and decreased postradiation pneumofibrosis.

Stauder, G., Beaufort, F., and Streichhan, P. Radiation induced adverse reactions in abdominal cancer patients and their reduction by hydrolytic enzymes. Dtsch Z Onkol, 23/1: -16, 1991.

Summary

In this randomized prospective clinical trial hydrolytic enzymes were given additionally to radiation in abdominal cancer patients and compared with radiation only. The concomitant oral enzyme therapy improved the tolerance of the radiation significantly. The enzyme treated patients had less deterioration of general condition and skin symptoms and less patients discontinued radiation. It reduced the number of drugs needed for the treatment of radiation adverse effects, especially antiemetics, gastrointestinal drugs, antidepressives, tranquilizers and other psychopharmaceuticals, analgetics, spasmolytics, diuretics and aldosteron antagonists. In most cases the enzyme therapy was well or very well tolerated.

K. Vinzenz and E. Schuh. Therapie mit hydrolytischen Enzymen bei der operativen Zahnentfernung sowie bei der Strahlenmucositis. In: Systemische Enzymtherapie, edited by H. Wrba, M.-W. Kleine, K. Dittmar F. W Miehlke, and R. E. Weissenbacher, 1996, p. 57-64.

Zavadova, E., Oesterreicher, J., Desser, L., Å ebkovĆ”, V. and Wald, M. Reduction of transforming growth factor-beta (TGF-beta) in sera of rats with postradiation lung fibrosis after rectal administration of a mixture of proteolytic enzymes (Phlogenzym).

Radiation lung fibrosis is a final stage of postradiation changes . It has been suggested that TGF- beta may induce a chronic activation of fibroblast maturation to fibrocytes and initiate postradiation lung fibrosis development. Recently, proteolytic enzymes have been shown to reduce fibrosis development. In this study we investigated the effect of proteinase mixture Phlogenzym on the production of cytokines IL-1, IL-4, IL-10 and TGF-beta after 8 and 42 weeks following sublethal irradiation of rats. The Wistar rats underwent a sublethal whole-thorax irradiation. One group of animals received a mixture of proteinases (60 mg/kg/day) per rectum every 12 hours from day 1 following irradiation to the end of experiment. As a control, saline-treated animals were used. The animals were observed for 8 and 42 weeks following irradiation. TGF-beta1, IL1, IL 4 and IL 10 were determined by ELISA. A significant decrease in TGF- beta1 as well as IL1, IL 4 , IL 10 in sera of rats receiving proteinases could be observed in comparision to controls. The decreased sera levels correlated with decreased fibrosis development in rats treated with proteolytic enzymes. Proteolytic enzymes bind to a2Macroglobulin. Subsequently this complex binds TGF-beta and other cytokines irreversibly. The complex a2M + protease + cytokine is very quickly removed by endocytosis. Although it is necessary to perform extended studies focused on anti-fibrotic and anti-inflammatory effects of proteinases, it may be assumed that proteolytic enzymes offer a new perspective in the prophylaxis of radiation lung fibrosis.

E. Buschmans. Fibrocystic breast disease: a therapeutic approach with an enzyme combination preperation. International Journal of Feto – Maternal Medicine 6:25-28, 2000.

N. Colacurci, D. Mele, Franciscis De, V. Costa, N. Fortunato, and Seta De. Effects of tibolone on the breast. Eur J Obstet Gynecol Reprod Biol 80 (2):235-238, 1998.
OBJECTIVE: to evaluate the effect of hormone replacement therapy and tibolone on the breast. STUDY DESIGN: prospective, controlled, randomized study. SETTING: Outpatient Menopause Clinic of the Second University of Naples. PARTICIPANTS: forty four women in spontaneous menopause without any risk factor for breast cancer were randomly allocated to three groups: 15 patients (group A) were treated with transdermal oestrogens 50 microg, 2 patches/week for 3 weeks per month, plus acetate nomegestrolo per os 5 mg/die for 12 days per cycle, 17 patients (group B) were treated with tibolone 2.5 mg/die. Twelve patients not given any medication represented the control group (group C). METHODS: at the time of recruitment and after at least 12 months of therapy the patients were subjected to a questionnaire aimed at quantifying the slight, moderate or severe presence of the tension/mastodynia symptoms and to a mammographic test to assess the parenchymal pattern according to a quantitative method: type 1 (less than 25% of mammary gland covered by dense tissue), type 2 (from 25% to 75% of total glandular area covered by dense tissue), type 3 (more than 75% of mammary parenchyma covered by dense tissue). Statistical analysis was carried out by means of Fisher’s exact test. RESULTS: after at least 12 months of treatment in Group A 5 out of 15 patients (33%) showed a trend of increase in mammographic density not statistically significant (P=0.22) when compared with group B in which one patient showed a swift from type 1 to type 2 and another from type 2 to type 3. The analysis of tension/mastodynia symptoms revealed a significantly difference between the two groups (P=0.02): in group A mastodynia appeared in three previously asymptomatic women and increased in five women, with a total increase in the symptomatology in 8 out of 15 patients (53.3%), in group B only in one case (5%) mastodynia turned from slight to moderate. CONCLUSION: in postmenopausal women oestroprogestogenic replacement therapy may be associated with an increase in mammographic density and with the onset or increase in mastodynia. On the contrary tibolone does not seem to affect normostructured mammas and may be considered a first-rate replacement therapy in case of mammas showing particular density or benign mastopathies

F. W. Dittmar and W. Luh. Treatment of fibrocystic mastopathy with hydrolytic enzymes. Int.J.Exp.Clin.Chemotherapy 6 (1):9-20, 1993.
In einer randomisierten doppelblinden Studie wurde an 96 Patientinnen mit Mastopathie über einen Zeitraum von 6 Wochen die Wirkung eines Enzymkombinationspräparates mit einem Plazebo verglichen. Durchführung: Von Studienbeginn an sollten die Patientinnen zweimal täglich 10 Dragees der Prüfmedikation erhalten. Zielkrieterien: Als Kriterien für die Wirksamkeit der Prüfmedikation waren im Studienprotokoll festgelegt worden: der durchschnittliche Durchmesser der 5 gröļ¢ten Zysten, sofern ihre Gröļ¢e mindestens 5 mm betrug, die Zystenzahl und die subjektive Beeinträchtigung durch die Erkrankung sowie ein Beschwerdenscore. Ergebnisse: Insgesamt konnte festgestellt werden, daļ¢ die beiden Untersuchungsgruppen gut vergleichbar und statistisch auswertbar waren. In der Gesamtbeurteilung sprechen die Ergebnisse dafür, die günstige Behandlung der Mastopathie mit proteolytischen Enzymen durch weitere Untersuchungen abzusichern und ggf. zu vertiefen

Ferrari, A. G. Pifarotti, M. Dindelli, M. T. Potenza, and E. Rabaiotti. Clinical trial of the efficacy and safety of seaprose S in patients with benign breast disease. Controlled trial vs bromeline. G Ital Ric Clin Ter 16/1 (1-6):-6, 1996.
This study was designed to compare the efficacy and safety of seaprose S and bromeline in the treatment of painful benign breast disease. Twenty-nine women entered the study, mean age 38.9 years (range 21-59), mean weight 55.1 kg (range 43-74), with painful benign breast disease. The trial was conducted following a controlled, between patients, randomized experimental design. Seaprose S was administered as a daily dose of 90 mg, and bromeline at a dose of 120 mg per day, both orally, for 14 days. Pain disappeared after seven days in 31.3% of cases with seaprose S, and 75% after 14 days, as compared wtih 25% and 50.1% with bromeline. Mammary tension was no longer present after seven days in 93.7% of the women treated with seaprose S, as compared with 75.1% with bromeline. Pain on palpation disappeared in 12.5% of cases after seven days with seaprose S, and in 37.5% after 14 days (compared with 0 and 16.7% with bromeline). Adverse reactions were reported in 6.3% of the patients taking seaprose S, compared with 15.4% of those given bromeline. It thus appears that seaprose S was effective and well tolerated in patients with painful benign breast disease, to a considerably more marked extent than bromeline

M. Halaska, K. Raus, P. BĆ²les, A. Martan, and K. G. Paithner. [Treatment of cyclical mastodynia using an extract of Vitex agnus castus: results of a double-blind comparison with a placebo]. Ceska Gynekol 63 (5):388-392, 1998.
The aim of study presented here was to gather the data about the tolerability and efficacy of Vitex agnus castus (VACS) extract. The study was designed as double-blind, placebo controlled in two parallel groups (each 50 patients). Treatment phase lasted 3 consequent menstrual cycles (2 x 30 drops/day = 1.8 ml of VASC) or placebo. Mastalgia during at least 5 days of the cycle before the treatment was the strict inclusion condition. For assessment of the efficacy visual analogue scale was used. Altogether 97 patients were included into the statistical analysis (VACS: n = 48, placebo: n = 49). Intensity of breast pain diminished quicker with VACS group. The tolerability was satisfactory. We found VACS to be useful in the treatment of cyclical breast pain in women.

Kee WH, Tan SL, Lee V, Salmon YM.The treatment of breast engorgement with Serrapeptase (Danzen): a randomised double-blind controlled trial. Singapore Med J 1989 Feb;30(1):48-54
We evaluated an anti-inflammatory enzyme drug Danzen (Serrapeptase: Takeda Chemical Industries, Ltd.) on 70 patients complaining of breast engorgement. These patients were randomly divided into 2 groups, a treatment group and a placebo group. A single observer, unaware of the group the patients were in, assessed the severity of each of the symptoms and signs of breast engorgement before treatment was commenced, and daily for 3 days, during which therapy was administered. Danzen was noted to be superior to placebo for improvement of breast pain, breast swelling and induration and while 85.7% of the patients receiving Danzen had “Moderate to Marked” improvement, only 60.0% of the patients receiving placebo had a similar degree of improvement. “Marked” improvement was found in 22.9% of the treatment group and 2.9% of the placebo group. These differences were statistically significant (P less than 0.05). No adverse reactions were reported with the use of Danzen. Danzen is a safe and effective method for the treatment of breast engorgement

Leonardi M. [Treatment of fibrocystic disease of the breast with myrtillus anthocyanins. Our experience] Minerva GinecolĀ  1993 Dec;45(12):617-21
The aim of this study was to further research into the therapeutic treatment of fibrocystic mastopathy. The study hypothesis included the clinical and instrumental control (echography) of patients with FCD before and after at least three months treatment with anthocyanosides. The protocol used was of the prospective and comparative type, whereas follow-up lasted three months. The study was performed in the outpatients’ clinic of Breast Physiopathology and Echography organised within the ambit of the services of the Gynecology and Obstetrics Division. In this particular instance both echography and clinical examinations were performed at the same clinic. A total of 257 patients took part in the programme of which 35 were excluded since they failed to attend subsequent controls. Women were selected on the basis of absence of malignant disease and presence of clinical, echographic or mammographic symptoms of fibroso-cystic mastopathy. In addition, all women presented mastodynia which made therapy indispensable. The socio-demographic: characteristics of the population were polymorphous since women were resident not only in the area of USSL 36 but also other Italian provinces. The diameter of any lesions found was measured together with the thickness of the mammary gland. The thickness was always measured of QSE level both before and after treatment. The results were encouraging. There was a marked improvement in 75 patients, equivalent to 33.78%, symptoms were reduced in 61 women (27.47%) and disappeared in 14 (6.30%), whereas treatment had no effect in 72 cases (32.43%). In conclusion, echopalpation (clinical examination + echography) was extremely valuable in the study of these patients, especially if aged under 40. Moreover, therapy for three months in patients with mastodynia, consequent to fibrous mastopathy, was efficacious in reducing symptoms and mammary tension. At the same time, it is important to emphasise the absence of virtual absence of collateral effects to treatment.

L. A. Li and V. V. Martyniuk. [Does a sector resection of the breast cure nodal mastopathy?]. Vestn Khir Im I I Grek 157 (6):77-79, 1998.
Results of the clinico-morphological investigation of 265 patients with localized mastopathy who were submitted to sectorial resection showed that in the margins of the operative wound there were morphological signs of mastopathy in 252 (95.1%) patients. The results obtained confirm the opinion that structural alterations of the tissues known to be the essential feature of fibroadenomatosis can not be local, they are of diffuse character. So, the sectorial resection performed for localized mastopathy can not be radical and is of no therapeutic significance. The indication to surgical intervention must be determined not so much by the necessary treatment as by the real risk of hypo-diagnosis of breast cancer. So, there is no need to fulfil the sectorial resection for localized mastopathy. It is enough to make operation of less volume (excision biopsy).

E. G. Loch, H. Selle, and N. Boblitz. Treatment of premenstrual syndrome with a phytopharmaceutical formulation containing Vitex agnus castus. J Womens Health Gend Based Med 9 (3):315-320, 2000.
A multicentric noninterventional trial (open study without control) to investigate the efficacy and tolerance of a drug in a large number of patients under routine medical conditions was performed for a new solid preparation from an extract of the fruit of Vitex agnus castus (VAC, Vitex, chaste tree, Chasteberry) in 1634 patients suffering from premenstrual syndrome (PMS). A specific questionnaire was developed for determining the effect of Vitex on psychic and somatic complaints, on the four characteristic PMS symptom complexes depression, anxiety, craving, and hyperhydration (DACH), and on single groups of symptoms. After a treatment period of three menstrual cycles 93% of patients reported a decrease in the number of symptoms or even cessation of PMS complaints. To a certain extent, this effect was observed within all symptom complexes and correlated with the global assessment of therapeutic efficacy. Whereas 85% of physicians rated it as good or very good, 81% of patients assessed their status after treatment as very much or much better. Analysis of frequency and severity of mastodynia as the predominant symptom revealed that complaints still present after 3 months of therapy were mostly less severe. Ninety-four percent of patients assessed the tolerance of Vitex treatment as good or very good. Adverse drug reactions were suspected by physicians in 1.2% of patients, but there were no serious adverse drug reactions. Hence, the risk/benefit ratio of the new Vitex preparation can be rated as very good, with significant efficacy for all aspects of the multifaceted and inhomogeneous clinical picture of PMS, with a safety profile comparable to other Vitex preparations.

Loginova N.S., Naumkina N.G., and Sukhikh G.T. Wobenzym in therapy of various forms of fibrocystic disease with individually selected immunomodulators. International congress “Advances in Immunology and Allergology at the Treshold of the XXI Century” May 3-6, 2000, Eilat, Israel, 2000.
Cancer of mammary glands is known to be registered 3-5 times more often in patients with fibrocystic disease (FCD), the risk increases 30 times as much in the signs of proliferation. We elaborated therapy regimen for patients with FCD by means of Wobenzym having antiinflammatory, immunomodulating effect. Immunomodulators were selected individually for every patient under the control of interferon status (IFS): Cycloferon, Ridostin, Polyoxidony. The treatment was performed in 36 women, aged from 23 to 52, having various forms of FCD: diffuse FCD: 1. multiple large filled cysts, 1.5-5.5 cm in diameter; 2. small cystic component prevailing; 3. glandular component prevailing. To assess the dynamic control of the quality of the therapy, we used radiothermometric method based on the measurement of internal temperature area (focal thermoassymetry).
Before the therapy, decreased abilities of lymphocytes to produce ļ” -ļ§ -IFN had been noted, elevated level of serum IFN was found in blood. After the treatment, 87.3% patients had the restored ability of lymphocytes to produce ļ” -ļ§ -IFN with the improved clinical picture, similar results were found in 23.4% of patients which underwent only basic therapy. Thus, Wobenzym is most efficient in combination with Cycloferon in the treatment of patients with mastopathy with small cystic, fibrous and glandular component prevailing.

Lorenz. [Danol (danazol) in the treatment of fibrocystic breast disease with mastodynia]. Cas Lek Cesk 128 (7):209-211, 1989.
The author investigated in a group of 12 premenopausal women with fibrocystic mastopathy with mastodynia, confirmed on mammography, the effectiveness of a synthetic ethisterone derivative–danazole. An objective effect (reduction of the number and/or diminution of nodularities in the mammary parenchyma) was achieved in 67%, disappearance of mastodynia in 100%. As to side-effects only amenorrhoea was observed in 92%, spotting in 8%, an increase of body weight (1-6 kg) in 83% of the treated women. Danol will, with regard to its effectiveness and very good tolerance, if more widely available, substantially extend our therapeutic possibilities in the above indication.

W. Lotze. [Therapy of mastodynia and simple mastopathy].Ā  Zentralbl Gynakol 112 (18):1151-1155, 1990.
Cycle-dependent breast complaints in most cases are based on a hormonal dysbalance with estrogen predominance and development of an interstitial edema. They preferably occur between 30-50 years of age with possibly appearing mastopathic tissue changes. Whereas the treatment with antiphlogistic, diuretic and other measures only effects symptomatically, a causal therapy effect can be achieved by systemic and local hormone applications. Within the bounds of a clinical study 92 women were submitted to a local treatment with a one per cent alcoholic progesterone ointment at least lasting a period of 3 months. In 52 Patient with primary ointment treatment an essential improvement of the complaints could be reached in 87% (p less than 0.05). In 40 women with secondary local hormonal application the improvement-rate was 70%. Side effects could be not established. The good therapeutic result and acceptance of this therapy form make clear that the permission of an alcoholic progesterone ointment as standard prescription would represent a therapeutic enrichment

E. Rammer and F. Friedrich. [Enzyme therapy in treatment of mastopathy. A randomized double-blind clinical study] Enzymtherapie zur Behandlung der Mastopathie. Eine randomisierte doppelblinde klinische Studie. Wien.Klin.Wochenschr. 108 (6):180-183, 1996
In this randomized double-blind clinical study the efficacy of an enzyme preparation (Wobenzym) was compared with hormone therapy (Lynestrenol) in 29 women with mastopathy. There was a significantly greater decrease in number of hardenings of the mammary gland after 2 months of enzyme therapy than Lynestrenol therapy: improvement in the former group was 100%, in the latter group 78.6%. No significant difference was observed regarding the numbers of lumps, or number and size of cysts, sensitivity to touch, feeling of tension, spontaneous pain, and pain on pressure. The efficacy of both medicines is valued as good. Wobenzym therapy was tolerated very well. No side effects appeared at all. Enzyme therapy is an alternative, low-risk therapy for the management of mastopathy, which does not interfere with the already upset hormonal balance of the patients

L. Santamaria, Orti Dell, and Santamaria Bianchi. Beta-carotene supplementation associated with intermittent retinol administration in the treatment of premenopausal mastodynia. Boll Chim Farm 128 (9):284-287, 1989.
Twenty-five women, 23-41 year old, suffering from premestrual cyclical mastodynia linked or otherwise to benign breast disease (BBD), with moderate or severe pain at least seven days before each menstrual period, were treated with daily beta-carotene (BC) supplementation associated with intermittent administration of retinol (all-trans-retinol 300,000 IU per day). In this therapy retinol was given for 7 days immediately before each menstrual period. After 6 months’ treatment, the results revealed marked reduction in breast pain, and sometime recovery, in 23-41 year old women with no toxic side effects. But no such advantages in 5 women with non-cyclical mastodynia treated as above were found. Above this age range, the advantages appear to be absent. All the women developed a healthy look because of a slight tanning of the skin due to beta-carotene supplementation. These data demonstrated a therapeutic synergism between BC and retinol.

H. M. Snowden, M. J. Renfrew, and M. W. Woolridge. Treatments for breast engorgement during lactation. Cochrane Database Syst Rev (2):CD000046, 2001
BACKGROUND: National surveys have shown that painful breasts are the second most common reason for giving up breastfeeding in the first two weeks after birth in the UK. One factor contributing to such pain can be breast engorgement. Views differ as to how engorgement arises, although restrictive feeding patterns in hospital are likely to have contributed in the past. These differing views are reflected in the range of solutions offered to treat engorgement in breastfeeding mothers and these treatments are assessed in this review. OBJECTIVES: To determine the effects of any proposed intervention to relieve symptoms of breast engorgement among breastfeeding women. SEARCH STRATEGY: The register of clinical trials maintained and updated by the Cochrane Pregnancy and Childbirth Group. CINAHL and MEDLINE were also searched. Date of last search: December 2000. SELECTION CRITERIA: All randomised and ‘quasi-randomised’ controlled trials, with or without blinding, that assess the effectiveness of treatments for the alleviation of symptoms in breastfeeding women experiencing engorgement. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer and verified by a second reviewer. MAIN RESULTS: Eight trials, involving 424 women, were included. Three different studies were identified which used cabbage leaves or cabbage leaf extracts;. no overall benefit was found. Ultrasound treatment and placebo were equally effective. Use of Danzen (an anti-inflammatory agent) significantly improved the total symptoms of engorgement when compared to placebo (odds ratio (OR) 3.6, 95% confidence interval (CI) 1.3 – 10.3) as did bromelain/trypsin complex (OR 8.02, 95% CI 2.8-23.3). Oxytocin and cold packs had no demonstrable effect on engorgement symptoms. REVIEWER’S CONCLUSIONS: Cabbage leaves and gel packs were equally effective in the treatment of engorgement. Since both cabbage extract and placebo cream were equally effective, the alleviation in symptoms may be brought about by other factors, such as breast massage. Ultrasound treatment is equally effective with or without the ultra-wave emitting crystal, therefore its effectiveness is more likely to be due to the effect of radiant heat or massage. Pharmacologically, oxytocin was not an effective engorgement treatment while Danzen and bromelain/trypsin complex significantly improved the symptoms of engorgement. Initial prevention of breast engorgement should remain the key priority

TobiassenĀ T, RasmussenĀ T, DöberlĀ A, RannevikĀ G. Danazol treatment of severely symptomatic fibrocystic breast disease and long-term follow-up–the HjĆørring project.Ā  Acta Obstet Gynecol Scand Suppl 1984Ā  123:159-76
The purpose of the investigation was to study various aspects of danazol treatment in patients with fibrocystic breast disease and pronounced mastodynia. To qualify for inclusion, the patients in this study had to have a mammographically confirmed prominent glandular structure and/or severe cystic breast disease, associated with pronounced cyclical mastodynia lasting at least one week per menstrual cycle for more than 6 months. They also had to be premenopausal and not undergoing hormonal therapy. Of 109 patients with a mean age of 40 +/- 6.2 (SD) years, who completed 6 months’ treatment with danazol, 65% had a pre-treatment history of more than 5 years. According to detailed mammographic characterization, only 18% of the patients had no visible cysts. Of the 82% with visible cysts, half presented with both small (less than 1 cm) and large cysts. The patients were treated in two consecutive groups, 55 patients receiving 400 mg a day and 54 patients 200 mg a day. The therapeutic response was similar following both dosages. Mastodynia responded rapidly and total elimination was noted in about 90% of cases. A marked decrease in prominence of palpable structure was observed in virtually all patients. Mammographically, a decrease in the amount of glandular tissue was observed. These changes during treatment were statistically highly significant (p less than 0.001), irrespective of dose or category of patient. Non-cystic nodularities gradually decreased in 85% and resolved completely in 58% of the cases, but the degree of resolution in the groups of patients with no or only small (less than 1 cm) visible cysts was significantly greater (p less than 0.02 or less) than in the group which also had large cysts and which included the most severe and intractable cases. The mammographical visualization of cysts, ductal system, and fibrous tissue increased initially due to the marked regression of obscuring glandular tissue. Thereafter, a decrease in the number and spread of small cysts was observed in a significant proportion of patients and in some cases a reduction in duct diameter could be demonstrated by means of galactography. Nipple discharge also decreased. The extent of fibrosis appeared to be unaffected by therapy. In the 46 patients with large cysts and, in most cases, a documented history of repeated cyst formation, danazol treatment was found to arrest the development of new cysts and to prevent recurrence for a considerable time thereafter.

H. G. Wenning and F. W. Dittmar. Hydrolytic Enzymes in Gynaecology: Fibrocystic Breast Diseases, PID. Eur.J.Inf.Immunol.Dis. 1 (1):39-41, 1996.

U. H. Winkler, A. E. Schindler, U. S. Brinkmann, C. Ebert, and C. Oberhoff. Cyclic progestin therapy for the management of mastopathy and mastodynia. Gynecol Endocrinol 15 Suppl 6:37-43, 2001.
The management of benign diseases of the breast aims to halt the progression of fibrocystic transformation and to eliminate the symptoms of pain and breast tenderness. Progestins can be used for this purpose. In a controlled, randomized, double-blind, parallel-group study we treated 31 women with mastopathy/mastodynia with the progestins medrogestone (10 mg/day) or dydrogesterone (10 mg/day) from day 14 to day 25 for six cycles. Before, during and at the end of therapy the following parameters were evaluated: subjective symptoms (pain, tenderness, impairment of daily activities), palpatory findings, sonographic diagnosis and sex hormone profiles. Cyclic administration of the low-dose progestins medrogestone and dydrogesterone proved to be an effective and safe treatment of mastodynia and mastopathy. The objective parameters palpatory findings and sonographic imaging of breast nodules and cysts improved in more than 50% of patients. Improvement was particularly marked in women with low progesterone levels in the second half of the cycle. After six treatment cycles, 75% of the patients treated with dydrogesterone and 86% of the patients treated with medrogestone were completely pain-free.

Enzyme therapy ameliorates inflammatory processes caused by exogenous or endogenous antigens. Enzyme therapy balances inflammatory mediators (cytokines) which leads to a decrease of inflammatory processes. This way of action is different to other anti-inflammatory drugs e.g. NSAIDs like Diclofenac and many others (These drugs act on the prostaglandins which are responsible for the symptoms of an inflammation).

The cytokines are the driving substances of inflammation in our body.

Inflammation is in principal a positive mechanism if it is an acute

inflammation, but is deleterious in diseases caused by chronification.

Chronic inflammatory processes can be due to endogenous antigens like in autoimmune diseases including rheumatoid arthritis, ankylosing spondilitis (AS), lupus, etc.

1 clinical study with 40 patients demonstrates the benefit of Enzyme Therapy (Baewald 1999).

Arteriosclerosis can be viewed as a chronic inflammation and involves multiple reasons like increased blood viscosity, hypertension, lipid accumulations and chronic inflammations like diabetes mellitus, obesity, rheumatoid arthritis, periodontitis etc.

The blood vessel has been revealed to be a dynamic organ that is capable of sensing changes in its surroundings, communicate via intracellular signals and subsequently alter its structure. This capacity is termed vascular remodeling and is modulated by a dynamic interplay of cytokines, growth factors, vasoactive substances and haemodynamic stimuli. Vascular remodeling may be a normal adaptive mechanism, which became in some circumstances a pathogen process.

Chronic inflammation in the vessel wall is characterized by activation and an increased permeability of the endothelium, chemotaxis and activation of macrophages, proliferation and migration of the smooth muscle cells from the media to the intima and accumulation of extra cellular matrix which leads to thickening of the vessel wall – atherosclerotic plaques (loss of vessel elasticity is termed arteriosclerosis, while fatty deposit build-up is termed atherosclerosis).

Atherosclerotic intima becomes more thrombotic than healthy arteries. This depends in part on the endothelial injuries and on rupture or ulceration of the atheromatous plaque.

Cell migration, proliferation and enhanced production of extra cellular matrix are important events in the biological repair processes that restore tissue integrity and physiological function after injuries. However, some partly unknown causes terminate this response and lead to progressive fibrosis and tissue damage in the vessel wall.

Several pro-inflammatory cytokines (IL-1 beta, TNF, IL-6) and TGF-beta released by circulating cells and cells of the vessel wall, as well as elevated C-reactive protein have been associated with the pathogenesis of arteriosclerosis of the coronary and peripheral arteries.

In recent years it has been postulated that TGF-beta may be involved in endothelial dysfunction, vascular smooth muscle cells proliferation and excessive extra cellular matrix accumulation in the blood vessel wall (McCaffrey 2000).

Suppression of chronic inflammation and TGF-beta overproduction is one of the possibilities to reduce the development and progress of arteriosclerosis and related diseases. In fact antibodies against TGF-beta have been shown to inhibit intimal hyperplasia (Wolf 1994) and in several other fibrotic conditions like glomerulosclerosis (Border 1994), Bleomycin induced lung fibrosis (Nakagome 2006) or restenosis (Chamberlain 2001).

There exist a high number of investigations concerning the effect of Enzyme Therapy on TGF-beta synthesis on the development of thrombosis and Thrombophlebitis as well as on angiopathies and heart diseases (see also ā€œThe TGF-beta-storyā€).

Results with Enzyme Therapy

Animal models

Dosenko 2002 compared animals with high cholesterol diet (animal model of arterioscleroses) and animals with high cholesterol diet plus enzyme therapy. Histopathological examination revealed morphological changes of fibrous structures of aorta, lyses of segments and loosened fibers of elastic membranes and degeneration of collagen fibers in the cholesterol group. In the enzyme treated animals they found a significant effect on the elastolytic system and a less pronounced degeneration of collagen and elastic fibers.

Metabolic injury to myocardium was initiated by injection of epinephrine in another animal model (Skutelis 2001). The control group received additional enzyme therapy. Higher fibrosis and higher TGF-beta concentration were described in the control group, and the benefit of enzyme therapy was significant.

Gaciong 1996 investigated the influence of Enzyme therapy on a model of arteriosclerosis induced by aortic allograft transplantation in rats. One group of these animals was treated with daily intraperitoneal injections of a protease formulation containing trypsin, bromelain and rutosid, and another group with placebo. Administration of proteases inhibited formation of neointima by 59.0% and decreased medial injury as estimated by the integrity of elastic fibres and smooth- muscle cell density.

Patients

Prof. Mazurov (chief of the heart clinic in St. Petersburg), treated patients with stable angina pectoris for 10 years, with enzymes in addition to traditional therapy. Mazurov found a normalization of thrombocytes activity and a normalization of IL-1 beta level, while levels of IL-2, IL-8 and TNF-alpha had a tendency to normalize. He also detected normalization of myocardial metabolism and an increase in plasma fibrinolytic activity (Mazurov 2000).

The efficiency of enzyme therapy is supported by studies performed by a group of Ukrainian doctors on the treatment of post myocardial infarction patients (Kovalenkov 2000). They describe a normalization of cholesterol levels and some immune parameters. Also very impressive are the results of a clinical study with enzyme therapy done by Sledzevskaia 1997. Patients with myocardial infarction and hyperlipidemia were administered proteolytic enzymes for 10 (group A) or 30 (group B) days. Both groups also received beta blockers, nitrates and aspirin. In group A lowering of cholesterol level by 12% and lipoproteins by 16% was observed after 10 days, while patients from group B (30 days enzyme therapy) showed decrease of cholesterol level by 24% and lipoproteins by 31%. The level of malonic acid dialdehyde showed no change for 10 days and after one month was lowered. These results support an antiatherogenic effect of Enzyme Therapy, which can be seen after 10 days and an antioxidant effect, which can be seen after long-term treatment.

In 2/3 of the patients with myocardial infarction and enzyme therapy, a lowered level of B and T lymphocytes and T helpers and in 1/2 of patients lowering of T suppressors and natural killers were found. The effect of the enzymes on the serum atherogenicity and inflammatory reactions was studied over the period of 6 months in the postmyocardial infarction patients at the rehabilitation stage by Ryabokon 2000. Inclusion of Enzyme therapy into the conventional treatment led to the normalization of an atherogenic potential and showed a positive effect on inflammatory process mediators.

3 clinical studies including 149 patients

If the skin over the bone remains intact, a fracture is referred to as closed or simple; if the bone breaks the skin; it is termed open or compound. A bone fracture can also occur as a result of certain medical conditions that weaken the bones, such as osteoporosis or certain types of cancer.

Bone healing or fracture healing is a proliferative physiological process, in which the body facilitates repair of Bone fractures.

While immobilization and surgery may facilitate healing, a fracture ultimately heals through physiological processes. 3 phases can be distinguished: 1. reactive phase; 2. reparative phase; 3. remodelling phase.

In terms of medical treatments, several options are available which facilitate faster reparation of bone. Bone graphs, bone morphogenetic proteins, and immobilizing surgical procedures are used in cases in which there is bone malformation and/or stimulation of bone growth is necessary.

A fracture may cause extreme pain and tenderness in the injured area due to swelling, a protruding bone or blood under the skin. In addition there may be numbness, tingling, or paralysis below the fracture.

The accumulation of liquid in the tissues, known as edema, occurs as well as hematoma formation. Next in the repair process there is the production of soft tissue known as a fibrocatilaginous callus, followed by a bony callus. These are the phases of fracture repair that are necessary before complete bone remodelling can occur.

Enzyme Therapy

Enzyme therapy has been demonstrated to reduce pain, inflammation and thrombosis development. Therefore, the use of systemic enzymes seems beneficial during bone healing processes as an additive therapy.

In 6 clinical studies, including 306 patients, the anti-edematous (40% reduction of edema), fibrinolytic, as well as pain reducing properties are described. The reduction of healing time with Enzyme Therapy was significant and postsurgical scars were without keloids. Enzyme therapy enabled to quickly restore a temporarily impaired function of the damaged extremity.

Chronic wounds often result from surgical procedure, traumatic insult, and metabolic, infectious or neoplastic disorders.

Pressure ulcer (decubitus), diabetic foot ulcer, leg ulcer, vascular ulcer, postoperative open wounds and enterocutaneous fistulae are frequent types of chronic wounds.

Leg ulcer:

About 1 in 50 people develop a venous leg ulcer at some stage. Venous leg ulcers are usually painless, but some are painful. Sometimes they don’t heal and become chronic conditions. Chronic foot and leg ulcers mainly affect the elderly. The most common cause of chronic leg ulcers is poor blood circulation in the legs. These are known as arterial and venous leg ulcers. People with diabetes are at special risk of developing foot ulcers, and foot care is an important part of diabetes management. Other causes may be injuries (traumatic ulcer), vascular diseases (stroke, angina and heart attack), tumors and infection.

Pressure ulcer:

Pressure ulcers (Decubitus) are common in a variety of patient settings and are associated with adverse health outcomes and high treatment costs.

Chronic wounds are a result of an extended inflammatory response; therefore it is not surprising that Enzyme Therapy is beneficial. This is because Enzyme Therapy acts to modulate reduce the time of healing processes in acute and chronic inflammation.

1. Enzyme ointments support removing of debris in the wound and is used since ancient time, for example with chewed leafs from Ficus (high concentration of ficin). Since 1980 about 5 clinical studies including 558 patients exist, which demonstrate that Proteolytic enzymes in ointment support wound healing

2. Oral enzyme therapy support healing of leg ulcer and plantar ulcer as demonstrated in 1 clinical study with 20 patients (Sabadosh 1999).

• Quality of life
• Remission time
• Prolongs survival

Besides the negligible side effects of this treatment, Enzyme-Therapy improves significantly the quality of life in cancer patients (Breast cancer, Colorectal cancer, Multiple Myeloma) and prolongs remission time and increases survival.

Colorectal cancer

Popiela (2001) published the results of a retrolective cohort analysis, in which they compared the outcome of 1242 patients with colorectal cancer (616 patients received Enzyme-Therapy, and 626 did not). The primary test criterion of efficacy for Enzyme-Therapy was the multivariate effect size of the changes from the disease baseline, and therapy-associated signs and symptoms (nausea, vomiting, changes in appetite, stomach pain or disorder, tiredness, depression, memory or concentration disorder, sleep disturbance, dizziness, irritability, dyspnoea at rest, dyspnoea during activity, headache, tumor pain, cachexia, skin disorders and infections). They observed a significant reduction in disease-associated signs and symptoms in patients treated with Enzymes alone, but not in those patients receiving Enzyme-Therapy in addition to other complementary treatments. A trend to prolongation of survival was demonstrated, particularly in the patients with disease stage Dukes D.

1 retrolective study with 1242 patients

In 3 clinical studies, including 282 patients, Enzyme-Therapy has been shown to be beneficial. These studies demonstrate that Enzyme-Therapy reduces postoperative swelling. Additional important results worth noting: the mouth opening (distance between the upper and the lower central incisor) after surgery in the enzyme group is statistically significantly less handicapped than in the placebo group and wound healing shows significant advantage for the enzyme group.

Dentists are practiced in Enzyme-Therapy suggest patients start to intake Enzymes tablets 3 days before surgery until 10 days after surgery.

In endometriosis, endometrial tissue, the tissue that lines the inside of the uterus, grows outside the uterus and attaches to other organs in the abdominal cavity such as the ovaries and fallopian tubes.

The result is internal bleeding, inflammation of the surrounding areas, and formation of painful scar tissue. The endometriotic tissues still detach and bleed. In addition, depending on the location of the growths, interference with the normal function of the bowel, bladder, small intestines and other organs within the pelvic cavity can occur.

The peritoneal fluid of women with endometriosis contains increased levels of activated macrophages, lymphocytes, cytokines and growth factors. Increased local secretion of angiostimulatory proteins by endometriotic deposits and accompanying immunologic cells promote the local inflammatory processes.

The scar tissue can block the fallopian tubes or interfere with ovulation. Another result of endometriosis is the formation of ovarian cysts called endometrioma that may also interfere with ovulation. Endometriosis symptoms include: painful menstrual periods; abnormal menstrual bleeding; pain during or after sexual intercourse; abdominal bloating, pain and cramping; fatigue; and allergies as well as other immune system-related dysfunction. In addition to causing chronic pelvic pain in millions of women and teens, the disease is also a leading cause of female infertility. Studies have also shown an elevated risk of certain cancers and autoimmune disorders in those with endometriosis. Currently, patients either undergo invasive surgery or are treated with hormone therapies, but the latter method is unsuitable for women wanting to start a family.

Enzyme-Therapy in Endometriosis:

Enzyme-Therapy reduces inflammation, reduces the overproduction of cytokines and reduces edema and pain. It was therefore logical to question the potential benefit of enzyme therapy in endometriosis.

In 2 clinical studies including 146 patients is demonstrated that Enzyme therapy reduces pain, inflammation and progression of Endometriosis.