Enzyme therapy of Antibiotic-resistant and Urogenital chlamydiosis MULTIDISCIPLINARY PROBLEMS IN CHOOSING PROTEOLYTIC ENZYMES AND THEIR ACTIVATORS FOR ENZYME THERAPY OF ANTIBIOTIC-RESISTANT AND UROGENITAL CHLAMYDIOSIS Pavels Ivdra, urologist, Riga Clinical Hospital "Gailezers" Janis  Zalkalns, professor, President of Latvian Association of Enzymologists Aija Zilevica, microbiologist, professor of LU Faculty of Medicine Inara Ancupane, MD, chlamydiologist, Latvian Association of Chlamydiologists Ivars Geldners, head of Department of Urology, Riga Clinical Hospital "Gailezers" Edgars Baumanis, urologist, Riga Clinical Hospital "Gailezers"				Pavels Ivdra
Janis Zalkalns	Aija Zilevica	Inara Ancupane	Ivars Geldners	Edgars Baumanis

Pavels IVDRA is the pioneer of enzyme therapy in Latvia, the co-author of this article, who has undertaken a systematic and purposeful enzyme therapy of chronic prostatitis with proteolytic enzymes of animal, plant and microorganic origin, fibrinolysin and heparin more than 30 years ago, i.e.at the end of the 60ties of this century.

P.Ivdra and E.Smiltens were the first to report about the enzyme therapy in chronic prostatitis at the scientific conference of the Surgeons-Urologists of the Baltic States which took place in Riga in 1973 {1}.

Simultaneously with us,the USA enzymologists M.Wolf and K.Ransberger in 1972, published the news about the possibilities of enzyme therapy, administering proteolytic enzymes per os {2}. For the treatment of chronic prostatitis with tripsin, himotripsin, fibrinolysin and heparin, P.Ivdra has been awarded the USSR certificate for the author's rights Nr 486750, having priority since January 5, 1972 {3}.

In 1976 P.Ivdra published articles in the journal "Urology and Nephrology" on the possibilities of parenteral introduction of proteolytic enzymes with a positive therapeutic effect in chronic prostatitis patients {4}.

Thanks to the order Nr 25-15, issued by V.Kaneps, professor, the Minister of Health Protection, 15 andrological beds were opened on 14.01.81 at Riga 7th Clinical Hospital and an adequate financing was provided for fibrinolysin and streptokinase medications.As a result, within the last 20 years, chlamydial and mixed antibiotic-resistant infectioous prostatitis patients were treated with firbrinolysin and streptokinase-containing medicines: streptolyasis, celyasis, avelysin, streptodecasis, streptase, streptokinase.

During the years 1981 - 2000 (20- year period), 1,943 chronic antibiotic-resistant prostatitis patients, aged 13 to 18 yrs., have been treated at Riga Clinical Hospital "Gailezers", department of Urology.

Various enzyme therapy methods have been acquired and specifities of fermentative catalysis studied. Oral enzyme therapy with proteolytic enzymes of animal, plant and microbiologic origin is long forgotten process.

Proteolytic enzymes,their activators and inhibitors are the groups of biologic catalysators which are still being intensively studied.In theoretical aspect, proteolytic enzymes are a working tool for enzymologists in finding the protein structures and fermentative catalysis mechanism. Proteolytic enzymes are widely used in medicine, agriculture, pharmacological and food industries and other branches of the national economy.

According to the current classification, proteolytic enzymes belong to the hydrolase class (class 3), the contents of which include peptid-hydrolase (3,4..) subgroup, which, in its turn, is divided into 4 groups {5}:

3.4.1. - aminopeptidases
3.4.2. - carboxypeptidases
3.4.3. - dipeptidases
3.4.4. - proteinases

For enzyme therapy physicians are using now only few proteinase enzyme medications and plasminogen activators ((SK)streptrokinase, urokinase and t-PA), tissue plasminogen activator. There are almost no contraindications for the use of proteinasis. For enzyme therapy of various diseases, including the treatment of antibiotic-resistant urogenital chlamydiosis, there are used proteolytic enzymes of animal origin(tripsin, himotripsin, pancreatin), microbiological origin (terillitin) and plant origin (papin, bromelain, agavain) separately or simultaneously in the form of polyenzyme drugs (Wobe-Mugos, Wobenzym, Flogenzym, Mulsan) per os, rectally as suppositories, but tripsin parentally in i/m injections as well.

If antibiotics, given as an additive to polyvalent proteolytic enzyme tablets (Wobenzym, Wobe-Mugos, Flogenzim) in the treatment of urogenital chlamydial infections are ineffective, then doctors, ex juvantibus, willy- nilly, have to acknowledge and diagnose the presence of antibiotic resistance {6,7}.

Regression of antibiotic resistance can be achieved only by simultaneously indicating the activators of fibrinolytic enzyme system (SK, UK, t-PA). Activation of blood and tissue plasminogen only by oral polyvalent proteolytic enzyme drug proteinases is impossible (Clinical case 1).

Clincal case 1.
Patient A.K. 57 yrs.old, has been ill for 2 years.

Dg: 1. Chronic chlamydial cystopyelitis.
      2. Reactive chlamydial polyarthritis.
      3. Antibiotic resistance.
      4. Dyscoagulemia.

Using DIF method with monoclonal antibodies, chlamydial antigen structures were found (+). In IIF method, Chlamydial trachomatis antibodies in blood 2(+) titre 1:16.

On admission to the Urology Unit, the patient was complaining of frequent, painful urination in every 0,5-1 hour, pains in the kidney area. Pains were noted in the shoulder, elbow and wrist joints. Edema of II-III fingers of the right hand. Pains in both knee joints, sometimes pains in the feet joints.

Case history
Due to polyarthritis, the patient was treated twice in 1999 in the Rheumatology Unit. For the pre-hospital period and hospital treatment, doctors indicated systemic enzyme therapy with Wobenzym tablets ( 3-10 tabl. 3 times a day) and other complex therapy. Enzyme-antibiotic therapy was ineffective because of dyscoagulemia and antibiotic resistance. 6 months after the treatment in the Therapeutic Unit, the patient was hospitalized in the Urology Unit of the clinical hospital "Gailezers" for enzyme therapy with SK and during 31 day treatment, the patient had received streptokinase i/v in the dosage of 3 000 - 350 000 e.u., in total 4 605 000 e.u. i/v, heparin 5000 u. i/v once a day for 30 days and antichlamydial antibiotics (erythromycin i/v, cephalosporins i/v. doxicyllin caps.).

Dyscoagulemia disappeared which was the proof of the effectivity of complex enzyme therapy (Table Nr 1). As a result, polyarthritis regressed, pains in the joints disappeared. The patient recovered, working capacities were restored.

Conclusion
If systemic enzyme therapy with Wobenzym tablets is ineffective, one should continue treatment with streptokinase.

Table Nr 1

COAGULOGRAM

Conclusion: Dyscoagulemia regressed with a course of positive sanagenous reaction. Antistreptokinase titre in plasma increased from 150 a.u. to 1600 a.u.

The main proteolytic enzyme in human blood and tissues is plasmin - fibrinolysin, which is also a proteinase (3.4.4.14.) {5}.

There is no deficiency of proenzyme-plasminogen in a patient's blood and tissues, but due to inhibiting effect, its activation may not take place. Enzymologists have understood that there is no use to treat with plasmin (fibrinolysin) drugs, but to use unlimited reserves of plasminogen in the patient's blood and tissues. Therefore, fibrinolysin production from human donor blood was stopped. Nonactive plasminogen which is present in the patient's blood and tissue, is activated by SK, urokinase or T-PA, achieving fibrinolytic and proteolytic effect. The choice of enzyme therapy is strictly determined to plasminogen activation by SK. SK is not a routine supplement to the therapy, but it dominates as one of the main cheapest plasminogen activation enzyme drugs with multidisciplinary sanogenous reaction available to all {8}.

The most optimal enzyme therapy in antibiotic resistant urogenital chlamydiosis is achieved if i/v fibrinolytic enzyme system activators - SK, urokinase or T-PA are indicated {9}. Streptokinase is the main enzyme drug for pathogenetic therapy, the key in regression of antibiotic resistance, but all oral enzymes and antibiotics are coming next {10}.

Effective etiopathogenetic baseline therapy is not with SK as an "additive" but as the chief component of enzyme therapy {11}. Tissue plasminogen activator (t-PA) is necessary in cases if, when SK is being introduced, one can diagnose a secondary induced hypercoagulemia or an inhibition of fibrinolytic activity {12, 13, 14, 15}.

Clinical case 2
Patient A.K., 29 yrs.old with chronic chlamydial prostatitis, was ill for more than 6 years. The patient was complaining of bad feeling, depression, pains in the perineum, groin, testes and periodic dicomfort in the genital organs. Since 1994, the patient was treated at State Centre of Sexually-Transmitted and Infectious Skin Diseases, where he was diagnosed Chlamydia trachomatis infection and was prescribed an adequate antibiotic and systemic enzyme therapy with Wobenzym tablets. Due to antibiotic resistance, he had repeatedly received oral dose of enzyme and other antichlamydial-antibacterial drugs several times, with no results though.

Before undergoing treatment in Riga Clinical Hospital "Gailezers", Urology Unit, the prostate gland was flat, suclus posterior smoothed, rigid, non-elastic,diffusely painful with a marked paraprocess around. Under DIF method with monoclonal antibodies, chlamydial antigen structures were verified (+). Under IIF method Chlamydia trachomatis antibodies 2(+) titre 1:16.

The enzyme therapy included: Streptokinase 250 000 - 750 000 u. i/v per day, for 41 days, in total 24 325 000 e.u.; heparin 5 000 u. i/v per day for 30 days = 150 000 u. i/v. Starting with day 13th, Actilysi (t-PA) 10 - 25 mg i/v per day for 15 days, in total 200 mg and antichlamydial antibiotics (erythromycin, doxicyllin, cephalosporin, zanocyn, etc.).

The patient given SK i/v together with Actilysi in small doses (from 10 to 20 mg per day) was observed to have a marked fibrinolytic effect because of interrelated activation of enzymes since they were potencing each other ( Table Nr. 2).

The enzyme therapy course lasted 43 days of a year. After threatment the prostate was well-outlined, sulcus posterior appeared, lobes were symmetrical of smooth surface, slightly elastic, painless. Paraprostatitis regressed too. Clamydial trachomatis antigen structure and antibody titre (-) were negative.

Conclusions:
Chlamydia, being always parasitic and host-cell-energodependant bacteria, which use cell energoresources, are the cause of the inhibition (depression) of proteolytic activation with a secondary expressed antibiotic resistance. Prior to treatment with SK and t-PA, the coagulogram indicators were in norm. Dyscoagulemia, hypercoagulemia were not diagnosed, however, there was resistance to SK. It was not possible to achieve a positive sanogenous response using only Wobenzym tablets and SK infusions i/v without tissue plasminogen activator (t-PA) in cases of chlamydial intracellular persistence. Actilyse promoted the elimination of intracellulary persisting chlamydial antigen structure.

By releasing cells from chalmydial antigen structure, the energoresources of cells were restored.As a result, the antibiotic resistance regressed and the same antibiotics being inactive so far, became effective.

Pharmacokinetic properties of SK in various phases of inflammation are not equal. In prostatitis patients, antiinflammatory properties of SK are observed in II, III and IV inflammation stages.SK guarantees the regression of the inflammation of urogenital plexus venosus, it improves the microcirculation. SK controls proliferation of connective tissues and stimulates the reparative regeneration of the smooth muscles of the prostate. SK possesses hepatoprotective properties. SK is the inductor of antigen elimination and intracellular antigen structures of chlamydial infection. SK has also immunomodulatory properties. SK being the enzyme drug of microbiological origin is the cheapest plasminogen activator and is available even to more indigent patients.In the treatment of middle social class patients one should use SK. Resources of SK procurement are boundless, production costs very low because the culture used is milk whey or meat broth, in which hemolytic streptococcal pure culture is cultivated, then SK is precipitated by 96 alcohol, etc.

Table Nr.2

COAGULOGRAM