Indications for Enzyme therapy with Streptase, Urokinase and Tissue Plasminogen Activator - t-PA in Chlamydial Prostatitis

Pavels Ivdra, Edvins Platkajis, Ivars Geldners
Riga Clinical Hospital No.7, Head doctor: E. Platkajis
Latvian Association of Physicians - Chlamydiologists

Pavels Ivdra	Edvins Platkajis	Ivars Geldners

Chronic chlamydial prostatitis

Prostatitis is one of the most common male urological diseases. Almost every third or fourth male, seeking a urologist's advice in an out-patient department, is a chronic prostatitis patient, from whom not less than 75-8O% of patients suffer from chlamydial monoinfections or mixed infection prostatitis, more prevalent being 2, 3, and 4 inflammatory phases. One must take into account the fact, that Chlamydia trachomatis is relatively pathogenous microoragism. For example, a husband is ill but his wife feels well, though she is a carrier of latent chlamydial infection and a source of reinfection. In a case of a mixed genesis infection, by defining the intensity of the destructive activity of the pathologic process and its consequences in the macroorganism, Chlamydia trachomatis induced infection plays the dominating role.Chlamydia are gram-negative bacteria, definitely parasitic and host-organism cell energo-dependant prokaryotype bacteria, which can develop only in vertebrate or non-vertebrate cell cytoplasm and cause human and animal diseases - anthropozoonozes.

Acute prostatitis caused only by chlamydial monoinfection, has almost never been seen clinically. Clinical picture of an acute prostatitis is determined by mixed STD and other opportunistic infections. Latent chlamydial prostatitis from the moment of an infection till its clinical manifestation is usually lasting several months and years.

In an early, i.e. alternative and exudative inflammatory phase, patients with chlamydial monoinfectious prostatitis rarely go to see the doctor. It can be explained by the fact that at the beginning of the disease,the interoreceptor irritation due to the inflammation of urogenital venous plexus,and ganglionitis of the prostate gland may result in increased libido and potency.

Hypersexuality induced by inflammatory processes is characterized by a longer interval of copulative time and the ability to do repeated introjections after ejaculation. Sexual excesses and hypersexual potencies resulting from the above mentioned pathological processes of the prostate gland are subjectively perceived by sick males as a positive phenomenon which does not call for a specialist's help.

In a case of positive sanogenous reaction ( from a doctors' point of view), when inflammatory processes are undergoing regression, and the prostate edema and the venous blood stasis are decreasing, the pathological interorecepotor irritation is reduced and the pathological hypersexuality and its realization abilities disappear.

Chronic chlamydial prostatitis patients perceive the loss of the pathological, hypersexual potency with negative emotions, considering it as maltreatment, after-effects of wrong therapy , blaming the doctors for their incompetence which causes problems in the interpersonal relationship.

This is the reason why doctors diagnose the chronic chlamydial prostatitis most commonly in a late, proliferative inflammatory stage. Unfortunately the patients seek a doctor's help only at the stage when the degeneratively dystrophic changes, connective tissue proliferation, scarring deformation of the prostate, paraprostatitis, inflammation of the urogenital venous plexus are manifest as a urogenital disorder syndrome with the loss of libido and potency.

Prior to starting a routine or enzyme therapy, one should differenciate the stage of chlamydial prostatitis: alternative, proliferative or productive phase or prostate sclerosis. Chronic chlamydial prostatitis is characteristic of morphological polymorphism of inflammatory processes.

If a patient does not get an adequate treatment, the intracellular, persistent chlamydial infection continues its destructive activity upon the prostatic tissues and the alterative inflammatory phase may go on for years. Sooner or later, it may be accompanied by an exudative phase with the prostate edema.

Prostatitis progressing, the third proliferative or productive inflammatory phase is characterized by the proliferation of connective tissues, scarring deformation of tissues. When palpating,rectally one may find polimorphous consistency of prostatic tissues, lobar asymmetry and scarring deformation. If no etiopathogenetic therapy is undertaken and the proliferation of connective tissues is going on, focal sclerotic changes with calcinates in the prostate parenchyma may set in which are diagnosed by ultrasonoscopy (USS). Not uncommonly even 16-18 years old adolescents, with a diagnosis of chronic chlamydial prostatitis may have the prostate edema, scarring deformation of the tissues and USS calcinates in the prostate parenchyma as well.

Intracellular persistence of a latent course of chlamydial infection is a result of a long-term alternative inflammation which is characterized by a secondary, progressing T-active and B-ly cell immunodefficiency. If being ill for a long time, a chlamydial patient's immune system loses its capacities to recognize antigen structures of chlamydia and to induce the antichlamydial antibody synthesis. Humoral and cell immunodefficiency progressing, they may be accompanied by some opportunistic infections with a secondary antibiotic resistance.

Due to a routine antichlamydial antibiotic therapy and enzyme therapy,with the administration of proteolytic and combined enzyme drugs of plant, animal and microorganic nature, e.g., Wobenzym, Wobe-Mugos, Flogenzym, etc., there are no problems as to the treatment of chlamydial prostatitis in the first and second inflammatory phases, the treatment is not complicated and about 70-75% of patients may be treated as out-patients (2).

When indicating the therapy, one must pay attention to the specific morphology of chronic chlamydial prostatitis, i.e. in several or single lobar acinuses of the prostate simultaneously one may distinguish more or less marked all four inflammatory phases, which require a different therapeutic approach.

When treating chronic prostatitis it may seem to be the second inflammatory phase with the prostate edema being prevalent. After regression of edema, by examining it rectally, one can often discern a polimorphous prostatic tissue consistency, scarring gland deformation which indicate to the presence of a proliferative inflammatory phase and the ineffectivity of a further routine therapy.

If ultrasonoscopy reveals the calcinates in the prostate parenchyma, it means that there is also the fourth phase of the inflammation, i.e. the foci of the prostate sclerosis. These chronic prostatitis patients of the third and fourth inflammatory phase are hard to be treated even in a hospital. The length of the treatment depends on the intensity of productive and sclerotic inflammatory processes, the degree, the level of proteolytically enzymatic defect and the reparative regeneration capacities of tissues.

In cases of antibiotic resistance the optimal enzymatic therapy is possible only when applying proteolytic and fibrinolytic activity enzymes and their activators: streptokinase, urokinase and tissue plasminogen activator (t-PA). Fibrinolytic enzymes and their activators may be indicated only for hospital treatment due to aggravating complications - allergy, anaphylaxis and bleeding (3,4,5,6).

In cases of allergy and anaphylaxis, streptokinase is contraindicated, but treatment should be done by urokinase and t-PA. Indications for streptase, urokinase and t-PA are the third and fourth inflammatory phases of chlamydial prostatitis, which are characterized by degeneratively dystrophic changes of the prostate, connective tissue proliferation, scarring deformation of the gland, atrophy, sclerosis, paraprostatitis, the inflammation of the urogenital venous plexus and secondary disorders of the reproductive functions.

Due to architectonic changes of the prostatic tissues, the translocation of the inflammatiory processes enhances the development of phlebothrombosis of the small pelvis, the inflammation of the urogenital venous plexus with a deformation of venous valves and consequently causing disturbances of erection and potency. At the same time one may experience an increased libido but lowered potency due to an incomplete erection of the penis which results from an intensified venous reflux from cavernous bodies of the genitals even at an adequate arterial afflux. Most commonly only in these cases the patients start thinking about the treatment and consultations to a sexopathologist or an urologist. A sexopathologist can do little in this case because in the proliferative inflammatory phase and in cases of venous blood flow disturbances in the cavernous bodies, the potency cannot be restored by indicating hormones (methyltesterone, proviron pills) yohimbin, sex-o-vit, ginseng and other potency stimulators. An optimal pathogenetic therapy can only be achieved by using streptokinase, urokinase and t-PA.
Enzyme therapy with streptase for the antibiotic resistant prostatitis is an optional method in an exudative phase as well.

Example No.1  The patient Z.P., 37 yrs.old (Case report No.455) is suffering from chronic prostatitis for 5 years. He has been treated in an out- patient department by a family doctor and urologists. Due to resistance to antibiotics, the out-patient therapy has been ineffective. The patient was hospitalized in the urologic department. He complained of frequent, painless urination, fatigue, tiredness, sweating, sore eyelids, pains in the joints of legs and arms, pains in the sacrum.

Objective Findings: By palpation the prostate gland appears edematous of paste-like consistency, diffuse pains. Chlamydial antigen structures are verified (+) by testing it with TIF method with monoclonal antibodies. Chlamydia trachomatis antibodies in the patient's blood are negative in NIF method. Typical hypercoagulemia (Coagulogram I) in coalgulogram.

Clinical Diagnosis:
1) Chronic chlamydial prostatitis in an exudative phase.
2) Reiter's syndrome.
3) Hypercoagulemia.

Coagulogram 1

Patient Z.P. 37 year old, Case history No. 455
Hemostasis indices	Norm	Test results before therapy	Test results after therapy
Hematocrit	45%	41%	45%
Blood clotting time	5-10', 37 'C 11-14' room 'C	11'	13'
Caolin time	70-80"	60"	70"
Fibrinogen A	80-100%	84%	80%
Spontaneous fibrinolysis	200-400 mg%	621 mg%	300 mg%
Plasma euglobulin fraction   fibrinolysis	120-240'	220'	180'
From XII-a factor dependent   fibrinolisis	5-7'	10'	4'40"
Fibrinolusis on fibrin plates	250 mm2	150 mm2	280 mm2
Ethanol test	(-)	(+)	-
Protaminsulphate test	(-)	(+)	-
Proteolytic resistence	110-140 units	160 units	150 units
Antistreptokinase titre in plasma	25-150 a.v.	150 a.v.	1400 a.v.

The patient received an enzyme therapy course with (SK) streptokinase, heparin and antichlamydial antibiotics. On the 13th day of treatment of streptokinase dose 200 000 e.u. i/v once a day, the patient developed complications in the form of arthralgia and hyperpyrexia. Consequently, SK dose was reduced by 100 000 e.u. and the enzyme therapy was continued. During 25 days the patient was receiving once a day streptokinase 10 000 - 200 000 e.u.. 25 days with the total dose of the treatment course of 3 005 000 e.u., heparin - 25 days of 8 500 units i/v once a day with the total dose of 210 000 units, erythromycin 0,1x2 days i/v for 15 days, doxycycline 0,1x3 days for 20 days, makropen 400 mgx3 days, in total 48 pills , and physical procedures.

As a result of the enzyme therapy, hypercoagulemia disappeared. Resistance to antibiotics regressed because the same antibiotics which in the ambulatory treatment had been ineffective, turned to be effective. The inflammatory process in the prostate also regressed. The prostate regained its normal size, got well- outlined, symmetrical, smooth, maintained sulcus posterior, elastic and painless. Subjective condition completely stabilized

Conclusion: 

In the third and fourth inflammatory phase of chlamydial prostatitis with signs of the gland tissue sclerosis, when the prostate is examined by USS, one can verify calcinates in the parenchyma, which means that not only the inflammation is the basis for sclerosis pathogenesis but ischemic disorders, discoagulemia and hypercoagulemia as well.

Pathogenetically determined morphological changes which are characteristic for each prostatitis phase separately, define and require an individually structured approach and length of therapy.

Antibiotic resistance in the treatment of chlamydial prostatitis is still one of the medical problems which has not been solved as yet. Although pharmaceutical industries offer up-to-date and effective antichlamydial antibiotics, for example, klaritromycine, roxithromycine, rulid, zanocine, duracef and the fourth generation cephalosporins, the treatment problems of urogenital chlamydiosis are not solved yet.

The study of the specific treatment of chlamydial induced prostatitis and problems of etiopathogenetic mechanism is being done in the 11th Urology Department of Riga 7th clinical hospital where 1748 chronic antibiotic resistant prostatitis patients aged from 15 till 80 years underwent treatment from 1981 to 1998 (18 years). From these chronic prostatitis in-patients, almost 90% have been diagnosed Chlamydia trachomatis infection which does not characterize the epidemiological situation in the country. They were hospitalized due to ineffectivity of ambulatory therapy and the concentration of this type of patients in a specialized urological ward. Besides, antibiotic resistant chlamydial prostatitis patients from various districts of Latvia are admitted to the Urology Department with a referral from district urologists, as well as antibiotic resistant chlamydial prostatitis patients whose treatment has been unsuccessful.

Adequate treatment of etiotropic chlamydial prostatitis requires a careful and thoughtful diagnosis of Chlamydia trachomatis infection.Under the direct immunofluorescence method (DIF) with monoclonal chlamydial antibodies we diagnosed chlamydial antigen structures (+) in 75% of prostatitis patients. From them, using indirect immunofluorescence (IIF) method, it was impossible to verify Chlamydia trachomatis antibodies in 30,8% of patients' blood. It can be explained by the fact, that in humoral and cell immunodefficiency cases, the induction and synthesis of antichlamydial antibodies are disturbed.

A latent, peristent chlamydial infection was diagnosed in 25% of chronic prostatitis patients. They were not diagnosed any chlamydial antigen structures (-) using DIF method with monoclonal antibodies. However, in 17% of patients of this group, when using IIF method, we diagnosed Chlamydia trachomatis antibodies in blood (+) in titre 1:16, whereas in almost 8% of patients it was impossible to diagnose either chlamydial antibody structures or antichlamydial antibodies in blood although simultaneously examining the wives and sex partners of these patients, we found (+) the chlamydial antigen structures from the cervix of the uterus and antichlamydial antibodies in blood (+) in titre 1:16 and 1: 64.

In cases of latent, deep chlamydial infections, the antigen structures in some males are difficult to reach, since they are not present in the urethra but are located deep in the prostatic tissues (7). In cell and humoral immunodeficiencies, Chlamydia trachomatis antibodies do not form in patients' blood, thus, differencial diagnosis is made difficult. One should consider the data of microbiological findings of a patient's sex partner. In case of unclear etiology, 8% of chronic prostatitis patients in latent chlamydiosis after the treatment course with streptase and urokinase, may diagnose antichlamydial antibodies in blood in a low titre (+) 1:16 (8).

Example No.2. Patient A.L., 61 yrs.old (Case report No. 23390, 1997) suffers from chronic prostatitis for more than 7 years. He has been treated ambulatory by an urologist in a regional town and in hospital. Antibiotics therapy has proved to be ineffective. Due to antibioticresistence the patient was hospitalized in the Urology Department of Riga 7th Clinical Hospital. He was indicated enzyme therapy with fibrinolytic enzymes and their activators.

On admission the prostate was scarred, sickle-type with a marked paraprostatitis, smoothed sulcus posterior, of polimorphous consistency, with severe diffuse pains. In ultrasonoscopy one ccould discern rough calcinates in the prostate parenchyma. Hypercoagulemia in coagulogram. Under DIF method with chlamydial antibodies there were diagnosed antigen structures (+). IIF method detected Chlamydia trachomatis antibodies in the patient's blood 3 (+) in titre 1:16.

Clinical Diagnosis:
1) Urogenital chlamydiosis.
2) Calculous chlamydial prostatitis in the third-fourth inflammatory phase.
3) Hypercoagulemia.
4) Antibiotic resistance.
5) Paraprostatitis.

In order to reduce hypercoagulemia and antibiotic-resistence, the treatment was begun by streptokinase with the dose of 25 000 - 300 000 e.u. i/v once a day. It was impossible to indicate a higher SK daily dose due to allergic reaction - arthralgias. One should mention that SK of 300 000 e.u. were insufficient because it did not induce even a minimum hypocoagulemic effect. Enzyme therapy with SK alone was ineffective. With an aim to reduce the time of treatment an extra dose of urokinase 100 000 UI i/v was indicated. After introducing an enzyme i/v, we diagnosed the resistence to urokinase because no hypocoagulemic effect was observed. Therefore, it was decided to use tissue plasminogen activator (t-PA). Next day the patient was infused 50 mg Actilyses i/v. In the control coagulogram, 30 min. after Actilyses infusion, one could see a marked hypocoagulemia. During 35 days stay in the Urology Department the patient received: streptase 7 550 000 e.u. i/v, urokinase 100 000 UI i/v, Actilysi 50 mg once a day for 2 days, in total 100 mg i/v, heparin 8 500-10 000 units i/v once a day, 32 days, in total 320 000 units, antichlamydial antibiotics per os and intravenously. After t-PA the allergic reaction to streptokinase disappeared. The inflammatory process in the prostate and paraprostatitis regressed. The patient was cured. However, taking into account the presence of calcinates, one should evaluate it as a long-lasting remission. After the course of treatment the microbiological and immunological tests were done but they did not reveal any chlamydial antigen structures. Under IIF method Chlamydia trachomatis antibodies in the patient's blood were not found.

Conclusion:

For the purpose of reducing the time for enzyme therapy and allergic reactions, one should use urokinase extra to streptase. If urokinase is ineffective, or there is a resistence, one should additionally use a tissue plasminogen activator - Actilysi.

In the proliferative prostatitis phase, part of patients with chronic antibiotic resistent chlamydial prostatitis may have a marked selective fibrinolytical activation enzymatic defect to streptokinase and urokinase which, after intravenous introduction of an enzyme or its activator is clinically seen as low sensitivity or complete resistance. Quite commonly this is the reason for lack of positive sanogenous reaction.

A positive sanogenous reaction of enzyme therapy must be considered as a regression of scarring deformation in the third-fourth inflammatory phase, reparative regeneration of the prostatic tissues.      Reparative regeneration of different tissues, for example, bone, connective tissues, liver, kidney, urinary bladder and other organs has been well studied clinically and in vitro. On the contrary, there is little knowledge about the reparative regeneration processes in the prostate gland in cases of chronic prostatitis, atrophy and sclerosis of the prostate. In the third-fourth inflammation phase, which is clinically manifest by scarring deformation of the gland, atrophy and sclerosis, the enzyme therapy with proteolytic, fibrinolytic enzymes and their activators enhance the reparative regeneration of the prostatic tissues.

When doing morphological studies, new compensating mechanisms were found to form in the places of arterio-venous anastamoses first. The reparative prostate regeneration in the third-fourth inflammation phase begins with the formation of new compensating mechanisms in the place of arterio-venous anastamoses.

It is known that in a partial microcirulatory blood circulation - arterioles, capillaries, venules (thrombosis, sclerosis, obliteration)- damage, the newly-formed blood-vessel anastamoses can partially play a role of a temporary adaptation mechanism to prevent blood-circulation disorders in the prostate gland. In cases of the prostate capillary system damage, blood-circulation may proceed along the newly-formed arteriovenous anastamoses bypassing the capillary system. Secondly, the initial sign of the regeneration is the appearance of smooth muscle proliferates of the prostate. It can be considered as the compensating regeneration of smooth muscles. Newly-formed proliferates of the smooth muscle in the sphincters of the glandular lobe of the excretory duct walls have also a compensating regenerative effect in chronic prostatitis, atrophy and sclerosis cases with a lower organ functioning.

In cases of delayed chronic pathological processes, i.e., in a productive inflammation phase with connective tissue proliferation, scarring changes in the parenchyma, calcinates and sclerosis of the prostate, one of the main initial therapeutic measures is the prevention of etiotropic cause of the inflammation.

The central problem is to study the regularity of the prostatic tissue regenerative reaction stimulation, depending on the specific character of the inflammation, the degree of its manifestation and the diversity of the regeneration forms.

As a result of enzyme therapy one can notice signs of regression of sclerotic changes in the prostate, i.e. regeneration of morphological prostatic tissue structures.In this respect, even a separate prostatic tissue component is of great importance in order to understand the meaning of smooth muscle regeneration.

The ability of smooth muscle regeneration has been proved long time ago, as well as the regeneration sources which have been studied and described. But the priority of clinical and morphological follow up of smooth muscle regeneration stages in chronic prostatitis third-fourth phases after enzyme therapy and heparinization belong to us.

Regression of tissue changes in chronic prostatitis second-fourth phases corresponds to the general rule of regenerative reactions, i.e. elimination of sclerotic changes may take place only in those organs, where regeneration is prevalent, or only by means of issue renovation or reproduction. But it is not observed in the places where the compensation of dysfunction occurs on the basis of intracellular regenerative reactions.

The idea of the renovation process of regeneration in chronic prostatitis and the atrophy of the prostate has in fact a generalizing meaning. It envisages a series of measures, active regulation and long-term stimulation of the regenerative process taking not less than 1-3 years.

The criterion for the effectivity of enzyme therapy in chronic prostatitis is the renovation process of structural elements and increase in their number which is aimed at preserving the necessary level for individual functional activity. The determining factor, certainly, is not to achieve the initial morphological structures of the prostate, but the function normalization first of all.

Specific tissue structure regeneration of the prostate should not obligatory be followed by a very exact reconstruction of tissue forms and their inner structures.

Example No.3  Patient N.R., 38 yrs.old (Case report No. 25075, 2853). On admission to the Urology Department he complained of severe fatigue, prostration from the early morning and reduced working abilities. He mentioned pains in the urinary duct, perineum and in the joints. He had been treated for chlamydial conjunctivitis by an oculist. Physicians have suggested Reiter's syndrome, because the patient had urethritis, prostatitis, conjunctivitis and polyarthritis. For two years the patient had experienced low libido and weak potency, weak erection and problems with ejaculation - ejaculation tarda. Oligospermia, akinospermia and necrospermia had been diagnosed.

Family history. Married 13 years ago, 2 children and the wife are healthy. He had fallen ill 2,5 years ago. He was treated ambulatory by an urologist, sexopathologist, oculist and a physician. Due to antibiotic resistance the current therapy had been ineffective.

Before the enzyme therapy, the prostate surface was flat, weak outlined, sulcus posterior levelled, scarred, rigid, firm, tender with a marked paraprocess. USS diagnosis - calcinates in the prostate paranchyma.

Diagnosis:
1) Chronic chlamydial prostatitis of third-fourth phase
(athrophy and sclerosis of the prostate).
2) Paraprostatitis.
3) Chronic chlamydial conjunctivitis.
4) Reiter's syndrome.
5) Antibiotic resistance.
6) Impotentio coejundi et generandi.

Due to antibiotic resistance he was indicated the enzyme therapy with streptase and heparin. At the beginning of the enzyne therapy with streptase daily dose of 25 000-50 000 e.u. i/v 6-8 hrs. after infusion there appeared allergic reactions with hyperpyrexia and arthralgia. All possibilities of enzyme therapy of streptase seemed to be exhausted, therefore urokinase was indicated, since it was known not to give any allergic nor anaphylactic reactions (4).

The patient was infused 100 000 UI of urokinase i/v. 30 min. after i/v urokinase infusion it was necessary to do coagulogram in which hypocoagulemia was not observed.

The patient was seen to have an enzymatic defect - resistance to urokinase ( see 2 coagulogram - 1 line). Next day t-PA Actilysi of 25 mg was infused i/v. 30 min. after infusion of Actilyses i/v one can observe minimal hypocoagulemic signs (see 2 coagulogram - 2 line). After a repeated infusion of Actilyses of 50 mg i/v, the allergic reaction to streptase disappeared and the sensitivity to urokinase appeared.We got the highest sanogenous effect of hypocoagulemia by introducing urokinase 100 000 UI i/v with streptokinase infusion of 250 000 e.u. following (see 2 coagulogram - 3 line). At the end of the enzyme therapy there was achieved a marked fibrinolytic enzyme system activation, because 15 min. after 25 mg of Actilyses i/v, when doing a coagulogram, we could register a very marked hypocoagulemia ( see 2 coagulogram - 4 line).

If at the beginning of therapy one noticed a resistance to streptase, urokinase and even to Actilysi, then at the end there was achieved a remarkable sensitivity to all 3 enzymes.

Due to allergic reactions, the patient was first treated in the Urology Department for 57 days, but repeatedly - 24 days. The total time of treatment - 81 beddays.

Coagulogram 2