Treatment with an Injectable BiologicalPreparation for Osteo-Arthrosis of theKnee: A Study Featuring 1845 Patients

by Michael Weiser, M.D. and Horst Metelmann

Key words: Zeel P injection solution, osteo-arthrosis of the knee, post-marketing drug survey.

SummayThis post-marketing drug survey was

conducted with the objective of obtainingnew knowledge on therapeutic adminis-tration of the antiarthrosis preparation ZeelP, as applied in medical practice. Admis-sion to this study was granted only topatients who were sufleringfiom arthro-sis of the knee. Administration of Zeel Pwas exclusively by intraarticular injec-tion. The period covered by this trial ex-tended throughout four months,fiom Sep-tember to December of 1992. A total of190 orthopedists took part in this drug-monitoring study. These physicians treated1845 patients with Zeel P and documentedthe results on standardized questionnaires:the collected data included case-histoy in-formation, adjuvant medication, non-me-dicamentous adjuvant therapy, the scopeof therapy provided, evaluation of thetherapy, and tolerance to the medication.This post-marketing drug survey was de-si~ed as an accompanying study: i.e.,during the progress of a series of injec-tions, the physicians assessed at each thera-peutic session knee stlfiess and the de-gree of pain.

The following overall information wasobtained:

1. On the average, each patient receivedintraarticular injection of one ampule ofZeel P, twice a week, over a period of 4-5weeks.

2. The effectiveness of Zeel P injectionsolution was statistically apparent. Alle-viation of complaints was statistically veri-

12

fied after thefirst two injections. Pain uponinitial knee movement, pain following ex-ercise, continuous pain, and st~~ess inthe joint all decreased signl~cantly in alinear manner during the course of treat-ment. This effectiveness was apparentthroughout the entire scale of pain inten-sity: no pain, slight pain, moderate pain,and severe pain.

3. At the end of treatment, 93.1% of thepatients assessed the therapy as positive:i.e., fi-om satisfactory to vey good.

4. The tolerance of Zeel P was good.The side-efleet rate, referenced to the entirenumber of injections administered, was0.45%. The only side eflects actually reg-istered were sips of local inflammation,which all abated.

1. Introduction

Following only cardiovascular dis-orders, rheumatic diseases rank sec-ond in frequency among all chronicillnesses in Europe [Bjelle, 1987]. Gen-erally, the designation rheumatism isapplied to all syndromes for whichthe only common characteristic is painin the musculoskeletal system. Caus-ative factors for the continuously in-creasing number of rheumatic illnessesmay be found among the attributes oflife practiced in industrialized coun-tries: e.g., lack of exercise, loss of mus-cular strength, inappropriate diet, andoverweight [Krebs, 1987]. It has beenestimated that 12- 25?4 of all patients

who avail themselves of services pro-vided by national health systems suf-fer from rheumatic disorders. As a re-sult, this complex of symptoms repre-sents one of the primary burdens borneby the health facilities of a country[Wagenhauser, 1984]. The national eco-nomic losses attributed to rheumaticdisorders are therefore highly signifi-cant. In Germany, the treatment of allpatients suffering from rheumatismalone requires several million trips tophysicians, and an equivalent numberof therapeutic applications. Each yearin Germany, approximately 50 millionman-days of work are lost because ofrheumatic disorders, and the numberof early retirees due to rheumatismrises continuously. Rheumatism hasin fact become the most expensive dis-ease in industrial countries [Krebs,1987]. During 1992 in Germany, forexample, physicians made diagnosesof arthrosis almost 17 million times,and prescribed medication for treat-ment of this indication around 20 mil-lion times.

In general, physicians administerantirheumatics in the form of non-steroidal antiinflammatory drugs(NSAID) and chondroprotective medi-cation. The antiarthrosis preparationZeel P injection solution is a combina-tion homeopathic medication, the for-mulation of which was developed onan empirical therapeutic basis. It ismanufactured in accordance with the

Biological Therapy / Vol. XIII / No. 11995

German Homeopathic Pharmacopoeia(HAB). The individual constituentscontained in Zeel P make it effective intreatment of disorders which includeosteo-arthrosis of the knee, spon-dylarthrosis, polyarthrosis, and peri-arthritis humeroscapularis. The actionof Zeel P injection solution is charac-terized by reliable effectiveness, and itsatisfies requirements of patients forlow-risk therapy [Hieber, 1971;Schlufter, 1975].

2. Methodology of the study2.1 Conduct of the study

This post-marketing drug studywas conducted with the objective ofobtaining new knowledge on the thera-peutic employment of the antiarthrosispreparation Zeel P. It was designed togain data on the application, effective-ness, and tolerance under conditionsof routine daily medical practice. Theperiod of the study covered fourmonths, from September to Decemberof 1992. A total of 190 orthopediststook part in this survey. These physi-cians treated 1845 patients with Zeel Pand documented the results on stan-dardized questionnaires. Data wereregistered only for patients who weresuffering from osteo-arthrosis of theknee. Application of Zeel P injectionsolution was by intraarticular injection.Otherwise, there were no further re-strictive criteria for including or ex-cluding patients: i.e., conduct and ex-tent of treatment were left absolutelyto the discretion of the attending phy-sicians (e.g., the number of tijectionsand any additional therapy condi-tions). The drug-monitoring study wasconducted on a prospective basis.

The attending physicians enteredthe following data on the question-naire:- Personal data on the patients: sex,age, weight, and height

- Cause and duration of the osteo-ar-throsis

- Previous therapy received by the pa-tients (medicamentous or non-medi-camentous)o

Since the drug monitoring was de-

signed to be conducted during theprogress of therapy, the physicianswere asked to rate the stiffness of thejoint as well as pain upon initial kneemovement, pain following exercise,and continuous pain during everytreatment session: in each case, beforethe injection. The pain rating scale wasas follows: no pain, slight pain, mod-erate pain, and severe pain. The phy-sician also registered data on the fol-lowing during each therapy session:adjuvant medication, non-medicamen-tous adjuvant therapy, the amount ofZeel P applied per injection, the em-ployment of a local anesthetic, and theappearance of side effects. If side ef-fects had appeared, the physician de-scribed them in detail on a separatereport form. At completion of treat-ment, the therapist made a final over-all evaluation of the results of the en-tire therapy. The following choiceswere possible:

- Very good = complete relief fromsymptoms

- Good = definite improvement

- Satisfactory = slight improvement

- Unsuccessful = no change l- Worsening.

2.2 Processing of data andstatistical analysis

Although data were missing onvarious parameters in a few cases, itwas possible to include all 1845 ques-tionnaires in the analysis procedure.With the aid of a special statistics pro-gram, the data of each questionnairewere entered and subsequently ana-lyzed by statistical techniques in orderto reveal their interrelationships andtheir inner structure (by methods ofinferential statistics for determinationof significance). This drug-monitoringstudy investigated the effects of Zeel Ptreatment on the degree of severity ofthe four main clinical symptoms ofosteo-arthrosis of the knee (see above).Statistical investigation was made forsamples taken from the following:

1. The entire population of 1845 pa-tients

Biological Therapy / Vol. XIII/ No. 11995

2. The subpopulation of 380 patientstreated only with Zeel P (mono-therapy).

Both the chronological axis (i.e., thenumber of therapy sessions), as wellas the degree of severity of the symp-toms (i.e., their intensity) were mea-sured on an ordinal scale. Conse-quently, coefficients of contingency(the nominal technique) and of rankcorrelation were used for statisticalanalysis [Landis et al., 1978; Manteland Haenszel, 1959; Mantel, 1963]. Aprocedure for nominal data (chi-squaretest) was used to investigate the con-tingency arising from therapeutic ses-sions and intensity of the symptoms.The rank correlation, i.e., the results ofinvestigating whether a linear correla-tion existed between frequency oftherapy and severity of the symptoms,was examined by means of a chi-square-distributed derivative from thePearson correlation (the Mantel-Haenszel chi-square test), and by re-gression analysis with the data gainedduring the course of treatment. Theaid provided by this analysis includesa correlation coefficient r, which rep-resents the relationship between twovariables: in this study, the severity ofpain or knee stiffness, and the fre-quency of therapy. The values of r canlie between -1 and +1. The closer thecorrelation coefficient lies to -1 (nega-tive correlation) or to +1 (positive cor-relation), the more reliable the linearrelationship between the two variables(when r = O, there is no correlation).

The purpose of employing statisti-cal analysis here for the data collectedduring the course of treatment was toanswer the following questions:

1. Is the effectiveness of the medica-tion statistically evident, and is there adifference in effectiveness betweentherapy for the entire population andfor the monotherapy subpopulation?

2. How does the intensity of theexamined symptoms change duringthe course of treatment: i.e., is there acorrelation between frequency oftherapy and severity of the symptoms?

3. Is Zeel P also effective in applica-tion for slight and moderate symp-toms?

13

>

4. How many injections are requiredto bring about statistical improvementin the symptoms?

3. Results of the survey3.1 Characterization of the patients

Personal data on the patients re-veal that there were considerably morewomen (61 .2?4) who participated inthe drug-monitoring study than men(38.4Yo). For 0.4/0, the patients sex wasnot indicated. As expected, a largeshare of the patients was over 50 yearsof age: 81?4 (see Table 1).

The most frequent cause of osteo-arthrosis of the knee was indicated asattrition: e.g., as resulting from over-weight, strenuous work, or sports. Thefollowing causes followed, but withmuch lower frequency (see Table 2):

- Endogenous disorders, e.g., fromaging and metabolic disturbances

- Acquired joint deformations, forexample, as a result of inflammatoryjoint diseases

- Congenital dysplastic conditions,e.g., from flat socket formation orsubluxation

- Medial meniscus damage

- Meniscectomy- Tibial plateau fracture

- Fracture of the patella

- Posttraumatic conditions

- Idiopathic causes.

Unilateral osteo-arthrosis of theknee was determined for 830 of thepatients (45.0%) and bilateral, for 1,011(54.870). For 4 patients there was nodata. For the bilateral cases, the physi-cians documented only the more se-verely afflicted knee. Data on dura-tion of the disorder reveal that approx.25?4 of the patients suffered from thesymptoms for less than one year;approx. 4570, between 1 and 5 years;and about 30/0, for longer than fiveyears. Around 4070 reported that theywere physically active at work; approx.60% were not in this situation. Onemust consider here, however, thataround 5470 of the patients were. olderthan 60, and that a large proportion of

14

them were retired. No data were avail-able on physical activity conducted inyears prior to this study.

Of the 1845 patients covered by thisdrug-monitoring study, 1253 (67.90%)had undergone therapy for osteo-ar-throsis of the knee within the sixmonths immediately prior to partici-pation in the study. Most frequently,these patients had received non-ste-roidal antiinflammatory drugs, and alesser number, the following: corticos-teroids, chondroprotective medication,the antiarthrosis preparation Zeel P(ampules), Zeel tablets, and Zeel T oint-ment. About 1370 of the patients hadundergone non-medicamentous ther-apy. The most frequent forms herewere electrotherapy, kinesitherapy,some form of radiation, and cryo-therapy (see Table 3).

3.2 Formulation of Zeel 1? injectionsolution:

one ampule of Zeel P injection so-lution contains the following constitu-ents:

Cartilago suis (extract, 1:10) 22.00 ng

Funiculus umbilicals suis (extract,1:10) 22.00 ng

Embryo suis (extract, 1:1 O) 22.00 ng

Placenta suis (without hormones)(extract, 1:10) 22.00 ng

Rhus toxicodendron (mother tinc-ture) 0.22mg

Amica (mother tincture) 0.22mg

Dulcamara (mother tincture) 22.00 pg

Symphytum (mother tincture) 22.0 ~g

Sanguinaria (mother tincture) 33.00 ~g

Sulfur (mother tincture) 39.60 pg

Nadid 0.22 ng

Coenzyme A 0.22 ng

(~)-a-lipoic acid 0.22 ng

Sodium oxalaceticum 0.22 ng

3.3 Adjuvant medication

Within the context of this drugmonitoring, the participating physi-cians were fundamentally allowed andeven encouraged to employ adjuvantmedication on the basis solely of theirown discretion. Of the 1845 patientshere, 479 (26.0%) received concomi-tant medication, and 1352 (73.3/0) re-ceived medicamentous rnonotherapy.For 14 patients, there were no data(see Table 4). The application of localanesthetic for alleviation of pain dur-ing intraarticular injection was not con-sidered to be employment of adjuvant

Characteristic z

Sex female male no data given11z9 (61.2) 709 (38.4) 7 (0.4)

Age up to 50 years 51-70 years >70 years no data given349 (18.9) 1030 (55.8) 465 (25.2J 1 (0.1)

VUeight UP to 60 kg 61-80 kg >80 kg no data given276 (14.9) 1141 (61.9) 421 (22.8) 7 (0.4)

Height up to 160 cm 161-180 cm > 180 cm no data given420 C22.8) 1317 (71.3) 101 (5.5) 7 ( 0 . 4 )

Table 1: Characterization of the patients (percent data in parentheses).

Attrition 1277 (58.7)Endogenous disorders 497 (22.8)Congenital dysplast. cond. 110 ( 5.1)Acquired joint deformation 218 (10.0)Misc. causes 74 ( 4.4)

T~ble 2: The most frequent causes of osteo-m?hrosis of the knee (percent data in pmaentheses;fol some patients them ZLMS more thm one cause).

Biological Therapy / Vol. XIII / No. 11995

NSAID 752 (37.0)Cmticosteroids 300 (14.7)Chondroprotective medication 270 (13.3)Zeel P injection solution 221 (10.9)Zeel T ointment 41 ( 2.0)Zeel tablets 29 ( 1.4)Knee surgery 153 ( 7.5)Non-medic, treatment 269 (13.2)

Table 3: Number of patients who had undergone therap~i for osteo-twthrosis of the knee-. ,ti .

within the six months immediately prior to participation in the study (percent data inparentheses; some patients received more than one type of therapy; NSAID = non-steroidalmztiinjlammatoy drugs).

medication. Of the 479 patients withadjuvant medication, around half re-ceived non-steroidal antiinflammatorydrugs (NSAID), and approx. 3070 tookZeel in tablet or ointment forms (seeTable 5). In general, the physicians ad-ministered the accompanying medi-cation throughout the entire course oftreatment. Local anesthetic (e.g.,Lidocain or Mepivaca@ was concomi-tantly administered to 1339 patients(72.6!%). The therapists employed ZeelP injection solution alone, as mono-therapy, in 20.6?4 of the cases (for 380patients).*

3.4 Non-medicamentous adjuvanttreatment

Non-medicamentous accompany-ing therapy was provided to911 of thepatients (49.4?4); 930 received none(50.40/0). No data was recorded for fourpatients. Electrotherapy was the mostfrequent non-medicamentous form,followed by cryotherapy and kine-sitherapy. As a rule here as well, thetherapists employed non-medicamen-tous accompanying therapy through-out the entire treatment phase (seeTable 6).

Treatment groups Number of patients

Zeel P + adjuvant medication+ local anesthetic 367 (19.9)

Z e e l P + adjuvant m e d i c a t i o n 112 (6.1)Zeel P + local anesthetic 972 (52.7)Z e e l P (medicamentous monotherapy) ~ 380 (20.6)No data recorded 14 (0.7)

Table 4: Numerical compilation of the various treatment groups (percent data in parenthe-ses).

Table 5: Number of patients who received medicamentous adjuvant medication (percent datain parentheses; some patients received more than one type of therapy; NSAID = non-steroidal antiinflammatory drugs).

3.5 Data on number of therapeuticmeasures

Within the context of this injectionseries, the participating therapists car-ried out a total of 17,159 outpatienttherapeutic measures. Calculations onthe basis of this data reveal an averagetreatment frequency of 9.3 therapeuticmeasures per patient (for 81/0 of allpatients). On the basis of two treat-ment measures per week, this amountsto an average duration of treatment of4-5 weeks per patient. All patientstaken together received a total of 16,974tijections (for an average of 9.2 injec-tions per patient), with overall con-sumption of 19,742 Zeel P ampules.This amounts to an average of 10.7ampules per patient. The physicianstherefore generally injected one am-pule per application; only in excep-tional cases did they inject two am-pules at one time.

3.6 Monitoring during therapyThe physicians were asked to rate

knee stiffness, as well as pain uponinitial knee movement, pain followingexercise, and continuous pain, duringevery treatment session: in each case,before the injection. In this manner,effectiveness of treatment was continu-ously monitored. The ratings beforethe first injection were used as basisvalues for the individual parameters.Figs. 1 -4 graphically represent theresults of the regression analysis per-formed on all data collected duringthe course of therapy. One of the pri-mary clinical symptoms of osteo-ar-throsis of the knee is stiffness, com-bined with a feeling of tension, afterrelatively long periods of inactivity. Atthe beginning of treatment, 12.0?% ofthe patients (basis value) complainedof severe knee stiffhess. At the end oftreatment, this figure was only 1.6?4 (adecrease of 8770). Before the initial in-jection, 25% of the patients experiencedno knee stiffness. After conclusion oftherapy, this number had more thandoubled: to 54?4. The plot of the fig-ures in Fig. 1 emphasizes this result.Knee stiffness decreased significantlyin a linear manner along with theprogress of treatment.

Biological Therapy / Vol. XIII/ No. 11995 15

rElectrotherapy 605 (44*3)Cryotherapy 270 (1$X8)

Kinesitherapy 269 (19.7)

Balneotherapy 91 (6.7)

Massage 21 (1.5)

Misc. Therapy 109 (8.OJl

Table 6: Number of patients who received non-rnedicamentous adjuuant therapy (somepatients received more than one form; percentjlgures in parentheses).

Similar results were obtained forpain with onset of movement, whichusually occurs upon initial exercise af-ter a relatively long period of inactiv-ity. At the beginning of monitoring,approx. 24/0 of the patients indicatedsevere pain upon onset of movement.After conclusion of treatment, this wasonly 1.lO/O, for a decrease of 95Y0. Inconjunction with this development, thenumber of patients without suchmovement-onset pain increased from6% to around 42Y0. In other words,there is also a linear relationship be-tween the severity of movement-on-set pain and the frequency of applica-tion (see Fig. 2).

pain following exercise (i.e., a dullpain after relatively long applicationof loads) also declined significantly ina linear manner. At the beginning oftreatment, 33!% of the patients reportedexperiencing severe pain after exer-

cise. By the end of therapy, this pro-portion had decreased by 92%. Dur-ing the same period of time, the num-ber of patients who experienced nopain after exercise increased from 0.80/0to 28.7/0 (see Fig. 3).

The analysis of the ratings for con-tinuous pain provides a result whichis fundamentally the same as for thetwo other types of pain. The numberof patients with severe continuous paindecreased by 93% during the course oftreatment, and the number of patientswithout continuous pain tripled, to alevel of 67.1/0. These parameters like-wise demonstrate a linear relationshipbetween severity of pain and frequencyof treatment (see Fig. 4).

3.7 Monotherapy with Zeel Pinjection solution

As stated earlier, 26/0 of the patientsreceived adjuvant therapy. Of these,

Fig. 1: Reduction in knee stlj%ess during the course of treatment (B.v. = basis value; r =correlation coefficient).

the primary form of therapy forapprox. 5070 of the adjuvant-therapycases consisted of administration ofnon-steroidal antiinflammatory drugs(NSAID). If the analvsis also includeslocal anesthetics, ab&t 79% of all pa-tients received some medication in ad-dition to Zeel P injection solution.Monotherapy, i.e., treatment exclu-sively with Zeel 1? injection solution,was administered to 20.6/0 of the pa-tients (380) who took part in the post-marketing drug survey. Additional,separate evaluation consequently tookplace for this group. The average treat-ment frequency and the total numberof ampules per patient were not strik-ingly different from the correspond-ing figures for the overall study popu-lation. Figs. 1 -4 also represent theevaluation of data on changes observedin knee stiffness and in the varioustypes of knee pain among the Zeel Pmonotherapy subpopulation. In thisgroup as well, the number of patientswho experienced severe knee stiffnessdecreased significantly during thecourse of treatment (a decrease of90.570). Simultaneously, the number ofpatients without knee stiffness in-creased by 650/0 (see Fig. 1). The fre-quency of severe pain with onset ofmovement also decreased during treat-ment in a linear manner. Whereasapprox. 170/0 indicated severe move-ment-onset pain at the beginning oftherapy, the figure was only 0.5?4 atthe end of treatment: a reduction of97?4. In parallel with this development,the proportion of patients withoutmovement-onset pain quintupled (seeFig. 2). In the monotherapy group, se- ~vere pain following exercise decreasedby 92/0. During the same period oftime, the number of patients withoutexercise-induced pain increasedtwenty-fold (see Fig. 3). Intraarticularinjection of Zeel P likewise significantlyreduced severe continuous pain: by90/0. The number of persons free fromsevere continuous pain had doubledby completion of therapy (see Fig. 4).

Fig. 5 once again summarizes thefrequency of freedom from the indi-vidual clinical symptoms recorded atthe beginning of treatment (basis val-

16 Biological Therapy / Vol. XIII / No. 11995

Knee pain with onset of movement (intensity) I2.0

1.6 r = 0.9901

1.2

.. .4>

ail patients+ .Zeei ~ mmotherapy patimts,..+

Fig. 2: Rd.iztion, dzirivg &e coume of tn?atment, in kn~puin upon onset c++ movemen ? @.V. = his due; y =@??wwon @@kkr@.

Pain RMowing exercise (intensity)2.2

1.8 r = 0.09895

1.0-

0 . 6 I I I I I I I I1 2 345678910

. (B.v.)Number of therapeutic measures applied

., ,.

~ all pdtients+ Zeel 1? monotherapy patients

Fig. 3: Reductbn, dwing the cotme of hmtment, in pain foilomng exercise (B.v. = basis due; r= cwrekationcof#kientA . . =% . .

Continuous pain (intensity) i;4 ? .< >;.,,,. ,. ~,. ,,.< .. b . . . .

\. . .,... .*-~ . ,..::. , .. ; ,,..?$.:. . /.,: :, ~

A,> .. . ..: :.: $ \ ..,. ... ; :.4.+ .. . , . . i.,$ ,. . ., . . . . . . $, . . ~:.~ : .- c /1 .

Knee stiffness 54.2

Pain withonset of movement

Pain following ~exercise

Continuous pain 67.1f

o Jo 80in percent

n Basis valueZl After 10 treatment sessions

patients. Based on the entire numberof injections administered (16,974), thisamounts to a side-effects quota of0.45/0. In all cases, the side effects con-sisted of local inflammation. The mostfrequent specific form of side effectswas effusion into a joint cavity: 44 cases(some patients suffered from morethan one type of side effect). In termsof the five cardinal symptoms of in-flammation according to classicalmedicine, the therapists diagnoseddolor (physical pain) in 41 cases, calor(excessive bodily heat) in 22 cases, andrubor (redness of the skin) in 9 cases.Joint swelling without effusion ap-peared only with one patient. All thedocumented side effects were revers-ible: i.e., permanent damage occurredin no cases. Treatment of the side ef-

0 fects was unnecessary in 24 cases. InFig. 5: Proportion of the patients (in percent) who werefiee of pain at the beginning of th~studv (basis values), and after ten treatment sessions with Zeel P iniection solution. 15 cases, conservative treatment suf-

&- ..

ficed (e.g., ice packs). The physicians

treatment was completely unsuccess-ful for only 6.2/0. The therapists di-agnosed worsening for merely 0.6%of the patients. On the whole, find-ings revealed that 93.10/0 of all pa-tients achieved a positive treatmentresult. The therapy results of themonotherapy group are comparableto those of the entire study popula-tion. Here as well, approximately halfof the patients enjoyed good results.The number of monotherapy patients

with very good outcome of therapy waseven five percent points greater thanthat of the overall population. On thewhole, 91.970 of the monotherapy pa-tients achieved positive results oftherapy (see Fig. 6).

3.9 Tolerance

If side effects were diagnosed dur-ing the treatment sessions, the physi-cians described them on a special re-port form. Side effects appeared for 69

applied medication for side effects with29 patients: e.g., Diclofenacr, Ibuprofen,or Dexamethason. Puncture of the jointeffusion was conducted for 36 patients.Of the 69 patients with side effects, 35of them prematurely terminated theirtreatment of osteo-arthrosis of the kneewith Zeel P. Of these 35, 25 indicatedthe side effects as the reason for theirstopping the therapy with Zeel P. Twopatients stopped because of lack oftherapeutic effectiveness, one patienthad to enter the hospital for inpatienttreatment, and one p&ent had t; travelabroad for a lengthy period of time.

With respect to the frequency of sideeffects, there was no noteworthy dif-ference between the monotherapygroup and the entire study popula-tion: 0.45$% for the overall group, and0.46?40 for the monotherapy patients(the percent indication is based on thetotal number of injections adminis-tered). Six persons in the monotherapyprematurely terminated their treat-ment: in all cases, local inflammationwas the cause (see above).

4. Interpretation of Results

Degenerative disorders of large andsmall joints are among the most com-monly encountered chronic disorders

Fig. 6: Final rating by the physician. in everyday medical practice. The ge-

18 Biological Therapy / Vol. XIII / No. 11995

neric term arthsis is primarily usedto cover all non-inflammatory, degen-erative structural damage suffered inthe area of the articular cartilage, thebordering bone, and the articular cap-sule. Osteo-arthrosis of the knee, oneof the most common form of arthrosis,is caused by metabolic anomalies,neuropathic and posttraumatic alter-ations, blood-circulation disorders inarticular cartilage, and disorders in theequilibrium between the loads appliedto articular cartilage and its ability tosustain such burdens.

Therapy with Zeel P injection solu-tion is based on the concept of restor-ing normal physiological conditions ina diseased joint. This is achieved bypromoting anabolic processes with si-multaneous retardation of catabolicfunctions. The objective of the post-marketing drug survey conducted herewas the obtaining of new knowledgeon the application, effectiveness, andtolerance of Zeel P injection solutionunder the conditions of daily medicalpractice.

A total of 1845 persons with osteo-arthrosis of the knee took part in thisstudy. The distribution of ages (81% ofthese patients were old er than 50) andof sex (61.2!% were female) within thetotal studv population corroboratesearlier-ga~~ed evidence: i.e., that it isespecially older persons, primarilywomen, who suffer from arthritic com-plaints. The nature of this disorder it-self explains this phenomenon. An es-sential factor in the development ofosteo-arthrosis of the knee is age-re-lated cartilage degeneration, since allbradytrophic tissues, not least becauseof their lack of vascular supply net-works, are subject to regressive agingprocesses, accompanied bv progressiveloss of elasticity. Women are particu-larly affected by these processes, be-cause the effects of age-related hor-monal alterations also include meta-bolic disorders. The causative factorsstated for osteo-arthrosis of the kneeare also typical for metabolic irregu-larities. For approximately 820/0 of thepatients in this study, the physiciansindicated attrition damages or endog-enous disorders as causes. As a result,

it maybe determined that the personstaking part in this drug-monitoringstudy constitute a representative cross-section with respect to age and sexdistribution, as well as etiology.

Documentation performed parallelto therapy revealed the following av-erage data: that the patients typicallyreceived two injections per week, eachconsisting of one ampule, over a pe-riod of 4 to 5 weeks. These results onapplication frequency and durationaccord with experience gained earlierwith Zeel P injection solution. The re-sults obtained on effectiveness also cor-roborate experience gained over manyyears with Zeel P injection solution.For characterization of effectiveness,the participating physicians rated theseverity of the four most importantclinical symptoms of osteo-arthrosis ofthe knee: pain upon initial knee move-ment, pain following exercise, continu-ous pain, and stiffness in the joint.Study results revealed that the num-ber of persons with severe symptomsdecreased on the average bv 90%, andthat the number of patien;s withoutcomplaints simultaneously and signifi-cantly increased during the course oftherapy. in other words, there is a di-rect (linear) relationship between theabatement in svmptoms and the fre-quency of medication application.There was no statistical difference inthis respect between patients with acl-juvant medication and those who weretreated exclusively with Zeel P injec-tion solution (monotherapy). This sig-nifies that therapeutic superiority ofcombination medicamentous therapyis not apparent.

The data obtained on the toieranceof Zeel P injection solution corrobo-rate the experience earlier gained thatthis combination preparation is welltolerated by patients. The side effectsrecorded were, without exception,cases of local inflammation which allabated. In no case did a patient sufferfrom systemic side effects such as thosewhich commonly occur in this contextin the gastrointestinal system. In treat-ment of osteo-arthrosis of the knee withantirheumatics, it is precisely the gas-trointestinal system which is frequently

(in approx. 150/0 of patients) afflictedwith side effects. These include the de-velopment of petechiae, erosion, aswell as ulceration of the duodenumand the stomach: anomalies which of-ten require supplementary medica-mentous treatment.

According to Karch and Lasagna(1975), adverse side effects are involvedonce it is determined that the thera-peutic agent has elicited an undesiredharmful effect when administered in adose which is customary for thetherap~: i.e., if it is possible to estab-lish a ~ausal relationship between thetherapeutic agent and the adverse sideeffect. An adverse effect initiated bythe failure of a specific therapy, or bythe mode of application per se, is notconsidered an undesired side effect. Ifone investigates in detail the occur-rence of the side effects observed inthis Zeel P post-marketing dru~ sur-vey, it may be seen that of the 69 pa-tients suffering from a side effect 50were administered a local anestheticin conjunction with Zeel P. The prob-ability of side effects therefore in-creased in this study upon applicatj onof local anesthetic. For these 50 pa-tients with simultaneous administrat-ion of a local anesthetic, therefore, acausal connection between the side ef-fects suffered and administration ofZeel P injection solution cannot be es-tablished with conclusive certainty.The remaining 19 patients received noadditional local injections in additionto Zeel P. If these circumstances areconsidered, then the side-effects rate,with reference to total injections, fallsto O. 110/O. Due to the individual needsof the patient, however, it is frequentlyessential to employ local anesthetic inconjunction with intraarticular injec-tions. The question therefore arises asto what extent the side effect resultsfrom the mode of application, andwhether the injected medication itselfis actually not responsible at all. Ac-cording to studies conducted byBernau et al. (1985), it is practicallyimpossible, even if a physician usesthe thinnest injection cannulae, to avoidinjecting into joint cavities the plugs ofskin punched out when a hypodermic

Biological Therapy / Vol. XIII/ No. 11995 19

needle pierces the skin. It is possiblethat these skin cells (e.g., keratinocytes)elicited the inflammation reactions ob-served in this study, as a result ofproduction of interleukin 1 (IL 1)[Dowd et al., 1988]. The local inflam-mation symptoms can, however, alsospontaneously develop occasionallybecause of the arthrosis-related condi-tions of irritation / inflammation ex-isting in the knee joint. In such cases,they would not necessarily representa direct consequence of the injectionof medication. Upon consideration ofall these potential factors capable ofeliciting side effects, a causal relation-ship between Zeel 1? injections and theobserved side effects is questionable.This statement is further supportedby the following fact: 35 of the 69 pa-tients with side effects prematurely ter-minated their treatment for gonar-throsis. The remaining 34 patients, onthe other hand, continued their treat-ment with Zeel P and despite the oc-currence of side effects achieved posi-tive therapeutic results. The continuedapplication of Zeel P, i.e., after the ini-tial observance of side effects, inducedrepeated side effects in only eight cases.Here, it was not certain whether newside effects were involved, or whetherthe old side effects had not yet fullysubsided. If one prepares a risk-ben-efit analysis on the basis of consider-ation of all these factors, one may con-clude that the benefits of Zeel P treat-ment are definitely greater for the pa-tient than is the risk involved.

The results from this post-market-ing drug survey corroborate the pre-vious experience which had beengained with this combination prepa-ration, and which has been describedin medical literature. Hieber [1971] and

Kasanmascheff [1971] treated 107 and101 patients, respectively, with Zeel Pinjection solution for gonarthrosis.They administered a total of 828 and631 intraarticular injections, respec-tively, and achieved a therapeutic suc-cess rate of 93.670 and 88.070, respec-tively. Schlufter [1975] treated 90 pa-tients for severe osteo-arthrosis of theknee with 553 intraarticular injectionsof Zeel P injection solution, andachieved a success quota of 85.5/0. In1991 Potrafki and Steinbach reportedon the treatment of 55 patients withZeel P injection solution for rheumaticdisorders (arthrosis and vertebral syn-dromes of the cervical spine, thoracicvertebral column, and lumbar spine)which resulted in significant relief ofpain and enhancement of articularfunctioning for approx. 82% of the pa-tients. These authors reported no sideeffects of local or systemic nature.

Finally, it may therefore be con-cluded that the therapeutic applicationof Zeel P injection solution is indicatedfor the treatment of osteo-arthrosis ofthe knee. Of the patients participatingin the post-marketing drug survey,93.1/0 positively assessed the overalltherapy. This post-marketing studytherefore verifies the effectiveness ofZeel P injection solution, the effectualformulation of this combination ho-meopathic preparation, as well as itsgood toleration by the patients.

References

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4. Hieber F. Zur intraarktikularen Be-handlung von Arthrosen und posttrauma-tischen Arthralgien mit Zeel. Fortschr. Med. 89;18:778-780.

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6. Krebs H. Confrontation Rheuma. Lecturesfrom Phonix Laboratorum GmbH, Bondorf.

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9. Mantel N. Chi-sqare tests with one de-gree of freedom: Extensions of the Mantel-Haenszel procedure. Journal of the AmericalStatistical Association 1963; 58:690-700.

10. Potrafki B, Steinbach A. Die anti-homotoxische Therapie bei Erkrankungeninnerhalb des rheumatischen Formenkreises.Biologische Medizin 1991; 4:664-665.

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intraartikularen Injektionen. Therapiewoche1975; 25,35:3-10.

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Address of the authors:

Michael Weiser, M.D.Horst Metelmannc/o Biologische Heilmittel Heel GmbHDr. Reckeweg-Strasse 2-476532 Baden-BadenGermany

20 Biological Therapy / Vol. XIII / No. 11995