Indications for the use as medicaments of multipotent parapox immunity inducers from attenuated, non-immunogenic pox viruses or parapox viruses

The use is disclosed of multipotent parapox immunity inducers from attenuated, non-immunogenic pox or parapox viruses (pox inducers) to produce medicaments with new indication ranges in human medicine.

BACKGROUND OF THE INVENTION 
The present invention relates to the use of multipotent parapox immunity 
inducers (pox inducers) prepared from pox and parapox viruses and the 
components thereof, individually or in combination, in the preparation of 
medicaments for novel fields of indications and therapies for which up to 
now no effective and most importantly no harmless medicaments are 
available. 
SUMMARY OF THE INVENTION 
Preferably, preparations derived from attenuated, non-reproductive and 
non-immunogenic pox and parapox viruses (also referred to as "pox 
inducers") intervene in the unspecific or paraspecific, respectively, 
phylogenetically older part of the complex immune system (natural immune 
system, innate immune system, primitive immune system) in a regulative, 
reparative and restorative manner. In the following, these pox inducers 
are therefore also referred to as "bioregulants". On a cellular level, the 
pox inducers activate macrophages, modulate NK cells and other 
lymphoreticular cells, while on a humoral level they control the formation 
of various cytokins, such as interleukin 1 .alpha., interleukins 2, 6, and 
12, tumor necrosis factor, CSA, or of interferons (cytokin release). An 
introduction into the treatment of animals with pox inducers and a review 
of the respective experimental results is presented in B. Mayr and A. 
Mayr: "Zum derzeitigen Stand der praklinischen Forschung uber die 
Wirksamkeit und Unschadlichkeit von Paramunitatsinducern aus Pockenviren. 
Eine Literaturstudie", Tierarztl. Praxis, vol. 23 (1995) 542-552. This 
novel prophylactic and therapeutical concept has been well-tried in 
veterinary medicine. 
Important and novel in the context of the present invention is the 
surprising finding that the cytokins released by pox inducers promote the 
formation of T helper cells subtype 1 (Th1) thereby--as known from the 
literature--blocking the formation of subtype 2 (Th2). In fact, Th2 cells 
control the humoral immune response which via mast cells for the 
production of IgE is capable of inducing immediate type allergic reactions 
(antibody-dependent allergy). Thus, according to the invention Th1 cells 
as the antagonists of Th2 cells may prevent immediate allergies or 
alleviate already existing immediate-type allergies, respectively. Th1 
cells act together with cellular pathogen-unspecific as well as 
pathogen-specific cells of the immune system and are associated (interact) 
with the cytokins interleukin 1 and 2, interferons, CSF and TNF, i.e. the 
cytokins released by the treatment with pox inducers. Therefore, there is 
no risk of inducing IgE-dependent allergies. 
As regards their effectivity and harmlessness, pox inducers have been 
well-tried since in human as well as in veterinary medicine. The processes 
for their preparation and their use as medicaments in the prophylaxis and 
therapy of certain diseases have been demonstrated in DE-C-44 05 841. 
The preparation of pox inducers is performed according to the processes 
described in DE-C-44 05 841. The starting viruses necessary for the 
production of pox inducers are generally obtained by amplifying the 
attenuated pox and parapox virus strains in cell cultures, preferably in 
the VERO cell line or in primary or secondary chicken embryonic fibroblast 
cell cultures. Only virus harvests having a titer of infectiousness of 
&gt;10.sup.7,0 KID.sub.50 /ml are used. The virus harvests of attenuated pox 
strains are inactivated by physico-chemical techniques, e.g. by at least 
0.05% of .beta.-propiolactone, based on the pox strain used. Following a 
purification by centrifugation at 4,000 g for 30 minutes (or other 
physico-chemical methods) the pox inducer is added with a stabilizer, such 
as a carbohydrate, a multivalent sugar, a protein, preferably gelatin 
(Polygeline (TM)) in an amount of 2.5%, based on the pox strain used. The 
resulting preparation is divided into portions, lyophilized, and stored at 
+4.degree. C. The preparation of the ready-for-use medicament is carried 
out by dissolving the lyophilisate in sterile aqua dest. as described in 
DE-C-44 05 841. A single dose corresponds to 1 ml of dissolved 
lyophilisate and should contain at least 640, preferably at least 1280 VSV 
effective units. 
As described in DE-C-44 05 841, complete virus particles but also 
structural elements of individual virus strains may be used in the 
preparation of pox inducers, e.g. fusion proteins, adsorption proteins or 
the 39 KD protein of parapox viruses, as well as so-called "empty capsids" 
of pox viruses. In these cases an inactivation step is no longer 
necessary. 
A detailed description of the individual preparative steps and 
possibilities of pox inducers from combinations of several pox or parapox 
virus strains, respectively, may be found in DE-C-44 05 841 which is 
explicitly incorporated herein by reference. 
Regarding the use as a medicament we were not only able to confirm the 
indications for pox inducers from combinations of pox viruses according to 
the invention listed in the present patent document but, surprisingly, 
with respect to prophylaxis and therapy have discovered completely novel 
possibilities of use for the pox inducers for which up to now medicaments 
for parenteral or oral administration have not been available which are 
effective and at the same time probably harmless also in the case of 
long-term application or overdosage. 
Accordingly, in extension of the teaching of DE-C-44 05 841 the present 
invention relates to novel indications for use of the pox inducers on the 
basis of pox and parapox viruses in the prophylaxis and therapy of 
diseases in humans. These novel indications are based on the surprising 
finding that these pox inducers are capable of regulating a disturbed 
immune system into the optimal physiological range not only with respect 
to an increase or a stimulation, respectively, of reduced or suppressed 
activitities but also with respect to a decrease of pathologically 
elevated immune parameters. To understand the regulatory effect of pox 
inducers in the sense of a bioregulation occuring in an association 
between the immune system, the hormonal system and the neural system one 
has to realize that the individual humoral as well as cellular activitites 
of the immune system affect and control each other in a stimulatory as 
well as a suppressing manner. i.e., if cellular as well as humoral 
(soluble) components of the complex immune system are induced by means of 
pox inducers a self-regulating system develops in the organism. For 
example, this may occur by an increase or decrease, respectively, of the 
number or activity of specific effector cells (e.g. macrophages, 
leucocytes, T cells, NK cells) or an increase or decrease in the 
production of cellular or humoral communication molecules (e.g. IL 1 or 2, 
interferons etc.). In these instances every organism will show a different 
individual reaction depending on the functional state of its defense 
system at the start of the therapy with pox inducers. Thus, the term 
"bioregulation" by pox inducers as used herein is meant in a much broader 
sense as is generally encompassed in the understanding of a so-called 
"immunotherapy". Thus, for example in a patient after a treatment with pox 
inducers the number of leucocytes may increase and, conversely, the number 
of NK cells may maintain their level of activity or may be reduced. 
Therefore, to balance dysregulations of the immune system it is not 
necessary for all of the immunological parameters to be stimulated or 
suppressed at the same time because only existing deficiencies or 
excessive values will be equalized. For this reason, the individualization 
into the normal physiological range by a treatment with pox inducers is a 
completely novel finding. Since at the same time an intervention of pox 
inducers in the individual defense system will also have a regulatory 
effect on the neural and humoral systems, pox inducers should not be 
defined as immunoregulants but instead it is suggested to consider them as 
bioregulants. Up to now a bioregulant of the type described has not been 
available in medicine which is harmless also in the case of severe 
overdosage, does not affect the "normal physiological values" of the 
immune system, and in the case of a dysfunction acts in a regulatory 
manner in the sense of a physiological normalization, which means 
stabilized or restored, respectively, in its overall functionality. Thus, 
pox inducers are excellently useful in prophylactic as well as 
metaphylactic applications to patients suffering from a dysregulated 
immune system, e.g. in the case of immune deficiencies of different 
genesis such as after an immunosuppressive therapy, immunosuppressive 
basic conditions or by exogenous influences such as stress situations, 
extraordinary burdens, long travels, acute infection events in the 
surroundings. For a prophylactic parapox immunization usually 2 to 3 
injections of a pox inducer preparation given on successive days 
immediately prior to an expected strain situation will be sufficient. 
Metaphylactic or therapeutic administrations of pox inducers should be 
carried out at least for 3 days or until the clinical symptoms clearly 
subside. Following severe disease conditions and mainly after getting over 
infectious diseases convalescence should be supported by 2 to 3 injections 
per week of a pox inducer preparation until complete recovery is achieved. 
Furthermore, the invention is based on the surprising finding that pox 
inducers individually or in combination are useful as adjuvant, 
accompanying therapeutics in the reduction or prevention, respectively, of 
unwanted damages associated with chemotherapy or radiotherapy in the 
fighting of tumors or prevention of metastases, respectively. According to 
present experiences in those cases the treatment using pox inducers is 
performed in different phases. At the beginning the patient receives 5 to 
10 times each a 1 ml injection (i.m.) of at least the 640 VSV effective 
units on successive days. In the following, 2 to 3 injections per week are 
administered for at least 3 weeks while later 1 injection per week will be 
administered. For tumor patients who are negative for all clinical and 
immunological tests the further treatment may be reduced to 2 injections 
per month. Cases which are not totally unambiguous should be given one 
injection per week for a prolonged period (weeks or months). 
A further surprising possibility of use of the pox inducers individually or 
in combination is their employment in prefinal tumor therapy, such as in 
the case of tumorous diseases which are inoperable and where a treatment 
is no longer possible, to alleviate unbearable pain and to improve the 
well-being and thus the life quality of the patients. In such cases the 
pox inducers are administered at least twice a week or otherwise daily 
depending on the subjective feeling of the patient. This treatment is 
compatible with the presently used analgetics such as morphine. It even 
results in a reduction up to a discontinuation of the previous application 
of analgetics. 
Furthermore, the invention is based on the observation that surprisingly a 
long-term therapy with pox inducers in HIV patients contributes to an 
improvement of the immunological state in part leading to a reduction of 
the HIV antigen content in the blood. Reports uniformly state an 
optimization of the well-being, an improvement in performance and a 
positive view towards getting over the disease. Opportunistic secondary 
infections are prevented or quickly brought to an end without 
postinfectious complications, such as herpes simplex, herpes zoster, 
pseudomonas infections, influenza infections. The mode of treatment equals 
that of the tumor patients. Also HIV-positive patients should be given pox 
inducers (if possible once a week) for their whole life-time in order to 
maintain an optimal defense of infections. If infections occur the 
intensive daily treatment with pox inducers is immediately commenced which 
will be only reduced if a clear clinical improvement is observed. 
Another use according to the invention is the long-term accompanying 
therapy of multiple sclerosis to alleviate the phases of the disease and 
to prolong the intervals between two phases. The treatment is effected as 
in the case of tumor patients. Also this treatment must be continued for 
the whole life-time. Up to now experiences in the treatment of children 
and elderly patients with pox inducers individually or in combination are 
available. 
Moreover, the invention relates to the use of pox inducers individually or 
in combination in operation prophylaxis to reduce or to prevent, 
respectively, hospital infections and to optimize wound healing. 
Preferably, the treatment is started 3 to 5 days prior to operation and is 
continued up to at least 3 days following the operation. An intramuscular 
administration is most favourable, but also an intranasal application of 
the undissolved lyophilisate (i.e. the powder) into the nasal cavity may 
be performed. 
Surprisingly, the treatment with pox inducers is also useful in 
substitution therapy (such as antibiotics) in the case of poor or absence 
of healing of wounds or skin sores if a conventional therapy fails. 
Typical examples for poorly healing wounds or skin sores are ulcus cruris, 
panaritium, and chronic open eczemas. In such cases besides parenteral 
application the local treatment across the concerned skin areas with 
appropriate preparations, e.g. powders, ointments, cremes, lotions, with 
the pH adjusted to about 7 to 8, has shown to be particularly useful. In 
such cases the patients receive an inducer injection daily until the wound 
has closed. A continuous local application using appropriate ointments, 
such as Bepanthen (TM), addionally promotes healing. 
The pox inducers on the basis of pox and parapox viruses used according to 
the invention for the novel indications are well-tolerated and harmless 
also in the case of overdosage and long-term treatment. Up to now a 
prophylactic or therapeutic, respectively, for parenteral application 
complying with these criteria is unknown. The harmlessness of a treatment 
is considered to be the most important criterion in medicine. To date a 
prophylactic or therapeutic, respectively, that exhibits sufficient 
effectivity to be useful in the fields of indications according to the 
invention mentioned is not yet available. 
The known so-called immunomodulators used at present, such as BCG, 
levamisole, C. parvum and Freund's adjuvant, on the one hand are not 
harmless and on the other hand are effective only in one direction, i.e. 
either stimulatory (stimulants, adjuvants etc.) or suppressive 
(immunosuppression). A medicament combining both properties while 
achieving optimal physiological parameters in the sense of the 
bioregulants defined herein is not available up to now. In addition, to 
date, for the other clinical areas of application or indications, 
respecitively, according to the invention, such as substituting tumor 
therapy, fighting of pain in the prefinal stage, treatment of AIDS in 
HIV-positive patients, long-term treatment of multiple sclerosis, support 
of wound healing, comparable harmless and effective medicaments are 
unknown.

EXAMPLES 
The application of the pox inducers used according to the invention for the 
indications described herein may be parenteral or local, e.g. intranasal, 
in the form of an aerosole spray, oral, rectal or vaginal. Preferably, the 
pox inducers are administered by the intramuscular mode. The manufacture 
of drug preparations is carried out in conventional manner. However, it is 
necessary to adjust the pH of the preparations to about 7 to 8. 
The following Examples are presented to further illustrate the invention. 
The pox inducers as described herein are combination preparations on the 
basis of pox or parapox viruses, respectively, which in the following are 
referred to as "Conpind" (TM applied). The content per dose is 1280 VSV 
effective units. One dose is dissolved in 1 ml of aqua dest. 
Example 1 
Since April, 1994, 17 patients in total were treated in an immunological 
doctor's surgery 6 times each by intramuscular administration of 1 ml of 
Conpind in an interval of 3 to 5 days. Prior to the start and after the 
end of the treatment the clinical and immunological data were obtained and 
reported. The individuals concerned were patients suffering from an 
increased proneness to infections of different genesis which had led to 
various severe clinical diseases such as recurrent erysipelas, recurrent 
herpes infections, colitis, sinusitis as well as allergies. The 
intramuscular injections were very well tolerated; no local or systemic 
side effects were observed. A clear improvement of the general condition 
even after a short treatment interval was observed in all of the 17 
patients. An increased appetite partly accompanied by weight gain as well 
as a positive effect on the mood were observed as positive side effects. 
All of the patients were followed up for at least 1 year. Within this 
period no new infections occurred in 10 of the patients while the 
proneness to infections was clearly reduced for the remaining 7 patients. 
In contrast to this very positive and uniform findings with respect to the 
clinical evaluation of the treatment with Conpind the behavior of the 
immunological parameters exhibited great individual differences. 
Pathologically increased values generally decreased in the course of the 
relatively short treatment interval of a maximum of 3 weeks while 
deficitary values increased. In contrast, immunological parameters which 
had been in a normal range prior to the start of the treatment remained 
unchanged. Therefore, they have not been listed separately in the 
following Table I. Table I exemplarily shows a list of typical 
immunological parameters of 3 patients. Studying the Table it will be 
recognized that in a single patient of the different values some have 
increased while others have decreased. Interestingly and surprisingly, 
even a 82-year-old female patient showed a positive response to the 
treatment. 
TABLE I 
__________________________________________________________________________ 
Bioregulatory effect of Conpind in 3 patients with immunological deficienc 
ies 
Effect of Conpind on immunological parameters 
Patient 
Indication 
Parameter 
Normal range 
Prior to CP 
After CP 
Evaluation 
__________________________________________________________________________ 
Pat. 2 (m.) 
Neurodermitis, 
Leucocytes 
4000-10000 
6700 4600 .dwnarw. 
25 years allergy, Lymphocytes 20-30% 38% 32% .dwnarw. 
alopecia T cells 60-80% 62% 71% .uparw. 
act. T cells 0-12% 3% 7% .uparw. 
B cells 7-23% 27% 20% .dwnarw. 
Pat. 6 (f.) Colitis ulcerosa Lymphocytes 20-30% 10% 18% .uparw. 
54 years T cells 60-85% 69% 73% 
.uparw. 
IL-2/CD4 cells 15-40% 12% 17% .uparw. 
Pat. 14 system. Leucocytes 4000-10000 4100 7000 .uparw. 
(m.) immuno- Lymphocytes 20-30% 35% 28% .dwnarw. 
38 years deficiency, Ts cells 19-48% 32% 42% .uparw. 
allergy IL-2/CD4 cells 15-40% 16% 21% .uparw. 
Pat. 12 (f.) Polyarthritis, Lymphocytes 20-30% 11% 15% .uparw. 
82 years reactive CD4/CD8 r. 0.8-2.8 0.9 1.4 .uparw. 
depression Ts cells 19-48% 41% 27% .dwnarw. 
__________________________________________________________________________ 
Example 2 
15 patients suffering from severe viral infections or viral infections 
where a treatment was no longer possible, respectively, were treated in a 
clinic with Conpind. The treatment was performed on a daily basis with one 
intramuscular Conpind dose until a clear improvement of the clinical 
symptoms was observed. Subsequently and until complete recovery, the 
patients received one Conpind dose per week. The 15 patients suffered from 
various herpes infections (h. simplex, h. genitalis, zoster), hepatitis B 
as well as recurrent viral infections of different genesis. As becomes 
clear from Table II also in this patient group individual immunological 
parameters in a single patient were shown to increase while others 
decreased. Generally the number of those patients was higher whose 
leucocyte and lymphocyte counts increased albeit only slightly. Also the 
CD4/CD8 ratio as well as Th cells increased significantly on average. In 
contrast no significant change was observed in the number of Ts cells. 
TABLE II 
__________________________________________________________________________ 
Bioregulatory effect of Conpind in 15 patients with viral infections 
Effect of Conpind on immunological parameters 
Patient 
Indication 
Parameter 
Normal range 
Prior to CP 
After CP 
Evaluation 
__________________________________________________________________________ 
Pat. 1 (m.) 
Recurrent viral 
Leucocytes 
4000-10000 
13300 14700 
.uparw. 
43 years infections Lymphocytes 0.8-2.8 11438 11466 -- 
CD4/CD8 r. 0.66 1.55 .uparw. 
Pat. 2 (m.) herpes zoster Leucocytes 4000-10000 6800 10000 .uparw. 
57 years Lymphocytes 0.8-2.8 1836 
4200 .uparw. 
CD4/CD8 r. 0.83 1.28 .uparw. 
Pat. 5 (m.) herpes genitalis Leucocytes 4000-10000 5800 5800 -- 
54 years Lymphocytes 0.8-2.8 2784 
2784 -- 
CD4/CD8 r. 1.63 1.53 .dwnarw. 
Pat. 8 (f.) herpes genitalis Leucocytes 4000-10000 7700 8100 .uparw. 
27 years Lymphocytes 0.8-2.8 2079 
2916 .uparw. 
CD4/CD8 r. 0.68 1.11 .uparw. 
Pat. 13 (f.) herpes genitalis Leucocytes 4000-10000 7700 10700 
.uparw. 
37 years Lymphocytes 0.8-2.8 2772 2782 -- 
CD4/CD8 r. 1.09 1.24 .uparw. 
Pat. 15 herpes zoster Leucoyytes 4000-10000 6900 5500 .dwnarw. 
Lymphocytes 0.8-2.8 2691 1485 
.dwnarw. 
CD4/CD8 r. 1.43 1.24 .dwnarw. 
__________________________________________________________________________ 
Example 3 
Fifteen patients suffering from different tumors were treated in an 
immunological doctor's surgery according to the same schedule as in 
Example 1 (6 doses of Conpind in an interval of 3 to 5 days). Four of the 
patients came into the surgery after successful operation and completed 
radiation treatment, 3 after resection of the tumor and 8 after a 
chemotherapy. The immunological state of the patients was examined prior 
to the start of treatment as well as following the last treatment. All of 
the patients were followed up for at least 1 year. The treatment was very 
well tolerated by all of the patients. No local or systemic side reactions 
were observed. In all of the patients the general condition was improved 
and, in addition, the treatment by Conpind had a positive effect on the 
appetite and mood of the patients. In some of the patients the tumors 
became smaller. No metastases occured in the follow-up period of 1 year. 
The Tables III to V summarize the effect of the treatment of the tumor 
patients with Conpind on immunological parameters with respect to 
individual cases. Values which were in the normal range prior to the start 
of the treatment and remained unchanged have been omitted. In this respect 
it is surprising that also in these patients individual parameters were 
increased while others were decreased. While these changes often occurred 
within the normal range they clearly indicated a positive response of the 
patient to the treatment. Furthermore, it is interesting that even very 
old patients such as the female patient No. 27 at an age of 93 showed a 
positive response to the treatment. It is still unknown which functional 
mechanisms are the basis of the mutual reactions between the individual 
parameters. However, it has been proven that following a Conpind treatment 
the individual parameters change towards physiological normalization in 
different ways and that in any case this bioregulation leads to a benefit 
for the health of the patient. 
TABLE III 
__________________________________________________________________________ 
Bioregulatory effect of Conpind on the immunological state of tumor 
patients following 
operation and radiotherapy 
Effect of Conpind on immunological parameters 
Patient 
Indication 
Type Normal range 
Prior to CP 
After CP 
Evaluation 
__________________________________________________________________________ 
Pat. 24 
Colon ca. 
Leucocytes 
4000-10000 
3800 4600 .uparw. 
(m.) radiation- Th cells 29-59% 29% 35% .uparw. 
58 years induced Ts cells 19-48% 33% 43% .uparw. 
immune suppr. NK cells 6-29% 42% 32% .dwnarw. 
Pat. 21 Metastazing Leucocytes 4000-10000 3800 9900 .uparw. 
(m.) parotis ca. NK cells 6-29% 34% 9% .dwnarw. 
43 years IL-2/CD4 cells 15-40% 22% 31% .uparw. 
Pat. 30 (f.) Mamma ca. Leucocytes 4000-10000 4200 5500 .uparw. 
54 years CD4/CD8 r. 0.8-2.8 2.3 2.6 .uparw. 
Th cells 29-59% 51% 57% .uparw. 
act. T cells 0-12% 13% 7% .dwnarw. 
IL-2/CD4 cells 15-40% 38% 15% .dwnarw. 
__________________________________________________________________________ 
TABLE IV 
__________________________________________________________________________ 
Bioregulatory effect of Conpind on the immunological state of tumor 
patients following 
resection of the tumor 
Effect of Conpind on immunological state 
Patient 
Indication 
Type Normal range 
Prior to CP 
After CP 
Evaluation 
__________________________________________________________________________ 
Pat. 22 
Colon ca. 
Leucocytes 
4000-10000 
4300 7800 .uparw. 
(m.) T cells 60-85% 55% 65% .uparw. 
58 years CD4/CD8 r. 0.8-2.8 0.8 1.4 .uparw. 
Th cells 29-59% 35% 49% .uparw. 
Ts cells 19-48% 46% 35% .dwnarw. 
NK cells 6-29% 38% 26% .dwnarw. 
Pat. 28 (f.) Colon ca. Leucocytes 4000-10000 3600 5200 .uparw. 
58 years Th/Ts ratio 0.8-2.8 0.8 1.9 .uparw. 
Ts cells 19-48% 42% 33% .dwnarw. 
__________________________________________________________________________ 
TABLE V 
__________________________________________________________________________ 
Bioregulatory effect of Conpind on the immunological state of tumor 
patients following 
chemotherapy 
Effect of Conpind on immunological parameters 
Patient 
Indication 
Type Normal range 
Prior to CP 
After CP 
Evaluation 
__________________________________________________________________________ 
Pat. 19 (f.) 
Lung ca. 
Lymphocytes 
20-30% 8% 11% .uparw. 
59 years act. T cells 0-12% 17% 12% .dwnarw. 
NK cells 6-29% 8% 32% .uparw. 
IL-2/CD4 cells 15-40% 60% 28% .dwnarw. 
Pat. 25 (f.) Malignant Leucocytes 4000-10000 9400 6700 .dwnarw. 
44 years melanoma Lymphocytes 20-30% 
16% 24% .uparw. 
CD4/CD8 r. 0.8-2.8 2.4 1.8 .dwnarw. 
Th cells 29-59% 48% 53% .uparw. 
Ts cells 19-48% 20% 26% .uparw. 
NK cells 6-29% 15% 11% .dwnarw. 
IL-2/CD4 cells 15-40% 20% 24% .uparw. 
Pat. 27 (f.) Recurrent Leucocytes 4000-10000 6400 8900 .uparw. 
93 years basalioma T cells 60-85% 90% 80% .dwnarw. 
CD4/CD8 r. 0.8-2.8 0.8 1.4 .uparw. 
IL-2/CD4 cells 15-40% 12% 21% .uparw. 
__________________________________________________________________________ 
Example 4 
The effect of a continuous treatment with Conpind on the development of 
harmful side reactions during or after radiotherapy or chemotherapy has 
been examined in 7 tumor patients. Four of these patients had undergone 
resection of the primary tumor while three of the patients had not been 
subjected to surgery because of the presence of metastases. All of the 7 
patients received chemotherapy e.g. with cisplatin or endoxan. In addition 
2 of the patients with operation and 1 patient without operation underwent 
radiotherapy. All of the patients received 1 daily dose of Conpind as well 
as 1 dose of Conpind each 2 to 3 times per week in the treatment intervals 
from the beginning of the radiotherapy or chemotherapy. None of the 
patients (2 male, 5 female) encountered the feared damages caused by 
chemotherapy or irradiation. The patients had a sense of well-being and 
were positively motivated. The Conpind treatment was continued after the 
end of chemotherapy or radiotherapy: In the following 5 weeks 1 dose of 
Conpind on each of 2 days per week, then 2 intramuscular doses of Conpind 
per month. Up to now the Conpind patients are in the best of health 
(parapox immunization started 31/2 or 2 years ago, respectively). 
According to retrospective studies, comparable patients during or after 
chemotherapy or radiotherapy encountered the well known severe organic and 
psychical injuries. 
Example 5 
In the case of 5 patients with inoperable and finally treated tumor 
diseases which despite of an appropriate pain-relieving treatment were 
suffering from the most severe pain and depressions and therefore were at 
risk of suicide the benefits of the Conpind treatment were used to 
modulate the pain and to relieve the depression. Three of the patients 
were suffering from colon carcinoma which already had formed metastases 
systemically over the whole body. Two of the female patients suffered from 
mamma carcinoma with metastases in the brain, spine, lung and in other 
organs. Death was expected to be imminent in the case of all 5 patients. 
In this stage, the patients received 1 intramuscular Conpind dose daily or 
every 2 to 5 days, respectively, until they died. The pain was decreased 
already after 3 to 5 applications and in some cases completely ceased. 
Striking and totally surprising was the change in the patients' psyche. 
They lost their depressions, became optimistic with respect to their 
recovery and experienced a subjective sense of well-being. Two of these 
patients even demanded to be discharged from the hospital because they 
were convinced that they would recover. However all of the 5 patients died 
within 2 to 5 months after the start of the Conpind treatment in a 
condition of optimistic well-being. 
In another patient suffering from generalized prostatic carcinoma who had 
to be treated with morphine, the morphine treatment could be immediately 
discontinued after the treatment with Conpind had been commenced without 
encountering detrimental consequences. 
Example 6 
Seven HIV-infected patients (5 still without symptoms, 2 with influenza 
symptoms at the start of Conpind treatment, 1 female patient with 
extensive herpes zoster) were treated with Conpind in three phases since 1 
to 3 years. In the first phase, they received 1 dose of Conpind daily over 
10 days. The subsequent second phase lasted 5 weeks. During this time, 
they were treated with 1 dose of Conpind on 2 days per week, followed by 
the third phase in which they received 1 dose of Conpind once to twice per 
month continuously up to now. All of the 7 HIV-infected patients remain 
asymptomatic to date and are in paid employment. The influenza symptoms of 
the 2 ill patients as well as of the female zoster patient disappeared 
already a few days after the start of the treatment. No post-zoster 
neuritis was experienced. For 1 patient the virus antigen content in blood 
was examined and was found to have decreased by more than 50% within 4 
weeks. At the wish of the HIV-infected patients the monthly Conpind doses 
were then given on a weekly basis. Under this treatment regimen the 
HIV-infected persons experienced a much greater sense of well-being. Their 
fear of the occurence of new depressions or diseases could be reduced in 
this manner. 
Example 7 
Experiences with respect to the positive effects of a long-term 
accompanying therapy are available for 5 multiple sclerosis patients. The 
patients are 25 years (2 cases, female) to 72 years (1 case, male) of age. 
The remaining 2 patients (male) are between 50 and 60 years old. The 
Conpind treatment was started 3 years ago and continued up to now. The 
patients received 1 dose of Conpind on 2 days each per week. All of the 5 
patients report a very good tolerability, a positive effect on the psyche, 
an increasing prolongation of the intervals between new MS phases as well 
as a milder course of new phases. A sixth female patient (13 years old) 
suffering from multiple sclerosis since 2 years but still able to walk was 
treated by intramuscular administration of 1 dose of Conpind because since 
3 weeks she suffered from a permanently progressing faecal and urinary 
incontinence. After only a single treatment with Conpind a complete 
remission of the incontinence could be achieved within 5 hours. 
Example 8 
The positive effect of prophylactic and accompanying Conpind treatments 
could be excellently documented in the case of patients facing an 
operation. The prophylactic daily application of Conpind (intramuscular, 
nasal--undissolved lyophilisate) with or without antibiotics 2 to 3 days 
prior to operation has turned out to be successful in numerous operations 
in at least 5 clinics. The intramuscular administration of Conpind is 
carried out 2 to 3 times (1 dose each) on successive days. The treatment 
may be repeated after the operation. In total, 60 patients with most 
different indications for operation (bypass, ablatio mammae, exstirpatio 
uteri etc.) have been treated in this manner. Generally, an improved wound 
healing (primary healing, no complications, shortening of the healing 
process) was reported. No case of hospital infection was encountered. 
Example 9 
Twelve patients with liver damages to a different extent following 
diagnosed hepatitis A, B or C infections were treated since 3 years with 
Conpind according to Example 6. The preparation was administered by 
intramuscular injection. The patients report freedom from pain, an 
improved general condition and the ability to work. A reduction in the 
relevant liver parameters, e.g. .gamma.-GT transaminases, was reported. No 
recurrencies occured up to now. Thus, pox inducers may be used in the 
regeneration of hepatocytes and in the treatment of chronic liver 
diseases. 
Concluding evaluation of the harmlessness of pox inducers individually and 
in combination. 
The harmlessness of the pox inducers PIND-AVI and PIND-ORF and the 
combination Conpind has been proven by long-term treatment in 
self-experiments and in the wide circle of family and friends. Between 
1972 and 1982, parapox immunity inducers from pox viruses (precursor 
preparations of Conpind, e.g. Duphapind.RTM., Baypamun.RTM., PIND-AVI, 
PIND-ORF, Paravi) were used regularly, i.e. at least once within 2 months, 
to remedy a proneness to infections and for stress prophylaxis by local 
(oral (gargling) or nasal (sniffing)) application. A local treatment 
consisted of 6 to 10 applications in intervals of 4 to 24 hours. 
Other persons of the circle of family and friends underwent a regular 
parenteral treatment with pox inducers since 1983. For this purpose, 6 to 
8 courses of treatment per year with 2 to 3 injections each of 1 dose of 
pox inducers ad us. vet. (no combination preparation, e.g. Duphapind.RTM., 
Baypamun P.RTM.) were used in prophylaxis and metaphylaxis. 
Since 1993, the same group of people uses Conpind for this purpose, 
frequently combining local and parenteral application in the case of an 
acute risk of infections. Up to now, negative side reactions or allergies 
were not observed in any of the cases mentioned, while the effectivity was 
completely maintained. Besides parenteral, oral and nasal application also 
the local application by means of ointments was successful in the case of 
poor wound healing or ulcera.