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Antivirus, antitumor, antimicrobial and immune correcting IZATIZON preparation

Patent  ¹1786   Instruction for the clinical study
The results of  IZATIZON
preparation use
Manuals for the use 
of   Izatizon preparation 
in veterinary

IZATIZON is an antiviral and antitumor drug for medicine and veterinary preferentially for external use (i.e. aerosolic application). It is the original liquid form of N-methylisatin- -thiosemicarbazone (Methisazone).

Spectrum of action: Herpes labialis, Herpes zoster, Marek disease, infective laryngotracheitis virus, bronchopneumonia of horses, bronchopneumonia of calves, ectromelia virus, variolovaccine virus, Venezuela equine encephalomyelitis virus, pig enteritis virus, goose enteritis virus, waterfowl enterovirus; A and B types influenza viruses, Adenoviruses, Retroviruses (i.e. HIV-1), etc. Tumor: melanomas.

Toxicity: LD50 for mice with intraperitoneal injection makes 21 mg/kg; for rats 30 mg/kg; enterally for rats it makes 226 mg/kg; and for mice 36 mg/kg. 10- and 30-fold use of drug (1/10-1/16 LD50) did not cause pathomorphological changes. Even prolonged use of therapeutic concentrations did not lead to toxic effect. No side effect as well as immunosuppressive action of Izatizon has been shown.

Chemical analogue: N-Methylisatin-thiosemicarbazone (methisazone). Izatizon is more effective and less of toxicity than methisazone. 100% curability of influenza virus-infected mice was demonstrated under optimal scheme of Izatizon application (the protective action of both remantadine and methisazone were of 40-52% in optimal experimen¬tal conditions).

Pharmacological analogue: Remantadine. Izatizon is more effective and possesses a more wide spectrum of antiviral action than remantadine and nucleoside inhibitors. Moreover, the Izatizon's commercial production is 25-1000fold cheap, more simple and more available than one of another antiviral drugs.

Practical application: Izatizon is unique chemical antiviral drug which is used in veterinary (Ukraine and Russia) for prevention and treatment of largescale fowl diseases. This drug was recommended for carrying out of clinical trials.

Patentability: Izatizon is patented in Ukraine.

Advantages of Izatizon:
a) low toxicity and no immunosuppressive and side effects;
b) wide spectrum of antiviral activity (i.e. HIV-1);
c) great increasing of interferon action against viruses;
e) neither mutagen, teratogen nor carcinogen properties;
f) cheap and simple chemical production;
g) new analogues might be created.



INSTRUCTION
for the clinical study of antivirus, antitumor, antimicrobial and immune correcting izatizon preparation

Izatizon is an original complex preparation (patent of Ukraine No 1786, 29.10.93), which is composed of preparations used as independent remedies in medical practice of former USSR, Ukraine, Russian Federation and other countries: methysason (marboran), dimethyl sulfoxide, polyethylene glycol (tween) of molecular weight 400. The preparation is approved in veterinary of Ukraine and Russia for prevention and treatment of virus and microbe-virus diseases of poultry, domestic and agricultural animals, furry animals and bees.

Physical-chemical properties - oily liquid of dark-yellow color, has a bitter taste and a specific smell. Hardens at -10° - -15° C. Possesses no flammable or explosive features.

Pharmacological properties. Izatizon belongs to the group of substances of little toxicity. Possesses antiseptic and antiphlogogenic action. Does not oppress hematosis, has no cumulative properties. Decreases the manifestations of anaphylactic shock when used during the inductive phase of immunogenesis, is able to regulate the indices of specific and non-specific resistance at disorders of the organism immune status by causing the activity increase of interferon and phagocytosis systems. Decreases the tonus of small intestine muscular system, increases the sensitivity to acetylcholine and barium chloride. The preparation's prolonged use (aerosol, skin and mucous tunic smearing, bandages, compresses etc.) causes no toxic manifestations.

LD-50 at intraperitoneal introduction is 13.9 - 45.0 mg/kg for rats and 11.4 - 32.4 mg/kg for mice; that at enteral introduction is 133.0 - 319.0 mg/kg and 25.0 - 47.0 mg/kg, respectively. Daily 30-fold intraperitoneal use of the 1/10 - 1/16 LD-50 doses caused no complications or postmortem changes. No toxic manifestations were detected at aerosol use during 30-days daily course. Izatizon is non-toxic in doses recommended for use.

The preparation spectrum. Izatizon is efficient for prophylaxis and treatment of diseases caused by virus and virus-microbe associations. Its spectrum includes: herpes viruses, mixoviruses, including influenza virus A, A-1, B, C, herpes labiales, herpes zoster, Marek disease, poultry infectional laryngotracheitis, bronchial pneumonia of horses and calves, ectromelia and smallpox vaccine viruses, virus of horses' Venezuela encephalomyelitis, virus of pigs' enteritis, waterfowls' enteroviruses; virus, microbe-virus and fungus diseases of bees, silkworm and oak silkworm; poliomyelitis and lymphatic leukemia viruses of baboons, viruses of useful insects and fish, as well as microorganisms: streptococci, staphylococci, pneumococci, pathogenic and yeast-like fungi etc.

Indications for use. Izatizon is recommended at:

  • mass infectious virus diseases (influenza, AIDS, epidemic encephalitis etc.);
  • virus hepatitis A, B, C;
  • acute diseases of upper airways (rhinitis, laryngotracheitis, bronchitis, bronchopneumonia, acute respiratory virus infections - ARVI);
  • lungs, bones and genitals tuberculosis;
  • oral cavity diseases (glossitis, gingivitis, stomatitis, periodontitis, parodontosis);
  • diseases of skin, glands and mucous tunic (herpes of skin and mucous tunic, including genitals; shingles, burns, erysipelas, festering wounds and trophic ulcers, abscesses, furuncles, carbuncles, mastitis, lymphadenitis, psoriasis, mycotic lesions);
  • urological and gynaecological diseases (nephritis, endometritis, salpingitis, trichomoniasis, clamidiosis, erosions, pointed condyloma, prostatitis, prostate adenoma);
  • diseases of cavities (peritonitis, pleurisy, cystitis, endometritis), joints (injuries, synoviites, arthrites, including virus non-specific infectious polyarthritis and psoriatic arthritis);
  • cerebral affections (meningitis, encephalitis, infantile cerebral paralysis, disseminated sclerosis);
  • pretumor and tumor diseases (wart, papilloma, melanoblastoma and other tumors);
  • neuritis and neuralgias, myesities;
  • allergic skin diseases (eczema, nettle-rash etc.);
  • diseases of ENT organs (otitis, mastoiditis, tonsillitis, pharyngitis, larynx papilloma, nose polypus);
  • haemorrhoids.
Way of use and doses. Izatizon is used as aerosol (inhalations at influenza and upper airways diseases), 2-5 ml per one taking, 3-4 times a day, the course of treatment is 5-10 days depending on disease acuteness. Izatizon is also used locally, as tampons and turundas, soaked by 1-2 ml of the preparations, into each nostril, exposition time being 5-40 min depending on the process acuteness and individual sensitivity, during 3-6 days according to the prescriptions. Izatizon as ointment should be used in the same way. Izatizon for prophylaxis should be used similarly 1-2 times a day during 3 days in lower doses (0.5-1.0 ml per taking).

At skin and mucous tunic lesions the aerosol irrigations, smearings, applications and bandages should be used. The amount of the preparation used is not limited and depends on the affected area. The intervals depend on the prescription, but should be no less than 12 hours. The course of treatment is 10-15 days. The liniment of 5-25 ml of izatizon into the affected area and bandages with the preparation for the night during 3-5 days are used against arthritis, neuritis, neuro- myesitis, lymphadenitis, mastitis, phlegmon, and neuralgia. At oral cavity lesions and tonsillitis izatizon is used as rinsing and smearing 2-4 times a day and as aerosol during 3-5 days, at otitis -gauze turundas, soaked in 1-2 ml of izatizone, every 12 hours. Duration of the course should be chosen according to the prescriptions, but no less than 5 days.

Izatizon could be used through rectum, 2-3 ml as microclysters using the syringe without needle and a nozzle made out of polyethylene tube, 4-5 cm long, or vaginally, as suppositories and vaginal beads, containing 0.35 ml of the preparation, three times a day and for night during 10-15 days. The tampons with izatizon could be used for night - one spoonful of the preparation per a tampon. This is the way of its use against systemic virus diseases, as well as prostate adenoma, pointed condyloma of external genitals, prostatitis, rectitis, haemorrhoids, vaginitis, and endometritis. At systemic lupus erythematosus and melanoblastoma izatizon should be used according to the mentioned scheme, externally as smearing and applications, through rectum, 2-3 ml as microclysters or suppositories and intranasally as aerosol or turundas during 30-45 days. After a month's break a second analogous course of treatment should be taken.

In case of stable forms of all the mentioned diseases, besides the external use, it is recommended to introduce izatizon rectally as microclysters (syringe plus rubber tube) after 48 hours, using 1-5 ml of preparation during 1-1.5 months. Usually three courses like this should be taken, the interval between them being 3-4 weeks. At cystitis and endometritis the preparation is introduced into urinary bladder or uterine cavity, 10-15 ml each 48 hours until the disease is totally cured.

In cases of infectious enteritis, as well as all the peritonitis forms izatizon is recommended for internal use, 1 teaspoonful in the morning and in the evening before meal during 10-15 days, and rectal use at nights, 2-5 ml every other day.

The optimal izatizon dose for internal use and for the introduction into rectum as microclysters is calculated depending on the body weight - 0.1 ml of the preparation per 1 kg of the patient's weight. For example, people who weight 60 kg should take 6 ml etc.

The optimal dose for children of different age groups decreases correspondingly:

  • from 1 to 7 years - the dose is 4 times decreased and comprises 0.0187 ml per 1 kg of body weight;
  • from 7.5 to 12 years - the dose is 2 times decreased and comprises 0.0375 ml per 1 kg of body weight;
  • after 13 years the dose is similar to that of adults.

Side-action: a short objectionable feeling on the treated skin or mucous tunics has been noticed for some of the patients. The contra-indications are not found. In case of unknown allergic reactions the treatment should be terminated.

Form of production: izatizon is produced in glass flacks of 100 ml, 50 ml and 10 ml and in aerosol balloons. Suppositories, vaginal beads and ointments are produced in chemist's shops and hospitals or serially in case of necessity.

Conditions for storage: the preparation should be stored at dark place, at temperature 18-20°C. The validity term is 10 years.



The results of IZATIZON preparation use

The observations have been conducted in accordance with Ministry of Health of Ukraine on the patients-volunteers who personally agreed to. The preparation was used externally by applying on skin and mucous membranes, using tampons and compresses and also oral, vaginal and rectal introductions have been done. The table illustrates generalized data of the results of izatizon use at different disease forms.

Diagnosis Number of
the patients
Number of
the cured patients
Improvement No
effect
Flu 37 30 5 2
Acute respiratory disease 54 54 - -
Erysipeloid of
- fingers   
- hands   
- feet   
- lower legs   
 
5
 
3
4
 
4
 
3
4
 
1
 
-
-
 
-
 
-
-
Erysipelas (erythematous
and recurrent forms)
44 29 15 -
Psoriasis 12 9 3 -
Trophic ulcers of lower
extremities against varicose
disease background
8 3 5 -
Streptococcal impetigo and
staphyloderma
3 2 1 -
First and second-degree
skin burns
25 25 - -
Skin slits 52 52 - -
Panaritium 17 17 - -
Purulent skin wounds of upper
and lower extremities
21 21 - -
Pulp space infection 2 2 - -
Diabetic angiopathy 12 10 2 -
Nonspecific viral
polyarthritis
5 2 2 1
Acute arthritis 7 7 - -
Viral ganglionitis 2 2 - -
Viral neuritis 7 5 1 1
Viral encephalitis 3 3 - -
Viral hepatitises and
Botkin's disease
8 5 3 -
Chronic adnexitis 18 15 3 -
Chronic prostatitis 21 18 2 1
Pointed condylomas of genital tracts 5 5 - -
Milker's nodules 11 11 - -
Skin papillomas 7 7 - -
Mucous membranes
papillomas
19 17 2 -
Plane warts 18 14 3 1
Acute rhinitis 35 30 5 -
Acute otitis 9 9 - -
Acute maxillary sinusitis 5 5 - -
Chronic maxillary sinusitis 12 8 2 2
Herpes of lips 109 102 7 -
Herpetic keratoconjunctivitis 27 27 - -
Skin herpes zoster 15 13 2 -
Genital herpes of
- women   
- men  
 
5
7
 
5
7
 
-
-
 
-
-
Clamidiosis of
- women   
- men  
 
12
5
 
10
3
 
1
1
 
1
1
Trichomoniasis of
- women   
- men  
 
10
4
 
7
3
 
3
1
 
-
-
Hemorrhoid 23 20 2 1



UKRAINE
MINISTRY OF AGRARIAN POLICY
STATE DEPARTMENT OF VETERINARY MEDICINE
24 Hreshchatik Str., 252001, Kiev. Tel: (044) 229-57-56. Fax: (044) 228-03-08. Teletype: 331115 Hlib

10.04.02 ¹ 15-14/105

APPROVED             
Chief State Inspector of Veterinary Medicine
of Ministry of Agrarian Policy of Ukraine
P.I. Verbitsky

M A N U A L S
for the use of Izatizon preparation

DESCRIPTION
Oily liquid of orange-yellow color.

COMPOSITION
100 ml of the preparation contains (g) 1-methylisatin semicarbazone-3-2.

PHARMACOLOGICAL PROPERTIES
Izatizon is a complex antiviral, antibacterial, antifungous and immune modulating preparation, which has wide spectrum of action, providing high medicinal-prophylactic, anti-inflammatory and anti-histamine effect, and increases the resistance of animals’ organism. In the conditions of aerosol use the preparation penetrates easily through biological barriers, blocks viruses’ reproduction, and oppresses propagation of pathogenic microorganisms.

USE
Treatment of viral, bacterial and fungous diseases of agricultural animals and bees. Prophylaxis of viral, bacterial and compound infections in fowl, minks, nutrias and rabbits as well as their treatment; immunity strengthening and increase of productivity of fowl, agricultural animals and useful insects.

DOSAGE
Intrauterinal at acute and purulent forms of cows’ endometritis; the preparation is diluted in the proportion 1:10 (20 ml of izatizon and 180 ml of physiological solution) and introduced in volume 200 ml using a syringe batcher 1 time every other day. The treatment course at acute endometritis comprises 5 days, and at purulent one it is 6 days. In obstetric and gynaecological pathology of cattle the preparation increases fertilization level in outgrown cows up to 93.5% (compared to 53.8 – 80% in the controls).
The inhalation treatment of calves aged 1-3 months, suffering from parainfluenza-3, is carried out in impermeable chambers, as which separate boxes in calf-shed lobbies could be used (the number is one animal per 1.5-2 m3). The aerosol form of the preparation is obtained using SAG-1 and a compressor, which feeds air under pressure of 3-4 atmospheres. Izatizon is dispersed counting 2.0 ml per 1 m3 of the room, once a day during 3 days, the exposition time being 30-40 min. Izatizon is used in a similar way for the prophylaxis of colts, piglets, calves and other agricultural animals against the infection of upper respiratory tract, enteroviral and intestinal infections; the preparation is added into fodder or into water (1-2 ml per 10 kg of live weight).
The aerosol treatment (SAG-1, pressure 3.5-4 atmospheres) by 2 ml of izatizon per 1 m3 of the room is used for the prophylaxis and treatment of fowl suffering from viral and bacterial diseases. The duration of one seance is 30-40 min, once a day during 3 days.
Izatizon is added into fodder or used as aerosol from March till September at viral, bacterial and compound infections of bees.
The treatment is carried out by aerosol into beehives with separated honeycombs using hand sprayer. Prior to spitting izatizon is diluted in warm water (in ratio 1:100 for prophylaxis and 1:50 for treatment); 10-15 ml of this solution is spent per each honeycomb. The treatment course consists of 4 treatments at intervals of 48 hours. Izatizon in balloons is used for honeycomb spitting by means of high dispersion aerosol making (duration 2-3 s), the exposition time being 5-10 min. If izatizon is added into fodder (pastes, syrup, candy, whole milk substitute), the ratio 1:100 for prophylaxis and 1:50 for treatment should be maintained.

CONTRA-INDICATIONS
Not determined

CAUTIONS
Schemes and way of use won’t permit any overdose.

PRODUCTION FORM
Flasks of dark glass of 25; 50; 100 and 1000 ml, aerosol balloons.

STORAGE
Dry and dark place; temperature ranging from +15oC to 25oC.
The term of storage is 3 years.

If the preparation does not correspond to the demands mentioned in the instruction or complications appeared after its taking, the use of this series should be terminated immediately, and SRCI of Veterinary Preparations, as well as supplier (manufacturer), should be informed. Three samples of this series, picked in commission and sealed, together with the detailed description of complications, should be sent by the following address:

State Research Control Institute of Veterinary Preparations and Food Supplements
11 Donetska Str., Lviv, 79019, Ukraine.

The instruction has been worked out by SRCI of Veterinary Preparations and Food Supplements of Ministry of Agrarian Policy of Ukraine, Institute of Molecular Biology and Genetics of NAS of Ukraine, and “Dobrodeya” research-and-production association. It has been examined and approved by academic council of SRCI of Veterinary Preparations and Food Supplements (protocol No 2 of 12.02.2002).


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