An Interdisciplinary Approach to Development of a New Combined Medicine for Musculoskeletal Disorders

. Musculoskeletal disorders represent a significant

Introduction.The military conflict in Ukraine posed a number of challenges for medical and pharmaceutical care for persons with damage to the musculoskeletal system, skeletal damage, craniocerebral injuries, open wounds, and pathologies of internal organs.Today, the standard of analgesia for severe and moderate pain intensity is analgesia, which involves the simultaneous administration of several drugs that affect most of the chains in the formation of the pain sensation.Of all non-opioid analgesics, analgin is most often used in combination with non-steroidal antiinflammatory drugs.Opioids are prescribed for severe pain and ineffectiveness of non-narcotic regimens.Pain relief schemes for patients with traumatic injuries include anesthesia [1].
Patients who have undergone limb amputation are in a very difficult situation.Their quality of life is significantly reduced, and the experience of phantom pain syndrome worsens their situation

Conditions of military conflict
Tranquilizing drugs Some of them may require the use of anesthetics, analgesics, and tranquilizers to ensure the desired level of treatment and comfort.The relevance, necessity, and timeliness of the pharmaceutical development of a new drug based on known active pharmaceutical ingredients is explained by the spread of injuries of the musculoskeletal system in wartime conditions, for which anesthetic (ketamine), analgesic (metamizole) and tranquilizing (diazepam) drugs must be used.
Main physicochemical properties: transparent colorless or slightly colored liquid.The drug Ketamine is in circulation on the pharmaceutical market of Ukraine.The composition of the solution for injection in ampoules: 1 ml of the solution contains ketamine hydrochloride 57.6 mg (calculated as ketamine 50.0 mg); excipients: benzethonium chloride, sodium chloride, water for injections.

Marketing research on the active pharmaceutical ingredient Ketamine
The method of analysis of marketing indicators of drugs was developed and described earlier [21].In the Table 2 authors present a list of drugs of N01AX03 Ketamine.

Yesketamine Kalceks
Solution for injections and infusions 25 mg/ml, 2 ml, 10 ml, No. 5 JSC "Grindex", Latvia 4. Ketamine-ZN Solution for injections 50 mg/ml, 2 ml, No. 10 LLC Kharkiv Pharmaceutical Enterprise "Zdorovia Narodu", Ukraine As can be seen from the data in the Table 2, ATC code N01AX03 Ketamine includes four drugs.The two drugs are produced by Ukrainian manufacturers and are available in the form of a solution for injections and infusions in ampoules, vials for intramuscular and intravenous administration.
Subsequently, the registration certificates of Ketamine drugs were analyzed (Table 3).

Clinical traumatological, clinical and pharmacological study of the active pharmaceutical ingredient Ketamine
Pharmacodynamics Ketamine has pronounced general anesthetic and analgesic effects.The action of the active pharmaceutical ingredient Ketamine is due to inhibition of various departments of the central nervous system.The active pharmaceutical ingredient Ketamine reduces somatic pain sensitivity to a greater extent than visceral pain sensitivity, which should be taken into account during cavity operations [22].

Pharmacokinetics
The active pharmaceutical ingredient Ketamine is characterized by high solubility in lipids and rapid tissue distribution.Plasma protein binding was 12%.Metabolized in the liver.It is excreted by the kidneys, mainly in the form of metabolites, it has no cumulative effect.
The areas of clinical application of Ketamine are given in the Table 4.

Special warnings
Ketamine is injected intravenously as a single instant or fractionally and dropwise, as well as intramuscularly.It is administered intravenously in a dose of 2-3 mg/kg regardless of the patient's age, intramuscularly in adults 4-8 mg/kg, in children 2-5 mg/kg of body weight.To maintain anesthesia, Ketamine administration is repeated in the amount of half the initial dose.Maintenance of anesthesia by continuous intravenous infusion of the drug is achieved by administration at a rate of 2 mg/kg per hour.The minimum effective dose of Ketamine when administered intravenously is 0.5 mg/kg of body weight (consciousness is lost after 1-2 minutes, the effect lasts approximately 2 minutes).In a dose of 1 mg/kg, it works for 6 minutes, 2 mg/kgfor 10-15 minutes.With intramuscular administration, the effect occurs more slowly, but it lasts longer (at a dose of 6-8 mg/kg, the effect develops after 6-8 minutes and lasts 30-40 minutes).When injected into a vein, the analgesic effect develops within 10 minutes and lasts for 2-3 hours.It should be taken into account that Ketamine increases blood pressure by 20% -30%, accelerates the rhythm of heart contractions, and increases the minute volume of the heart.Cardiac stimulation can be reduced by diazepam [23].
Side effects and contraindications of Ketamine are given in the Table 5. Arterial hypertension Preeclampsia and eclampsia 6.
From the side of the central nervous system Epilepsy in childhood Interaction with other medicines Ketamine can be used together with analgesics (metamizole sodium).At the same time, the dose of Ketamine is reduced.
Storage conditions: store in a place inaccessible to children, protected from light, at a temperature of 15ºС to 25ºС.

Ketamine control regimen
Clinical and pharmacological groupfor general anesthesia N01A X03 [24].Classification and legal grouppoisonous drug.Nomenclature and legal groupaccording to a doctor's prescription.
Therefore, it is promising to combine Ketamine in the ampoule dosage form with watersoluble analgesics and sedative tranquilizers.
Main physicochemical properties: transparent, colorless, or slightly yellowish or greenishyellowish liquid.
Physical and chemical properties: easily soluble in water, difficult to dissolve in alcohol.
The drug Metamizole Sodium is in circulation on the pharmaceutical market of Ukraine.The composition of the solution for injections in ampoules: 1 ml of the solution contains Metamizole Sodium 500 mg; excipients: sodium metabisulfite (E223), disodium edetate, sodium hydroxide, water for injections.

Marketing research on the active pharmaceutical ingredient Metamizole Sodium
The Table 6 presents a list of drugs of N02BB02 Metamizole sodium in ampoule dosage form [26].As can be seen from the data in the Table 3, five ampoule preparations assigned to ATC code N02BB02 Metamizole sodium.All of these drugs are produced in Ukraine in the form of a solution for injections in ampoules.
Subsequently, the registration certificates of ampoule preparations Metamizole sodium were analyzed (Table 7).Medicinal products in the form of a solution for injections, which include Metamizole sodium, contain 500 mg of the active pharmaceutical ingredient in 1 ml.Five medicinal products registered in Ukraine have an unlimited term of registration.Metamizole sodium is produced by Ukrainian pharmaceutical manufacturers.

Clinical and traumatological, clinical and pharmacological study of the active pharmaceutical ingredient of Metamizole Sodium
The pharmacodynamics of the Metamizole Sodium is shown on the Fig. 1.

Pharmacokinetics
After administration, Metamizole Sodium is hydrolyzed to an active metabolite (when administered intravenously, unchanged metamizole is detected in plasma in small amounts).The connection of the active metabolite with proteins is 50-60%.Metabolized in the liver, excreted by the kidneys.It is quickly and evenly distributed in tissues.The maximum concentration is reached 1-1.5 hours after intramuscular administration.The elimination half-life (T1/2) is about seven hours.Excreted with urine.
The areas of clinical application of Metamizole Sodium are shown on the Fig. 2.

Special warnings
With parenteral administration of Metamizole Sodium, medical control is necessary (high frequency of allergic reactions, including those with a fatal outcome) and the presence of conditions for anti-shock therapy.Patients with atopic bronchial asthma and pollinosis have an increased risk of developing hypersensitivity reactions.Apply with caution to patients: elderly may lead to an increase in the frequency of adverse reactions, especially from the digestive system; with inflammatory bowel diseases.When prescribing to patients with acute cardiovascular pathology, careful control of hemodynamics is necessary.Use with caution in patients with myocardial infarction, during treatment with cytostatics, chronic alcoholism, burdened allergic anamnesis, blood diseases.Necessary to monitor the picture of peripheral blood (leukocyte formula).When using the drug, the development of agranulocytosis is possible, therefore, if an unmotivated rise in temperature, chills, sore throat, difficulty swallowing, stomatitis, as well as inflammation of the external genitalia and anus is detected, the drug should be discontinued immediately.Subcutaneous administration of the drug is not used due to possible tissue irritation.During the treatment period, the urine may turn red (due to the release of the metabolite), which has no clinical significance.
Side effects Suppression of hematopoiesis, hemorrhages, hypotension, nephritis, allergic reactions.With intramuscular administration, infiltrates at the injection site are possible.
Contraindications to the clinical use of Metamizole Sodium are given in the Table 8.

Interaction with other medicinal products
The toxic effect of Metamizole Sodium increases with simultaneous use with other nonnarcotic analgesics, tricyclic antidepressants, hormonal contraceptives.The effect of Metamizole Sodium is enhanced by histamine H2-blockers, propranolol (anaprilin), weakened by barbiturates.The analgesic effect of Metamizole Sodium is enhanced by sedatives and tranquilizers (diazepam, sibazone).Metamizole Sodium increases the activity of oral hypoglycemic agents, indirect coagulants, ibuprofen, glucocorticosteroids and indomethacin, the sedative activity of alcohol.When used simultaneously with other nonsteroidal anti-inflammatory drugs, their analgesic and antipyretic effects are potentiated and the likelihood of unwanted side effects increases.When used simultaneously with ethanol, the effect of ethanol increases.
Method of application and dosage.Metamizole Sodium: prescribed intramuscularly and intravenously.The method of administration and dose depend on the severity of the disease and are determined individually.The analgesic effect with intravenous administration is higher than with intramuscular administration.The injected solution should be at body temperature.To prevent a sharp drop in blood pressure, intravenous administration should be carried out slowly.The patient should be in a supine position.Necessary to control blood pressure, heart rate and breathing.The procedure requires conditions for anti-shock therapy.A long needle should be used for intravenous administration.
Control regime of Metamizole Sodium.
Therefore, seems promising to combine Metamizole Sodium in ampoule dosage form with water-soluble anesthetic (ketamine) active pharmaceutical ingredients and sedative tranquilizers.
Main physicochemical properties: transparent, colorless, or yellowish-green liquid.Physical and chemical properties: sparingly soluble in water, soluble in alcohol.
The drug Diazepex, Sibazon is in circulation on the pharmaceutical market of Ukraine.
The composition of the solution for injections in ampoules: 1 ml of solution contains diazepam 5 mg; auxiliary substances: ethanol 96%, propylene glycol, polyethylene oxide, water for injections.

Marketing research of the active pharmaceutical ingredient Diazepam
In the Table 9 presented a list of ampoule preparations of the ATC code N05BA01 Diazepam.

Sibazon
Solution for injection 5 mg/ml, 2 ml, No. 5 LLC Kharkiv Pharmaceutical Enterprise "Zdorovia Narodu" (all stages of production, quality control, series release), Ukraine JSC "Halychpharm" (all stages of production, quality control), Ukraine The data in the Table 9 shows, that ATC code N05BA01 Diazepam includes two ampoules of preparations.The drugs are produced by Ukrainian and foreign manufacturers in the form of a solution for injections in ampoules.
Subsequently, the registration certificates of Diazepam drugs were analyzed (Table 10).Pharmacokinetics After intramuscular administration, Diazepam is absorbed incompletely and unevenly, the maximum concentration is reached after 60 minutes.After intravenous administration in adults, the maximum concentration is reached after 15 minutes and depends on the dose.It is quickly distributed in the tissues of organs, primarily in the brain and liver, passes through the placental and blood-brain barriers.Biotransformed in the liver (50%).Accumulates in the brain, providing a long-lasting and pronounced anticonvulsant effect.Diazepam belongs to the long-acting tranquilizers, the half-life of intravenous administration is 32 hours.
The half-life of Diazepam can be increased in elderly patients and patients with liver disease.In patients with renal failure, the half-life of Diazepam does not change.Absorption of Diazepam when administered intramuscularly may vary, especially when administered into the gluteal muscles.Therefore, this route of administration can be used only in case of impossibility of oral or intravenous administration.
Fields of clinical application and special warnings of Diazepam are given in the Table 11.

Recovery of symptoms of insomnia and anxiety
Abrupt discontinuation of Diazepam treatment may cause a rebound phenomenon.It is manifested by an aggravation of the condition followed by a rapid reduction of symptoms (mood changes, anxiety or sleep disturbances, restlessness).

Duration of treatment
The duration of treatment should be as short as possible depending on the indications, but should not exceed four weeks for insomnia, 8-12 weeks for anxiety states.The duration of treatment should be increased only after careful assessment of the patient's condition.Patients should be informed about the initiation and duration of treatment and the gradual reduction of the dose should be explained.In addition, the patient should be warned about the possible occurrence of withdrawal syndrome to reduce the state of restlessness, especially when stopping therapy with the drug.Due to the risk of withdrawal syndrome, it is not recommended to change benzodiazepines with a short duration of action during treatment.
Tolerance Regular use of Diazepam for several weeks can lead to a decrease in the effectiveness of the action.
Amnesia Benzodiazepines can cause anterograde amnesia.Anterograde amnesia may occur at therapeutic doses, the risk increases at higher doses.Amnestic effects can be associated with inappropriate behavior.

Special groups of patients
Elderly patients (from 65 years old) and weakened patients need a dose reduction.Due to the muscle relaxant effect, there is a risk of falls and fractures in this group of patients.Diazepam can delay the psychological recovery of patients from the symptom complex caused by the severe loss of a loved one.Diazepam should be administered intravenously with particular caution in the treatment of critically ill elderly patients and patients with cardiac or respiratory failure, given the possibility of apnea and/or cardiac arrest.Simultaneous use of Diazepam with barbiturates, alcohol, or other substances with a depressing effect on the central nervous system increases the risk of circulatory depression or suppression of the respiratory center.It is not recommended to use Diazepam in patients with severe liver failure and organic liver damage.For patients with chronic liver disease, the dose should be reduced.Needs to be taken into account when prescribing Diazepam to children and adult patients from the risk groups (e.g., patients with liver disease or epilepsy patients), that 1 ml of the drug contains 100 mg of ethanol.During the treatment with Diazepam and for 3 days afterwards, no alcoholic beverages can be consumed.

Simultaneous use of alcohol, depressants
Alcohol and other depressants should not be consumed during treatment with Diazepam.Such a combination enhances the clinical effects of Diazepam, including the severe sedative effect clinically associated with the treatment of respiratory or cardiovascular depression.The drug contains propylene glycol, which can cause symptoms similar to those that occur with alcohol abuse.It is not recommended to use Diazepam in patients with psychosis.

Application in depression
Diazepam should not be used as monotherapy for depression or anxiety.Suicidal tendencies may appear in these patients.Diazepam should be used with great caution in patients with a history of drug and addictive addiction.Such patients should be under strict supervision during treatment with Diazepam.They belong to the risk group of addiction and mental dependence.Diazepam is not recommended for the treatment of primary psychotic disorders.
The ability to influence the speed of reaction when driving vehicles or other mechanisms Diazepam can reduce the speed of motor and mental reactions.On the day of using Diazepam, you should not drive vehicles and work with mechanisms.Anxiety, amnesia, impaired concentration, and muscle weakness adversely affect the ability to drive and operate machinery.In the case of insufficient sleep and alcohol consumption during treatment, the probability of impaired attention increases.The patient should be warned not to drive vehicles and operate mechanical equipment for three days after taking Diazepam.

Side effects
Long-term use of Diazepam, even in therapeutic doses, can lead to physical and mental dependence.Sudden discontinuation of Diazepam treatment after long-term use leads to a withdrawal syndrome.In order to reduce local reactions, Diazepam should be injected into the large veins of the elbow joint.Intramuscular injection of Diazepam may cause pain, redness, and sporadic tenderness at the injection site.
Violations, lesions, and side effects of Diazepam are given in the Table 12.

No. Disorders and lesions
Side effects 1.
From the cardiovascular system Arterial hypotension, suppression of blood circulation (after rapid intravenous administration of the drug), heart rhythm disturbances, heart failure, bradycardia, rapid heartbeat, in some casescardiac arrest, orthostatic collapse 3.
From the respiratory system Apnea, decreased breathing rate, dyspnea, suppression of the respiratory system (after rapid intravenous administration of the drug), respiratory failure 4.
From the mental side Physical and mental dependence, decreased emotional reactions, depression, speech disorders (in particular, dysarthria), irritability, sleep disorders, aggressiveness, delirium, fits of rage, nightmares, hallucinations (some of sexual nature), psychoses, behavioral disorders, delirium and seizures, suicidal tendencies.Long-term use of the drug (even in therapeutic doses) can lead to the development of physical dependence: stopping therapy can cause a withdrawal syndrome or a rebound phenomenon 6.

Changes in laboratory parameters
Increased activity of transaminases and alkaline phosphatase 8. From the urinary system Incontinence or retention of urine (spastic ischuria) 9.

From the immune system
Allergic reactions in the form of skin hyperemia, skin rashes and itching, bronchospasm, laryngospasm, inactive pharmaceutical ingredient lactic shock, hypersensitivity reactions, including inactive pharmaceutical ingredient lactic reactions 10.
From the musculoskeletal system Pain in the joints 11.From the hematopoietic system Leukopenia, neutropenia, agranulocytosis, anemia, thrombocytopenia, disorders of the morphological composition of the blood, jaundice 12.
From the skin and subcutaneous tissue Rashes, allergic dermatitis, urticaria 13.
From the metabolism Metabolic disturbances, including metabolic acidosis, an increase in the size of the anion gap and osmotic hypertension, as a consequence of the toxic effect of propylene glycol

Contraindication
Hypersensitivity to Diazepam, glaucoma, poisoning with alcohol and sedatives, liver failure, acute respiratory failure, alcohol or drug addiction, chronic psychoses, intoxication with alcohol, psychotropic drugs, shock, coma, severe liver failure, phobias, and obsessive states.Diazepam should not be used as monotherapy for the treatment of patients with depression or anxiety because of the potential for suicidal behavior in such patients.

Interaction with other medicinal products
Antipsychotic drugs.There is an increased risk of arterial hypotension, bradycardia, and respiratory depression with parenteral use of Diazepam and intramuscular administration of olanzapine.
Sodium oxybate.Diazepam increases the effect of sodium oxybate.Antibacterial agents.Metabolism of Diazepam can slow down isoniazid, erythromycin.The effect of Diazepam can be increased and prolonged.
Antiviral means.Simultaneous use should be avoided, as potentiation of the action is observed, the risk of excessive sedation and respiratory depression increases.
Antifungal drugs.The effect of Diazepam can be increased against the background of simultaneous use of fungicides (ketoconazole, fluconazole).
Antihypertensive drugs.The simultaneous use of Diazepam with antihypertensive agents can lead to an increase in the hypotensive effect.Enhancement of the sedative effect is possible with simultaneous use with alpha-blockers.
Medicines that reduce the acidity of gastric juice.Cimetidine, omeprazole, and esomeprazole may inhibit the metabolism of Diazepam.
Disulfiram.Disulfiram can suppress the metabolism of Diazepam, which leads to an increase in the sedative effect.
Levodopa Diazepam can antagonize the effect of levodopa.Theophylline.Theophylline can reduce the effect of Diazepam.Skeletal muscle relaxants.The simultaneous use of baclofen with Diazepam can lead to an increase in the sedative effect.
Method of application and dosage.The dose of Diazepam should be determined individually for each patient.Single dose, frequency and duration of use are set individually.Acute anxiety-phobic and anxiety-depressive states.Adults should be prescribed intravenously or intramuscularly in a dose of 1-2 ml (5-10 mg).With alcoholic delirium, the initial dose is 2 ml (10 mg) intravenously, then 1-2 ml (5-10 mg) every 3-4 hours until the acute symptoms disappear.The highest single dose is 30 mg, the highest daily dose is 70 mg.Status epilepticus: adults are prescribed 1-2 ml (5-10 mg) intravenously slowly.Muscle spasms in neurodegenerative diseases, spinal injuries: adults are prescribed 2-4 ml (10-20 mg) intravenously slowly or intramuscularly.If necessary, the injection should be repeated after 3-4 hours, followed by the transition to taking Diazepam in the form of tablets.Tetanus: the initial dose for adults is 2 ml (10 mg) intravenously slowly or intramuscularly, then switch to intravenous drip administration of the drug at a rate of 5-15 mg/h.Muscle spasms of peripheral origin (lumbago, cervical radiculitis): appoint 2-4 ml (10-20 mg) intramuscularly 1-2 times to adults until the acute symptoms disappear.Then continue the therapy with the drug in the form of Diazepam.Anesthesiology, surgery: for adults are prescribed 2-4 ml (10-20 mg) intramuscularly the evening before surgery, 1-2 ml (5-10 mg) intramuscularly or intravenously slowly 30-60 minutes before surgery or immediately before surgery.After surgery, enter 1-2 ml (5-10 mg) intramuscularly.To achieve a short-term narcotic sleep during therapeutic and surgical interventions (minor surgical operations, dislocations, fractures, diagnostic measures), adults are administered 2-6 ml (10-30 mg) intravenously slowly.
Overdose with Diazepam Symptoms: sudden retardation, excessive drowsiness, deep prolonged sleep, nystagmus, apnea, depression of the cardiorespiratory system, excitement, bradycardia, reduced response to pain stimuli, impaired coordination of movements, decreased blood pressure, suppression of reflexes, short-term loss of consciousness, which passes into coma, a fatal outcome is possible.Symptoms of minor overdose: confusion, drowsiness, lethargy, impaired consciousness, reduced reflexes or paradoxical depression.
Diazepam overdose treatment.
If necessary, carry out symptomatic therapy.It is also necessary to ensure the patency of the respiratory tract, control the heart rate, blood pressure, and body temperature.Take measures to maintain the activity of the respiratory and cardiovascular systems.Specific antidote flumazenil (intravenous).Patients requiring antidote therapy are subject to careful monitoring in hospital settings.Flumazenil should be used with caution in patients with epilepsy who are treated with Diazepam.Barbiturates should not be used in case of psychotropic agitation.
Storage conditions: store in the original packaging at a temperature not higher than 5ºС.Keep out of reach of children.
Control regime of Diazepam.Clinical and pharmacological grouppsycholeptics, anxiolytics, benzodiazepine derivatives of ATC code N05BA01.Classification and legal grouppsychotropic drug.Nomenclature and legal groupby a special doctor's prescription form F-3.
Therefore, Diazepam in ampoule dosage form can be promisingly combined with watersoluble anesthetics (ketamine) and analgesics (metamizole).
We present the composition of the proposed new medicine (Fig. 3).The proposed composition of the new drug includes two solutions.Positioning of the availability of new medicine.The use of a new medicine requires licensing of activities related to the circulation of psychotropic drugs.
Positioning of clinical and pharmacological properties of new medicine.Anesthetic, analgesic, tranquilizing, sedative properties.
Positioning of areas of medical application of new medicine.Traumatology, surgery, psychiatry, neurology, cardiology, oncology, phthisiology.
Indications for medical use.Injuries of the locomotor system Open wound surfaces, painful shock.Surgical intervention in field, military, hospital conditions.Post-traumatic syndrome, depression, comorbid pain, panalgia.
Conclusion.An interdisciplinary study was conducted on the relevance, necessity and timeliness of the pharmaceutical development of a new combined drug for lesions of the musculoskeletal system based on known active pharmaceutical ingredients using clinical, surgical, traumatological, clinical and pharmacological, classification and legal, nomenclature and legal, forensic and pharmaceutical, organizational and legal, marketing approaches to the justification of the composition, clinical and pharmacological properties, control regime, availability, areas of medical application, quality and safety profile.Proven that the use of anesthetic, analgesic, and

General anesthesia means Ketamine
Analgesics and antipyretics.Pyrazolones Мetamizole sodium Psycholeptic drugs.Anxiolytics.Benzodiazepine derivatives Diazepam tranquilizing drugs is relevant in wartime conditions for medical-pharmaceutical assistance for injuries of the locomotor system in military and civilian persons.The characteristics of active pharmaceutical ingredients (ketamine, analgin, diazepam) were studied in order to substantiate the composition based on a combination of evidence-selected active pharmaceutical ingredients.Conflict of interest.The authors have approved the article for publication and declare that the research was conducted in the absence of any conflict or potential conflict of interest.
Funding.The authors state that this research received no grant from any funding agency in the public, commercial, or not-for-profit sectors.
Ethical approval.Ethical clearance was obtained from the administration of the Yuri Semenyuk Rivne Regional Clinical Hospital.Permission statement for conducting the experiments and/or collecting of data was received from the administration of the Yuri Semenyuk Rivne Regional Clinical Hospital.Before any data collection, the main purpose of the study was clearly explained to each department (concerned personnel).

Fig. 3 .
Fig. 3. Clinical and pharmacological groups and active pharmaceutical ingredients in the composition of a new medicine.

Table 1 .
Traumatic lesions of the musculoskeletal system and pharmacotherapy.

Table 3 .
Validity of registration certificates of drugs of ATC code N01AX03 Ketamine.

Table 5 .
Side effects and contraindications of Ketamine.

Table 6 .
List of drugs of ATC code N02BB02 Metamizole sodium

Table 7 .
Validity of registration certificates of drugs of ATC code N02ВВ02 Metamizole sodium.

Table 8 .
Contraindications to the use of Metamizole Sodium.

Table 9 .
List of drugs of ATC code N05BA01 Diazepam.

Table 10 .
Validity of registration certificates of drugs of ATC code N05BA01 Diazepam.Medicinal products in the form of a solution for injections, which include Diazepam, contain 5 mg of the active pharmaceutical ingredient in 1 ml.Two medicinal products registered in Ukraine have an unlimited term of registration.Diazepam is produced by the Ukrainian pharmaceutical manufacturer and the foreign JSC "Grindex".Clinical and pharmacological study of the active pharmaceutical ingredient Diazepam PharmacodynamicsDiazepam is a benzodiazepine tranquilizer.It has an anxiolytic, sedative, anticonvulsant, central myorelaxant effect, increases the threshold of pain sensitivity, regulates neurovegetative reactions.

Table 11 .
Clinical application and special warnings of Diazepam.