CLINICAL APPLICATION OF NIVALIN

Nivalin in practical anesthesiology as antagonists of nondepolarizing muscle relaxants

Nivalin was first used by Deredjan and Krasteva to abolish residual neuromuscular blockade caused by nondepolarizing muscle relaxants. Afterwards, other authors (surgeons and anesthesiologists) confirmed the good efficacy of Nivalin as antagonist of d-tubocurarine, pancuronium bromide, etc.

Clinical investigations of the decurarization effect of Nivalin have been conducted on 7,000 patients in this country and elsewhere. The age of patients was within a very broad range, from 3 to 99 years [12]. Virtually all areas of surgery are included with different operations by size, complexity and duration. Depending on the patient's body mass, muscle relaxant type, and premedications and anesthetics used, Nivalin varied up to 30 mg as i.v. infusion in saline solution. The total dose used was usually given in two steps: initially 15-20 mg, followed by additional 10-15 mg after 4-5 min, unless complete decurarization with recovered respiration developed (Mitev and Athanasov, 1965). The effect of Nivalin appeared within 1-1.5 min as restored spontaneous ventilation.

At a dose of 0.3 mg/kg body weight Nivalin neutralized the effect of 0.03 mg/kg pancuronium and 0.15 mg/kg d-tubocurarine. Comparative clinical trials showed a decurarization dose of 0.41 (0.02 mg/kg) for Nivalin relative to 0.032 (0.008 mg/kg) for neostigmine.

The optimal decurarization dose of Nivalin is 0.3 mg/kg

Electromyographic control and comparison of the decurarization effects of Nivalin and neostigmine showed that the effect of Nivalin has slower onset but a more prolonged that that of neostigmine.

The muscarine-like and cardiotoxic effects of Nivalin are much less potent than those of neostigmine and can be neutralized completely with 0.2 mg atropine.

Nivalin is the drug of choice for decurarization following the use of nondepolarizing neuromuscular blockers in elderly patients, in patients with cardiovascular disorders, in asthmatics, diabetics and children.

Nivalin in postoperative atonic ileus and urinary retention

The ability of Nivalin to activate gastrointestinal and ureter motility, as well detrusor muscle function, was examined and used during the postoperative period by leading surgeons. The effect was compared to that of other preparations: Prostigmin, Didergot and Doryl. Nivalin was found to be most effective - in 81.2% of all cases, with least effect on the heart, least muscarine-like effects and, at the same time, with the most steady and sustained action.

Nivalin is applied 12 h after operation at a single dose of 5-10 mg. If necessary, the dose may be repeated after 3 to 6 h. Nivalin is injected intramuscularly or subcutaneously, and in more severe cases intravenously.

Nivalin in the treatment of diseases of the central and peripheral nervous system

The ability of Nivalin to cross the blood-brain barrier, its broad therapeutic index, its safety and low toxicity with rare and mild adverse effects, as well as the possibility to use it by different routes of administration (oral, subcutaneous, intramuscular, intravenous, intraocular, electrophoretic) make it a DRUG OF CHOICE for diseases of the central and peripheral nervous system where there is a need to POTENTIATE ACETYLCHOLINE-MEDIATED NEUROTRANSMISSION.

Nivalin may be used for long-term treatment in courses of 30-40-60 days. If needed each course may be repeated after 30-40 days interval.

Nivalin in cerebral diseases

It has been suggested that brain injury is accompanied by the so-called "functional asynapsy" (after Grashchenkov), where structurally intact neurons are functionally inactive because of disturbed trophic and biochemical processes due to disturbed circulation of cerebral oedema. Nivalin helps to abolish those disturbances at the level of the ascending activating system of brainstem reticular formation where neurotransmission is acetylcholine-mediated.

The effect of Nivalin in different types of encephalitis was studied in 152 patients at the Institute of Neurology and Psychiatry, Sofia Medical Academy. The preparation was applied for 30 to 60 days at doses of 2.5 mg gradually increasing to 10-20 mg daily. The best results were obtained when s.c or i.m Nivalin treatment started in the earlier stages of disease and was supplemented with vit. B1, B6, B12, strychnine and physiotherapy.

Nivalin was used in various forms of cerebral palsy in children - pyramidal, extrapyramidal, hypotonic, and mixed (397 children were treated at the Pediatric Department of the Institute of Neurology and Psychiatry, Sofia, Medical Academy and at the Bankya Pediatric Hospital). Nivalin was injected subcutaneously or intramuscularly at increasing doses up to 10-15 mg daily for 45-60 days. The best results were obtained in children with hypotonic cerebral paralysis. Nivalin treatment was combined with remedial gymnastics and B-group vitamins. The authors think that in case of EPILEPSY Nivalin treatment is CONTRAINDICATED!

Nivalin was used for the treatment of transient ischemic attacks and other complications of stroke by Kilimov in 1961. Clinical experience so far shows that the best effect of Nivalin is obtained if treatment starts in the earlier stages of disease in combination with remedial gymnastics. Dosage is increased from 2.5 mg daily to 10-15 mg daily. A treatment course can last for up to 40-45 days and may be repeated after 1-1.5 months. The same dosage regimen was used in the treatment of aphasic syndrome (Daskalov and Athanasova, 1980), combined with speech therapy.

Nivalin in spinal cord diseases

Shenk at al. (1956) observed positive effects of Nivalin treatment of complications following spinal cord motor neuron lesions by poliovirus. The epidemiological character of poliomyelitis, especially in childhood, and ensuing disabling permanent paralysis and paresis make Nivalin an indispensable agent. The characteristics of Nivalin treatment of poliomyelitis are as follows:

1. Early onset of treatment at the end of the febrile period, i.e. 3 to 4 days after injection.
   
2. Prolonged treatment duration - 50-100 days.
   
3. Repeated therapeutic course.
   
4. Gradual dose increases up to 0.05 mg in divided doses.
   
5. Combination with remedial gymnastics and B-group vitamins.
   

Treatment of residual post poliomyelitic motor disorders in children is usually preceded by a "functional test with Nivalin" - precise and detailed physical examination of the motor function is performed before and 30 min after single Nivalin injection to evaluate the adequate dosage regimen and treatment strategy [13].

Nivalin dosage in childhood is based on the following age intervals:

from 3 to 5 years, 0.5 mg; from 5 to 6 years, 075 mg; from 7 to 9 years, 1 mg; from 10 to 12 years, 1.25 mg; from 13 to 14 years, 1.5 mg; from 15 to 17 years, 2.5 mg.

If the age bracket is related to the respective body weight taken as a mean from the statistical antropometric charts, the doses for post-poliomyelitis children will be from 0.03 to 0.05 mg/kg body weight, which is considerably lower than the dose used for decurarization.

The therapeutic results from Nivalin treatment of residual poliomyelitis motor lesions depend on the size and number of involved motor neurons, and the severity and history of disease.

Nivalin treatment of this severe, disabling disease is a bright opportunity.

The positive results of Nivalin treatment are attributed to its eutrophic effect on synapses, and to the recruitment of new "collateral" temporary inhibited synapses which provide compensatory involvement.

Nivalin in disease of the peripheral nervous system

Nivalin has found wide application in the treatment of facial nerve lesions, neuritis, polyneuropathy, radiculoneuropathy of various etiology, trigeminal neuralgia in combination with group B-vitamins, physiotherapy and Nivalin ionophoresis. The preparation has been shown to exhibit analgesic effects, especially in trigeminal neuralgia, by Cozanitis et al. 1983. The same author points to the structural similarity between galanthamine and morphine, but the analgesic properties of Nivalin are not yet related to that fact.

Nivalin has been used and may be effectively used for toxic lesions of the VIII cranial nerve by ototoxic antibiotics (Pikone, 1962).

In addition to the injectable and oral administration, Nivalin may be applied by electrophoresis in disease of the peripheral nervous system.

Nivalin and its application by electrophoresis

Galanthamine hydrobromide undergoes electrolytic dissociation in solution and the pharmacologically active part, galanthamine, has positive electric charge (cation). By ionophoresis Nivalin may be introduced through the skin into the subcutaneous tissue where it forms a storage depot. Thus its local bioavailability increases and it has more direct action on the affected nerve, avoiding undesired systemic adverse effects. Nivalin is introduced from the positive electrode (anode) by placing a hygroscopic plate (usually a piece of filter paper) soaked with 1-2 ml of 0.25% Nivalin solution between the electrode and the skin. The anode dimensions are 6 x 6 or 4 x 9 cm. Electric current intensity of 0.20 mA/cm², but not more than 0.1 mA/cm² for infants and small children. The session duration is gradually increased from 10 to 15-25 min with a total of 15 sessions. If needed, treatment may be repeated after 30 days.

Nivalin in the treatment of eye diseases

In 1960 Vassilev and Dabov reported the results from Nivalin treatment of 97 glaucoma patients at a meeting of the French Ophthalmologic Association. The authors claimed best results with initial glaucoma and partially with congestive glaucoma. Nivalin was applied in individual dosage regimens as eye drops and ointment.

Nivalin was used in lagophthalmus following facial nerve paralysis until the function of the orbital muscle was recovered, as well in presis of n. abducens of various ethnology, where very good results were obtained in eliminating deviation and diplopia.

Very good results were obtained from the treatment of myasthenic eyelid ptosis with Nivalin. Satisfactory results were obtained in conditions with incomplete atrophic lesions of the optic nerve.

Nivalin in diseases associated with impaired neuromuscular transmission

In 1957 Edelstein first used Nivalin for patients with progressive muscular dystrophy. The encouraging results prompted Georgiev et al. To continue research in that area and develop the principal dosage regime and design of that therapy (1960). The authors used Nivalin in 32 patients with myopathies - progressive muscular dystrophy, myasthenia gravis, dystrophia myotonica, neuromuscular atrophy, spinal muscular atrophy and myotonia congenita. The dose of Nivalin was increased by 2.5 mg in 2-3 days and reached 10 mg, in single cases 20 mg. Treatment duration was from 17 to 55 days. The authors stated that Nivalin action had slower onset than neostigmine, but was more sustained with less adverse effects.

No effect was observed in 6 cases with long history of disease. Best results were obtained with myasthenia gravis.

Similar results were obtained by Bergamini and Badgiore (1960), De Renci (1961), Nastev et al. (1960), Table 2. Pernov et al. distributed their dosage regimen in two periods - period of low doses and period of high doses. They emphasize the long duration of treatment courses and the need to repeat them within intervals of 40-50 days.

It should be noted, in conclusion, that Nivalin is a successful element of the complex therapy used for this complicated and severe pathology.

Table 2. Treatment of diseases with disturbed neuromuscular transmission

Nivalin treatment in functional sexual disorders in men

Kilimov (1962) obtained good results with Nivalin treatment of impotentio coeundi, using therapeutic courses of 30 days duration. A long-term study (Traykov and Paskov) from 1964 to 1973 on 170 male patients showed that Nivalin is effective in cases of psychogenic impotence, without organic lesions of the genitourinary system and without endocrine disorders in 63.5% of the cases. Nivalin was administered orally, as tablets, in gradually increasing doses up to 30 mg daily in 2-3 divided intakes. Nivalin treatment stabilized the erectile function, providing stable erection, and eliminated ejaculation praecox.

Nivalin as an antidote

The antagonism between Nivalin and anticholinergic agents gives ground for its use as their antidote. In 1977 Cozanitis reported successful control of complications ensuing from scopolamine intoxication by injecting a bolus i.v. dose of 20 mg Nivalin. This case and further experimental studies provided evidence for the central effects of galanthamine hydrobromide. EEG data show that it abolished scopolamine-induced wave synchronization.

The anticurare effect of Nivalin at the level of synaptic transmission by cholinesterase inhibition, its stable and steady pharmacokinetics, and good tolerability and safety make it suitable for different diseases and lesions of the nervous system with various degrees of severity.

Nivalin in the treatment of enuresis in children

Pernov et al. (1962) first reported successful treatment of enuresis in children with Nivalin. They treated a group of 12 children, from 4 to 14 years of age, where the condition was due to functional or organic causes. Only one patient could not be healed. The treatment course continued for 30 days. In more refractory cases repeated treatment was applied.

In 1980 Chakarov used Nivalin electrophoresis to treat 75 children with enuresis. Excellent result was obtained in 22.7%, good result in 45.9% and no improvement in the remaining 31.4%. With this pathologic condition the effect of Nivalin was stable - after 15 months the percentage of healed patients (excellent result) droped only to 20.6%.

Indications for use of Nivalin

Nivalin is used in various areas of medicine:

• Anesthesiology and surgery - to abolish the effects of nondepolarizing neuromuscular blockers and treat postoperative paresis and bladder complications;
• Neurology - poliomyelitis (immediately after the febrile period and during recovery and residual period), neuritis, myopathies, myasthenia, progressive muscular dystrophy, cerebral paralysis in childhood, cerebral palsy in neonates, enuresis, residual paresis following hemorrhagic stroke, and some forms of impotence;
• Psychiatry - mental retardation;
• Physiotherapy - electrophoretically in neuritis of the auditory, facial and other nerves; neuritis; neuropathy, endarteritis obliterans, angioneurosis, acrocyanosis, dyshidrosis and neurodermitis;
• Toxicology - poisoning with morphine and its analogues;
• Radiology - to facilitate functional diagnostics of the gastrointestinal tract: cholecystography and cholangiography.
  

Contraindications for use of Nivalin

Bronchial asthma, bradycardia, angina pectoris, heart failure, epilepsy, hyperkinetic dyskinesis.

Drug interactions of Nivalin

Nivalin antagonizes the effects of morphine and its analogues with respect to respiratory depression. Nivalin is pharmacologically incompatible with M-cholinoreceptor blocking drugs (atropine, homatropine), ganglion-blocking drugs (hexamethonium, Pentamine, Pachycarpin, nondepolarizing muscle relaxants (Diplacin), quinine and procaine.

Dosage and route of administration of Nivalin

Nivalin is administered parenterally: subcutaneously (s.c.), intramuscularly (i.m.) and intravenously (i.v). Treatment starts with the lowest effective dose, and the dose is gradually increased. The maximal single dose for adults is 15 mg s.c. and the maximal divided daily dose is 20 mg.

Nivalin is very well tolerated in childhood. Treatment duration depends on the type of disease, but is most often 40-60 days. Two to three treatment courses may be applied in intervals of 1-1.5 months. Higher therapeutic doses may be given as divided dosage, 2-3 times daily.

As anticurare drug Nivalin is administered intravenously; daily dose for adults is 10 to 20 mg.

Nivalin is injected intramuscularly in diagnostic cholecystography and cholangiography at a dose of 1 to 5 mg for adults. In children with brachial plexus paralysis increasing i.m. doses from 0.5 to 5 mg daily may be prescribed for 40 days.

Nivalin is administered orally as tablets and syrup.

Tablets for adults are prescribed at a daily dose of 10-40 mg. The daily dose may be administered in 2-3 divided doses. Especially in myasthenia gravis the daily dose is divided in 3 intakes. Tablets are swallowed without chewing 1 h after meals. If needed, the therapeutic course may be repeated after 1-1.5 months.

• Syrup for children and adults
  
• Infants from 1 to 2 years: 2 x 1/2 teaspoonfuls
  
• Children from 3 to 5 years: 2 x 1 teaspoonfuls
  
  • From 6 to 9 years: 3 x 1 teaspoonfuls
    
  • From 10 to 14 years: 3 x 2 tablespoonfuls
    
• Children above 14 and adults: 3 x 1 tablespoonfuls
  

Nivalin is used for ionophoresis in 1-2 ampules of 2.5 mg. The electric current intensity is 1-2 mA and the session duration 10 min.

Nivalin is used topically for neuritis, neuropathy, radiculitis and plexitis. For this purpose a piece of filter paper is soaked with 1-2 ml of 0.25% Nivalin (solution) and is placed over affected skin area.

For glaucoma 1% Nivalin solution may be applied conjuctivally at 1-2 drops 2-3 times daily between the attacks, or as Nivalin eye bath during acute attack.

Adverse effects

Nivalin is well tolerated at adequate and correctly adjusted dosage. Hypersalivation, sweating, vomiting, dizziness and less often bradycardia may appear in cases of overdose and hypersensitivity.

Precautions

When undesired side effects appear and in case of overdose, the daily dose should be reduced and Nivalin treatment should be withdrawn for 2-3 days. Treatment may then continue at lower daily doses. When needed, atropine may be used as antidote.

Dosage form

1. Nivalin ampoules of 1 mg; 2.5 mg and 10 mg, as 1 ml unit dose in package containers of 10, 50 or 100 each.
   
2. Nivalin tablets of 1 mg and 5 mg, 50 tablets in one unit package.
   
3. Nivabex syrup - combination of Nivalin and group B vitamins - bottles of 125 ml.
   
4. Nivalin syrup 0.5 mg/ml, bottles of 125 ml.
   

Storage

Store in cool place, protected from direct sunlight.