Combitropil

Combitropil Uses, Dosage, Side Effects, Food Interaction and all others data.

Cinnarizine provides quick relief of various symptoms of cerebral and peripheral circulation disorders. Cinnarizine protects attacks of vascular headache such as migraine. Cinnarizine normalizes cerebral circulation time and improves cerebral irrigation in patients suffering from the disorders of cerebral circulation. Cinnarizine normalizes arterial pulsations in patients suffering from vasospastic disorders. Cinnarizine significantly increases the rate of inflow or pulsation and the blood flow in the most affected limb as well as the walking distance of patients suffering from intermittent claudication.

Cinnarizine acts as an antihistamine, labyrinthine sedative and a peripheral antivasoconstrictor. Inarzin is a selective calcium antagonist, inhibiting the influx of Ca2+ intracellularly. It prevents the Ca2+ dependent contraction of arterial smooth muscle by inhibiting Ca2+ influx through smooth muscle calcium channels and thereby, improves vestibular symptoms and prevents peripheral arterial disease.

Cinnarizine is an antihistamine and a calcium channel blocker. Histamines mediate a number of activities such as contraction of smooth muscle of the airways and gastrointestinal tract, vasodilatation, cardiac stimulation, secretion of gastric acid, promotion of interleukin release and chemotaxis of eosinophils and mast cells. Competitive antagonists at histamine H1 receptors may be divided into first (sedating) and second (non-sedating) generation agents. Some, such as Cinnarizine also block muscarinic acetylcholine receptors and are used as anti-emetic agents. Cinnarizine through its calcium channel blocking ability also inhibits stimulation of the vestibular system.

Piracetam's mechanism of action is not fully understood. The drug influences neuronal and vascular functions and influences cognitive function without acting as a sedative or stimulant. Piracetam is a positive allosteric modulator of the AMPA receptor. It is hypothesized to act on ion channels or ion carriers, thus leading to increased neuron excitability. GABA brain metabolism and GABA receptors are not affected by piracetam

It has been found to increase blood flow and oxygen consumption in parts of the brain, but this may be a side effect of increased brain activity rather than a primary effect or mechanism of action for the drug.

Piracetam improves the function of the neurotransmitter acetylcholine via muscarinic cholinergic (ACh) receptors, which are implicated in memory processes. Furthermore, piracetam may have an effect on NMDA glutamate receptors, which are involved with learning and memory processes. Piracetam is thought to increase cell membrane permeability. Piracetam may exert its global effect on brain neurotransmission via modulation of ion channels (i.e., Na+, K+). It has been found to increase oxygen consumption in the brain, apparently in connection to ATP metabolism, and increases the activity of adenylate kinase in rat brains. Piracetam, while in the brain, appears to increase the synthesis of cytochrome b5, which is a part of the electron transport mechanism in mitochondria. But in the brain, it also increases the permeability of the mitochondria of some intermediaries of the Krebs cycle.

Piracetam is known to mediate various pharmacodynamic actions:

Neuronal effects:

Piracetam modulates the cholinergic, serotonergic, noradrenergic, and glutamatergic neurotransmission although the drug does not display high affinity to any of the associated receptors (Ki >10μM). Instead, piracetam increases the density of postsynaptic receptors and/or restore the function of these receptors through stabilizing the membrane fluidity . In the forebrain of aging mice, the density of NMDA receptors was increased by approximately 20% following 14 days of piracetam treatment. Based on the findings of various animal and human studies, the cognitive processses including learning, memory, attention and consciousness were enhanced from piracetam therapy without inducing sedation and psychostimulant effects . Piracetam mediate neuroprotective effects against hypoxia-induced damage, intoxication, and electroconvulsive therapy .

Combitropil
Uses
Dosage
Side Effect
Precautions
Interactions
Uses during Pregnancy
Uses during Breastfeeding
Accute Overdose
Food Interaction
Half Life
Volume of Distribution
Clearance
Interaction With other Medicine
Contradiction
Storage

Trade Name	Combitropil
Generic	Cinnarizine + Piracetam
Type
Therapeutic Class
Manufacturer
Available Country	Russia
Last Updated:	September 19, 2023 at 7:00 am

Uses

It is mainly used for the symptomatic treatment of nausea and vertigo due to Meniere's disease and other labyrinthine disturbances and for the prevention and treatment of motion sickness. It is also used in the management of various vascular disorders.

Cerebral circulatory disorders:

Prophylaxis and maintenance therapy for symptoms of cerebral vascular spasms and arteriosclerosis such as dizziness, ear buzzing (tinnitus), vascular headache, unsociability and irritability, fatigue, sleep rhythm disorders such as premature awakening, involutional depressions, loss of memory and lack of concentration, incontinence and other disorders due to aging.
Sequel of cerebral and cranial trauma.
Post-apoplectic disorders.
Migraine.

Peripheral circulatory disorders: Prophylaxis and maintenance therapy for symptoms of vascular spasms and arteriosclerosis (obliterating arteritis, thromboangitis obliterans, Raynaud's disease, diabetes, acrocyanosis, perrio, etc.) such as: intermittent claudication, trophic disturbances, pregangrene, trophic and varicose ulcers, paraesthesia, nocturnal cramps, cold extremities.

Disorders of balance:

Prophylaxis and maintenance therapy for symptoms of labyrinthine arteriosclerosis, vestibular irritability, Meniere's syndrome, such as vertigo, dizziness, giddiness, syncopal attacks, tinnitus, nystagmus, nausea and vomiting.
Prophylaxis of motion sickness.

Cerebral vascular accidents and cerebral insufficiencies: Ischaemic or even haemorrhagic acute accidents, chronic manifestations of the above accidents or of cerebral atherosclerosis.

Mental retardation in children: Ease of resuming individual contact, sociability and learning, improved intellectual performances and school results.

Behaviour and psychotic problems in old age: Memory deficits, particularly with regard to fixation and evocation asthenia adaption disorders, disturbed psychomotor reactions. Patients suffering from myoclonus of cortical origin.

Combitropil is also used to associated treatment for these conditions: Balance Disorders, Dizziness, Motion Sickness, Nausea, Peripheral Artery Disease (PAD), Raynaud's Phenomenon, Inadequate cerebral circulation, Peripheral vasculopathyAlcohol Dependency, Alcohol Withdrawl, Cognitive Deficits caused by Injuries, Craniocerebral, Cognitive Dysfunctions, Cognitive Impairments, Comatose caused by Blood Vessel (Vascular) Dysfunction, Comatose caused by CNS Toxicity, Comatose caused by Traumas, Learning Disorders, Myoclonus, Sickle Cell Disease (SCD), Giddiness caused by Injuries, Craniocerebral

How Combitropil works

Cinnarizine inhibits contractions of vascular smooth muscle cells by blocking L-type and T-type voltage gated calcium channels. Cinnarizine has also been implicated in binding to dopamine D2 receptors, histamine H1 receptors, and muscarinic acetylcholine receptors.

Piracetam interacts with the polar heads in the phospholipids membrane and the resulting mobile drug-lipid complexes are thought to reorganize the lipids and influence membrane function and fluidity . Such interaction has been reported in a study that investigated the effects of neuronal outgrowth induced by beta amyloid peptides; while amyloid peptides cause lipid disorganization within the cell membranes leading to neuronal death, piracetam demonstrated to decrease the destabilizing effects of amyloid peptide . The authors suggest that piracetam induces a positive curvature of the membrane by occupying the polar groups in the phospholipids to counteract the negative curvature induced by amyloid peptides , which in turn would decrease the likelihood of membrane fusion . This mechanism of action is thought to improve membrane stability, allowing the membrane and transmembrane proteins to maintain and recover the three-dimensional structure or folding for normal function such as membrane transport, chemical secretion, and receptor binding and stimulation .

Through restored membrane fluidity, piracetam promotes restored neurotransmission such as glutamatergic and cholinergic systems, enhances neuroplasticity and mediates neuroprotective and anticonvulsant effects at the neuronal level . It is also demonstrated that piracetam also improves the fluidity of platelet membranes. At the vascular level, piracetam decreases adhesion of erythrocytes to cell wall and reduces vasospasm which in turn improves microcirculation including cerebral and renal blood flow .

Dosage

Combitropil dosage

Peripheral vascular disease:

Adult: 75 mg bid or tid.

Cerebrovascular disorders:

Adult: 75 mg once daily.

Motion sickness:

Adult: 30 mg 2 hr before travel then 15 mg 8 hrly during the journey if necessary.
Child: 5-12 yr 15 mg 2 hr before travel then 7.5 mg 8 hrly during the journey as necessary.

Vertigo and vestibular disorders:

Adult: 30 mg tid or 75 mg 1-2 times daily.
Child: 5-12 yr 15 mg tid.

Oral: Adults:

In cerebro-cortical insufficiency disorders, usual dose is one tablet (800 mg) 3 times a day.
In myoclonic seizures, a dose of 7.2 gm daily, increasing by 4.8 gm per day every 3 to 4 days up to maximum of 20 gm daily, given in 2 or 3 divided doses.

Oral: Children:

The daily dosage depends on the weight of the child, 50 mg/kg of body weight in 3 divided doses. Once the desired results has been obtained, reduce the initial dose by half.

Parenteral formulations: When parenteral administration is needed (e.g. swallowing difficulties, unconsciousness) Piracetam can be administered intravenously.When treating severe symptoms, 12 g daily may need to be administered as an intravenous infusion.

Piracetam is compatible (physico-chemical compatibility) with the perfusions of:

Glucose 5%, 10%, 20%
Fructose 5%, 10%, 20%
Sodium chloride 0.9%
Dextran 40 (10% in a 0.9% NaCl solution)
Ringer Mannitol 20%
HES solution (Hydroxy Ethyl Starch) 6% and 10%

The stability of these solutions has been demonstrated up to 24 hours.

Side Effects

Side effects such as somnolence and gastrointestinal disturbances are extremely rare. They are transient and may be readily prevented by achieving the optimal dosage gradually. Combination therapy with other drugs is possible. Whenever indicated, caution should be taken in hypotension (high doses). Rarely, extrapyramidal symptoms in elderly on prolonged therapy.

The side effects reported include nervousness, agitation, irritability, anxiety and sleep disturbances. The incidence of these during clinical trials was (≤ 5%) and they were more often noted in the older patients taking > 2.4 gm daily. In the majority of cases, a dose reduction sufficed to make these symptoms disappear. Some patients may complain of fatigue or drowsiness, gastrointestinal problems, e.g. nausea, vomiting, diarrhoea and stomachache have also been reported but their incidence during clinical trials was ≤ 2%. Other symptoms e.g. vertigo, headache, trembling and sexual stimulation have occasionally been reported.

Toxicity

The cases of overdose with piracetam is rare. The highest reported overdose with piracetam was oral intake of 75g which was associated with diarrhea and abdominal pain; the signs were most likely related to the extreme high dose of sorbitol contained in the used formulation. In cases of acute, significant overdosage, stomach emptying by gastric lavage or induced emesis is recommended as there are no known antidotes for piracetam . Management for an overdose will most likely be symptomatic treatment and may include hemodialysis, where the extraction efficacy of the dialyser is 50 to 60% for the drug .

Oral LD50 in a mouse acute toxicity study was 2000 mg/kg .

Precaution

Patient with hypotension (high dose), Parkinson's disease, porphyria. Renal and hepatic impairment. Childn. Pregnancy and lactation.

Interaction

Concurrent use of alcohol, CNS depressants or tricyclic antidepressants may potentiate the sedative effects of either these drugs or of Cinnarizine. Therefore, it is advisable to avoid these drugs while taking Cinnarizine.

In a single case, confusion, irritability and sleep disorders were reported in concomitant use with thyroid extract. At present, no interaction has been observed with the following anti-epileptic drugs, clonazepam, carbamazepine, phenyton, phenobarbitone and sodium valporate, based on a small number of studies.

Volume of Distribution

Vd is approximately 0.6L/kg. Piracetam may cross the blood-brain barrier as it was measured in the cerebrospinal fluid following intravenous administration . Piracetam diffuses to all tissues except adipose tissues, crosses placental barrier and penetrates the membranes of isolated red blood cells .

Elimination Route

Piracetam displays a linear and time-dependent pharmacokinetic properties with low intersubject variability over a large range of doses. Piracetam is rapidly and extensively absorbed following oral administration with the peak plasma concentration is reached within 1 hour after dosing in fasted subjects. Following a single oral dose of 3.2 g piracetam, the peak plasma concentration (Cmax) was 84 µg/mL. Intake of food may decrease the Cmax by 17% and increase the time to reach Cmax (Tmax) from 1 to 1.5 hours. Tmax in the cerebrospinal fluid is achieved approximately 5 hours post-administration .

The absolute bioavailability of piracetam oral formulations is close to 100% and the steady state plasma concentrations are achieved within 3 days of dosing .

Half Life

The plasma half life of piracetam is approximately 5 hours following oral or intravenous administration. The half life in the cerebrospinal fluid was 8.5 hours .

Clearance

The apparent total body clearance is 80-90 mL/min .

Elimination Route

Piracetam is predominantly excreted via renal elimination, where about 80-100% of the total dose is recovered in the urine. Approximately 90% of the dose of piracetam is excreted in the urine as unchanged drug .

Pregnancy & Breastfeeding use

Pregnancy Category C. The safety of Cinnarizine in human pregnancy has not been established. Therefore, it is not advisable to administer Cinnarizine in pregnancy.

Lactation: It is not known if Cinnarizine is excreted in human breast milk. Use of Cinnarizine during breast feeding is not advised.

Piracetam should not be prescribed during pregnancy or when breast feeding, except under exceptional circumstances. Piracetam is able to cross the placenta.

Contraindication

Contraindicated in Known hypersensitivity to Cinnarizine, Parkinson’s disease, Hypotension

Piracetam is contra-indicated in patients with severe renal insufficiency (creatinine clearance < 20 ml/min) and hepatic impairment. As the principal route of elimination for Piracetam is via the kidney, special care must be taken when treating patients known to suffer from renal insufficiency. Monitoring of renal function is recommended in such cases. The increase in half-life is directly related to the decrease in renal function and creatinine clearance. This is also true for the older patient in whom creatinine clearance is dependent on age. When the creatinine clearance is < 60 ml/min, or serum creatinine is >1.25 mg/100 ml, the dosage prescribed should be calculated as following:

CrCl 60-40 ml/min: Dosage should be 1/2 of normal dose

CrCl 40-20 ml/min: Dosage should be 1/4 of normal dose

Special Warning

Neonates: Cinnarizine is not indicated in neonates.

Children: No formal pharmacokinetic study has been conducted in children.

Elderly: In the elderly, the half-life of piracetam is increased and the increase is related to the decrease in renal function in this population (see Section Dosage and Administration).

Renal impairment: Piracetam clearance is correlated to creatinine clearance. It is therefore recommended to adjust the daily dose of piracetam based on creatinine clearance in patients with renal impairment

Hepatic impairment: The influence of hepatic impairment on the pharmacokinetics of piracetam has not been evaluated. Because 80 to 100% of the dose is excreted in the urine as unchanged drug, hepatic impairment solely would not be expected to have a significant effect on piracetam elimination.

Acute Overdose

Symptoms: Consciousness alterations ranging from somnolence to stupor and coma, vomiting, extrapyramidal symptoms, hypotonia; seizures may occur in young children.

Management: Symptomatic and supportive treatment. May consider admin of activated charcoal within 1 hr of ingestion.

Piracetam appears to be devoid of toxicity even at very high doses and, therefore, the need for specific measures to be taken in case of an overdose is avoided. Drug Interactions: In a single case, confusion, irritability and sleep disorders were reported in concomitant use with thyroid extract. At present, no interaction has been observed with the following anti-epileptic drugs, clonazepam, carbamazepine, phenytoin, phenobarbitone and sodium valproate, based on a small number of studies.