Oxybrain

Uses

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.

Vinorelbine is used for:

• In combination with cisplatin for first-line treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)
• As a single agent, for the treatment of patients with metastatic NSCLC

Oxybrain is also used to associated treatment for these conditions: Alcohol 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, CraniocerebralAdvanced Non Small Cell Lung Cancer, Esophageal Cancers, Locally Advanced Non-Small Cell Lung Cancer, Metastatic Breast Cancer, Recurrent Cervical Cancer, Soft Tissue Sarcoma (STS), Recurrent, IV-B Cervical cancer

How Oxybrain works

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 .

Vinca alkaloids are structurally similar compounds composed of two multi-ringed units, vindoline, and catharanthine. Vinorelbine tartrate is a vinca alkaloid in which the catharanthine component is the target of structural modification , .

This structural modification contributes to unique pharmacologic properties.The antitumor activity of vinorelbine tartrate is believed to be owed to the inhibition of mitosis at metaphase via its interaction with tubulin .

Vinorelbine is a mitotic spindle poison that interferes with chromosomal segregation during mitosis, also known as cell division. It pauses cells at the G2/M phases, when present at concentrations close to the half maximal inhibitory concentration (IC50). Microtubules, which are derived from polymers of tubulin, are the main target of vinorelbine.

The chemical modification used to produce vinorelbine allows for the opening of the eight-member catharanthine ring with the formation of both a covalent and reversible bond with tubulin .

The relative contribution of different microtubule-associated proteins in the production of tubulin vary between neural tissue and proliferating cells and this has important functional implications. The ability of vinorelbine to bind specifically to mitotic rather than other microtubules has been shown and may suggest that neurotoxicity is less likely to be a problem than with the molecular mechanism of action .

As with other anti-microtubule agents, vinorelbine is known to contribute apoptosis in malignant cells. The exact mechanisms by which this process occurs are complex and many details are yet to be elucidated. The disarray of the microtubule structure has a number of effects, including the induction of tumor suppressor gene p53 and activation/inactivation of a number of protein kinases involved in essential signaling pathways, including p21 WAF1/CIP1 and Ras/Raf, PKC/PKA. These molecular changes lead to phosphorylation and consequently inactivation of the apoptosis inhibitor Bcl2. This, in turn, results in a decrease in the formation of heterodimers between Bcl2 and the pro-apoptotic gene BAX, stimulating the sequence of cell apoptosis .

Vinorelbine tartrate also possibly interferes with amino acid, cyclic AMP and glutathione metabolism, calmodulin-dependent Ca++-transport ATPase activity, cellular respiration, and nucleic acid and lipid biosynthesis .

Dosage

Oxybrain dosage

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.

Intravenous (Adult):

Cervical cancer:30 mg/m2/dose days 1 and 8 of a 21-day treatment cycle.

Breast cancer, Ovarian cancer :25 mg/m2/dose every 7 days.

Non-small cell lung cancer:

• As single agent: 30 mg/m2wkly as infusion over 20-30 minutes (after diluting in 125 ml normal saline or glucose 5%) or as slow bolus over 5-10 minutes (after diluting in 20-50 ml normal saline or glucose 5%). Delay subsequent doses if neutrophil count is <2000 cells/mm3until recovery.
• As combination therapy with cisplatin: 25-30 mg/m2every 7 days.

Oral(Adult):

Non-small cell lung cancer:60 mg/m2once wkly for 3 wk, may increase subsequently to 80 mg/m2once wkly. If neutrophil count is < 500 cells/mm3or between 500-1000 cells/mm3on 2 separate occasions, keep dose at 60 mg/m2for next 3 doses.

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

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.

Neurotoxicity, peripheral paraesthesia, loss of deep tendon reflexes, abdominal pain, severe constipation, diarrhoea, alopecia, severe local irritation. Dose limiting granulocytopenia, leukopenia and anaemia. Intestinal obstruction, paralytic ileus, nausea, vomitinh, increased in LFT, chest pain, fatigue. Local pain and thrombophlebitis with repeated Inj.

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 .

Due to the wide array of adverse effects of this drug, the toxicity of is categorized into organ systems .

Hematologic: Granulocytopenia was the primary dose-limiting toxicity with vinorelbine tartrate therapy; it is generally reversible and not cumulative. In one study, granulocytopenia resulted in hospitalizations for fever and/or sepsis in 8% of NSCLC and 9% of breast cancer patients . Infectious (septic) deaths occurred in about 1% of patients. Grade 3 or 4 anemia occurred in about 1% of lung cancer and approximately 14% of breast cancer patients. Blood transfusions were administered to 18% of patients who received vinorelbine tartrate therapy. The incidence of Grade 3 and 4 thrombocytopenia was found to be less than 1% .

Neurologic: Mild to moderate peripheral neuropathy may occur. Symptoms of paresthesia and hypesthesia are reported as the most commonly reported neurologic toxicities of this drug. The loss of deep tendon reflexes (DTR) occurs in less than 5% of patients, according to one study. The development of severe peripheral neuropathy is rare .

Dermatologic: Alopecia has been reported in only about 12% of patients and is usually reported as mild. Vinorelbine tartrate is a moderate vesicant, leading to injection site reactions. Symptoms include erythema, pain at the injection site and vein discoloration occurred in about 1/3 of all patients. Chemical phlebitis along the vein, near the site of injection, has been reported .

Respiratory: Shortness of breath was reported in 3% of NSCLC and 9% of breast cancer patients, and was severe in 2% of each patient population. Interstitial pulmonary changes have been documented in a few patients .

Gastrointestinal: Mild or moderate nausea symptoms occurred in 32% of NSCLC and 47% of breast cancer patients treated with vinorelbine tartrate. Severe nausea was occurred infrequently (1% and 3% in NSCLC and breast cancer patients, respectively). Prophylactic administration of anti-emetics was not routine in patients treated with single-agent vinorelbine tartrate. Constipation occurred in about 28% of NSCLC and 38% of breast cancer patients. The paralytic ileus incidence of less than 2% of patients. Vomiting, diarrhea, anorexia and stomatitis were found to be mild or moderate and occurred in less than 20% of study patients .

Hepatic: Transient elevations of liver enzymes were reported without clinical symptoms. Cardiovascular: Chest pain was reported in 5% of NSCLC and 8% of breast cancer patients. Most reports of chest pain were in patients who had either a history of cardiovascular disease or tumor within the chest. There have been rare reports of myocardial infarction; however, these have not been shown definitely attributable to vinorelbine tartrate .

Other: Muscle weakness (asthenia) occurred in about 25% of patients with NSCLC and 41% of patients with breast cancer. It was usually mild or moderate but showed a linear increase with cumulative doses .

Several other toxicities reported in approximately 5% of patients include jaw pain, myalgia, arthralgia, headache, dysphagia, and skin rash. Hemorrhagic cystitis (bladder inflammation with blood in urine) and the syndrome of inappropriate ADH secretion were both reported in less than 1% of patients. The treatment of these entities are mainly symptomatic .

The carcinogenic potential of Vinorelbine has not been adequately studied. Vinorelbine has been demonstrated to affect chromosome number and likely the chromosome structure in vivo (polyploidy in bone marrow cells from Chinese hamsters and a positive micronucleus test in mice were observed) .

Precaution

Hepatic impairment. Compromised bone marrow reserve due to prior irradiation or chemotherapy; recovering marrow function from the effects of previous chemotherapy. Prior radiation therapy; past history or pre-existing neuropathy. CBC with differentials to be monitored prior to admin of subsequent doses. Delay subsequent doses, if neutrophil count < 2000 cells/mm3. Each admin to be followed by at least 250 ml of normal saline to flush the vein. Avoid extravasation. If extravasation occurs, stop infusion immediately, and flush the vein with normal saline solution; admin the remaining solution in another vein. Do not father a child during and up to six mth after treatment and females of childbearing potential to use effective method of contraception during treatment and three mth thereafter. When admin orally, capsules must be swallowed whole with water and not chewed or sucked.

Interaction

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.

Increased risk of granulocytopenia with cisplatin. Increased risk of neurotoxicity with paclitaxel, itraconazole, ketoconazole. Increased radiosensitising effects with prior or concomitant radiation therapy. Increased pulmonary toxicity with mitomycin. Increased myelotoxicity with zidovudine. Earlier onset and/or an increased severity of side effects with CYP3A inhibitors. Possible increase in vincristine levels with aprepitant. Possible infection with live vaccines.

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 .

The volume of distribution is large, indicating extensive extravascular distribution .

The steady-state volume of distribution values range from 25.4 to 40.1 L/kg, according to one study .

Widely distributed, with highest amounts found in elimination organs such as liver and kidneys, minimal in heart and brain .

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 .

Vinorelbine is rapidly absorbed with peak serum concentration reached within 2 hours .

Vinorelbine is highly bound to platelets and lymphocytes and is also bound to alpha 1-acid glycoprotein, albumin, and lipoproteins .

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 .

The terminal phase half-life averaged 27.7 to 43.6 hours; the mean plasma clearances ranged from 0.97 to 1.26 L/hr/kg .

Clearance

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

The plasma clearance of vinorelbine is high, approaching the same as hepatic blood flow in humans, and its volume of distribution is large, indicating extensive extravascular distribution. In comparison to vinblastine or vincristine .

The clearance was found to be in the range of 0.29-1./26 L/ per kg in 4 clinical trials of patients receiving 30 mg/m2 of vinorelbine .

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 .

Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces after intravenous administration to humans .

Urinary excretion of unchanged drug accounts for less than 20% of an intravenous dose, with fecal elimination accounting for an additional 30% to 60% .

After intravenous administration of radioactive vinorelbine, approximately 18% and 46% of administered radioactivity was recovered in urine and feces, respectively .

Pregnancy & Breastfeeding use

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

Pregnancy Category D. There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Contraindication

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

Hypersensitivity to vinorelbine or other vinca alkaloids; severe current or recent infection (within last 2 wk); neutropenia; thrombocytopenia; severe hepatic impairment. Intrathecal admin. Do not give concomitantly with radiotherapy if liver is in treatment field. Pregnancy, lactation.

Special Warning

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.

Hepatic Impairment:Intravenous:

• Cervical cancer: Dose adjustments may be needed.
• Breast cancer, Ovarian cancer: Dose adjustments may be needed.
• Non-small cell lung cancer: Massive liver metastases(>75% of liver volume replaced by the tumour): Decrease dose by 1/3. Bilirubin 2.1-3 mg/100 ml: Reduce IV dose by 50%. Bilirubin >3 mg/100 ml: Reduce IV dose by 75%.

Oral:

• Massive liver metastases(>75% of liver volume replaced by the tumour): Decrease dose by 1/3. Bilirubin 2.1-3 mg/100 ml: Reduce IV dose by 50%. Bilirubin >3 mg/100 ml: Reduce IV dose by 75%.

Acute Overdose

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.

Storage Condition

Store in a cool and dry place at a temperature below 30˚C , Keep away from sunlight. Keep out of the reach of children.

Intravenous: Store at 2-8°C. Protect from light. Oral: Store at 2-8°C.

Innovators Monograph

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