Zyflex Nano

Uses

Methyl salicylate is a topical counter-irritant used for the symptomatic relief of acute musculoskeletal pain in the muscles, joints, and tendons.

Ointments or liniments containing methyl salicylate are applied topically as counter irritant for relief of acute pain associated with lumbago,sciatica and rheumatic conditions. Local analgesics for human and veterinary medicine.

Thiocolchicoside is a semi-synthetic colchicine derivative used as an analgesic and anti-inflammatory.

Thiocolchicoside is a skeletal muscle-relaxant drug used in the treatment of orthopedic, traumatic and rheumatologic disorders . It is indicated as an adjuvant drug in the treatment of painful muscle contractures and is indicated in acute spinal pathology, for adults and adolescents 16 years of age and older . Recent studies have examined its effect on muscle tone, stiffness, contractures, and soreness experienced by athletes during sporting competitions .

Zyflex Nano is also used to associated treatment for these conditions: Acute Muscle Pain, Arthritis, Back Pain Lower Back, Backache, Contusions, Joint Pain, Ligament pain, Muscle Inflammation, Muscle Injuries, Muscle Strain, Muscle swelling, Pain, Pain of the Bone and Bones, Pain, Nerve, Partial-Onset Seizures, Postherpetic Neuralgia, Soreness, Muscle, Sprains, Tendon pain, Minor aches, Muscle, joint painsBack Pain, Acute, Chronic Back Pain, Extra-Articular Rheumatism, Muscle Inflammation, Muscle Spasms, Musculoskeletal Pain, Nonspecific Pain Post Traumatic Injury, Osteoarthritis (OA), Pain, Post Surgical Pain, Post-traumatic pain, Postoperative pain, Rheumatoid Arthritis, Soreness, Muscle, Spasms, Spinal pain, Vertebral column pain, Inflammation localized, Localized pain, Mild to moderate pain, Musculoskeletal spasms

How Zyflex Nano works

Counter-irritation is thought to be effective at alleviating musculoskeletal pain as the irritation of the sensory nerve endings is thought to alter or offset pain in the underlying muscle or joints that are served by the same nerves . This is thought to mask the underlying musculoskeletal pain and discomfort. When applied topically, methyl salicylate is thought to penetrate the skin and underlying tissues where it reversibly inhibits cyclooxygenase enzyme and locally and peripherally prevents the production of inflammatory mediators such as prostaglandin and thromboxane A2.

Thiocolchicoside, is a synthetic sulfur derivative of colchicoside, a naturally occurring glucoside contained in the Colchicum autumnale plant. Thiocolchicoside has a selective and potent affinity for g-aminobutyric acid A (GABA-A) receptors and acts on muscular contractures by activating the GABA inhibitory pathways thereby behaving as a potent muscle relaxant . Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human cortex . GABAergic neurons are involved in myorelaxation, anxiolytic treatment, sedation, and anesthetics. GABA can also modulate heart rate and blood pressure.

It also has an affinity for the inhibitory glycine receptors (i.e., have glycomimetic and GABA mimetic activity), therefore acts as a muscle relaxant. Glycine is an inhibitory neurotransmitter and acts as an allosteric regulator of NMDA (N-methyl-D-aspartate) receptors. It is involved in the processing of motor and sensory data, thereby regulating movement, vision, and audition. Inhibitory neurotransmitter in spinal cord, allosteric regulator of NMDA receptors .

In one study, thiocolchicoside inhibited the function of recombinant human strychnine-sensitive glycine receptors composed of the alpha1 subunit with a potency (median inhibitory concentration of 47 microM) lower than that apparent with recombinant GABA(A) receptors. The drug also inhibited the function of human nicotinic acetylcholine receptors made of the alpha4 and beta2 subunits, however, this effect was partial and moreover only apparent at high concentrations. Thiocolchicoside demonstrated no effect on the function of 5-HT(3A) serotonin receptors .

Toxicity

Oral LD50 values (mg/kg) for mouse, rat and rabbit are 1110, 887 and 1300, respectively. Oral LD50 values for child and adult human (mg/kg) are 228 and 506, respectively. Although systemic toxicity from topical administration is rare, methyl salicylate can be absorbed in intract skin to cause stimulation of the central nervous system respiratory center, disturbance of lipid and carbohydrate metabolism, and disturbance of intracellular respiration. Severe toxicity can result in acute lung injury, lethargy, coma, seizures, cerebral edema, and death. In case of salicylate poisoning, the treatment consists of general supportive care, gastrointestinal decontamination with activated charcoal in cases of salicylate ingestion, and monitoring of serum salicylate concentrations. Bicarbonate infusions or hemodialysis can be used to achieve enhanced salicylate elimination .

Has been shown to cause chromosomal aneuploidy and male infertility. Should be avoided during all stages of pregnancy, lactation and puberty. Is a potential risk factor for cancer.

In 2013, The European Medical Association (EMA) mandated that the use of thiocolchicoside-containing medicines by mouth or injection should be restricted across the European Union (EU). These drugs are now recommended only as an add-on treatment for painful muscle contractures resulting from spinal conditions in adults and adolescents 16 years old and older. Additionally, the dose of thiocolchicoside by mouth or injection should be limited. This is due to experimental evidence suggesting that thiocolchicoside was metabolized into M2 or SL59.0955, that has the propensity to damage dividing cells, resulting in aneuploidy (an abnormal number or arrangement of chromosomes). As a result, the CHMP (committee for medicinal products for human use) examined the safety profile of this medicine and consider what regulatory action might be appropriate .

The CHMP reviewed the evidence, with consideration of opinions from experts in medicines safety, and concluded that aneuploidy may occur with M2 at levels not significantly greater than those measured after recommended doses of thiocolchicoside ingested orally. Aneuploidy is a strong risk factor for fetal harm, decreased fertility in men, and could theoretically increase the risk of developing cancer .

The maximum recommended oral dose is 8 mg every 12 hours; treatment length should not exceed 7 consecutive days. When given intramuscularly (IM), the maximum dose is 4 mg every 12 hours, for a maximum of 5 days .

In addition to the above toxicity, a study was done on the hepatotoxic potential of thiocolchicoside. It was observed that serum AST and ALT levels increased following of the administration oral thiocolchicoside at 8 mg/day. Two weeks after discontinuing thiocolchicoside therapy, liver enzymes had decreased to levels within the normal range. Although infrequent, thiocolchicoside should be considered a rare hepatotoxic agent in clinical practice .

Volume of Distribution

After absorption, methyl salicylate is distributed throughout most body tissues and most transcellular fluids, primarily by pH dependent passive processes. Salicylate is actively transported by a low-capacity, saturable system out of the CSF across the choroid plexus. The drug readily crosses the placental barrier.

The apparent volume of distribution of thiocolchicoside is estimated to be approximately 42.7 L after an intramuscular injection of 8 mg .

Elimination Route

Approximately 12-20% of topically applied methyl salicylate may be systemically absorbed through intact skin within 10 hours of application, and absorption varies with different conditions such as surface area and pH. Dermal bioavailability is in the range of 11.8 – 30.7%. For the assessment of potential oral exposure to salicylates, bioavailability is assumed to be 100% .

Oral bioavailability is ~25% After intramuscular administration, thiocolchicoside Cmax occur in 30 min and .reach values of 113 ng/mL after a 4 mg dose and 175 ng/mL after a 8 mg dose. The corresponding values of AUC are respectively 283 and 417 ng.h/mL. The pharmacologically active metabolite SL18.0740 is found at lower concentrations with a Cmax of 11.7 ng/mL occurring 5 h post administration and an AUC of 83 ng.h/mL .

After oral administration, no thiocolchicoside is detected in plasma. Only two metabolites are observed: The pharmacologically active metabolite SL18.0740 and an inactive metabolite SL59.0955. For both metabolites, maximum plasma concentrations occur 1hour after thiocolchicoside administration. After a single oral dose of 8 mg of thiocolchicoside the Cmax and AUC of SL18.0740 are about 60 ng/mL and 130 ng.h/mL respectively. For SL59.0955 these values are much lower: Cmax around 13 ng/mL and AUC ranging from 15.5 ng.h/mL (until 3h) to 39.7 ng.h/mL (until 24h) .

Half Life

The plasma half-life for salicylate is 2 to 3 hr in low doses and about 12 hr at usual anti-inflammatory doses. The half-life of salicylate may be as long as 15 to 30 hr at high therapeutic doses or when there is intoxication.

Approximately 7.7h .

Clearance

Primarily extrarenal elimination (75% of the total body clearance) .

Elimination Route

Excreted by kidneys as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl glucuronide (5%), and gentisic acid (less than 1%).

Thiocolchicoside is not eliminated unchanged, rather as one of three metabolites found in either feces (~79 %) or in urine 20%. 3- demethylcolchicine (M2) and 3-O-glucurono-demethylcolchicine (M1) are found in both urine and feces, where as di-demethylcolchicine is found only in feces .

Innovators Monograph

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