THIOZONE C

Indications

• Pain and inflammation in osteoarthritis
• Pain and inflammation in rheumatoid arthritis
• Pain and inflammation in ankylosing spondylitis

Dosage

Adults: Adult: 100 mg twice daily, increased if necessary to 200 mg twice daily.

Mechanism of action

Celecoxib acts as a selective noncompetitive inhibitor of the COX-2 enzyme, which is primarily induced during inflammation. By inhibiting COX-2, celecoxib decreases the synthesis of various inflammatory mediators, including prostaglandins, which contribute to pain and inflammation. Additionally, celecoxib has anticancer properties by binding to cadherin-11 and inhibiting PDK-1 signaling, as well as by inhibiting carbonic anhydrase enzymes.

Pharmacodynamics

Celecoxib's primary pharmacological effect is the inhibition of pain and inflammation through COX-2 inhibition. Although it has a lower risk of gastrointestinal bleeding compared to non-selective NSAIDs, caution is warranted due to potential thrombotic risks associated with COX-2 inhibition. Studies have shown that celecoxib's cardiovascular safety profile is comparable to that of moderate doses of other NSAIDs like naproxen and ibuprofen, although monitoring is advised, especially in patients with cardiovascular risk factors.

Pharmacokinetics

Celecoxib is well-absorbed after oral administration, with peak plasma concentrations typically reached within 3 hours. It is extensively metabolized in the liver, primarily via cytochrome P450 enzymes (CYP2C9 and CYP3A4). The elimination half-life of celecoxib is approximately 11 hours. Renal excretion accounts for about 57% of the metabolites, while the rest is excreted via the faeces. Dose adjustments may be necessary in patients with hepatic impairment or those taking interacting medications.

Contra-indications

• history of hypersensitivity to aspirin or any other NSAID
• active gastrointestinal bleeding
• active gastrointestinal ulceration
• cerebrovascular disease
• inflammatory bowel disease
• ischaemic heart disease
• mild to severe heart failure
• peripheral arterial disease

Adverse effects

• fluid retention
• gastrointestinal discomfort
• hypertension
• myocardial infarction
• nausea
• skin reactions
• edema
• dyspepsia
• arrhythmias
• depression
• drowsiness

Interactions

• increased exposure with antiarrhythmics
• increased exposure with flecainide
• increased exposure with propafenone
• increased exposure with nitisinone

Precautions

• Monitor blood pressure before and during treatment
• Caution in patients with renal impairment
• Caution in patients with hepatic impairment
• Risk of thrombotic events
• Risk of gastrointestinal bleeding

Pregnancy

Avoid (teratogenic in animal studies)

Breast-feeding

Avoid-present in milk in animal studies

Storage

Store at room temperature, protect from light and moisture

Formulations

• Celecoxib 100 mg capsules
• Celecoxib 200 mg capsules

Indications

• Muscle spasms
• Rheumatic pain
• Traumatic pain
• Spastic sequelae of hemiparesis
• Parkinson's disease-related symptoms
• Acute and chronic lumbar and sciatic pain
• Cervico-brachial neuralgia
• Persistent torticollis
• Post-traumatic and post-operative pain

Dosage

Children: Refer to the BNF for Children for paediatric dosing guidance.

Adults: Refer to the BNF for detailed dosing recommendations.

Mechanism of action

Thiocolchicoside selectively binds to GABA-A receptors, activating GABA inhibitory pathways and acting as a muscle relaxant. It also has an affinity for glycine receptors and partially inhibits nicotinic acetylcholine receptors, contributing to its muscle relaxant properties. The drug is noted for its potential convulsant activity, necessitating caution in individuals susceptible to seizures.

Pharmacodynamics

Thiocolchicoside functions primarily as a muscle relaxant through its action on GABA-A receptors, preventing muscle contractions and providing relief from painful muscle spasms. It exhibits competitive antagonistic properties at GABA receptors and shows significant effects on glycine and nicotinic acetylcholine receptors. It is effective in alleviating symptoms associated with central and reflex muscle contractures, as well as conditions like spastic hemiparesis and neurodyslectic syndrome.

Pharmacokinetics

The specific pharmacokinetic profile of thiocolchicoside, including absorption, distribution, metabolism, and excretion details, is not provided. For optimal therapeutic management, refer to established guidelines and consult pharmacokinetic resources.

Contra-indications

• Hypersensitivity to thiocolchicoside or any of its components
• History of seizures or epilepsy
• Severe renal impairment

Adverse effects

• Drowsiness
• Dizziness
• Gastrointestinal disturbances (nausea, vomiting)
• Allergic reactions (skin rash, urticaria)
• Muscle weakness
• Severe hypotension
• Convulsions in predisposed individuals

Interactions

• CNS depressants (e.g., alcohol, benzodiazepines) may enhance sedative effects
• Antiepileptic drugs may reduce the effectiveness of thiocolchicoside
• Other muscle relaxants may increase the risk of adverse effects

Precautions

• Use with caution in patients with hepatic impairment
• Monitor patients for signs of seizures
• Caution in elderly patients or those with a history of falls
• Not recommended for use in children unless prescribed by a specialist

Pregnancy

There are limited data on the use of thiocolchicoside during pregnancy. It should only be used if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether thiocolchicoside is excreted in human milk. Caution is advised when administering to nursing women.

Storage

Store in a cool, dry place, away from direct sunlight. Keep out of reach of children.

Formulations

• Tablets
• Injectable solution

Mechanism of action

Unlike most NSAIDs, which inhibit both types of cyclooxygenases (COX-1 and COX-2), celecoxib is a selective noncompetitive inhibitor of cyclooxygenase-2 (COX-2) enzyme. COX-2 is expressed heavily in inflamed tissues where it is induced by inflammatory mediators. The inhibition of this enzyme reduces the synthesis of metabolites that include prostaglandin E2 (PGE2), prostacyclin (PGI2), thromboxane (TXA2), prostaglandin D2 (PGD2), and prostaglandin F2 (PGF2). Resultant inhibition of these mediators leads to the alleviation of pain and inflammation. By inhibiting prostaglandin synthesis, non-steroidal anti-inflammatory drugs (NSAIDs) cause mucosal damage, ulceration and ulcer complication throughout the gastrointestinal tract. Celecoxib poses less of an ulceration risk than other NSAIDS, owing to its decreased effect on gastric mucosal prostaglandin synthesis when compared to placebo. Celecoxib exerts anticancer effects by binding to the cadherin-11 (CDH11)protein, which is thought to be involved in the progression of tumors, and inhibiting the 3-phosphoinositide-dependent kinase-1 (PDK-1) signaling mechanism. In addition, celecoxib has been found to inhibit carbonic anhydrase enzymes 2 and 3, further enhancing its anticancer effects. As mentioned in the pharmacodynamics section of this drug entry, celecoxib may cause an increased risk of thrombotic events. The risk of thrombosis resulting from COX-2 inhibition is caused by the vasoconstricting actions of thromboxane A2, leading to enhanced platelet aggregation, which is uncontrolled when the actions of prostacyclin, a platelet aggregation inhibitor, are suppressed through the inhibition of COX-2. Nonsteroidal anti-inflammatory drugs (NSAIDs) are well-known causes of acute renal insufficiency and gastropathy in patients with chronic inflammatory diseases. This action is presumed to result from nonselective inhibition of both constitutive and inducible forms of prostaglandin H synthases, also known as the cyclooxygenase enzymes (i.e., COX-1 amd COX-2). Celecoxib (Celebrex) is a COX-2 enzyme inhibitor and has emerged as a preferred therapeutic agent for the treatment of rheumatoid arthritis as compared to other NSAIDs. Celecoxib has recently been the subject of criticism for its side effects, mainly arterial thrombosis and renal hemorrhage, although it is considered a superior drug in protecting the gastrointestinal tract. In the present study, we report that celecoxib not only inhibited COX-2, but also exhibited the property of inhibiting adenylyl cyclase, an important enzyme forming the intracellular second messenger 3',5'-adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). Celecoxib also inhibited cholera toxin-stimulated cAMP formation, which indicated its ability to permeate cell membranes in order to reach intracellular adenylyl cyclase. It inhibited in vitro adenylyl cyclase activity in both human colonic epithelial cells and purified adenylyl cyclase from Bordetella pertussis. The IC50 of celecoxib for B. pertussis adenylyl cyclase was calculated to be 0.375 mM. Lineweaver-Burk analysis showed that the type of enzyme inhibition was competitive. The apparent Km and Vm of adenylyl cyclase was calculated as 25.0 nM and 7.14 nmol/min/mg, respectively. Celecoxib changed the Km value to 66.6 nM without affecting the Vmax. The current study suggests that apart from inflammation, celecoxib therapy could be further extended to diseases involving cAMP upregulation either by endogenous reactions or exogenous agents. These new data showing inhibition of adenylyl cyclase should be considered in light of the drug's pathological effects or in patients specifically excluded from treatment (e.g., asthmatics). Cardiovascular disease is one of the leading causes of death worldwide, and evidence indicates a correlation between the inflammatory process and cardiac dysfunction. Selective inhibitors of cyclooxygenase-2 (COX-2) enzyme are not recommended for long-term use beca

Pharmacodynamics

Celecoxib inhibits cyclooxygenase 2 (COX-2) enzyme, reducing pain and inflammation. It is important to note that though the risk of bleeding with celecoxib is lower than with certain other NSAIDS, it exists nonetheless and caution must be observed when it is administered to those with a high risk of gastrointestinal bleeding. **A note on the risk of cardiovascular events** Significant concerns regarding the safety of COX-2 selective NSAIDs emerged in the early 2000s. [Rofecoxib], another member of the COX-2 inhibitor drug class, also known as Vioxx, was withdrawn from the market due to prothrombotic cardiovascular risks. Following an FDA Advisory Committee meeting in 2005, in which data from large clinical outcome trials were evaluated, the FDA concluded that the risk for cardiovascular thrombotic events for both COX-2 selective NSAIDs and nonselective NSAIDs was evident. It was determined that the benefits of celecoxib treatment, however, outweighed the risks. Postmarketing cardiovascular outcomes trial (PRECISION) revealed that the lowest possible dose of celecoxib was similar in cardiovascular safety to moderate strength doses of both naproxen and ibuprofen. Patients who had previous cardiovascular events including acute MI, coronary revascularization, or coronary stent insertion were not evaluated in the trial. It is not advisable to administer NSAIDS to these groups of patients.

Mechanism of action

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.

Pharmacodynamics

Thiocholchicoside is a muscle relaxing agent that works through selective binding to the GABA-A receptor. It prevents muscle contractions by activating the GABA inhibitory motor pathway. This medication acts as a competitive GABA receptor antagonist and inhibits glycine receptors with similar potency as nicotinic acetylcholine receptors. It has powerful convulsant activity and should not be used in individuals at risk for seizures. Used in combination with glafenine and meprobamate to tranquilize patients undergoing hysterosalpingography. In the treatment of painful muscle spasms. Thiocolchicoside acts both in contractures with a central cause and in contractures of reflex type, rheumatic and traumatic. It also alleviates symptoms of spastic sequelae of hemiparesis, Parkinson's disease and iatrogenic Parkinson symptoms, particularly neurodyslectic syndrome. Some other conditions that may benefit from this medication are acute and chronic lumbar and sciatic pain, cervico-brachial neuralgia, persistent torticollis, post-traumatic and post-operative pain.