MYRIN P Forte CONTENT: Pyrazinamide 400 mg, rifampicin 150 mg, ethambutol HCl 275 mg, INH 75 mg Should be taken on an empty stomach(Take 1 hr before or 2 hr after meals. May be taken w/ meals or antacids to reduce GI discomfort. Do not take w/ Al-containing antacids.). CONTRAINDICATIONS: Hypersensitivity. Alcoholism, optic neuritis, impaired hepatic function, severe renal insufficiency, hyperuricemia, gouty arthritis, jaundice, retrobulbar neuritis. Patients who are unable to appreciate & reposrt visual side effects or changes in vision eg young childn & patients w/ mental illness or deficiency. Patients <40 kg. Lactation. Pyrazinamide: Severe hepatic damage. Concurrently taking medications associated w/ liver injury, drink excessive amounts of alcohol, underlying liver disease or history of INH associated liver injury. PRECAUTIONS: Perform baseline & periodic assessment of hepatic function, blood uric acid. Preexisting liver disease or at increased risk for drug-related hepatitis (eg alcohol abusers). Discontinue pyrazinamide when signs of hepatocellular damage occur. History gout. Not for use in latent TB infection. Pyridoxine deficiency. Full ophth exam before & during treatment. Discontinue if hyperuricemia is accompanied by acute gouty arthritis. Red-orange discoloration of urine, feces, sputum, saliva & tears. Soft contact lenses may be permanently stained. Produces pink-brown color w/ Acetest & Ketostix. False +ve reactions w/ copper sulfate urine glucose tests. Periodic assessment of organ system functions including renal, hepatic & hematopoietic should be made during therapy. Patients at risk for peripheral neuropathy, epilepsy, DM, decreased renal function. May impair ability to drive or operate machinery. Pregnancy. Childn <13 yr. Elderly. Pharmacology: Pharmacodynamics: The mechanism of action of ethambutol is not fully known. It diffuses into mycobacteria and appears to suppress multiplication by interfering with RNA synthesis. It is effective only against mycobacteria that are actively dividing. Rifampicin inhibits bacterial RNA synthesis by bonding strongly to the β-subunit of DNA-dependent RNA polymerase, preventing the attachment of the enzyme to DNA and thus, blocking initiation of RNA transcription. Isoniazid is a bactericidal antitubercular agent, which is active against actively dividing mycobacteria, and its mode of action may relate to inhibition of mycolic acid synthesis and the disruption of the cell wall in susceptible organisms. The mechanism of action of pyrazinamide is unknown. Pyrazinamide may be bacteriostatic or bactericidal depending on its concentration and the susceptibility of the organism. Pharmacokinetics: Data from a relative bioavailability study in healthy volunteers receiving Myrin/Myrin-P Forte in the fasted state show that each of the active ingredients (rifampicin, isoniazid, ethambutol, or with pyrazinamide), is bioequivalent to the respective reference drug product when these products are given together. Ethambutol: Ethambutol is readily absorbed from the gastrointestinal tract. A single dose of 25 mg/kg produces a peak plasma concentration of 2-5 mcg/mL between 2-4 hrs. It is distributed into most tissues including the lung and localized within pulmonary alveolar and axillary lymph node macrophages. Within 24 hrs after administration, nearly 75% of an ingested dose of ethambutol is excreted as the unchanged drug, and up to 15% is excreted as the 2 metabolites in urine via glomerular filtration and tubular secretion. The mean elimination half-life (t½) is approximately 3 hrs. Ethambutol accumulates in patients with impaired renal function. Ethambutol crosses the placenta and is excreted in breast milk. Rifampicin: Rifampicin is well absorbed following oral administration. A peak plasma concentration of 7-9 mcg/mL is reached within 2-4 hrs after a dose of 600 mg. Food decreases the absorption of rifampicin. Rifampicin undergoes enterohepatic recirculation after absorption. It diffuses well into most body tissues including the cerebrospinal fluid and is metabolized primarily into the deacetylated metabolite. This deacetylated metabolite possesses the antibacterial activity of the unchanged drug. Approximately 65% of a dose of rifampicin is excreted in the feces and nearly 30% in the urine less than half of which may be unchanged drug. The elimination t½ of rifampicin following initial doses varies from 2-5 hrs and decreases to 2-3 hrs after repeated administration due to increased hepatic metabolism. Although renal clearance of rifampicin is reduced in patients with impaired renal function, dosage adjustment in these patients is not necessary. The clearance of rifampicin is significantly decreased in patients with liver disease. (See also Contraindications, Warnings, Precautions and Adverse Reactions for more information regarding the use of rifampicin in patients with hepatic insufficiency.) Rifampicin crosses the placenta and is excreted in breast milk. Isoniazid: Isoniazid is rapidly absorbed and peak plasma concentrations are attained 1-2 hrs after oral ingestion. Food decreases the bioavailability of isoniazid. Tissue distribution of isoniazid is extensive. Significant levels of isoniazid are achieved in several body fluids (pleural, ascitic and cerebrospinal fluids) and tissues. Isoniazid is metabolized primarily by acetylation and dehydrazination. The rate of acetylation is genetically determined. The plasma concentrations and t½ of the drug are, therefore, dependent on the acetylation rate of individuals. The mean elimination t½ in adults varies widely from 1.2-5 hrs. Nearly 75-95% of a dose of isoniazid is excreted mainly as metabolites in urine within 24 hrs. Consideration should be given to the accumulation of the drug in patients with renal impairment. Patients with acute or chronic liver disease have higher serum isoniazid concentrations and exhibit a longer serum t½ for isoniazid. Dosage adjustment may be necessary in these patients to avoid adverse effects of the drug. Isoniazid crosses the placenta and is excreted in breast milk. Pyrazinamide: Pyrazinamide is well absorbed from the gastrointestinal tract. The bioavailability of pyrazinamide is unaltered by food. Pyrazinamide is widely distributed in most body fluids and tissues including the liver, lungs and cerebrospinal fluid. Pyrazinamide is hydrolyzed to its active metabolite, pyrazinoic acid, which is subsequently hydroxylated to 5-hydroxy pyrazinoic acid. The elimination t½ of pyrazinamide is approximately 9-10 hrs in patients with normal renal and hepatic function. The plasma t½ may be prolonged in patients with impaired renal or hepatic function. Pyrazinamide is excreted primarily by glomerular filtration. Nearly 70% of an oral dose is excreted mainly as metabolites in the urine. Decrease in visual acuity due to optic neuritis. GI disturbances (heartburn, epigastric distress, anorexia, nausea, vomiting, cramps, & diarrhea); insomnia, headache, mental confusion, toxic psychoses, increased reflexes, muscle twitching & paresthesias. Discontinue use if signs of hepatocellular damage or hyperuricemia accompanied by acute gouty arthritis manifest. GLIMIPERIDE Mechanism of action Sulfonylureas bind to an ATP-dependent K+(KATP) channel on the cell membrane of pancreatic beta cells. This inhibits a tonic, hyperpolarizing efflux of potassium, thus causing the electric potential over the membrane to become more positive. This depolarization opens voltage-gated Ca2+ channels. The rise in intracellular calcium leads to increased fusion of insulin granulae with the cell membrane, and therefore increased secretion of (pro)insulin. There is some evidence that sulfonylureas also sensitize β-cells to glucose, that they limit glucose production in the liver, that they decrease lipolysis (breakdown and release of fatty acids by adipose tissue) and decrease clearance of insulin by the liver. The KATP channel in turn is a complex of the inward-rectifier potassium ion channel Kir6.2 and sulfonylurea receptor SUR1 which associate with a stoichiometry of Kir6.24/SUR14. ADVERSE REACTIONS: GI disturbance, rarely thrombocytopenia , leukopenia, hemolytic anemia, occasionally allergic reactions occur. In the initial weeks of treatment, the risk of hypoglycemia may be increased. ASPIRIN Aspirin's ability to suppress the production of prostaglandins and thromboxanes is due to its irreversible inactivation of the cyclooxygenase (COX) enzyme. Cyclooxygenase is required for prostaglandin and thromboxane synthesis. Aspirin acts as an acetylating agent where an acetyl group is covalently attached to a serine residue in the active site of the COX enzyme. This makes aspirin different from other NSAIDs (such as diclofenac and ibuprofen), which are reversible inhibitors. Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A2 in platelets, producing an inhibitory effect on platelet aggregation. This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks.[5] 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A2 release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.[6] Prostaglandins are local hormones (paracrine) produced in the body and have diverse effects in the body, including but not limited to transmission of pain information to the brain, modulation of thehypothalamic thermostat, and inflammation. Thromboxanes are responsible for the aggregation of platelets that form blood clots. Heart attacks are primarily caused by blood clots, and their reduction with the introduction of small amounts of aspirin has been seen to be an effective medical intervention. The sideeffect of this is that the ability of the blood in general to clot is reduced, and excessive bleeding may result from the use of aspirin. Reye's syndrome is a potentially fatal disease that causes numerous detrimental effects to many organs, especially the brain and liver, as well as causing hypoglycemia.[11] The exact cause is unknown, and while it has been associated with aspirin consumption by children with viral illness, it also occurs in the absence of aspirin use. The disease causes fatty liver with minimal inflammation and severe encephalopathy (with swelling of the brain). The liver may become slightly enlarged and firm, and there is a change in the appearance of the kidneys. Jaundice is not usually present.[12] Early diagnosis is vital; while most children recover with supportive therapy, severe brain injury or death are potential complications. HERACLENE B12 Action: Vitamin B12 normally plays a significant role in the metabolism of every cell of the body, especially affecting the DNA synthesis and regulation but also fatty acid synthesis and energy production.[39] However, many (though not all) of the effects of functions of B12 can be replaced by sufficient quantities of folic acid (vitamin B9), since B12 is used to regenerate folate in the body. Most vitamin B12 deficiency symptoms are actually folate deficiency symptoms, since they include all the effects of pernicious anemia and megaloblastosis, which are due to poor synthesis of DNA when the body does not have a proper supply of folic acid for the production of thymine.[40] When sufficient folic acid is available, all known B12 related deficiency syndromes normalize, including dibencozide.10-methylene-THF results in problems with DNA synthesis. the form of vitamin B12 most often found in vitamin tablets. Stay on the safe side and avoid use. Without B12. including the megaloblastic anemia of pernicious anemia. It is converted by a nonB12-dependent process to 5. The drug specifically and irreversibly inhibits the P2Y12 subtype of ADP receptor. assessment of MMA levels is not routinely recommended in the elderly.11. For example. Special Precautions & Warnings: Pregnancy and breast-feeding: Not enough is known about the use of dibencozide during pregnancy and breast-feeding. yet 25–33% of them do not have B12 deficiency. All of the DNA synthetic effects. Anxiety. However. Dibencozide seems to be safe for most people.12 Released cytokines attract T lymphocytes to the site. is a methyltransferase enzyme.11 For persons with intact cell-mediated immunity. This functionality is lost in vitamin B12 deficiency. that is absorbed from the intestine. also known as methionine synthase. coenzyme M methyl transferase How does it work? Dibencozide is a form of vitamin B12. Methyl (-CH3) group transfers between two molecules. are part of the innate immune system and provide an opportunity for the body to destroy the invading mycobacteria and prevent infection. In humans. Methyltransferases. which creates a micro-environment that limits replication and the spread of the . which is necessary for myelin synthesis (see mechanism below) and certain other functions of the central nervous system. initial development involves production of proteolytic enzymes and cytokines by macrophages in an attempt to degrade the bacteria. These are typified by the following two enzymes: 1. serum values may be maintained while tissue B12 stores become depleted. Therefore. Increasing muscle mass and strength. and may break down during storage.9 Bacteria in droplets that bypass the mucociliary system and reach the alveoli are quickly surrounded and engulfed by alveolar macrophages. however 20–25% of patients over the age of 70 have elevated levels of MMA. Several mechanisms and macrophage receptors are involved in uptake of the mycobacteria. P2Y12 protein is found mainly but not only on the surface of blood platelet cells and is an important regulator in blood clotting. two major coenzyme B12-dependent enzyme families corresponding to the first two reaction types. since B12 helps to regenerate the tetrahydrofolate (THF) active form of folic acid. Helping the body process protein. CLOPIDOGREL Clopidogrel is a prodrug. folate is trapped as 5-methyl-folate. also known as methionine synthase. Thus the best-known "function" of B12 (that which is involved with DNA synthesis.14 The subsequent phagocytosis by macrophages initiates a cascade of events that results in either successful control of the infection. Activation of this receptor complex is the "final common pathway" for platelet aggregation and is important in the cross-linking of platelets by fibrin. but the onset of action is slow. the microorganisms continue to grow until they reach sufficient numbers to fully elicit the cell-mediated immune response. such as ileal disease or surgical removal of part of the intestine.12 The complement system also plays a role in the phagocytosis of the bacteria. MUT is an isomerase which uses the AdoB12 form and reaction type 1 to catalyze a carbon skeleton rearrangement (the X group is -COSCoA).10-methylene-THF. Rearrangements in which a hydrogen atom is directly transferred between two adjacent atoms with concomitant exchange of the second substituent. Reactions in which a halogen atom is removed from an organic molecule. which can be detected by a skin test. which is important in aggregation of platelets and cross-linking by the protein fibrin.7. 3. These nodular-type lesions form from an accumulation of activated T lymphocytes and macrophages. PBPs bind to the DAla-D-Ala at the end of muropeptides (peptidoglycan precursors) to crosslink the peptidoglycan. and can be measured clinically as an increased methylmalonic acid (MMA) level. an elevated MMA. even in the air spaces of a host with no previous exposure to M tuberculosis. The peptidoglycan layer is important for cell wall structural integrity. dibencozide is not as stable as cyanocobalamin. thereby competitively inhibiting PBP crosslinking of peptidoglycan. There is no "gold standard" test for B12 deficiency because as a B12 deficiency occurs. The final transpeptidation step in the synthesis of the peptidoglycan is facilitated by transpeptidases known as penicillin-binding proteins(PBPs). but not the elevated levels of homocysteine. Cephalosporins disrupt the synthesis of the peptidoglycan layer of bacterial cell walls. save those narrowly connected with the vitamin B12-dependent enzymes MUT.8 the most abundant immune effector cells present in alveolar spaces. THF may be produced in the conversion of homocysteine to methionine.13 The complement protein C3 binds to the cell wall and enhances recognition of the mycobacteria by macrophages. MTR.4. called primary progressive tuberculosis. The IIb/IIIa complex functions as a receptor mainly for fibrinogen and vitronectin but also for fibronectin and von Willebrand factor. though sensitive to B12 deficiency. or progression to active disease.[1] The blockade of this receptor inhibits platelet aggregation by blocking activation of the glycoprotein IIb/IIIa pathway. and can be measured clinically as an increased homocysteine level in vitro. Platelet inhibition can be demonstrated two hours after a single dose of oral clopidogrel. which is involved in the synthesis of thymine. are known.11 The mycobacterial lipoarabinomannan is a key ligand for a macrophage receptor.4. Isomerases. 2. For this reason. the mycobacteria continue to multiply slowly.pernicious anemia. an oxygen atom of an alcohol. or an amine. or may be obtained in the diet. Dehalogenases. Coenzyme B12's reactive C-Co bond participates in three main types of enzymecatalyzed reactions. Opsonization by C3 is rapid. Increased homocysteine can also be caused by a folic acid deficiency. MMA is elevated in 90–98% of patients with B12 deficiency. Panic attacks.[1] CEFIXIME Cephalosporins are bactericidal and have the same mode of action as other betalactam antibiotics (such as penicillins) but are less susceptible topenicillinases. so that a loading-dose of 300–600 mg is usually administered. such as Me-H4MPT. Vitamin B12 is important in chemical reactions throughout the body. is probably overly sensitive.10 These macrophages. the cells that constitute cell-mediated immunity.15 After being ingested by macrophages. Depression. the next defensive step is formation of granulomas around the M tuberculosis organisms16 (Figure 1⇓). Reduced availability of 5. the action of which may be related to an adenosine diphosphate (ADP) receptor on platelet cell membranes. Enzymes in this class have not been identified in humans. serum B12 values above the cutoff point of deficiency do not necessarily indicate adequate B12status[14] The MUT function cannot be affected by folate supplementation.11.8 The outcome is essentially determined by the quality of the host defenses and the balance that occurs between host defenses and the invading mycobacteria. Macrophages then present mycobacterial antigens on their surface to the T cells.10-methylene-THF still remain adequate with enough dietary folate). MMA) and homocysteine. Other functions of B12 related to DNA synthesis related to MTR dysfunction (see below) can often be corrected with supplementation with the vitamin folic acid. an important step in the extraction of energy from proteins and fats (for more see MUT's reaction mechanism). which is normally converted to methionine by MTR. Pathophysiology Once inhaled. followed by latent tuberculosis. The mucus produced catches foreign substances. Beta-lactam antibiotics mimic the D-Ala-D-Ala site. which may be a carbon atom with substituents. Gastrointestinal (GI) conditions: Some GI conditions. Improving mental concentration. X. the next line of host defense.11 This initial immune process continues for 2 to 12 weeks. which uses the MeB12 and reaction type 2 to catalyze the conversion of the amino acid homocysteine (Hcy) back intomethionine (Met) (for more see MTR's reaction mechanism). and 5methyltetrahydrofolate-homocysteine methyltransferase (MTR). cell-division. and the cilia on the surface of the cells constantly beat the mucus and its entrapped particles upward for removal.7 Regardless of whether the infection becomes controlled or progresses. and also intestinal wall cells which are responsible for absorption.8 This system provides the body with an initial physical defense that prevents infection in most persons exposed to tuberculosis. resolve if sufficient folate is present (since levels of 5. There are no reported side effects. and ultimately in ineffective production cells with rapid turnover. the infectious droplets settle throughout the airways. thus decreasing the need for fresh sources of THF from the diet.8 with bacterial cell division occurring every 25 to 32 hours. from which THF cannot be recovered unless a MTR process reacts the 5-methyl-folate with homocysteine to produce methionine and THF. Other conditions.[41][42] 1.11 Macrophages are readily available phagocytic cells that combat many pathogens without requiring previous exposure to the pathogens. Unfortunately.[43] This functionality is lost in vitamin B12 deficiency. and anemia) is actually a facultative function which is mediated by B12-conservation of an active form of folate which is needed for efficient DNA production.8. and not all who have it actually have B12deficiency. in particular blood cells. The majority of the bacilli are trapped in the upper parts of the airways where the mucus-secreting goblet cells exist. and the buildup of their respective substrates (methylmalonic acid.[44] Other cobalamin-requiring methyltransferase enzymes are also known in bacteria. 2. MUT's reaction converts MMl-CoA to Su-CoA. can reduce that amount of Vitamin B12. The failure of blood cell production results in the once-dreaded and fatal disease. 8.18 Lesions in persons with less effective immune systems progress to primary progressive tuberculosis. however. the bacilli are able to adapt to survive.13 By 2 or 3 weeks. The necrotic tissue undergoes liquefaction. to enhance survival. low pH.mycobacteria. M tuberculosisorganisms can change their phenotypic expression. The semiliquid necrotic material can then drain into a bronchus or nearby blood vessel. often referred to caseous necrosis.8.18 In fact. This condition restricts further growth and establishes latency. the necrotic environment resembles soft cheese. If discharge into a vessel occurs. and the fibrous wall loses structural integrity. such as protein regulation. healed lesions.4. occurrence of extrapulmonary tuberculosis is likely. Lesions in persons with an adequate immune system generally undergo fibrosis and calcification. and is characterized by low oxygen levels. granuloma formation is initiated yet ultimately is unsuccessful in containing the bacilli. In patients infected with M tuberculosis.12 This environment destroys macrophages and produces early solid necrosis at the center of the lesion. successfully controlling the infection so that the bacilli are contained in the dormant. 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