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Calculations :Calculate the percentage w/w of chloroform 160 mg super p-force oral jelly visa, taking into consideration 1 effective 160mg super p-force oral jelly. Discuss the two aforesaid integrators and also affirm which one gives better results purchase 160 mg super p-force oral jelly with visa. How would you carry out the assay of the following drugs : (i) Cetostearyl alcohol, (ii) Ethyloestrenol, and (iii) Lincomycin hydrochloride. Give details for the assay of : (a) Water present in mentrophin, and (b) Chloroform present in colchicine. By the late 1960’s, analysts invariably used to have the bliss of excellent experience of achieving the goal of superb separations of complex mixtures in seconds rather than in minutes, with the aid of electronic integrators to get an exact access of areas under elution bands, and above all the ‘computer-printouts’ of the complete analysis with the flick of a finger. In many favourable instances the smallest possible quantities ranging from nanogram to picogram* could be detected with utmost ease and convenience. Hence, either a stable vapour from the mixture is obtained directly or indirectly converting the substance in it to such derivatives that are thermally stable. Furthermore, the spectrum of these selective interactions may also be enhanced by an appropriate chemical modification of the silica surface i. These silica particles are mostly uniform, porous, with spherical or irregular shape, and having diameter ranging from 3. Bonded-Phase Supports : The bonded-phase supports usually overcome plethora of the nagging prob- lems which is mostly encountered with adsorbed-liquid phases. The nature of the R group of the silane solely determines the surface polarity of the bonded phase. Note : The exact mechanism by which the respective bonded phases actually alter the nature of the sorption mechanism is still not yet clear. When such microparticulate-bonded-phases are packed compactly into a column by means of a suit- able device, the small size of these particles offers a significant resistance to solvent flow ; therefore, the mobile phase has to be pumped through the column under a high positive pressure. In-line Detector : It broadly helps to sense the separated solutes, after they exit through the column. Invariably the detector is an electrical signal whose variation is displayed on a potentiometer recorder or a computing integrator or a video-screen. Therefore, such component(s) have to be appropriately converted into their corre- sponding detectable form once they emerge from the column. All these vital components will be discussed with adequate details, wherever necessary, in the various sections that follow : Solvent reservoir Flow Sample splitting valve injection port Degassers Separation column Guard column Mixing valve Equilibration Constant pump and coil temperature gradient system chamber To waste Recorder Vacuum pump Data processing Detector Time Figure 30. The mobile phase, that may be either a single liquid or a mixture of two or more liquids, is pumped at high pressure into a temperature controlled oven, where it first, gains its entry into an equilibration coil to bring it to the operating temperature, and secondly, through a ‘guarded column’ specially designed and strategically positioned to protect the analytical column from impurities and ultimately extend its lifetime. The pressures mentioned above correspond to mobile-phase flow rates of approximately 1-5 cm3 min–1 through the column. Flow : The flow can be measured periodically at the column outlet by collecting the liquid for a known period, and thereafter, either measuring the volume or weighing it physically. Temperature : In reality, the maintenance of strict ‘temperature control’ plays a vital role in measuring the retention-data correctly and precisely. They are : (a) Constant Pressure Pump : A constant-pressure pump acts by applying a constant pressure to the mobile-phase. The flow rate through the column is determined by the flow resistance of the column. Importantly, in a constant-pressure pump the flow rate will change if the flow resistance changes. Whereas in the constant flow pumps the changes in flow resistance are compensated duly by a change of pressure. The piston is moved in and out of a solvent chamber by an eccen- tric cam or gear. The forward-stroke closes the inlet-check value while the outlet valve opens and the respective mobile phase is duly pumped into the column. Consequently, the return-stroke-closes the outlet valve and it refills the chamber. Mobile-phase outlet Seals Check valves Piston Solvent chamber Eccentric cam Mobile-phase inlet Figure 30. The stage-A depicts the drive while the refill zone is vacant ; while the stage-B evidently shows the two-heads functioning simultaneously thereby the drive and the refill both zones could be visualized. The major drawback associated with this type of injec- tors is ‘leaching effect’ of the mobile-phase just in contact with the septum, thereby resulting in the formation of ‘ghost peaks’ or ‘pseudo peaks’. The flow of the mobile-phase through the column is stopped for a while, and when the column reaches an ambient pressure the top of the column is opened and the sample introduced at the top of the packing. These valves enable samples to be introduced reproducibly into pressurized columns without causing the least interruption of the mobile-phase flow. Here, the sample is loaded at atmospheric pressure into an external loop in the microvolume- sampling valve, and subsequently injected into the mobile-phase by a suitable rotation to the valve. However, the volume of sample introduced usually ranges between 2 µl to over 100 µl ; but can be varied either by altering the volume of the sample loop or by employing specific variable-volume sample valves. Mobile phase To column Mobile phase To column Adjustable Sample in Sample out Sample in Sample out length sample loop (a) Sampling mode (b) Injection mode Figure 30. Therefore, it is always preferred for most quantitative work by virtue of its very high degree of precision and accuracy. The column performance or the efficiency of a column entirely depends on the amount of spreading that takes place. In comparison to the porous-layer beads, as detailed in (b) above, the porous-silica particles yield significant improvements not only in column efficiency but also in sample capacity and speed of analysis. They critically respond to a particular physical or chemical characteristic of the solute (in question), which should be ideally and absolutely independent of the mobile-phase being used. But complete independence of the mobile-phase is hardly to be seen, however, signal discrimination is good enough to enable distinctly measurable experimental procedures with solvent changes, such as : gradient-elution. As only a narrow spectrum of compounds undergo electrochemical oxidation, such detectors are quite selective ; and this selectivity may be further enhanced by moni- toring the potential applied to the detector so as to differentiate between various electroactive spe- cies. Naturally, electrochemical detection essentially makes use of conducting mobile phases, for instance : inorganic salts or mixtures of water with water-miscible organic solvents. The five important types of detectors shall be discussed along with their simple diagrammatic sketches, in the sections that follow : 30. Initially, dual-wavelength instruments having 254 and/or 280 nm were introduced which is presently being replaced by more sophisticated and up-dated variable wavelength detectors spread over wide range between 210-800 nm capable of performing more selective detection possible. A strategically placed grating diffracts the outcoming radiation and subsequently meets an array of photodiodes whereby each photodiode receives a different narrow wavelength band. Another extremely important and useful characteristic feature of a diode-array detector is that it may be ‘programmed’ so as to affect changes in the detection wavelength at particular points in the chromatogram. Fluorescent compounds : A relatively small proportion of inorganic and organic compounds exhibit natural fluorescence, whereas a larger number of pharmaceutical substances and environmental contaminants [e. However, non-fluorescent compounds can be converted to fluorescent derivatives by treatment with appropri- ate solvents. Radiation from a Xenon-radiation or a Deuterium-source is focussed on the flow cell through a filter. The fluorescent radiation emitted by the sample is usually measured at 90° to the incident beam.
This possible drug interaction should be considered when metronidazole is prescribed for patients on this type of anticoagulant therapy safe super p-force oral jelly 160mg. The simultaneous administration of drugs that induce microsomal liver enzymes 160mg super p-force oral jelly with mastercard, such as phenytoin or phenobarbital discount super p-force oral jelly 160mg with amex, may accelerate the elimination of metronidazole, resulting in reduced plasma levels; impaired clearance of phenytoin has also been reported. Metronidazole should not be given to patients who have taken disulfiram within the last 2 weeks. Instances of a darkened urine have also been reported, and this manifestation has been the subject of a special investigation. Although the pigment which is probably responsible for this phenomenon has not been positively identified, it is almost certainly a metabolite of metronidazole and seems to have no clinical significance. Infusion (ventilated): Dilute 3mg/kg in 50ml 5% dextrose and run at 0-5ml/hr (0-5mcg/ kg/min) Intranasal: Sedation: 0. The following paradoxical reactions have been observed: Excitability, irritability, aggressive behavior, agitation, nervousness, hostility, anxiety, sleep disturbances, nightmares and vivid dreams. Hepatic: Hepatomegaly, transient elevations of serum transaminases and alkaline phosphatase. Patients with renal impairment on milrinone infusions may develop progressive vasodilation leading to escalating noradrenaline requirements. If noradrenaline requirement is increasing consider whether it is appropriate to cease milrinone. Significant hypotension due to peripheral vasodilation is common and is generally treated with noradrenaline. Milrinone may aggravate outflow tract obstruction in hypertrophic subaortic stenosis. Respiratory depression occurs most frequently in the elderly and debilitated patients as well as in those suffering from conditions accompanied by hypoxia or hypercapnia when even moderate therapeutic doses may dangerously decrease pulmonary ventilation. Morphine should be used with extreme caution in patients with chronic obstructive pulmonary disease or cor pulmonale, and in patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or preexisting respiratory depression. In such patients, even usual therapeutic doses of morphine may decrease respiratory drive while simultaneously increasing airway resistance to the point of apnea. Hypotensive Effect Morphine sulphate controlled-release tablets, like all opioid analgesics, may cause severe hypotension in an individual whose ability to maintain his blood pressure has already been compromised by a depleted blood volume, or a concurrent administration of drugs that lower blood pressure. Respiratory: Respiratory depression, apnoea, respiratory arrest, Gastrointestinal: Dry mouth, biliary tract spasm, laryngospasm, anorexia, diarrhoea, cramps, taste alteration, constipation, ileus, intestinal obstruction, increases in hepatic enzymes. Cardiovascular: Flushing of the face, chills, tachycardia, bradycardia, palpitation, faintness, syncope, hypotension, hypertension. If stored at cool temperatures precipitation may occur – this will redissolve at room temperature. Moxifloxacin, given as an oral tablet, is well absorbed from the gastrointestinal tract. Aerobic Gram-Positive Microorganisms: Staphylococcus aureus (methicillin-susceptible strains only), Streptococcus pneumoniae (including penicillin-resistant strains), Streptococcus pyogenes. Aerobic Gram-Negative Microorganisms: Haemophilus influenzae, Haemophilus parainfluenzae, Klebsiella pneumoniae, Moraxella catarrhalis. Convulsions and neuropsychiatric complications Convulsions have been reported in patients receiving quinolones. Hypersensitivity Reactions Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving quinolone therapy. Pseudomembranous Colitis Pseudomembranous colitis has been reported with nearly all antibacterial agents, including moxifloxacin, and may range in severity from mild to life-threatening. Peripheral Neuropathy Rare cases of sensory or sensorimotor axonal polyneuropathy affecting small and/or large axons resulting in paraesthesias, hypoesthesias, dysesthesias and weakness have been reported in patients receiving quinolones. Tendon Effects Ruptures of the shoulder, hand, achilles tendon or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving quinolones. Oral administration of quinolones with antacids containing aluminum or magnesium, with sucralfate, with metal cations such as iron, or with multivitamins containing iron or zinc, or with formulations containing divalent and trivalent cations such as (didanosine) chewable/buffered tablets or the paediatric powder for oral solution, may substantially interfere with the absorption of quinolones, resulting in systemic concentrations considerably lower than desired. Central Nervous System: Insomnia, nervousness, anxiety, confusion, somnolence, tremor, vertigo, paraesthesia. Naloxone prevents or reverses the effects of opioids including respiratory depression, sedation and hypotension. In such cases, an abrupt and complete reversal of narcotic effects may precipitate an acute abstinence syndrome. Several instances of hypotension, hypertension, ventricular tachycardia and fibrillation, and pulmonary edema have been reported. These have occurred in postoperative patients most of whom had pre-existing cardiovascular disorders or received other drugs which may have similar adverse cardiovascular effects. Although a direct cause and effect relationship has not been established, naloxone injection should be used with caution in patients with pre-existing cardiac disease or patients who have received potentially cardiotoxic drugs. In post-operative patients, larger than necessary dosages of naloxone may result in significant reversal of analgesia. Hypotension, hypertension, ventricular tachycardia and fibrillation, and pulmonary oedema have been associated with the use of naloxone postoperatively Naloxone! It enhances cholinergic action by facilitating the transmission of impulses across neuromuscular junctions. Neurologic: Dizziness, convulsions, loss of consciousness, drowsiness, headache, dysarthria, miosis and visual changes. Cardiovascular: Cardiac arrhythmias (including bradycardia, tachycardia, A-V block and nodal rhythm), cardiac arrest, syncope and hypotension. Respiratory: Increased oral, pharyngeal and bronchial secretions, dyspnea, respiratory depression, respiratory arrest and bronchospasm. Gastrointestinal: Nausea, salivation, cramp, emesis, diarrhoea, flatulence and increased peristalsis. Oedema, burning sensation, blisters, rash, or pinching at the application site were also noted. Gastrointestinal reactions: Nausea, vomiting, dyspepsia, abdominal pain, diarrhoea Neurological System: Abnormal dreams Nicotine! Note: administration of nimodipine via a central line is preferred as nimodipine causes thrombophlebitis when administered peripherally. For patients who are unable to tolerate infusion at 1mg/hr, commence infusion at 0. After the first dose of nimodipine is given, reduce infusion by 1 mL every hour for 5 hours, then cease infusion. If the patient becomes hypotensive after oral nimodipine is given, cease the infusion immediately. If hypertensive therapy is being pursued or the patient develops significant hypotension during nimodipine treatment, the dose should be reduced or nimodipine should be withheld. Such patients should have their blood pressure and pulse rate monitored closely and should be given a lower dose. Cardiovascular System: Bradycardia, probably as a reflex result of a rise in blood pressure, arrhythmias. Allow solution to come to room temperature to minimise pain at the injection site.
Precautons Renal impairment; actve disorders of gastrointestnal tract; neutropenia; interactons (Appendix 6c discount 160mg super p-force oral jelly otc, 6d); pregnancy (Appendix 7c) buy super p-force oral jelly 160 mg visa. Adverse Efects Anaemia; electrolyte disturbances; dizziness; disturbances of blood lipids; gastrointestnal disturbances super p-force oral jelly 160 mg online. Note: Discontnue all other antcholinesterase medicatons for at least 8 hours prior to administraton. Contraindicatons Mechanical gastrointestnal or urinary tract obstructon; peritonits. Precautons Renal impairment; peptc ulcer; lactaton (Appendix 7b); heart blockage, slow heart- beat; bradycardia, hypotension; urinary tract infecton; epilepsy; asthma; interactons (Ap- pendix 6c); pregnancy (Appendix 7c). Adverse Efects Abdominal cramps, diarrhoea; pupil dilataton; excess saliva; headache; joint pain; severe allergic reactons; faintng; interrupted breathing; irregular heart beat; seizures; vision changes; anxiety. Precautons Monitor weight; blood pressure, blood glucose and electrolytes, antbiotc coverage may be required, doses should be tapered and not withdrawn suddenly; hepatc impairment (Appendix 7a); lactaton (Appendix 7b); pregnancy (Appendix 7c); interactons (Appendix 6c, 6d). Adverse Efects Inital transient exacerbaton; elevaton of intraocular pressure; optc nerve damage; posterior subcapsular cataract formaton; delayed wound heeling; weight gain; moon face; avascular necrosis; osteoporosis; psychosis and mood change, increased chance of opportunistc infectons. Injecton: Store protected from light, in a single dose or in mult dose containers. Contraindicatons Recent intestnal or bladder surgery; gastrointestnal or urinary tract obstructon; afer suxamethonium; pneumonia; peritonits. Precautons Asthma; urinary tract infecton; cardiovascular disease including arrhythmias (especially bradycardia or atrioventricular block); hyperthyroidism; hypotension; peptc ulcer; epilepsy; parkinsonism; avoid intravenous injecton; renal impairment; pregnancy (Appendix 7c); lactaton. Adverse Efects Muscarinic efects generally weaker than with neostgmine: increased salivaton, nausea, salivaton, vomitng, abdominal cramps, diarrhoea; signs of overdosage include bronchoconstricton, increased bronchial secretons; lacrimaton, excessive sweatng, involuntary defecaton and micturiton, miosis, nystagmus; bradycardia, heart block, arrhythmias, hypotension; agitaton, excessive dreaming, weakness eventually leading to fasciculaton and paralysis, thrombophlebits; rash associated with bromide salt; diaphoresis, increased peristalsis. A classifcaton based on severity before the start of treatment and disease progression is of impor- tance when decisions have to be made about management. It can be divided by severity into intermitent, mild persistent, moderate persistent and severe persistent. Antasthmatcs are useful in the management of the disease since therapy has a stepwise approach which must be discussed with the patent before commencing therapy. The level of therapy is increased as the severity of the asthma increases with stepping-down if control is sustained (see tables on treatment below). Inhalaton: Medicatons for asthma can be administered in several diferent ways, including inhalaton, oral and parenteral (subcutaneous, intramuscular or intravenous routes). The main advantage of delivering drugs directly into the airways via inhalaton is that high concentratons can be delivered more efectvely and rapidly to the airways, and systemic adverse efects avoided or minimized. It is important that patents receive careful instructon in the use of pressurized (aerosol) inhalaton (using a metered- dose inhaler) to obtain optmum results. Afer exhaling as completely as possible, the mouthpiece of the inhaler should be placed well into the mouth and the lips fr mly closed around it. Afer holding the breath for 10 seconds or as long as is comfortable, the mouthpiece should be removed and the patent should exhale slowly. It is important to check that patents contnue to use their inhalers correctly as inadequate technique may be mistaken for drug failure. They may be of beneft for patents such as the elderly, small children and the asthmatc who fnd inhalers difcult to use or for those who have difculty synchronizing their breathing with administraton of the aerosol. A large volume spacing device is also recommended for inhalaton of high doses of cortcosteroids to reduce oropharyngeal depositon which can cause candidosis. The use of metered-dose inhalers with spacers is less expensive and may be as efectve as use of nebulizers, although drug delivery may be afected by choice of spacing device. They are administered over a period of 5-10 min from a nebulizer, usually driven by oxygen in hospital. Systemic adverse efects occur more frequently when a drug is given orally rather than by inhalaton. Drugs given by mouth for the treatment of asthma include β2-agonists, cortcosteroids and theophylline. If the patent is being treated in the community, urgent transfer to hospital should be arranged. Pregnancy: Poorly controlled asthma in pregnant women can have an adverse efect on the fetus, resultng in perinatal mortality, increased prematurity and low birth-weight. Administraton of drugs by inhalaton during preg- nancy has the advantage that plasma drug concentratons are not likely to be high enough to have an efect on the fetus. Acute exacerbatons should be treated aggressively in order to avoid fetal hypoxia. Acute Exacerbaton of Asthma: Severe asthma can be fatal and must be treated promptly and energetcally. Acute severe asthma atacks require hospital admission where resuscitaton facilites are imme- diately available. In emergencies where a nebulizer is not available, salbutamol 100 µg by aerosol inhalaton can be repeated 10-20 tmes preferably using a large-volume spacing device. Patents should also be given a cortcosteroid ; for adults, prednisolone 30-60 mg by mouth or hydrocortsone 200 mg intravenously; for children, prednisolone 1-2 mg/kg by mouth (1-4 years, max. Most patents do not beneft from the addi- ton of intravenous aminophylline or a parenteral β2-agonist; both cause more adverse efects than nebulized β2-agonists. Nevertheless, an occasional patent who has not been taking theophylline, may beneft from a slow intravenous infusion of aminophylline. The use of epinephrine (adrenaline) in asthma has generally been superseded by β2-selectve adrenoceptor agonists. Treatment should never be delayed for investgatons, patents should never be sedated and the possibility of pneumoth- orax should be considered. Patents who deteriorate further despite treatment may need intermitent positve pressure ventlaton. Step down Review Step up If control treatment every 3 to is not achieved, 6 months. Chronic Obstructve Pulmonary Disease: Chronic obstructve pulmonary disease (chronic bronchits and emphysema) may be helped by an inhaled short-actng β2-adrenoceptor agonist used as required or when the airways obstructon is more severe, by an inhaled antcholinergic (antmuscarinic) bronchodilator or both if necessary. Although many patents are treated with an inhaled cortcosteroid its role in chronic obstructve pulmonary disease is not clear at present. A limited trial of high-dose inhaled cortcosteroid or an oral cortcosteroid is recommended for patents with moderate airfow obstructon to determine the extent of the airway reversibility and to ensure that asthma has not been overlooked. Long-term oxygen therapy prolongs survival in some patents with chronic obstructve pulmonary disease. When salbutamol is given by inhalaton (100-200 µg) the efect can last as long as 4 h thus making it suitable for both the treatment (see tables) and preventon of asthma. Salbutamol can also be taken orally in a dose of 2-4 mg up to 4 tmes daily but is less efectve and causes more adverse efects. Adverse Efects Cardiovascular adverse efects (arrhythmias, palpitatons and tachycardia) may occur with salbutamol, but are infrequent with inhaled preparatons.
Similar to norepinephrine and epinephrine 160mg super p-force oral jelly free shipping, α-methylnorepinephrine exerts α2-receptor negative feedback that results in antihypertensive effects buy discount super p-force oral jelly 160mg online. Its use is now deprecated following introduction of alternative safer classes of antihyperten- sive agents discount 160mg super p-force oral jelly fast delivery. In a broad sense, α-methyldopa is a substrate, that is, enzyme activator, of several enzymes and can be considered as a precursor of α-methylnorepinephrine, an agonist analog of norepinephrine. Of inter- est, from a drug design perspective, whereas metyrosine is an α-methyl derivative of tyrosine, carbidopa and α-methyldopa are α-methyl derivatives of levodopa. Droxidopa is an analog of both levodopa and norepinephrine that was approved since 1989 in Japan for the treatment of neurogenic hypotension associated with Parkinson’s disease . As of 2008, the drug is under clinical trials in Australia, Europe, Canada, and the United States. Contrary to α-methyldopa, which is metab- olized to a norepinephrine analog, droxidopa is a prodrug of norepinephrine. Droxidopa can either cross the blood–brain barrier or remain in the periphery where it is converted to norepinephrine. In this section, we will touch on serine proteases and serine protease inhibitors that modulate blood coagulation. The monomeric globular 58 residue polypeptide is known to inhibit several serine proteases, namely, trypsin, chy- motrypsin, plasmin, and kallikrein. Hence, as an injectable drug, aprotinin was used since 1964 to reduce bleeding during complex surgery. As an alternative to aprotinin, aminocaproic acid, and tranexamic acid were devel- oped from lysine (Figure 5. In particular, both drugs bind reversibly to zymogen plasminogen, so that it cannot be activated to plasmin. Injectable tranexamic acid has roughly eight times the antifbrinolytic activity of its older analog, aminocaproic acid. Tranexamic also inhibits serine pro- teases known as plasminogen activators, which activates plasminogen to plasmin, as their names suggest (Section 5. The drug is also commonly used in cardiac, dental, obstetric, and orthopedic surgery. Of interest, although both aminocaproic acid and tranexamic acid were available in both oral and injectable forms, the manufacturers decided to only support one dosage form. Fresh frozen plasma and the prothrom- bin complex concentrate are used to medically correct for prothrombin defciencies. Hence, the prothrombin complex concentrate is often used to resolve intractable bleeding caused by the anticoagulant drug warfarin. Once purifed, thrombin is used to specifcally cleave between Pro-Arg and Gly of the cleavage site sequence, thereby removing the purifcation tag from the protein of interest. In general, plasminogen activators are injected enzymes that are indicated for clotting-related conditions including pulmonary embolism, myocardial infarction and stroke. The activators are classifed according to the source where the enzyme drugs are obtained, such as recombinant tissue plasminogen activators, alteplase, monteplase, reteplase, and tenecteplase, from endothelial cells; urokinase from urine; streptokinase and anistreplase from Streptococcus bacteria. Protein C is a vitamin K-dependent serine protease that is activated by thrombin into activated protein C. Once activated, the enzyme is a major physiological anti- coagulant and exhibits both anti-infammatory and antiapoptotic activities. In particular, although coumarin derivatives such as warfarin are very use- ful and powerful anticoagulant drugs, they are plagued with problems associated with drug–drug and drug–disease interactions, and a very narrow therapeutic window that requires very careful therapeutic drug monitoring. To resolve these unspecifc ther- apeutic interactions, direct thrombin inhibitors were developed as anticoagulants to bind at the active site of thrombin and inhibit its blood coagulating activity. Although the bivalent inhibitors bind at both the active site and exosite 1 of thrombin, the univa- lent inhibitors bind more specifcally to the active site. Although few direct thrombin inhibitors are available to patients, further development and market accessibility to direct thrombin inhibitors would provide very excellent and most likely safer alter- natives to coumarin derivatives. In 1884, John Haycraft demonstrated that medicinal leeches, Hirudo medicinalis, secreted a substance, hirudin, with potent anticoagulant properties . Until the discovery of heparin, these leeches were the only mean of preventing blood from clotting. Unfortunately, natural hirudin exists in various isoforms and is diffcult to extract in suffcient therapeutic amount from natural sources, that is, leeches. Bivalirudin is a synthetic 20-amino acid peptide derivative of hirudin, con- taining a tripeptide active direct thrombin inhibitor (d-Phe)-Pro-Arg attached to Pro and a tetrapeptide Gly linker, followed by a dodecapeptide analog of the C-terminus of hirudin, that is (d-Phe)-Pro-Arg//Pro-Gly-Gly-Gly-Gly-(hirudin C-terminus) . Of interest, the Pro-Arg sequence is shared between bivalirudin and the aforemen- tioned linker chain used in recombinant fusion protein construct, so that thrombin can recognize and process the respective peptide (Section 5. Although hirudin is an irreversible inhibitor of thrombin, bivalirudin is a reversible inhibitor that is slowly processed by thrombin between the Pro-Arg and Pro sequences of the drug. As a result of bivalirudin reversibility, there is a low risk of severe bleeding asso- ciated with bivalirudin when compared with standard combination heparin therapy. Unfortunately, due to their large sizes, bivalent direct thrombin inhibitors, lepirudin, desirudin, and bivalirudin, need to be administered by injection, and thereby limiting their use for long-term treatment. Univalent direct thrombin inhibitors are considerably much smaller than bivalent inhibitors. The (d-Phe)-Pro-Arg sequence represents the P3–P2–P1 residues of biva- lent thrombin inhibitor bivalirudin. The (d-Phe)-Pro-Arg motif was heavily modifed in the design of univalent inhibitor melagatran . In the body, the ethyl ester moiety in ximelagatran is hydrolyzed, whereas the hydroxyl group is removed to uncover the main binding portion of the inhibitor. Argatroban is an extensively modifed derivative of the (d-Phe)-Pro-Arg motif . It is noteworthy that argatroban does not ft in the active site of thrombin in an extended backbone conformation, resulting in a nonsequential numbering of the residues as P3–P1–P2. However, the univalent direct thrombin inhibitor must be administered intravenously because of the highly basic P1 Arg side-chain that interferes with gastrointestinal absorption . To partially alleviate the alkalinity of the P1 residue and improve drug tolerability, the carboxylic acid at the 2-position of the P2 piperidine amide acts as an internal counter-ion for the P1 guanidine function. Dabigatran etexilate is an orally administered prodrug that is metabolized to uni- valent direct thrombin inhibitor dabigatran through ethyl de-esterifcation and the removal of a long hexyloxycarbonyl function from a benzamidine moiety . The leaving groups of prodrugs ximelaga- tran and dabigatran etexilate are drawn in gray. Interestingly, dabigatran etexilate does not take advantage of potential interactions with the S2 subsite because it lacks a P2 residue. Interestingly, the molecule benzamidine itself is a reversible competitive inhibitor of trypsin, trypsin-like enzymes and serine proteases. The P2 residue, which is absent in dabigatran etexilate, exists as a nonaromatic cyclic 4-, 5-, or 6-member ring system in the motif or other univalent thrombin inhibitors, respectively.
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