By T. Porgan. Regent University. 2018.

Both have been shown to modulate P-gp-mediated efflux in vitro with quinidine being the stronger inhibitor of the two (143 generic seroquel 300mg on line,292) discount 300 mg seroquel fast delivery. Tamoxifen is an estrogen receptor antagonist that weakly binds to P-gp and exerts inhibitory effects in vitro at concentrations above 1 mM (297). In a dose escalation study, a vinblastine and tamoxifen combination proved to be neurotoxic (298). Neurotoxicity also occurred in a trial with high-dose tamoxifen and etoposide, and at this dose, the plasma concentration of tamoxifen was below the concentration reported to reverse etoposide resistance in P-gp-expressing cell lines (297,298). Tamoxifen has very complex pharmacokinetics, which are not fully understood presently. The drug exhibits high plasma protein binding (98%), enterohepatic recirculation, distribution into fatty tissue, and a long terminal half-life (299). Because of these severe toxic The Role of P-Glycoprotein in Drug Disposition 387 effects of tamoxifen, such as dizziness, tremor, unsteady gait, grand mal seizure, and myelosuppression, no further trials have been conducted with this drug. These compounds represent a more focused attempt to develop potent P-gp modulators that would be much less toxic than first- generation inhibitors, so that adequate P-gp inhibitory concentrations can be achieved clinically without the risk of toxic effects. The (À) isomer of the L-type calcium channel blocker (þ)-niguldipine is dexniguldipine. Currently, only a few studies have been conducted to evaluate the use of this compound as a P-gp modulator. Dexverapamil is just as effective at blocking P-gp-mediated efflux as its enantiomer verapamil, but this compound is seven times less potent at inhibiting the contractile force of isolated human heart muscle tissue (303). This reduc- tion in the dose-limiting factor of verapamil has led to clinical trials with dexverapamil as a possible P-gp-reversing agent. A trial involving combination therapy of dexverapamil and pacli- taxel in heavily pretreated patients with metastatic breast cancer showed that the combination resulted in hematological toxicity that was greater than paclitaxel alone along with increased mean peak paclitaxel concentrations and delayed mean paclitaxel clearance (306). Like the second-generation modulators, these compounds represent further attempts to produce agents whose primary activity involves the inhibition of P-gp-mediated efflux with reduced toxic effects. Many of these compounds have been shown to possess low nanomolar potency as P-gp inhibitors in vitro. S9788 has been shown to be five times more potent than verapamil in inhibiting P-gp in vitro (316). The triazinodiaminopiperidine derivative S9788 represents one of the first attempts in the development of a high-affinity agent used specifically to reverse P-gp-mediated resistance. It is possible to achieve nontoxic plasma concentrations of S9788 that are known to reverse P-gp-mediated efflux in vitro (317). In a preliminary study, coadministration of S9788 did not enhance the toxicity of doxorubicin, and the pharmacokinetic profile of doxorubicin was not altered by S9788 (318). The potency and safety of this compound has led to the initiation of further clinical trials with this compound as a P-gp modulator. The actions of transporters in the elimination of their substrates in the liver, kidney, and intestine (exsorption) have recently been elucidated. The elimination of organic cations by the kidney is highly dependent on active transport (322). It is known that intestinally expressed P-gp can act to limit the absorption of its substrates and, like in the liver and kidney, the presence of P-gp in the intestine can make it an efficient organ of elimination. Some examples of drug interactions caused by coadminis- tration of compounds that affect P-gp-mediated efflux are given below. The cardiac glycoside digoxin, widely used for the treatment of congestive heart failure, has a very narrow therapeutic window and any inter- actions that alter the blood concentration of this agent are potentially dangerous (324,325). Digoxin has been shown to be a substrate of P-gp both in vitro (240) and in vivo (326). Because of the strict monitoring of digoxin pharmacokinetics, valuable information regarding the interaction between this agent and other P-gp substrates has been elucidated. Digoxin absorption is known to be affected by P-gp efflux and additionally, in humans, digoxin is primarily eliminated unchanged renally with minimal metabolism; thus changes to digoxin disposition can to some degree be attributed to changes in P-gp-mediated efflux activity (327,328). The ratio of renal clearance of digoxin to creatinine clearance decreased with the coadministration of clarithromycin (0. The role of P-gp efflux in this interaction was confirmed using an in vitro kidney epithelial cell line (326). The administration of itraconazole, a P-gp inhibitor, with digoxin resulted in an increased trough concentration and a decrease in the amount of renal clearance, possibly by an inhibition of the renal tubular secretion of digoxin via P-gp (329). The P-gp modulator verapamil has also been shown to decrease the renal clearance of digoxin (330). It has been shown that quinidine can alter the secretion of digoxin in the kidney and also in the intestine (234). The plasma concentrations of digoxin following intravenous injection increased twofold when quinidine (1 mg/hr) was coadministered. The coadministration of quinidine decreased the amount of digoxin appearing in the intestine by approxi- mately 40%.

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It suppresses the secretions of all the organs cheap seroquel 50 mg on line, especially of the mucous membranes seroquel 50 mg amex, inducing dryness of the throat and mouth and a tendency toward constipation. The evidences of cerebral fulness are: restless excitation, mental exhilaration, headache, dilated pupils, intolerance of light, impairment of vision, uncertainty of muscular movement, the latter finally amounting to incoordination, with motor paralysis. There is delirium of a talkative character, in some, cases violent or furious, with illusions and hallucinations. In extreme delirious excitement, if the dose is a fatal one, there is feeble pulse, cold skin shallow respiration, and paralysis of the inhibitory nerves of the heart and heart-muscle, resulting in death. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 61 In the influence of this remedy upon the capillaries of the skin, loading them up so actively, there is a contributory influence upon the capillaries of the spinal cord, which decreases the amount of blood in this locality, exercising often an exceedingly beneficial influence, especially when the patient suffering from spinal or cerebral congestion has cold skin, cold extremities, a cold, clammy sweat, dilated pupils, and great sluggishness of action. It is a pure stimulant to this organ, through its influence on the cardiac muscle and accelerator nerves. Notwithstanding the lack of proof in the laboratory, in the individual there is more force in the pulse, and there is extreme activity, as stated above, in the capillary circulation, especially when there is profound congestion, with cold relaxed skin, difficult breathing from pulmonary hyperemia, with a small compressible pulse and a deathlike pallor, followed, in extreme cases, by cyanosis. Then the stimulating influence of 1/ or 1/ of a grain of atropine will show itself unquestionably in a 80 60 very few moments. Strychnine expends its influence upon the nerve-centers, but the influence of atropine is upon the peripheries in an unquestionable manner, making it probably the most active of the diffusible stimulants. It thus relieves the pulmonary hyperemia, overcomes cyanosis and promotes free, deep breathing. Specific Symptomatology—There is a characteristic syndrome present in congestive types of many diseases which rationally indicates the need for belladonna. Preliminary congestion is a common condition in very many diseases and the influence of this drug, in antagonizing congestion and in producing a normal and effective equalization of the circulation brings it first to the mind of those who are studying actual conditions, in an endeavor to decide upon the needed remedy. The syndrome referred to consists in chilliness, mental dulness, and inactivity; dull eyes with dilated pupils, eyes partly open when asleep; skin cool and relaxed, with occasional free sweating; cool extremities; general sluggish capillary circulation. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 62 The Homeopathists claim that belladonna is especially indicated where the patients are full-blooded; seldom in anemic patients. Children, very active and with big brains, who are disturbed nights by night-terrors or dreams or show other evidences of restlessness are relieved by belladonna. The remedy acts best in full-blooded patients, where there is active localized heat, pain, redness, and swelling, evidences of local inflammation. When there are a full, bounding pulse, dull flushed face, dull eyes, dilated pupils, and throbbing carotids, the remedy is beneficial. Negroes, and those in warm climates, are especially susceptible to the action of belladonna. Belladonna is not a specific fever-remedy, but in a febrile disorder there is some local engorgement somewhere; there is local capillary hyperemia and, if the remedy is not contraindicated by an already too active condition of the capillary circulation, it will be found of service in all acute congestive disorders with temperature. I have made it a practice for thirty-five years to combine this remedy with the directly indicated fever- remedy, until the symptoms of local engorgement were overcome, then to continue with the fever-remedy alone. When so prescribed, the influence of the remedy to restrain secretion need not be considered, as this influence is usually antagonized by the agent that is used to control the temperature. This is especially true of aconite administered in conjunction with it, which makes a most reliable combination. Given early with aconite, when fever alone is present, hyperemia does not occur and the inflammation is aborted. If the disease is localized in any organ, displaying the phenomena named above, its influence often is quickly apparent. In diphtheritis, tonsillitis, croup, bronchitis, pneumonia, pleuritis and peritonitis, belladonna stimulates the capillary circulation in the engorged organs, thus quickly preventing the local effects of the acute congestion or inflammation. At the same time it has a marked influence upon the fever when used in conjunction with the other indicated measures. If half a drop of the tincture of belladonna be given every two hours, alternated with one grain of alum in syrup, excellent results often are obtained. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 63 In the therapeutics of all continued fevers this agent has an essential place in some stage of the fever. In the sthenic stage of these fevers, combined with aconite, it is sufficient for many of the indications. If there is an intermission or a marked remission, it may be continued alone, during the period. In typhoid fever, it is an important auxiliary during almost the entire duration of the fever. It stimulates the heart to diffuse the blood uniformly throughout the entire capillary circulation, and thus prevents cerebral engorgement. The brain symptoms exhibit many of the belladonna indications and are quickly relieved by it. In meningeal inflammation, both of adults and children, it is often sharply indicated.

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