By H. Agenak. Saint Louis University. 2018.

Cyclosporin A The immunosuppressive cyclic undecapeptide cyclo- sporin A has been used in several clinical trials as a modulator of P-gp purchase 3mg ivermectin with mastercard. Several studies have been performed using cyclosporin A as a P-gp modulator in combination with etoposide buy generic ivermectin 3mg on-line, doxorubicin cheap 3 mg ivermectin overnight delivery, and paclitaxel as described below 3 mg ivermectin with amex. Background work with mice was performed to assess the feasibility of using cyclosporin A as a modulator of P-gp-mediated drug resistance buy 3 mg ivermectin amex. The serum levels of doxorubicin following cyclosporin A treatment were unchanged, indicating that cyclosporin A was altering the drug concentrations in the tumor without affecting its plasma concentration. The effects of cyclosporin A on the pharmacokinetics of etoposide have been determined and were shown to be dose dependent. Results from studies using clinically relevant plasma concentrations of cyclosporin A (1000–5000 ng/mL) as a P-gp inhibitor resulted in mean 48%, 52%, and 52% decreases in the systemic, renal, and nonrenal clearances of intravenously administered etoposide (232,290). Similar decreases in the systemic, renal, and nonrenal clearances of doxorubicin were observed with administration of cyclosporin A (232,291). Tamoxifen, Quinine, and Quinidine Quinine and quinidine are both alkaloid drugs (quinine is the S-diastereoisomer of quinidine) used as antiar- rhythmic drugs. Both have been shown to modulate P-gp-mediated efflux in vitro with quinidine being the stronger inhibitor of the two (143,292). 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.

However discount 3mg ivermectin amex, computers are immensely valuable in advancing and progressing the art and science of rational drug design generic ivermectin 3 mg free shipping. Until the dawning of the 20th century buy ivermectin 3mg online, it was believed that all reality was eminently describable through Newton’s Laws ivermectin 3 mg without prescription. However proven 3mg ivermectin, through the work of Bohr and others, it was eventually realized that classical Newtonian mechanics failed at the atomic level of reality—atoms did not behave like billiard balls. An alternative approach was needed for the quantitative evaluation of molecular phe- nomena. In the first three decades of the 20th century, there occurred many significant advances in theoretical physics and physical philosophy. Planck showed that energy is emitted in the form of discrete particles or quanta; Einstein expanded upon this theory with the proposal that an atom emits radiant energy only in quanta, and that this energy is related to the mass and to the velocity of the light; Schrödinger incorporated these evolving ideas of the new quantum theory into an equation that described the wave behavior of a particle (wave mechanics); Heisenberg formulated a complete, self- consistent theory of quantum physics, known as matrix mechanics; and Dirac showed that Schrödinger’s wave mechanics and Heisenberg’s matrix mechanics were special cases of a larger operator theory. The capacity for a robust, mathematical description of molecular-level phenomena seemed to be at hand. Since the Schrödinger equation (which lies at the mathematical heart of quantum mechanics) permitted quantitative agreement with experiment at the atomic level, the physicists of the 1930s predicted an end to the experimental sciences, including biology, suggesting that they would merely become a branch of applied physics and mathematics. Although in princi- ple the Schrödinger equation afforded a complete description of Nature, in practice it could not be solved for the large molecules of medical and pharmacological interest. Early hopes that quantum mechanics would solve the problems of drug design were dashed in despair. Over the past thirty years, however, three advances have changed the practical use- fulness of molecular quantum mechanics: 1. The advent of semi-empirical molecular orbital calculations and density functional theory, which employ mathematical assumptions to simplify the application of quantum mechanics to drug molecules of intermediate to large size. The development of molecular mechanics, which incorporates quantum mechanical data into a simplified mathematical framework derived from the classical equations of motion to permit reasonable calculations on biomolecules of large size. The construction of “supercomputers” capable of performing the massive calcula- tions necessary for considering very large biomolecules. Accordingly, quantum pharmacology has become an attainable goal and calculational computer modeling permits large molecules to be studied meaningfully. Starting with the X-ray structure of the macromolecule, a space- filling molecular model is created, including hydrate envelopes around it. By separately generating the three-dimensional model of a hypothetical drug, a modeler can manipu- late the two by modern fast computers and can directly examine the fit of the ligand in the active site; the investigator can change the substituents, conformation, and rotamers of the drug on the screen, and can repeat the docking. This enormous progress in computer hardware and software, elucidation of macro- molecular structure and ligand–receptor interactions, crystallography, and molecular modeling is hopefully bringing us to the threshold of a breakthrough in drug design. We are now able to design lead compounds de novo on the basis of the structure of the recep- tor macromolecule. However, computerized drug design is still only an instrument that reduces empiricism in an experimental science; the inherent approximations of innu- merable conformers and molecular parameters of drug and receptor, and the method- ological inaccuracies and difficulties of comparison, will never allow the elimination of insight and trial. Screening for antitumor activity has been carried on for more than 30 years by the U. National Cancer Institute, with tens of thousands of compounds being tested on tumors in vivo and in vitro. More recently, a computerized prescreening method has been applied to this process, saving time and expense, and hence the screening is not as random as it used to be. A successful random search for antibacterial action was conducted by several pharmaceutical companies in the 1950s. They tested soil samples from all over the world, which resulted in the dis- covery of many novel structures and some spectacularly useful groups of antibiotics, notably the tetracyclines (3. In fact, microbial sources have supplied an enormous number of new drug prototypes, sometimes of staggering complexity. Some would argue that drug discovery through screening provides the “irrational” counterpart to rational drug design. As mentioned, screening of compounds has a long and rather illustrious history and has produced many useful anticancer and antibiotic drugs. The discovery of the anticonvulsant drug phenytoin provides an early example of drug discovery through screening. By the latter half of the nineteenth century numerous hydantoin analogs had been synthesized, but only one, 5-ethyl-5-phenylhydantoin (nirvanol), demonstrated any clinical utility. Wernecke introduced nirvanol in 1916 as a “less toxic hypnotic”; however, enthusiasm rapidly waned when its chronic toxicity became recognized.

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Among 70 published cases of pregnant women taking quinine at Summary 273 high doses in an attempt to induce abortion suggest the drug may be teratogenic (Dannenberg et al cheap ivermectin 3mg on line. At least 11 women died as a result of quinine overdose and many who did not expire experienced toxic effects of the drug purchase ivermectin 3 mg amex. No fewer than 41 infants with major congenital anomalies were born to women who took large doses of quinine during pregnancy quality ivermectin 3mg. Causality cannot be proven using these data because the information comprised of only case reports buy 3mg ivermectin visa. Nonetheless purchase ivermectin 3mg fast delivery, large doses of quinine appear to pose an increased risk of some specific abnormalities that parallel toxicity from the drug often seen in adults. Eighteen of 60 infants (30 percent) born to women who ingested large amounts of quinine during pregnancy were congenitally deaf (Dannenberg et al. Ototoxicity is a common and well-documented complication of quinine therapy in adults. Large doses of quinine during the first trimester of pregnancy are anecdotally associ- ated with major congenital anomalies, including central nervous system anomalies (especially hydrocephalus or otolithic damage), limb defects, cardiac defects, and gas- trointestinal tract anomalies (Nishimura and Tanimura, 1976). No characteristic pattern of anomalies or syndrome was identified, and the association of these anomalies with maternal quinine ingestion remains empirically uncertain, but seems plausible. Nonspecific antidote treatment and supportive therapy should be given because no specific antidote for quinine overdose is available. Ergotamine overdose Overdose of ergotamine during pregnancy was published in a case report of a woman at 35 weeks’ gestation who took 10 tablets of ergotamine tartrate in a suicide gesture. Two hours later uterine contractions began with no relaxation between contractions. Two weeks after the over- dose, a macerated stillbirth with no gross abnormality was delivered. Impaired placen- tal perfusion and fetal anoxia associated with ergotamine was speculated to have caused the fetal death (Au et al. Spontaneous onset of preterm labor following ingestion of ergot also occurred with therapeutic levels of the drugs, but at usual therapeutic levels prematurity was the only complication, and there were no fetal deaths. Two antidotes to ergot alkaloid overdose (prazosin and nitroprusside) are now available that were unavailable to patients described above (Au et al. Nitroprusside should be avoided during pregnancy because it conjugates to cyanide and accumulates in the fetal liver. If there is no specific antidote, a nonspecific aggressive treatment should be instituted as early as possible (see Appendix). Homicide and other injuries as causes of maternal death in New York City, 1987 through 1991. No tocolytic agent is uni- versally effective, although more than 100 000 pregnancies will receive tocolysis ther- apy. Pregnant women treated with tocolytics are at increased risk for serious cardiopulmonary com- plications that are directly attributed to the tocolytic drug. Tocolytic therapy invariably occurs outside embryogenesis, so congenital anomalies are not an issue. The primary concern is for adverse maternal, fetal, and neonatal effects (Sanchez-Ramos et al. The three principal indications that guide the use of tocolysis in the treatment of preterm labor are: (1) prophylaxis, (2) acute therapy, and (3) maintenance. Instances do exist when exposure to tocolytic agents occurs during organogenesis, and is used for other indications: terbutaline (asthma), indomethacin (pain), and nifedipine (hypertension). Use for these indications is discussed in the chapters on antiasthma (Chapter 5), analgesic (Chapter 8), and cardiovascular drugs (Chapter 3), respectively. Pharmacokinetics of tocolytic drugs Pharmacokinetic data on tocolytic drugs in pregnancy are limited to five studies of four drugs (Table 15. Half-life and steady-state concentrations are generally not different between pregnant and nonpregnant states. Beta-adrenergic receptor agonists Ritodrine and terbutaline are beta-agonist drugs, structurally related to epinephrine, and are used as tocolytics. This type of tocolytic binds to beta-adrenergic receptors on the outer myometrial cell membrane and acti- vates adenylate cyclase. Another pathway is the phosphorylation of myosin light chain kinase which inactivates the enzyme, thus inhibiting subsequent phosphorylation of the myosin light chain.

In pericarditis and endocarditis its sedative action lessens the frequency of the pulse 3 mg ivermectin mastercard, irritability cheap 3mg ivermectin otc, and its attendant inflammation 3 mg ivermectin amex, in a manner equaled by no other remedy order ivermectin 3mg amex. Cases of exopthalmic goitre are reported as having been cured by lycopus ivermectin 3 mg low price, and it would be well to give it a thorough trial in this most intractable disease. Goss said that in palpitation and valvular disease of the heart, lycopus is good; in hemoptysis it is so positive in its action that he seldom used any other remedy. He considered it a sedative as well as an astringent in its action, controlling the capillary circulation by diminishing the caliber of the vessels, thereby reducing the flow of the blood. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 289 In diseases of the respiratory apparatus lycopus has been found to be very useful. Hale lauds lycopus highly for its efficiency when used in cases of incipient phthisis and in chronic inflammatory diseases of the lungs. Chronic irritable cough, arising from the smouldering inflammation in the lungs, can be cured by its administration. It has been used repeatedly in the high temperature of typhoid fever with uniformly good results; it not only effectually reduced the excessive heat, but in so doing, it did not depress in the least the vital forces of the patient. To a certain extent it acts on the heart as a nerve sedative by lessening its action, also by constringing the blood vessels; hence, diminishing the flow of blood. We have in this valuable remedy much that is expected of aconite or veratrum, antipyrin, antifebrin, as an agent to reduce the heat in high temperature without many of their baleful effects. It is also good in hepatitis, if complicated with pneumonitis, in two-drop doses, once every three hours. In hematuria, if associated with calculi or catarrh of the bladder, lycopus is of benefit alternated with chimaphila umbellata. Halbert and others combine lycopus with chionanthus and perhaps belladonna in the treatment of diabetes. They claim that it influences patients that are naturally fleshy, previously very heavy, and who lose their excess of weight by this disease. It is decidedly beneficial in the treatment of diabetes, curing a few cases after all other remedies have failed. It has proven beneficial in chronic diarrhea and dysentery, inflammatory disease of drunkards and in intermittents. It promotes digestion, invigorates the appetite, allays gastric and enteric irritability. Langford says that lycopus will benefit more gastric difficulties than any other remedy that he has ever used, but does not specify the most particular indications that would suggest it. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 290 Dr. Eads gives lycopus, fifteen drops every thirty minutes with cold compresses to the nape of the neck, for persistent nose bleeding. There are many cases of scalding urine with frequency from vesical irritation that will be overcome by lycopus in full doses. Synonyms—Beaver Tree, Sweet Magnolia, White Bay, Swamp Sassafras, White or Red Laurel. Therapy—In the treatment of intermittent fevers, after the active stage has passed, magnolia has been used. It is not an agent for inflammatory conditions, but restores the tone of the gastro-intestinal tract, which has been lost through the persistence of prostrating fevers, or active malarial conditions. In chronic rheumatism, accompanied with prostration, and loss of appetite, with mal assimilation, the remedy may be used to advantage. Ellingwood’s American Materia Medica, Therapeutics and Pharmacognosy - Page 291 Administration—The active principle of the agent is apt to precipitate if a combination is made with the iodide of potassium, as is often done with other vegetable alteratives. To avoid this the iodide solution should be rendered slightly alkaline by adding a few drops of the liquor potassae before the combination is made. Physiological Action—In overdoses, in some cases the agent produces tremor of the limbs, lack of muscular power, dullness of the mind, drowsiness and active diuresis. Its influence upon the secretion of the entire glandular structure of the digestive and intestinal tract is steady, sure, and permanent, although not always as immediately marked as some other agents. John Aulde in 1911 advised this remedy for its immediate influence upon the digestive apparatus, the blood, and the secretions. He said constipation is relieved and the bowel movements become regular and natural. The complexion clears, the muscular strength increases, and the skin and urinary organs become more active. I have found it indeed serviceable in syphilis and in scrofula, the general indications being peculiar to indigestion such as coated tongue, fetid breath, and a.

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