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Other biochemical and physiological factors that are likely to affect this process include protein binding order discount viagra sublingual online erectile dysfunction drugs australia, blood flow to gut cheap 100 mg viagra sublingual overnight delivery erectile dysfunction doctor in kuwait, and specificity for intestinal P-gp-mediated efflux activity order viagra sublingual uk erectile dysfunction tea. P-gp can affect the rate at which drugs are eliminated from tissues and from the plasma via elimination through the liver, intestine, and/or kidney. The oral, systemic, and tissue clearances (rate of elimination) are affected by P-gp efflux, and thus the terminal half-lives of P-gp substrates may be related to the efflux activity seen in the organism. The effect of P-gp-mediated efflux activity on excretion has been clearly shown through experiments with vinblastine and paclitaxel in mdr1a(À/À) mice. The results of these experiments have shown how P-gp-mediated efflux activity accelerates tissue clearances and also systemic clearances of its substrates. Additionally, these studies have highlighted the role of the intestine in elimi- nation. While the role of intestinally expressed P-gp in limiting absorption is recognized, these experiments have helped elucidate its role in making the intestine a significant route of elimination. In normal mice, the elimination of vinblastine in the feces within 24 hours of administration was determined to be approximately 25% of the dose as unchanged drug at two doses (1 and 6 mg/kg) (218). In the mdr1a-deficient mice, the amount of unchanged drug recovered in the feces was reduced to 9. The amount of vin- blastine remaining in the brain tissue of the P-gp-deficient mice was approxi- mately 1000-ng/g tissue at the 6-mg/kg dose 24 hours after administration, whereas the amount of vinblastine remaining in the brain tissue of normal mice at the same dose was only 22 ng/g tissue (218). The normal mice showed much more rapid elimination of vinblastine from both the plasma and tissue than the mdr1a-deficient mice, and a significant reduction in terminal elimination half- life and reduced clearances of vinblastine were observed for each of these dose levels for the P-gp-deficient mice (12,218). As seen with vinblastine, clearances of paclitaxel were reduced and elimination of half-life increased in the mdr1a(À/À) mice (217). Following an oral dose (10 mg/kg), 90% of the dose was recovered in feces of the wild-type mice compared with only 2% seen in the 382 Troutman et al. The contributions of the mdr1a P-gp to the hepatic and intestinal clear- ances of paclitaxel, digoxin, vinblastine, and doxorubicin have been determined by comparing the amounts of biliary and intestinal secretion of each drug in wild-type and mdr1a(À/À) mice (Table 4). The amounts of biliary excretion of paclitaxel and the hydroxylated metabolites were not significantly different between the wild-type mice and the mdr1a-deficient mice (217). Like paclitaxel, absence of the mdr1a P-gp seems to have a minimal effect on the biliary secretion of digoxin and vinblastine, whereas the intestinal secretion of these compounds is significantly affected (219,269). An opposite situation exists for the intestinal and biliary secretion of doxorubicin. Nearly five times the amount of unchanged doxorubicin was secreted into the bile of the wild-type mice versus the mdr1a(À/À) mice, whereas the intestinal secretion of doxor- ubicin was approximately equal (*10% of the dose) in both sets of mice (219). These results illustrate that in mice, mdr1a P-gp is active in the intestinal excretion of paclitaxel, digoxin, and vinblastine, and that the mouse liver has the ability to utilize alternate pathways of elimination for these compounds. Con- versely, the biliary excretion of doxorubicin in mice appears to be highly dependent on mdr1a P-gp-mediated efflux activity, whereas intestinal mdr1a P-gp plays less of a role in the intestinal excretion of doxorubicin (Table 4) (270). Alteration of P-gp-mediated efflux activity can have consequences to these substrates’ disposition. Furthermore, inter- and intrapatient variability in P-gp expression and function can be a potential source of pharmacokinetic variability. The following sections summarize findings fol- lowing changes to P-gp-mediated efflux activity resulting from coadministration of P-gp substrates and inhibitors and those related to genetic variability in P-gp. Outcomes from Alteration of P-gp Efflux Activity Mediated by Coadministration of Substrates and Inhibitors The efflux activity mediated by P-gp is a saturable process and as such is subject to interactions between substrates and inhibitors. Lin notes that interactions between P-gp The Role of P-Glycoprotein in Drug Disposition 383 384 Troutman et al. This multiplicity of mechanisms makes assessment of interaction difficult and further nearly impossible to predict a priori (271). While it is certain that coadministration of P-gp substrates results in changes to disposition, it is often unclear to what degree these changes may occur as a result of alteration of efflux. Finally, P-gp expression can be induced, and this phenomenon has the potential to lead to interactions. Although a precise understanding of the implications of P-gp interactions is yet to be realized, some insight into how coadministration of substrates and inhib- itors interact can be gained from clinical findings. A summary of the findings in each area and conclusions around P-gp interactions that they provide is given below. Results obtained from trials with first generation inhibitors have been somewhat disappointing; however, some promising results were obtained in hematolymphoid malignancies (275,276). There are several possible reasons why this line of therapy has not been suc- cessful. Importantly, a key reason why first- and second-generation inhibitors have not been successful is the change in systemic pharmacokinetics, which some have imparted to the chemotherapeutic agent; this change is often increased absorption or decreased elimination, leading to greater systemic concentrations and subsequent toxicity (277,278). For this reason, third-generation inhibitors have been developed that more specifically interact with P-gp, and consequently these selective inhib- itors have shown less propensity to alter the systemic pharmacokinetics of the chemotherapeutic agents (278). These agents represent drugs in clinical use for other indications that had been shown to inhibit P-gp efflux through in vitro experiments. Because of the relatively low binding affinity of these compounds for P-gp and the need to increase the doses of these modulators to toxic levels, few of these agents have been further studied for use in clinical modulation of P-gp. However, early trials with these drugs have provided invaluable information regarding the consequences of inhibiting P-gp. These first-generation inhibitors include vera- pamil, cyclosporin A, tamoxifen, quinidine, and quinine. Racemic verapamil was shown to reverse P-gp-mediated resistance to vincristine and vinblastine in vitro and in vivo in P388 leukemia (279). These early findings and the fact that verapamil was a clinically used drug with an established record of safety provided the rationale for its use clinically as a P-gp modulator. The maximum tolerated dose of verapamil has been reported to be 480 mg/day orally (leading to blood levels of 1 mM) with the dose-limiting toxicity being hypo- tension (280). Dose escalation studies with intravenously administered verapamil found that for the dose range of 0. Oral verapamil has been shown to increase peak plasma levels, prolong the terminal half-life, and increase the volume of distribution at steady state of doxorubicin (282). The steady-state concentration and systemic and renal clearances were found to be statistically similar for various doses of verapamil and doxorubicin, and for doxorubicin administered alone. Additional trials were designed to assess the usefulness of verapamil in improving the efficacy of chemotherapeutic regimens for the treatment of small cell lung cancer (284,285), refractory multiple myeloma (286), and breast cancer (287). The results of these trials showed that verapamil had only a modest positive effect on the overall effectiveness of the regimen. Cyclosporin A The immunosuppressive cyclic undecapeptide cyclo- sporin A has been used in several clinical trials as a modulator of P-gp. Several studies have been performed using cyclosporin A as a P-gp modulator in combination with etoposide, doxorubicin, and paclitaxel as described below.
In some cases the rate of enzyme inactivation can be quantified without an assay for enzyme activity discount 100 mg viagra sublingual amex erectile dysfunction 20s. If the rate of metabolite formation can be determined over a time period that is sufficiently short that significant enzyme inactivation does not occur (kcat > kinact) 100mg viagra sublingual otc erectile dysfunction doctor nj, then the exponential term in Eq discount viagra sublingual 100mg fast delivery erectile dysfunction icd 9 2014. Equation (12) illustrates that the apparent Vmax for formation of a metabolite will decline as the incubation time increases when simultaneous enzyme inactivation occurs (Fig. The partition ratio can be obtained from estimates of kinact and kcat or can be determined directly. This is achieved by simultaneously quantifying the moles of enzyme inactivated and the moles of metabolite formed for given incubation conditions. Clearly, if any two parameters from kinact, kcat, and r are known, then the third can be calculated. The ribbons represent the change in absorbance difference for scans from 5 to 120 minutes. The dashed line is the line of best fit of the data with the Michaelis-Menten equation. Extent of Interaction When one drug has the capability to inactivate an enzyme, the elimination of a second drug that relies on that enzyme may be impaired. The net effect of exposure to an enzyme inactivator is to enhance the rate of degradation of active enzyme from the endogenous pool. Under baseline conditions the rate of change of active enzyme concentration, dE(t)/dt, is determined by the balance between the rate of de novo synthesis and the rate of degradation. Enzyme synthesis rate is generally assumed to be a zero-order process, whereas the rate of degradation is a first-order process (80): dEðtÞ ¼ R0 À kE Á EðtÞ ð16Þ dt where R0 is the rate of enzyme synthesis and kE is the endogenous degradation rate constant. This expression is reminiscent of the model used to predict interactions involving reversible, competitive inhibi- tion (see chap. The concentration of inhibitor that should be used in this predictive model is the concentration at the enzyme, but in practice plasma concentrations are often used as a surrogate. In this nonlinear system, the effect of an inactivator on steady-state enzyme concentrations can be predicted by iteratively solving the differential equations that describe the rate of change of enzyme and inactivator concentration. Time Course of Inactivation An important characteristic of inhibition of drug metabolism by an inactivator is the time dependence of both the onset and offset of the effect. The time course of the change in enzyme concentration from the baseline, Ess, to that in the presence of inactivator, E0 , is given by ss Àkt 0 EðtÞ ¼ Ess Á e þ Ess ð29Þ where E(t) is the enzyme concentration at some time t. This relationship indicates that the half-life of the decline in enzyme concentration (0. Therefore, the Mechanism-Based Inhibition of Human Cytochromes P450 531 greater the potency of the inactivator, the faster the onset of the interaction. In contrast, the rate of offset of the interaction is given by 0 Àk Át E ¼ E þ R Á 1 À e E ð30Þ ðtÞ ss 0 In this case the half-life for the return to baseline enzyme concentration (0. Thus, the offset of the interaction is independent of the properties of a given inactivator. Although the conclusion that irreversible inhibition is determinant in these examples is reasonable, caution must be exercised because it is often not possible to rule out a role for reversible inhibition arising from high tissue drug concentrations and/or the presence of inhibitory metabolites. However, clinically important drug interactions between erythromycin and midazolam (1), dextro- methorphan (86), cyclosporin A (87), alfentanil (88), triazolam (89), alprazolam (90), and carbamazepine (91) have been observed clinically. In a key clinical study, liver specimens were obtained by surgical biopsy of six patients receiving erythromycin propionate (2 g daily for 7 days) (3). Biopsies were obtained before and after the consumption of 8 oz of grapefruit juice three times a day for six days in 10 healthy men (93). The time course of recovery indicated an average recovery half-life of 23 hours and is consistent with enzyme regeneration after mechanism-based inhibition. Clarithromycin is characterized by a Ki value in vitro of 10 mM and average serum concentrations of 0. As with grapefruit juice, intestinal biopsy studies have been employed to obtain direct evidence of mechanism-based inhibition in vivo for clarithromycin. A similar phenomenon has been observed with the well-established 1 mechanism-based inhibitor, diltiazem (108). The demonstration of mechanism-based inhibition in vitro should not be assumed to result in significant inhibition in vitro. However, the partition ratio approach to in vivo prediction is not recommended because an in vivo partition ratio that accounts for competing routes of elimination is generally not available and the contribution of new enzyme synthesis is ignored. However, the core interaction model used in these approaches was described earlier (Eqs. The degradation rate constant, kE, is characterized by considerable uncertainty due to the difficulties estimating the value in vivo; estimates of kE using a variety of approaches are presented in Table 3. Sorivudine is converted by gut flora to (E)-5-(2-bromovinyl) uracil, which inactivates dihydropyrimidine dehydrogenase and impairs the metabolism of 5-fluorouracil by this enzyme. This interaction led to 15 deaths in Japan from 5-fluorouracil toxicity due to elevated exposure to the drug. This basic approach was also used to predict the inhibitory effect of verapamil enantiomers and their major metabolites, norverapamil and N-desalkyl verapamil (D617), on midazolam clearance. The model predicted the nonlinear disposition of paroxetine with an accumu- lation ratio that is fivefold higher than the expected accumulation if linear kinetics were assumed; this was in excellent agreement with the observed five- to sixfold greater accumulation. These predictions are in reasonable agreement with observed data but the incorporation of in vitro microsomal binding was essential for good predictive accuracy. Quantitative prediction of irreversible inhibition at the level of the gut wall remains challenging because of the added uncertainty in the effective inhibitor concentration at this site. However, a model that successfully predicted the grapefruit juice–felodipine interaction at the gut wall has been described and used to recommend consumption strategies for mini- mizing the severity of the interaction, although prospective evaluations of the predictions were not described (125). An attractive strategy for predicting the clinical significance of irreversible inhibition is to use human hepatocytes wherein the ‘‘natural’’ turnover of enzymes might be preserved and in vivo cellular concentrations of inhibitors and metabolites would be achieved. This property could affect a drug’s own metabolism or the metabolism of coadministered drugs, which could lead to serious drug interactions. Even though in vitro Ki values have been determined for a number of drugs and have been used to predict an in vivo interaction, the effect of mechanism-based inhibitors can be observed at in vivo concentrations below these Ki values. A theoretical basis and application have been presented that applies in vitro estimates of mechanism-based inhibitors to accurately predict in vivo drug interactions. In vitro forcasting of drugs which may interfere with the biotransformation of midazolam. Thiophene derivatives as new mechanism- based inhibitors of cytochromes P-450: inactivation of yeast-expressed human liver cytochrome450 2C9 by tienilic acid. Oxidation of tienilic acid by human yeast- expressed cytochromes P-450 2C8, 2C9, 2C18 and 2C19: evidence that this drug is a mechanism-based inhibitor specific for cytochrome P-450 2C9. Electrospray ionization mass spectrometric analysis of intact cytochrome P450: identification of tienilic acid adducts to P450 2C9. Inhibition of cyclosporine and tetrahydrocan nabinol metabolism by cannabidiol in mouse and human microsomes. Characterization of cytochrome P450 3A inactivation by cannabidiol: possible involvement of cannabidiol-hydroxyquinone as a P450 inacti- vator. Suicide inactivation of rat liver cytochrome P-450 by chloramphenicol in vivo and in vitro. Identification of the heme adduct and an active site peptide modified during mechanism-based inactivation of rat liver cytochrome P450 2B1 by secobarbital.
The list of drugs thought to be responsible for causing myocarditis is added to daily so no account of them can be totally up to date order 100mg viagra sublingual with amex erectile dysfunction treatment in qatar. Hypersensitivity (allergic) myocarditis have lesions which are not dose or time dependent and may occur any time during delivery of the drug purchase generic viagra sublingual online erectile dysfunction at 25. In general purchase viagra sublingual online kidney disease erectile dysfunction treatment, hypersensitivity myocarditis is manifested morphologically with an interstitial inflammatory infiltrate which includes many eosinophils. Heart size is usually not markedly affected in acute hypersensitivity myocarditis. Toxic myocarditis and vasculitis induced by drugs is dose related and the effects are cumulative. The inflammatory infiltrate surrounding the damaged myocytes is predominantly that of neutrophils although a mixed infiltrate may also be seen. The anthracycline drugs, particularly adriamycin, also may cause an acute myocarditis-pericarditis syndrome; however, these drugs usually cause a chronic myocardial damage which will not be described here. Drugs associated with toxic myocarditis Arsenicals Anthracyclines Plasmocid Lithium compounds Paraquat Catecholamines Barbiturates Quinidine Antihypertensives Cyclophosphamide Amphetamine Theophylline Fluorouracil Phenothiazines Histamine-like drugs Table 2. Drugs associated with hypersensitivity myocarditis Sulfonamides Streptomycin Isoniazid Sulphonyurease Penicillin Methyldopa Thiazide diuretics Phenylbutazone Diphtheria toxoid Horse serum Tetanus toxoid E. The clinical features of an acute myocarditis usually include a history of a recent flu-like illness with fever, myalgias, fever and shortness of breath. On examination the patient usually has an enlarged cardiac silhouette and heart failure. Usually, however, it is designated according to its anatomic features, such as (1) serous, (2) serofibrinous, - (3) fibrinopurulent, (4) purulent, and (5) hemorrhagic. Pericarditis also may be idiopathic (non-specific) or due to acute bacterial infection, uremia, or associated with myocardial infarction, rheumatic, neoplastic or traumatic. In some conditions such as heart failure an excessive serous transudate may occur into the pericardium slowly or rapidly. In this case there are usually no adhesions Cardiomyopathy, Myocarditis & Atrial Myxoma - Gerald Berry, M. Hemopericardium in which blood enters the pericardial sac may be caused by trauma, such as a knife wound, myocardial rupture or coronary artery rupture. More recently the use of the cardiac biopsy may result in perforation of the ventricle and hemopericardium. Hemorrhage into the pericardium may cause tamponade which is a clinical emergency. Blood should be removed from the pericardial sac rapidly to allow diastolic expansion of the heart and also to prevent organization of the blood. Serofibrinous and fibrinous pericarditis: This is the most frequent type and commonly occurs in uremia, rheumatic fever or infarction. Clinically, this type of pericarditis may cause pain and result in a loud friction rub. Suppurative or purulent pericarditis: This is due to bacteria, mycotic or parasitic organisms. Sometimes it is also due to direct invasion of tuberculosis or pneumonia from the lung. This type of pericarditis leads to granularity of the serosal surface with occlusion and organization into a dense thickened pericardial sac which may even be calcified. Hemorrhagic pericarditis: A hemorrhagic pericarditis is one in which blood is present in addition to the features of one of the other inflammatory exudates. The causes include tuberculosis, severe acute infections and neoplastic (tumor) involvement of the pericardium. A rare occurrence is a pericardial effusion containing cholesterol which is associated with myxedema. Healed Pericarditis: Pericarditis results in chronic adhesive (obliterative) pericarditis, or chronic constrictive pericarditis. Chronic adhesive pericarditis consists of adherent pericardium and it usually causes no embarrassment of the heart thus differing from chronic constrictive pericarditis. Chronic constrictive pericarditis is a result of healing of inflammatory exudate and is characterized by marked fibrous thickening of the pericardium which becomes so rigid that it mechanically interferes with heart action and the Cardiomyopathy, Myocarditis & Atrial Myxoma - Gerald Berry, M. Pick’s disease is a syndrome consisting of chronic constrictive pericarditis with severe venous congestion of the liver that may lead to fibrosis and ascites (note: there is another Pick’s disease in the brain! The subject has not received a great deal of attention in textbooks because the etiology of this disease is not yet clear and also, up until recently, there has not been any good treatment. It is now likely that there would be questions on this subject in the National Boards. This lecture covers not only idiopathic cardiomyopathies, but also specific heart muscle disease (secondary cardiomyopathies) and so covers a great deal of cardiac pathology. Tumors of the heart are very rare and only one or two are important for you to remember, such as myxomas and secondary metastases to the heart. The pathology of the three main types of idiopathic cardiomyopathies and their physiologic effect. Cardiomyopathy is a condition affecting primarily the myocardium unassociated with significant narrowing of the extramural coronary arteries, or systemic hypertension, or anatomic valvular disease, or congenital malformation of the heart and vessels or intrinsic pulmonary parenchymal, or vascular disease. In other words, the diagnosis depends partly on the exclusion of other common types of heart disease. These forms of myocardial disease (cardiomyopathies) are described in diverse journals; moreover, definitions are often sketchy or controversial; the diagnosis is often made by exclusion of the usual causes of cardiac failure; and Cardiomyopathy, Myocarditis & Atrial Myxoma - Gerald Berry, M. It has been recently proposed by the Task Force on Cardiomyopathies, World Health Organization, and the Scientific Council on Cardiomyopathies, International Society and Federation of Cardiology, that nomenclature for these disease entities be made more specific and less ambiguous. According to the new classification, the term cardiomyopathy should be used to describe the group previously known as “primary cardiomyopathy” or “heart muscle disease of unknown cause,” and that “secondary cardiomyopathy” should be replaced by the term “specific heart muscle disease. In this type, the heart is enlarged, the ventricles markedly dilated and the clinical signs are those of systolic pump failure. The morphological changes are nonspecific, but include interstitial fibrosis and long attenuated myofibers. Intracardiac mural thrombi are often seen because of depressed cardiac output and stasis. Once symptoms begin, one-half of the patients are dead within a year and two-thirds within two years. The cause of death is heart failure, embolization, or terminal ventricular arrhythmias. The ultrastructural changes seen are reminiscent of the early stages of myocardial embryogenesis. In this condition, the interventricular septum is thicker than the left ventricular free wall and the ventricular cavities are reduced in size. The septal myocardium shows pathognomonic features of severely disorganized multidirectional myocytes. Gradually the terms “idiopathic subaortic stenosis” and “obstructive” cardiomyopathy are dwindling in usage and importance, reflecting the realization that hypertrophic cardiomyopathy is essentially a disease of heart muscle rather than an outflow tract obstruction.
They have high water solubility and are rapidly excreted discount viagra sublingual 100 mg otc erectile dysfunction normal age, leading to a rather short half-life order cheap viagra sublingual online erectile dysfunction doctor calgary. They can also be irritating to the gastrointestinal tract during the pharmaceutical phase cheap viagra sublingual 100mg with amex impotence exercise. These three- membered rings will readily open in the presence of most nucleophiles. Aziridines tend to behave as alkylating agents and thus have carcinogenic effects. Some drugs containing tetrahydrofurans (oxalanes) tend to be readily air oxidized, and thus have a poor shelf life and are unstable even prior to being administered; other tetrahydrofuran-containing drugs are metabolically stable. Furans (oxoles) behave more like aromatic compounds than ethers; accordingly, they undergo aromatic hydroxylation. Pyrroles (azoles) undergo aromatic hydroxylation; pyrro- lidines (azolidines) undergo conjugation with either glucuronic acid or sulfuric acid. Thiophenes (thioles) are subject to aro- matic hydroxylation; tetrahydrothiophenes (thiolanes) undergo oxidation of the sulfur to give sulfoxides or sulfones. Two common forms are oxazole (1,3-oxazole) and isoxazole (1,2-oxazole), both of which undergo aromatic hydroxylation. These are five-membered ring heterocycles containing two nitrogens, one basic and one neutral. Two common forms are pyrazole (1,2-diazole) and imidazole (1,3-diazole); both are prone to aromatic hydroxylation. Piperidine functions as a secondary amine and undergoes hydroxylation with either glucuronic acid or sulfuric acid. This is a bicyclic (one five-membered ring plus one six-membered ring) aromatic heterocycle. Since most indole-containing drugs are substituted with the remainder of the drug being positioned at the 3 position, the aromatic hydroxylation tends to occur at the 4–7 position. This is a bicyclic heterocycle containing two six-membered rings and two oxygens, one endo- cyclic, one exocyclic. Since the coumarin contains an intramolecular lactone ester, it undergoes hydrolysis to yield a carboxylic acid and a phenol. Of these barriers, the blood–brain barrier is by far the most important to the drug designer. There appeared to be some invisible barrier that prevented certain molecules from enter- ing into the brain. Drug molecules are distributed throughout the body by the bloodstream and the capillary is the point at which a drug leaves the bloodstream to bind to a receptor. Within the brain, cap- illaries are composed of cells, called endothelial cells, that are connected to each other by tight junctions. These junctions are a first-line impediment, slowing the journey of the drug molecule from within the capillary to a receptor site on a neuron. The astrocyte wraps itself around the capillary to provide yet another line of defense between the drug in the capillary and the neuronal receptor to which it is traveling. In the brain, in order for a drug molecule to leave a capillary and successfully journey to a neuronal receptor, it must traverse multiple barriers. The walls of capillaries in the brain are dif- ferent from those in non-brain tissues. Next, in the brain, another type of cell, called an astrocyte, forms an additional barrier that must be traversed. There are a number of molecular substrates that the brain requires for its nor- mal functioning; these substances are not biosynthesized within the brain and are not able to enter the brain by passive diffusion. Because of their importance to normal brain neu- rochemistry, evolution has resulted in the existence of protein carriers to transport them into the brain. D-glucose and L-phenylalanine are two such molecules, and there are a number of others. A prodrug is a drug molecule that is biologically inactive until it is activated by a metabolic process. Improve the flavor of a drug An ester, for example, can be used to “mask” a carboxylate. Within the body, the ester is hydrolyzed, releasing the drug in its bioactive carboxylate form. In that application, it must pass through the liver — the principal drug-metabolizing organ — in which it loses an N–ethyl group to become a convulsant and emetic. This compound is not a prodrug in the strict sense, but rather represents a molecular modification. Replacement of a “vulnerable moiety” such as a methyl group by a less readily oxi- dized chlorine was used to transform the short-acting tolbutamide (3. The ester group is fairly stable in the tissues but is very rapidly hydrolyzed in the serum to the polar carboxylic acid, which cannot penetrate the blood–brain barrier. The introduction of a hydrophilic “disposable moiety” can restrict a drug to the gastrointestinal tract and prevent its absorption. Such a type of drug is represented by the intestinal disinfectant succinyl-sulfathiazole (3. On the other hand, lipophilic groups can ensure peroral activity, as in the case of the penicillin derivative pivampicillin (3. This can be a great convenience for the patient, especially in areas with remote medical facilities. Drug designers have attempted for many years to use selective drug-transport moi- eties, and have met with moderate success. The idea is to attach a drug, such as an anti- tumor agent, to a natural product that will accumulate selectively in a specific organ and act as a “Trojan horse” for the drug. The attachment of alkylating agents to estro- gens has been tried in the treatment of ovarian cancer, and amino acids have also been used as drug carriers. A recent ingenious application of the carrier concept is the uti- lization of antibodies — which can, at least in principle, be tailored to any site — as drug carriers. The large-scale preparation of antibodies is, of course, a major difficulty in this approach; however, the new monoclonal antibodies hold great promise. This concept goes back to the turn of the twentieth century, and in fact many prodrugs were not at the time really recognized as such. For instance, castor oil is a laxative because it is hydrolyzed intestinally to the active ricinoleic acid. Selective bioactivation (toxification) is illustrated in the case of the insecticide malathion (3. This acetylcholinesterase inhibitor is desulfurized selectively to the toxic malaoxon, but only by insect and not mammalian enzymes. Higher organisms rapidly detoxify malathion by hydrolyzing one of its ester groups to the inactive acid, a process not readily available to insects. This makes the compound doubly toxic to insects since they cannot eliminate the active metabolite.
The drug can aggravate urinary tract blockage and should be used cautiously by persons with enlarged prostate discount viagra sublingual line erectile dysfunction radiation treatment. Glutethimide 187 A severe overdose can produce what looks like skin burns buy generic viagra sublingual 100 mg on line erectile dysfunction pump canada, and muscle spasms or even convulsions may occur cost of viagra sublingual erectile dysfunction pills walgreens. Case reports note that long-term use of glutethimide can decrease a person’s calcium levels; one report tells of bones softening in a person who took the drug routinely for 10 years, and another report notes seizures occurring due to low calcium. After a dozen years of daily glutethimide ingestion, one person had lost so much muscle control that speech was diffi- cult, unassisted walking was impossible, and control of urination and bowel movements was no longer possible. Others, how- ever, mention persons who took the drug for years without noticeable ill ef- fect. Users of the combination report increased sociability and feelings of intellectual in- sight in discussions that were actually about nothing. Some of these deaths involve dosages of each drug that were theoretically safe, outcomes implying that glutethimide and codeine may boost each other’s actions. Users of the com- bination have experienced typical unwanted actions of both drugs in addition to headaches, grouchiness, tremors, cramps, and trouble sleeping. Among persons taking medical doses of glutethimide for months, a withdrawal syndrome can include hallucinations, fever, delirium, and con- vulsions. For addiction treatment, phenobarbital can be substituted for glutethimide, and a person can then be gradually weaned off the phenobarbital. The drug reduces effectiveness of warfarin, a medicine that fights heart attack and stroke by reducing blood clotting. Glutethimide is also supposed to be avoided if someone is taking the anti-blood-clotting sub- stance coumarin. Army aerospace test found that using alcohol with glutethimide did not harm breathing. That finding has rather narrow signifi- cance for most persons, but a more generally relevant finding came from an experiment showing that glutethimide raised blood alcohol levels of persons who had been drinking. Glutethimide is related to thalidomide, perhaps the most noto- rious pharmaceutical cause of human birth defects. In experimentation with rats and rabbits glutethimide did not produce physically apparent birth de- fects. The death rate among rabbit offspring was 6%, however, compared to a 2% rate among offspring with no fetal drug exposure—a rate three times higher for the glutethimide group than for the nondrug group. One experi- ment found the death rate of rats with prenatal glutethimide exposure to be three times that of rats with no drug exposure. Surviving rats with fetal ex- 188 Glutethimide posure to glutethimide exhibit abnormal behavior, but their own offspring behave normally. Pregnant women have routinely received glutethimide for insomnia, nausea, and vomiting. Nursing moth- ers who take the drug may have enough glutethimide in their milk to make their infants sleepy. Because the drug promotes drowsiness, it is sometimes prescribed to be taken at bedtime, aiding both sleep and calmness. One experiment found the compound to be more effective than clorazepate dipotassium in helping anxiety. Another study found that halazepam can diminish anxiety significantly on the very first day of administration. Halazepam is also used to treat symptoms of alcohol with- drawal and has had some experimental success in alleviating schizophrenic psychoses. Physicians have observed that halazepam can reduce stress and depression and can improve epilepsy. An experiment found that halazepam did not increase belligerence, unlike some benzodiazepine class drugs. Canine studies show that in the body the drug converts into nordiazepam and oxa- zepam, which are also metabolites of diazepam. With stronger dosages elderly persons sometimes experience difficulty in manual dexterity and other muscle control; during an experiment several elderly individuals fell. In an experiment some alcoholics had difficulty distinguish- ing halazepam from placebo, an outcome suggesting that the drug has low potential for abuse (as abusers of alcohol and other drugs should be particu- larly susceptible). Nonetheless, a person’s body can develop physical depen- dence with halazepam, which is a traditional sign of addictive potential. One group of researchers found withdrawal symptoms to be so mild, however, that a placebo could control them. The heartburn medicine cimetidine is suspected of inter- fering with halazepam’s effects. No cancer developed in rats and mice at daily dosage levels 5 to 50 times the maximum human dose. Experiments with rats and rabbits have produced no evidence that the drug causes birth defects. For most of the twentieth century drug addiction and heroin were synonymous in the United States; all substance abuse was assumed to lead to heroin. Only in the 1980s did heroin become displaced as the devil drug, supplanted in public fear and disapproval by cocaine. Being a Schedule I substance, heroin has no officially approved medical use in the United States. Heroin is produced from morphine, and body chemistry converts a heroin dose back into morphine. One study of pain relief found heroin comparable to hydromorphone, a standard med- ication administered to fight severe pain. Physicians have judged heroin to be a safe anesthetic for use during childbirth, with no apparent ill effect on mother or child. The drug is also used to treat porphyria, a body chemistry disorder making people sensitive to light and occasionally making them vio- lent. Heroin users of both genders have reported increased sexual activity upon starting the compound, with decline in that activity as usage continues. That sequence would be consistent with the drug at first reducing psycholog- ical anxiety, an effect gradually evolving into indifference about the world. Extrapolating from severity of withdrawal symptoms, any particular size heroin dose taken by intravenous injection is five times stronger than one taken by inhaling heated vapor (“chasing the dragon”). Other measurements show a dose to be four times more potent when taken intravenously instead of by inhaling powder. Sometimes intravenous injection of heroin produces a rush of feeling lik- ened to a total body sexual orgasm. Heroin may allow some nonmedical users to experience euphoria, but more typically an intoxicating dose increases psy- Heroin 193 chic distance between the user and the world, making reality seem unimpor- tant. People using lesser doses of heroin in that way may function more productively, or they may experience trouble because they feel confident enough to get into situations they would otherwise avoid. Researchers find, however, that injectors of a heroin variety called “black tar” have an increased risk for botulism infection at the injection site, no matter how hygienic their equipment and technique.
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