Grifulvin V

Nicole C. Pezzino, PharmD

• Assistant Professor of Pharmacy Practice, Wilkes University, School of Pharmacy, Wilkes-Barre
• Clinical Pharmacist in Community/Ambulatory Pharmacy, Nanticoke, Pennsylvania

https://www.wilkes.edu/campus-directory/nicole.pezzino.aspx

After oral exposure of tellurides 10­20% of the ingested dose is absorbed (Gerhardsson et al fungus gnats basement 125 mg grifulvin v purchase with amex. The kidney fungus in sinus discount grifulvin v 125 mg line, bone anti fungal wall treatment generic 250 mg grifulvin v with mastercard, and liver accumulate tellurium and it is estimated that bone stores may have a half-life of up to 2 years or more (Gerhardsson et al antifungal oils order grifulvin v 125 mg on line. Tellurium Tellurium (Te) is a metalloid chemically related to selenium and sulfur. Discovered in the 1780s, tellurium is named after the Latin Toxicity Of toxicological importance are elemental tellurium, the gases hydrogen telluride and tellurium hexafluoride, and the watersoluble sodium or potassium tellurites and tellurates (Gerhardsson et al. Tellurates and tellurium are of generally low toxicity, but tellurites are typically more toxic. Acute intoxication by inhalation results in sweating, nausea, a metallic taste, and garlic smelling breath. In fact, garlic breath is an indicator of exposure to tellurium by dermal, inhalation, or oral routes. The cases of tellurium intoxication reported from industrial exposure do not appear to have been life threatening. Two deaths occurred within 6 hours of accidental poisoning by mistaken injection of sodium tellurite (instead of sodium iodine) into the ureters during retrograde pyelography (Gerhardsson et al. The victims had garlic breath, renal pain, cyanosis, vomiting, stupor, and loss of consciousness. In rats, chronic exposure to high doses of tellurium dioxide produces renal and hepatic injury (Gerhardsson et al. Rats fed metallic tellurium at 1% of the diet develop demyelination of peripheral nerves (Goodrum, 1998), probably due to the inhibition of cholesterol biosynthesis (Laden and Porter, 2001). Lifetime exposure to sodium tellurite at 2 mg Te/L drinking water had no effect on tumor incidence in rats. Tellurium compounds produce hydrocephalus in rats after gestational exposure between day 9 and 15. Thallium (from the Greek word thallos meaning "a green shoot or twig") was discovered in 1861. The thallium ion has a similar charge and ion radius as the potassium ion, and its toxic effects may result from interference with the biological functions of potassium. Thallium is obtained as a by-product of the refining of iron, cadmium, and zinc, and is used as a catalyst in alloys, and in optical lenses, jewelry, low-temperature thermometers, semiconductors, dyes, pigments, and scintillation counters. Thallium compounds, chiefly thallous sulfate, were used as rat poisons and insecticides. Industrial poisoning is a risk in the manufacture of fused halides for the production of lenses and windows. Naturally high thallium concentration in soils and consequent uptake into edible plants in Southwest Guizhou, China caused locally chronic thallium poisoning (Xiao et al. Following the initial exposure, large amounts are excreted in urine during the first 24 hours, but after that urinary excretion becomes slow and the feces becomes an important route of excretion. The half-life of thallium in humans has been reported to range from 1 to 30 days and depends on the initial dose. Thallium can transfer across the placenta and is found in breast milk, and may cause toxicity in the offspring (Hoffman, 2000). Other signs and symptoms also occur depending on the dose and duration of exposure. Depilation begins about 10 days after ingestion and complete hair loss can occur in about 1 month. Other dermal signs may include palmar erythema, acne, anhydrosis, and dry scaly skin due to the toxic effects of thallium on sweat and sebaceous glands. After oral ingestion of thallium, gastrointestinal symptoms occur, including nausea, vomiting, gastroenteritis, abdominal pain, and gastrointestinal hemorrhage. Neurological symptoms usually appear 2­5 days after acute exposure, depending on the age and the level of exposure. A consistent and characteristic feature of thallium intoxication in humans is the extreme sensitivity of the legs, followed by the "burning feet syndrome" and paresthesia. Central nervous system toxicity is manifest by hallucinations, lethargy, delirium, convulsions, and coma. The acute cardiovascular effects of thallium initially manifested by hypotension and bradycardia due to direct effects of thallium on sinus node and cardiac muscle.

These Table 11-6 Xenobiotics Associated with Oxidative Injury Acetanilide Naphthalene Nitrofurantoin Sulfamethoxypyridazine Aminosalicylic acid Sodium sulfoxone Dapsone Phenazopyridine Primaquine Chlorates Sulfasalazine Phenylhydrazine Nitrobenzene Phenacetin Phenol Hydroxylamine Methylene blue Toluidine blue Furazolidone Nalidixic acid Sulfanilamide Figure 11-5 fungus body 250 mg grifulvin v. Oxygen can "capture" one of the iron electrons antifungal for nails order grifulvin v 250 mg free shipping, resulting in the generation of methemoglobin (HgbFe3+) and superoxide (O2 ­) [Eq fungus on fingernail 125 mg grifulvin v buy with visa. Heinz body formation can be induced by in vitro exposure to oxidizing agents and patients with oxidative hemolysis often show increased in vitro formation of Heinz bodies antifungal infant discount grifulvin v 125 mg visa. Oxidative denaturation of the globin chain decreases its affinity for the heme group, which may dissociate from the globin chain during oxidative injury (Kumar and Bandyopadhyay, 2005). Free heme itself is toxic to cells and can induce tissue injury through formation of reactive oxygen species. The ferric iron in the heme ring may react with chloride to form a complex called hemin. Hemin is hydrophobic and intercalates into the erythrocyte membrane from which it is removed by interaction with albumin. However, if the rate of hemin formation exceeds the rate of removal by albumin, hemin accumulates in the membrane, where it can cause rapid lysis of the erythrocyte. Oxidative hemolysis is usually reversible if the process is promptly recognized and the offending chemical is removed. Occasionally the hemolysis may be sufficiently severe to result in death or serious morbidity. Hemolytic anemia may occur in patients with deficiency of glutathione synthetase due to the reduced intracellular concentration of glutathione (Njalsson and Norgren, 2005). Nonoxidative Chemical-Induced Hemolysis Exposure to some xenobiotics is associated with hemolysis without significant oxidative injury (Beutler, 2006a,b). Inhalation of the gas can result in severe hemolysis, with anemia, jaundice, and hemoglobinuria. Lead poisoning is associated with defects in heme synthesis and a shortening of erythrocyte survival. The cause of the hemolysis is uncertain, but lead can cause membrane damage and interfere with the Na+ /K+ pump. The pathogenesis may relate to inhibitory effects on the hexose monophosphate shunt and the Embden-Meyerhof pathway. Ingestion of excess chromium may result in a hemolytic anemia and thrombocytopenia, although the mechanism is not known (Cerulli et al. Significant hemolysis may also occur with biologic toxins found in insect and snake venoms (Beutler, 2006a,b). The generation of free radicals may also lead to peroxidation of membrane lipids (Jandl, 1987; Kumar and Bandyopadhyay, 2005). This may affect the deformability of the erythrocyte and the permeability of the membrane to potassium. The alteration of the Na+ /K+ gradient is independent of injury to the Na+ /K+ pump and is potentially lethal to the affected erythrocyte. Damage to the membrane can also permit leakage of denatured hemoglobin from the cell. Free hemoglobin may irreversibly bind nitric oxide, resulting in vasoconstriction. Released hemoglobin may form nephrotoxic hemoglobin dimers, leading to kidney damage. Oxidative injury thus results in a number of changes that decrease the viability of erythrocytes. Protection against many of the free radical-induced modifications is mediated by reduced glutathione (Njalsson and Norgren, 2005). Significant oxidative injury usually occurs when the concentration of the xenobiotic is high enough (either due to high exposure or decreased metabolism of the xenobiotic) to overcome the normal protective mechanisms, or, more commonly, when there is an underlying defect in the protective mechanisms. It is often clinically asymptomatic until the erythrocytes are exposed to oxidative stress. The stress may come from the host response to infection or exposure to xenobiotics. This leads to the series of oxidative injuries described above with Immune Hemolytic Anemia Immunologic destruction of erythrocytes is mediated by the interaction of IgG or IgM antibodies with antigens expressed on the surface of the erythrocyte. A number of mechanisms have been implicated in xenobioticmediated antibody binding to erythrocytes (Arndt and Garratty, 2005). Some drugs, of which penicillin is a prototype, appear to bind to the surface of the cell, with the "foreign" drug acting as a hapten and eliciting an immune response.

The final oxygenating species (FeO)3+ can be generated directly by the transfer of an oxygen atom from hydrogen peroxide and certain other hydroperoxides fungus gnats hermit crabs 250 mg grifulvin v order overnight delivery, a process known as the peroxide shunt antifungal hand wash discount grifulvin v 125 mg fast delivery. Hydroxylation of an aliphatic or aromatic carbon; Epoxidation of a double bond; Heteroatom (S- antifungal weight loss generic grifulvin v 125 mg buy on line, N- antifungal bathroom cleaner 250 mg grifulvin v buy overnight delivery, and I-) oxygenation and N-hydroxylation; Heteroatom (O-, S-, and N-) dealkylation; Oxidative group transfer; Cleavage of esters; Dehydrogenation. In the first three cases, oxygen from the (FeO)3+ complex is incorporated into the substrate, which otherwise remains intact. In the fourth case, oxygenation of the substrate is followed by a rearrangement reaction leading to cleavage of an amine (N-dealkylation) or an ether (O- and S-dealkylation). Oxygen from the (FeO)3+ complex is incorporated into the alkyl-leaving group, producing an aldehyde or ketone. In the fifth case, oxygenation of the substrate is followed by a rearrangement reaction leading to loss of a heteroatom (oxidative group transfer). The sixth case, the cleavage of esters, resembles heteroatom dealkylation in that the functional group is cleaved with incorporation of oxygen from the (FeO)3+ complex into the leaving group, producing an aldehyde. In the seventh case, two hydrogens are abstracted from the substrate with the formation of a double bond (C=C, C=O, or C=N), with the reduction of oxygen from the (FeO)3+ complex to water. It should be noted that this long list of reactions does not encompass all the reactions catalyzed by cytochrome P450. Examples of reactions catalyzed by cytochrome P450: Hydroxylation of aliphatic carbon. Examples of aliphatic and aromatic hydroxylation reactions catalyzed by cytochrome P450 are shown in. The hydroxylation of aromatic hydrocarbons may proceed via an oxirane intermediate. Alternatively, aromatic hydroxylation can proceed by a mechanism known as direct insertion. The orthohydroxylation and para-hydroxylation of chlorobenzene proceed via 2,3- and 3,4-epoxidation, whereas meta-hydroxylation proceeds by direct insertion, as shown in. This isotope effect is less marked when aromatic hydroxylation proceeds via an arene oxide intermediate. Arene oxides are electrophilic and, therefore, potentially toxic metabolites that are detoxified by such enzymes as epoxide hydrolase. Depending on the ring substituents, the rearrangement of arene oxides to the corresponding phenol can lead to an intramolecular migration of a substituent (such as hydrogen or a halogen) from one carbon to the next. Like arene oxides, aliphatic epoxides are also potentially toxic metabolites that are inactivated by other xenobiotic-metabolizing enzymes. Examples of reactions catalyzed by cytochrome P450: Hydroxylation of aromatic carbon. As previously discussed in the section on epoxide hydrolase, not all epoxides are highly reactive electrophiles. Although the 3,4-epoxidation of coumarin produces an hepatotoxic metabolite, the 10,11-epoxidation of carbamazepine produces a stable, relatively nontoxic metabolite. Both enzymes are efficient catalysts of Soxygenation, and both contribute significantly to the sulfoxidation of various xenobiotics. Conversely, the conversion of pyridine to its N -oxide is primarily catalyzed by cytochrome P450. The sulfur radical cations of numerous xenobiotics are sufficiently stable to allow oxygen rebound with the heteroatom itself, which results in S-oxygenation. However, this is not generally the case with nitrogen radical cations, which undergo rapid deprotonation at the -carbon, which in turn results in N-dealkylation. In general, therefore, cytochrome P450 catalyzes the N-dealkylation, not the N-oxygenation, of amines. N-Oxygenation by cytochrome P450 can occur if the nitrogen radical cation is stabilized by a nearby electron-donating group (making the nitrogen electron rich) or if protons are either absent. In the case of primary and secondary aromatic amines, N-oxygenation by cytochrome P450 usually results in the formation of arylhydroxylamines, as illustrated in. Numerous xenobiotics are N-, O-, or S-dealkylated by cytochrome P450, and some examples of these heteroatom dealkylation reactions are shown in. The dealkylation of xenobiotics containing an N-, O-, or S-methyl group results in the formation of formaldehyde, which can easily be measured by a simple colorimetric assay to monitor the demethylation of substrates in vitro. The expiration of 13 C- or 14 C-labelled carbon dioxide following the demethylation of drugs containing a 13 C- or 14 C-labelled methyl group has been used to probe cytochrome P450 activity in vivo (Watkins, 1994). Although caffeine has three N -methyl groups, all of which can be removed by cytochrome P450, the major pathway in humans involves N3-demethylation of caffeine to paraxanthine (see.

Renal clearance diminishes with advancing age antifungal laundry purchase 250 mg grifulvin v with visa, due to parallel annual decreases of 0 antifungal pill side effects grifulvin v 250 mg order line. Blood levels of the parent compounds remained relatively constant during adulthood antifungal lip cream purchase grifulvin v 250 mg visa, but metabolite levels or amounts metabolized frequently varied during the pediatric and geriatric years (Sarangapani et al fungi phylum 250 mg grifulvin v purchase visa. Gender Some of the physiological and biochemical differences between men and women have the potential to alter tissue dosimetry and health effects of certain solvents. The investigators located few data on gender-dependent dermal or pulmonary absorption of solvents or other chemicals. Distribution of water- and lipid-soluble solvents can vary substantially between men and women (Schwartz, 2003). Women typically have smaller volumes of distribution for polar solvents, but larger volumes of distribution for lipophilic solvents (Gandhi et al. Lean body mass decreases from 76 to 52%, and body fat increases from 33 to 49% in females between the ages of 25 years and 65­70 years. Nomiyama and Nomiyama (1974) found that women retain less inhaled acetone and ethyl acetate than similarly exposed men. The major sex differences in P450-mediated hepatic metabolism in rats are not seen in humans or most other mammals (Nakajima, 1997). Some of the differentially expressed genes involve drug and steroid metabolism, but the biological significance of these variances is unknown. No marked gender differences in P450-catalyzed oxidation reactions have been identified in humans (Schmucker et al. Women were found to have a higher blood:air partition coefficient, a higher percent of body fat and higher maximum rate of benzene metabolism than men. Women exhibited higher blood benzene levels and a 23­ 26% increase in benzene metabolism, potentially placing them at greater risk than men with equivalent exposures. Relatively little is known about potential influences of contraceptives, hormone replacement therapy, or pregnancy on the metabolism and disposition of xenobiotics (Gleiter and GundertRemy, 1996). The menstrual cycle with its hormone changes may influence the metabolism of some xenobiotics (Fletcher et al. Plasma volume increases 50% in pregnant women, resulting in a decrease in albumin concentration and plasma protein binding of many drugs (Fletcher et al. Cardiac output increases 50%, due to increases in stroke volume and heart rate (Silvaggio and Mattison, 1994). Uterine blood flow, renal plasma flow, and glomerular filtration rise substantially, though no information on hepatic blood flow is apparently available. Simulated vinyl chloride levels, for example, were 4 orders of magnitude lower in the neonates. Fetal/neonatal isopropanol levels were forecast to be orders of magnitude lower than maternal levels. Genetics A variety of genetic polymorphisms for biotransformation have been found to occur at different frequencies in different ethnic groups (Daly et al. Polymorphisms for xenobiotic-metabolizing enzymes may affect the quantity and quality of enzymes and the outcomes of exposures to solvents (Ingelman-Sundberg et al. It is important to note that culturally linked environmental factors also contribute to ethnic differences in metabolism and disposition of solvents and other chemicals. It is often difficult to disentangle the influences of genetic traits from those of different lifestyles, socioeconomic status, and geographic settings. Reported frequencies of these rare alleles were 2% in Caucasians, 2­5% in African Americans, and 24­27% in Japanese (Kato et al. The prevalence of this genotype ranges from 10% in Mexican Americans to 60­65% in Chinese and Koreans (Nelson et al. These pathways, however, can lead to production of cytotoxic, mutagenic metabolites in the kidney. Increased susceptibility to different cancers has been reported to be associated with certain genetic polymorphisms, which occur with different frequencies in different ethnic groups (Daly et al. Genetic polymorphisms, variable transporter activities, genetic variants of receptors and regulatory proteins, and environmental factors can play roles in individual variability in P450 induction (Tang et al. Exogenous Factors P450 Inducers Considerable effort has been devoted to investigation of effects of enzyme inducers on solvent metabolism and toxicity. Preexposure to many of these can thus markedly increase the metabolic activation and adverse effects of certain solvents. Although levels/activities are highest in liver, induction in extrahepatic tissues can result in increased metabolic activation in situ that may be toxicologically significant.

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References

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