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Secretory granules are unique to symptoms retinal detachment purchase probenecid 500 mg visa polypeptide hormone- and catecholamine-secreting endocrine cells and provide a mechanism for intracellular storage of substantial amounts of preformed active hormone symptoms xylene poisoning purchase probenecid 500mg. When the cell receives a signal for hormone secretion symptoms zoloft overdose generic probenecid 500mg otc, secretory granules are directed to medicine youth lyrics purchase probenecid 500 mg free shipping the periphery of the endocrine cell, probably by the contraction of microfilaments. Steroid hormone-secreting cells are characterized by prominent cytoplasmic lipid bodies that contain cholesterol and other precursor molecules. The lipid bodies are in close proximity to an extensive tubular network of smooth endoplasmic reticulum and large mitochondria which contain hydroxylase and dehydrogenase enzyme systems. These enzyme systems function to attach various side chains to the basic steroid nucleus. Steroid hormone-producing cells lack secretory granules and do not store significant amounts of preformed hormone. They are dependent on continued biosynthesis to maintain the normal secretory rate for a particular hormone. Many diseases of the endocrine system are characterized by dramatic functional disturbances and characteristic clinicopathological alterations affecting one or several body systems. The affected animal or human patient may have clinical signs that primarily involve the skin (hair loss caused by hypothyroidism), nervous system (seizures caused by hyperinsulinism), urinary system (polyuria caused by diabetes mellitus, diabetes insipidus, and hyperadrenocorticism), or skeletal system (fractures induced by hyperparathyroidism) (Capen, 2006b). The literature suggests that chemically induced lesions of the endocrine organs are most commonly encountered in the adrenal glands, followed in descending order by the thyroid, pancreas, pituitary, and parathyroid glands. In the adrenal glands, chemically induced lesions are most frequently found in the zona fasciculata/zona reticularis and to a lesser extent in either the zona glomerulosa or medulla. In a survey, conducted by the Pharmaceutical Manufacturers Association, of tumor types developing in carcinogenicity studies, endocrine tumors developed frequently in rats, with the thyroid gland third in frequency (behind the liver and mammary gland), followed by the pituitary gland (fourth), and adrenal gland (fifth). Selected examples of commonly encountered toxic endpoints involving endocrine organs in laboratory animals are discussed in this chapter. Mechanistic data is included whenever possible to aid in the interpretation of findings in animal toxicology studies and to determine their significance in risk assessment (Alison et al. The pars intermedia forms the thin cellular zone between the adenohypophysis and neurohypophysis. The gland receives its blood supply via the posterior and anterior hypophyseal arteries which originate from the internal carotid arteries. Arteriolar branches penetrate the pituitary stalk near the median eminence, lose their muscular coat, and form a capillary plexus. These vessels drain into the hypophyseal portal veins which supply the adenohypophysis. The hypothalamic­hypophyseal portal system functionally is important as it transports the hypothalamic releasing- and release-inhibiting hormones directly to the adenohypophysis where they interact with their specific populations of trophic hormone-producing cells. The adenohypophysis in many animal species completely surrounds the pars nervosa of the neurohypophyseal system in contrast to human beings where it is situated on the anterior surface. The pars distalis is the largest portion and is composed of the multiple populations of endocrine cells that secrete the pituitary trophic hormones. The secretory cells are surrounded by abundant capillaries derived from the hypothalamic­hypophyseal portal system (Capen, 1996a). The pars tuberalis consists of dorsal projections of supportive cells along the infundibular stalk. The releasing and release-inhibiting hormones are synthesized by neurons in the hypothalamus, transported by axonal processes, and released into capillary plexus in the median eminence. Secretory cells in the adenohypophysis formerly were classified either as acidophils, basophils, or chromophobes based on the reactions of their secretory granules with pH-dependent histochemical stains. Chromophobes are pituitary cells that by light microscopy do not have stainable cytoplasmic secretory granules. Each type of endocrine cell in the adenohypophysis is under the control of a specific releasing hormone from the hypothalamus. These releasing hormones are small peptides synthesized and secreted by neurons of the hypothalamus. They are transported by short axonal processes to the median eminence where they are released into capillaries and are conveyed by the hypophyseal portal system to specific trophic hormone-secreting cells in the adenohypophysis. Each hormone stimulates the rapid release of preformed secretory granules containing a specific trophic hormone. Control of pituitary trophic hormone secretion also is affected by negative feedback by the circulating concentration of target organ (thyroid, adrenal cortex, and gonad) hormones. The pars nervosa (posterior lobe of the human pituitary) represents the distal component of the neurohypophyseal system.

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Approximately 50% of patients with neurofibromatosis develop optic nerve gliomas; bilateral tumors are pathognomonic for neurofibromatosis type 1 medicine versed cheap probenecid 500mg free shipping. Tuberous sclerosis (Chapter 456) is less frequently associated with optic nerve gliomas treatment modalities buy 500 mg probenecid mastercard, but retinal glial hamartomas are seen in combination with angiofibromas of the eyelids medicine effects purchase probenecid 500mg without prescription. Endogenous Infections Systemic infection may cause uveitis medicine 751 m generic probenecid 500 mg line, enophthalmitis, retinitis, or choroiditis. Tuberculosis (see Chapter 358) involves the uvea in approximately 1% of pulmonary cases. Small yellow choroidal lesions may be seen, and retinal periphlebitis may occur secondarily. Intermediate- and second-strength purified protein derivative testing may be positive. Clinical response to a 3-week trial course of isoniazid strongly suggests tuberculosis. Ocular complications of acquired syphilis (see Chapter 365) occur in approximately 5% of patients with secondary syphilis, although symptoms may occur during any stage of the disease. The more common presentations include anterior uveitis, neuroretinitis, and the syphilitic Argyll Robertson pupil in which miotic pupils react poorly to light but briskly to accommodation. Cytomegalovirus retinitis may present as subacute unilateral visual loss or vitreous "floaters" in immune compromised patients. Large areas of hemorrhagic infarction are seen with minimal vitritis (Color Plate 18 A). Until recently, ocular toxoplasmosis (see Chapter 425) was thought to represent reactivation of congenital disease in nearly all cases; however, studies now suggest that many cases of toxoplasmosis retinitis are acquired after birth. The typical retinal fundus lesion comprises an active yellow satellite adjacent to an old chorioretinal scar with a dense overlying vitritis, the so-called headlight-in-the-fog. Treatment requires systemic combinations of pyrimethamine, clindamycin, sulfonamides, prednisone, and folinic acid. These regimens are moderately efficacious and potentially toxic; treatment is therefore limited to severe intraocular inflammation that threatens the macular area. Idiopathic Inflammatory and Autoimmune Autoimmune diseases may produce incidental ocular findings or may have their greatest effects in ocular tissues. Inflammation of the extraocular muscles and orbital fat causes proptosis, corneal exposure, and limited ocular motility. Optic neuropathy may result from extreme proptosis with stretching of the nerve or from compression at the orbital apex. Active inflammation may be treated with systemic corticosteroids or external-beam irradiation in conjunction with aggressive topical lubrication. Emergent surgical decompression may be required when the optic nerve is threatened, but it may not reduce (and may aggravate) inflammation. Surgical decompression of severe 2234 proptosis is usually deferred until inflammation is controlled and the clinical examination is stable for several months. Secondary surgeries to correct chronic exposure, diplopia, lid malposition, and proptosis may then be considered. Sarcoidosis (see Chapter 81) is a common cause of intraocular inflammation among Americans of African descent, and chronic uveitis is seen in 25% of sarcoid patients. Anterior uveitis is treated topically with prednisolone acetate in decreasing doses, depending on degree of inflammation, and with daily cyclopegics (cyclopentolate 2%, atropine 1%). Uveitis accompanies many autoimmune diseases and there is often no correlation between ocular and systemic inflammatory activity. Ankylosing spondylitis (see Chapter 287) causes acute, recurrent anterior uveitis in 25% of patients. Two to 12 per cent of patients with inflammatory bowel disease (see Chapter 135) develop anterior uveitis, which is also commonly found in patients with psoriatic arthritis but not with psoriasis alone (see Chapters 287 and 522). Treatment with topical corticosteroids is usually sufficient to control the ocular disease. Chronic anterior uveitis may severely reduce vision in patients with juvenile rheumatoid arthritis (see Chapter 286). The ocular disease may be insidious and devastating; routine examinations are critical.

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Hydralazine has been used to in treatment discount probenecid 500 mg fast delivery assess the role of aldehyde oxidase in human drug metabolism in vivo medicine ketorolac buy probenecid 500 mg on line. An analogous reaction allows aldehyde oxidase to medicine for high blood pressure generic 500 mg probenecid with visa catalyze the reductive ring opening of zonisamide and 1 treatment centers for depression purchase 500mg probenecid,2-benzisoxazole, which results in the formation of an oxo-containing metabolite and ammonia (Sugihara et al. Xenobiotic reduction by aldehyde oxidase in vitro requires anaerobic conditions or the presence of a reducing substrate, such as N 1 -methylnicotinamide, 2hydroxypyrimidine, or benzaldehyde. These "co-substrates" reduce the enzyme, which in turn catalyzes azo-reduction, nitro-reduction, etc. These unusual requirements make it difficult to assess the degree to which aldehyde oxidase functions as a reductive enzyme in vivo. Substrates for these enzymes include several naturally occurring amines, such as the monoamine serotonin (5-hydroxytryptamine), the diamine putrescine, and monoacetylated derivatives of the polyamines spermine and spermidine. Oxidative deamination of a primary amine produces ammonia and an aldehyde, whereas oxidative deamination of a secondary amine produces a primary amine and an aldehyde. Monoamine oxidase is located throughout the brain, and is present in the liver, kidney, intestine, and blood platelets in the outer membrane of mitochondria. The oxygen incorporated into the substrate is derived from water, not molecular oxygen; hence, the enzyme functions as a true oxidase. Both enzymes are irreversibly inhibited by phenelzine, a hydrazine that can be oxidized either by abstraction of hydrogen from the -carbon atom, which leads to oxidative deamination with formation of benzaldehyde and benzoic acid, or by abstraction of hydrogen from the terminal nitrogen atom, which leads to formation of phenylethyldiazene and covalent modification of the enzyme, as shown in. Some epidemiological studies have shown a positive correlation between herbicide exposure and the incidence of Parkinsonism in some but not all rural communities. Haloperidol can also be converted to a potentially neurotoxic pyridinium metabolite (Subramanyam et al. Aromatization of cyclohexane carboxylic acid, a reaction catalyzed by rabbit and guinea pig liver mitochondria. Both enzymes use oxygen as an electron acceptor, which results in the production of hydrogen peroxide. Diamine oxidase is a cytosolic, copper-containing, pyridoxal phosphate-dependent enzyme present in liver, kidney, intestine, and placenta. Its preferred substrates include histamine and simple alkyl diamines with a chain length of 4 (putrescine) or 5 (cadaverine) carbon atoms. For this reason, the major pathway of histamine metabolism in the brain is by methylation (see section "Methylation"). Aromatization of xenobiotics is an unusual reaction, but some examples have been documented. A mitochondrial enzyme in guinea pig and rabbit liver can oxidize several cyclohexane derivatives to the corresponding aromatic hydrocarbon, as shown in. Mitochondria from rat liver are less active, and those from cat, mouse, dog, monkey, and human are completely inactive. The first step appears to be the formation of hexahydrobenzoyl-CoA, which is then dehydrogenated to the aromatic product. The conversion of androgens to estrogens involves aromatization of the A-ring of the steroid nucleus. Several different peroxidases catalyze the biotransformation of xenobiotics (in addition to performing important physiological functions), and these enzymes occur in a variety of tissues and cell types. Peroxidases do not play an important role in the first-pass metabolism or clearance of drugs and most other xenobiotics because their contribution is usually negligible compared with cytochrome P450 and other oxidative enzymes. However, peroxidases do play an important role in xenobiotic toxicity, especially the activation of drugs associated with idiosyncratic hepatotoxicity, blood dyscrasias. This peroxisomal enzyme catalyzes the disproportionation of hydrogen peroxide to water and oxygen (2H2 O2 2H2 O + O2). At low concentrations of hydrogen peroxide, catalase can catalyze the oxidation of ethanol (see. Iron is bound to four pyrrole nitrogens with the nitrogen on the imidazole ring of histidine serving as the usual fifth ligand. The sixth coordination position is vacant so that peroxidases can interact with hydrogen peroxide (or other hydroperoxides), just as the sixth coordinate position of hemoglobin and myoglobin (both of which have low peroxidase activity) is available to bind molecular oxygen. This ironbound oxygen formally contains only six (instead of eight) valence electrons, making it a powerful oxidizing species. There is an inverse relationship between the rate of conversion of halides to hypohalous acids and their physiological plasma concentrations: chloride = 100­140 mM, bromide = 20­100 M, and iodide = 0.

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The degree of uptake depends upon the details of exposure conditions medicine hat mall probenecid 500 mg with visa, being proportional to medicine zalim lotion cheap 500 mg probenecid fast delivery solute concentration (assuming it is dilute) medicine for stomach pain probenecid 500mg sale, time medications with sulfur purchase 500mg probenecid, and the amount of skin surface exposed. In addition, two intrinsic factors contribute to the absorption rate of a given compound: its hydrophobicity, which affects its ability to partition into epidermal lipid, and its rate of diffusion through this barrier. A measure of the first property is the com- monly used octanol/water partitioning ratio (K ow). This is particularly relevant for exposure to contaminated water, as occurs during bathing or swimming. However, partitioning of a chemical into the skin is greatly affected by its solubility in or adhesion to the medium in which it is applied (including soil). Similarly, very hydrophobic compounds, once in the stratum corneum, may diffuse only very slowly into less hydrophobic regions below. Although only small amounts of chemicals may penetrate the stratum corneum, those of high potency may still be very dangerous. For example, hydrophobic organophosphorus and carbamate pesticides can be neurotoxic to humans and domestic animals by skin contact. Children and adolescents harvesting tobacco are especially susceptible to poisoning by contact with nicotine, a natural pesticide present in moisture on the leaves (McKnight and Spiller, 2005). Conditions of topical treatment of livestock for pest control must take into consideration not only the tolerance of the animals but also residues in meat and milk resulting from skin penetration. High-level skin exposure to chemicals considered safe at low levels can be dangerous, evident from the nervous system toxicity and deaths of babies exposed to hexachlorophene mistakenly added to talcum powder for their diapers (Martin-Bouyer et al. Previous findings of N -nitrosamines that penetrate skin well (such as N -nitrosodiethanolamine) in cutting oils and cosmetics raised concern and led to their monitoring and to reduction of exposure. Considerable empirical information has been collected on some chemicals of special interest (including pharmaceuticals, pesticides, and pollutants) for use in quantifying structure/penetration relationships. From such information, relations can be obtained for skin penetration (Pcw) using empirically derived constants (C1, C2, C3) that have the form shown below (Potts and Guy, 1992). Because rates of transfer of very hydrophobic agents into the aqueous phase of the spinous layer are slow, saturation of the stratum corneum provides a depot, leading to continued penetration into the body for relatively long time periods after external exposure to a chemical stops. More recent modeling efforts have taken into account vehicles and additives to improve predictability of complex chemical mixtures (Riviere and Brooks, 2005). Diffusion through the epidermis is considerably faster at some anatomical sites than others. A list in order of decreasing permeability gives the following hierarchy: foot sole > palm > forehead > abdomen (Scheuplein and Blank, 1971). Scrotal skin reportedly has the highest permeability for some topical chemicals (Fisher, 1989). Under ordinary conditions, absorption through the epidermal appendages is generally neglected, despite the ability of chemicals to bypass the stratum corneum by this route, because the combined appendageal surface area is such a small fraction of the total available for uptake. However, because loading of the stratum corneum is slow, penetration through the appendages can constitute an appreciable fraction of the total for short exposures. As indicated below, in some cases these properties have been exploited for therapeutic uses. Transdermal Drug Delivery the ability of the stratum corneum to serve as a reservoir for exogenously applied chemicals is well illustrated by the recent development of methods for the delivery of pharmaceuticals. Application of drugs to the skin can produce systemic effects, a phenomenon observed unintentionally before the ability of the skin to serve as a delivery system was appreciated. For example, topical exposure of young girls to estrogens has led to reports of pseudoprecocious puberty, whereas in young or adult males, such exposure has produced gynecomastia (Amin et al. Specially designed patches are currently in use to deliver estradiol, testosterone, nitroglycerin, scopolamine, clonidine, fentanyl, and nicotine for therapeutic purposes, and others are under development. The advantages of this approach over oral dosing include providing a steady infusion for extended periods (typically 1­7 days), thereby avoiding large variations in plasma concentration, preventing exposure to the acidic pH of the stomach, and avoiding biotransformation in the gastrointestinal tract or from first-pass removal by the liver. The contrast in plasma concentration kinetics between different methods of delivery is particularly evident for agents that are rapidly metabolized, such as nitroglycerin, which has a half-life of a few minutes. A variety of chemicals, chosen carefully to minimize irritation or allergenicity, have been incorporated into pharmaceutical preparations to enhance absorption and penetration.

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