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They are not m etabolized but are elim inated unchanged glycosides electrostatically attached to anionic m em brane phospho- alm ost entirely by the kidneys erectafil 20 mg generic erectile dysfunction pump implant video. Am inoglycosides are filtered by the lipids interfere with the norm al action of som e enzym es (ie purchase 20mg erectafil otc zma impotence, phos- glom erulus at a rate alm ost equal to that of water 20 mg erectafil for sale erectile dysfunction trick. In parallel with enzym e inhibi- the lum inal fluid of proxim al renal tubule, a sm all but toxicologi- tion, undigested phospholipids originating from the turnover of cell cally im portant portion of the filtered drug is reabsorbed and m em branes accum ulate in lysosom es, where they are norm ally stored in the proxim al tubule cells. The overall result is lysosom al phospholipidosis due to glycosides into proxim al tubule cells involves interaction with nonspecific accum ulation of polar phospholipids as “m yeloid bod- acidic, negatively charged phospholipid-binding sites at the level ies,” so called for their typical electron m icroscopic appearance. Lysosomes (large arrow) contain dense lamellar and concentric struc- tures. Brush border, mitochondria (small arrows) and peroxisomes are unaltered. At higher magnification the structures in lysosomes show a periodic pattern. A Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents 11. The overloaded lysosom es continue to swell, even if the drug is then withdrawn. In vivo this overload m ay result in loss of integrity of the m em branes of lysosom es and release of large am ounts of lysosom al enzym es, phospholipids, and am inoglycosides into the cytosol, but this has not been proven. Thus, these am inoglycosides can gain access to and injure other organelles, such as m itochondria, and disturb their functional integrity, which leads rapidly to cell death. As a consequence of cell necrosis, A, intratubular obstruction by cell debris increased intratubule pressure, a decrease in the glom erular filtration rate and cellular infiltration, B, m ay ensue. In parallel with these lethal processes in the kidney, a striking regeneration process is observed that is characterized by a dram atic increase in tubule cell turnover C and proliferation, C, in the cortical interstitial com partm ent. FIGURE 11-6 200 A, Relationship between constant serum levels and concom itant renal cortical accum ulation of gentam icin after a 6 hour intra- V = 149. The rate of accum ulation is expressed in max µ m icrogram s of am inoglycoside per gram of wet kidney cortex per Km= 15. Each 150 point represents one rat whose am inoglycosides were m easured in both kidneys at the end of the infusion and the serum levels assayed twice during the infusion. Each block represents the 800 Continuous infusion ** mean of seven rats ±SD. Significance is shown only between cortical Total daily dose: levels achieved after continuous infusion and single injections (aster- 10 mg/kg i. Thus, a given daily drug does not produce the same ** degree of toxicity when it is given by different routes. Indeed, renal cortical uptake is “less efficient” at high serum concentration than at 200 low ones. A single injection results in high peak serum levels that over- come the saturation limits of the renal uptake mechanism. The high plasma concentrations are followed by fast elimination and, finally, 0 absence of the drug for a while. This contrasts with the continuous 1 2 4 6 8 low serum levels obtained with more frequent dosing when the uptake B Days of administration at the level of the renal cortex is not only more efficient but remains available throughout the treatment period. Subjects were patients with norm al renal 25 function (serum creatinine concentration between 0. Before surgery, patients received 40 gentam icin (4. The single-injection 10 schedule resulted in 30% to 50% lower cortical drug concentra- 20 Continuous infusion tions of netilm icin, gentam icin, and am ikacin as com pared with Continuous infusion continuous infusion. For tobram ycin, no difference in renal accu- 5 10 m ulation could be found, indicating the linear cortical uptake of 0 0 this particular am inoglycoside. These data, which supported 0 4 8 12 16 20 24 0 4 8 12 16 20 24 decreased nephrotoxic potential of single-dose regim ens, coincided Time, hrs with new insights in the antibacterial action of am inoglycosides A (concentration-dependent killing of gram -negative bacteria and prolonged postantibiotic effect). Renal Injury Due To Environmental Toxins, Drugs, and Contrast Agents 11. Several risk factors have been identified and classified as patient related, Patient-Related Factors Aminoglycoside-Related Factors Other Drugs am inoglycoside related, or related to con- current adm inistration of certain drugs. Older age* Recent aminoglycoside therapy Amphotericin B The usual recom m ended am inoglycoside Preexisting renal disease Cephalosporins dose m ay be excessive for older patients Female gender Larger doses* Cisplatin because of decreased renal function and Magnesium, potassium, or Treatment for 3 days or more* Clindamycin decreased regenerative capacity of a dam - calcium deficiency* aged kidney. Preexisting renal disease Intravascular volume depletion* Cyclosporine clearly can expose patients to inadvertent Hypotension* Dose regimen* Foscarnet overdosing if careful dose adjustm ent is Hepatorenal syndrome Furosemide not perform ed. H ypom agnesem ia, Sepsis syndrome Piperacillin hypokalem ia, and calcium deficiency m ay Radiocontrast agents be predisposing risk factors for conse- Thyroid hormone quences of am inoglycoside-induced dam - age. Liver disease is an im portant clinical risk factor for am inoglycoside * Similar to experimental data. Acute or chronic endotoxem ia am plifies the nephrotoxic potential of the am inoglycosides. FIGURE 11-9 PREVENTION OF AM INOGLYCOSIDE Prevention of am inoglycoside nephrotoxicity. Coadm inistration NEPHROTOXICITY of other potentially nephrotoxic drugs enhances or accelerates the nephrotoxicity of am inoglycosides. Com prehension of the phar- m acokinetics and renal cell biologic effects of am inoglycosides, Identify risk factor allows identification of am inoglycoside-related nephrotoxicity risk Patient related factors and m akes possible secondary prevention of this im portant clinical nephrotoxicity. Drug related Other drugs Give single daily dose of gentamicin, netilmicin, or amikacin Reduce the treatment course as much as possible Avoid giving nephrotoxic drugs concurrently Make interval between aminoglycoside courses as long as possible Calculate glomerular filtration rate out of serum creatinine concentration 11.

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In 63 countries cheap 20mg erectafil with mastercard impotence stress, most of them data and methods of measurement 20 mg erectafil erectile dysfunction use it or lose it. For instance purchase erectafil 20 mg amex xylometazoline erectile dysfunction, low-income countries where many people need should the incidence of catastrophic expenditure fnancial risk protection, more than 40% of all and impoverishment be given equal weight in health expenditure took the form of direct out-of- describing the extent of fnancial risk protection pocket payments. Is it better to improve fnancial risk 62 countries less than 20% of health expenditure protection on average, or to set a minimum level was out-of-pocket. Although the majority of the of protection for everyone? How does fnancial 62 are high-income countries, among them are risk protection refect the broader goal of social Algeria, Bhutan, Cuba, Lesotho and Tailand. What targets or milestones should be Te governments of these countries have shown set for measures of fnancial risk protection until how, despite low average incomes, the poorest universal coverage is fully achieved? Which con- people can be protected from having to make ditions of ill-health, perhaps with costly treat- disastrously large cash payments for health. Between 2005 and 2010 the proportion any of these measures capture the value associ- of health spending made through out-of-pocket ated with peace-of-mind – the assurance that payments fell, on average, in all but one WHO is conferred by accessible, afordable, and reli- region (46). Te exception was Africa, where the able health services? Twenty-three countries research, and in some cases public debate, on the across all regions and income levels achieved a mechanisms of fnancial risk protection, and on reduction of at least 25% in the proportion of the methods of measurement. Measuring fnancial risk protection The measurement of financial risk protection should ideally capture the number of people enrolled in some kind of health insurance scheme and the number of people who are eligible to use – and able to afford – health services provided by government, private sector or civil society. Direct and indirect indicators of fnancial risk protection Direct indicators Explanation Incidence of catastrophic health The number of people or the proportion of the population at all income levels expenditure due to out-of-pocket who spend a disproportionate share of their incomes on out-of-pocket pay- payments ments each year. Financial catastrophe is defned as out-of-pocket expenditure exceeding 40% of household income net of subsistence needs. Mean positive overshoot of Shows the average amount by which households afected by catastrophic catastrophic payments expenditures pay more than the threshold used to defne catastrophic health spending. Incidence of impoverishment due to The number of people or proportion of the population pushed below the pov- out-of-pocket payments erty line because of out-of-pocket payments. The poverty line is crossed when daily income falls below a locally-defned threshold, typically around US$1–2 per day. For people who are living near the poverty threshold, even small payments push them below the threshold. Indirect indicators Out-of-pocket payments as a share of There is a high correlation between this indicator and the incidence of fnancial total health expenditure catastrophe. Government health expenditure as a This recognizes that in all countries the poor need to be covered by fnancial risk share of GDP protection from general government revenues; they are rarely all covered when this proportion is less than 5%. GDP, gross domestic product; US$, United States dollars. There are, however, some difficulties in determining who is actually financially protected and to what extent, as two examples will make clear. First, health insurance as such does not guarantee full financial risk protection. Many forms of insurance cover only a minimum set of services, so that those insured are still required to make out-of-pocket payments of different types, including informal cash payments (1). Second, government-financed services may be inadequate. For instance, they may not be available close to where they are needed, there may be too few health workers or no medicines, or the services may be perceived to be unsafe. In India, for example, everyone is eligible to use government health services, but direct out-of-pocket payments are still among the highest in the world (44). By contrast, it is more straightforward, and often more precise, to measure the consequences for people who do not have financial risk protection. The table above describes four direct indicators and two indirect indicators of protection which can be measured by household expenditure surveys that include spending on health, as illustrated in the main text. The techniques used to measure these indicators are well established as a result of investment in relevant research, and the survey data are readily available (45). To assess inequalities in financial risk protection, these indicators can also be measured for different population groups, and can be stratified by income (or expenditure or wealth), place of residence, migrant status and so on. In reality, there is a diversity of ser- vated and skilled health workers who are accessible to vices delivered on several levels, depending on the people they serve; (iii) integrated, high-quality, the nature of the health condition and the type patient-centred services at all levels from primary of intervention. Te elements of each row in to tertiary care; (iv) a combination of priority pro- Fig. A framework for measuring and monitoring the coverage of health services Levels of health system/service delivery Priority health conditions Non- Community- Primary Secondary Tertiary personal based (facility) (hospital) (hospital) MNCH Indicators of HIV/TB/malaria service coverage, including NCDs and promotion, risk factors prevention and treatment Injuries Health system inputs Outputs: availability, readiness, quality, utilization HIV, human immunodefciency virus; MNCH, maternal, newborn and child health; NCDs, noncommunicable diseases; TB, tuberculosis. Note: “Non-personal” health services are actions applied either to communities or populations – such as mass health educa- tion, policy development or taxation – or to the nonhuman components of the environment – such as environmental health measures. Community-based health services are defned as individual and community health actions delivered in the commu- nity (e. They are often considered to be part of the primary health care service. In Mexico, for example, 472 interventions and to whole populations (nonpersonal) (49). As were covered by fve separate health protection illustrated by its position in Fig.

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Modafinil induces wakefulness without teen-agers in Fujisawa city trusted 20mg erectafil impotence pumps. The prevalence of associated with cataplexy in 509 narcoleptic patients cheap erectafil 20mg mastercard erectile dysfunction medicine pakistan. Sleep narcolepsy: an epidemiologic study of the Finnish twin cohort order erectafil 20 mg impotence psychological. Hippocampus norepineph- preferentially controlled by adrenergic mechanisms: evidence rine, caudate dopamine and serotonin and behavioral responses using monoamine selective uptake inhibitors and release en- to the stereoisomers of amphetamine and methamphetamine. The effect of mal recessive canine narcolepsy with an immunoglobulin heavy- gamma-hydroxybutyrate on nocturnal and diurnal sleep of nor- chain switch-like segment. Activity of mesencephalic seven cases of gamma-hydroxybutyric acid overdose [see com- dopamine and non-dopamine neurons across stages of sleep and ments]. Narcolepsy and its modafinil and amphetamine induced wakefulness, a compara- treatment with stimulants. The sleep disorder canine narcolepsy plexy in a female dog. Relative efficacy of drugs for the treatment of sleepiness in narcolepsy. Neurons containing brain: organization and functional implications. Prog Neurobiol Orexin in the lateral hypothalamic area of the adult rat brain 1997;51:337–361. Desmethyl metabolites of oxidase by amphetamine and related compounds. Biochem Phar- serotonergic uptake inhibitors are more potent for suppressing macol 1976;25:2073–2077. Immunological features of narco- 2 adrenergic compounds on canine narcolepsy, a disorder of lepsy in Japan. J Pharmacol Exp Ther 1990;253: New York: Springer-Verlag, 1988:150–157. Pharmacologic aspects of human and ence 1994;59:523–530. Modulation of cataplexy via local drug noradrenergic uptake inhibitors on dopaminergic D3 agonist- administration into pontine reticular formation. Local administration of deficiency in human narcolepsy. Muscle atonia is triggered cataplexy in the narcoleptic canine. Brain Res 1996;733: by cholinergic stimulation of the basal forebrain: implication 83–100. Alerting effects of naps in neurotransmission in rat striatum, limbic forebrain, cortical patients with narcolepsy. Problems and coping strategies identified by narco- Pharmacol 1991;344:16–28. Compliance with pathologic associations of sleep paralysis in the general popula- stimulant medications in patients with narcolepsy. The latency of activa- hypnopompic hallucinations: pathologic phenomena? Br J Psy- tion of neurones in the lateral hypothalamus and substantia chiatry 1996;169:459–467. In: Sleep and its receptors: a family of hypothalamic neuropeptides and G pro- disorders. Fluvoxamine and clomipramine in the Neurol Scand 1975;52:337–353. Motor dyscontrol in narcolepsy: Psychiatry 1973;36:1076–1081. Neurons contain- hydroxybutyrate versus placebo in treating narcolepsy-cataplexy: ing hypocretin (Orexin) project to multiple neuronal systems. Biol Psychiatry 1989;26: J Neurosci 1998;18:9996–10015. The effects of plexy with yohimbine and paroxetine: case report. Prevalence of multiple sclerosis in C, Passouant P, ed. Studies on the relation of narco- critical analysis of the literature. The effects of 600 Chapter 131: Pathophysiological and Pharmacologic Aspects of the Sleep Disorder Narcolepsy 1921 mg of slow release caffeine on mood and alertness. New York: Marcel Dekker, Environ Med 1996;67:859–862. Principles and practice cats: correlation with level of behavioral arousal. Blood pressure and heart rate responses produced 154. Activity of substantia by d-amphetamine: correlation with blood levels of drug. J Phar- nigra units across the sleep-waking cycle in freely moving cats.

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