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Amantadine

Stephanie Barbetta, MD

  • Assistant Professor
  • Department of Emergency Medicine
  • Temple University School of Medicine
  • Philadelphia, Pennsylvania

Pellagra resulting from dietary deficiency of niacin is rarely seen in developed countries antivirus windows free generic amantadine 100 mg with visa. Causes other than dietary include alcoholism hiv infection rate by country amantadine 100mg with amex, carcinoid syndrome and Hartnup disease hiv infection personal stories purchase line amantadine. Nicotinic acid Vitamin A deficiency Primary deficiency is common in developing countries hiv infection rate malaysia order genuine amantadine line. Secondary deficiency resulting from fat malabsorption is seen with pancreatic insufficiency and disorders of the gastrointestinal tract natural anti viral warts cheap 100 mg amantadine mastercard. Vitamin A supplementation at pharmacological doses is standard for patients with cystic fibrosis hiv infection in the us order amantadine online pills. Adverse effects include peripheral vasodilatation, unpleasant flushing, itching and fainting. It also functions as an antioxidant, mopping up free radicals produced endogenously or in the environment. However, randomised trials have not shown any beneficial effect thus far of vitamin C on either cancer incidence or primary or secondary prevention of coronary heart disease. Ascorbic acid is inadequate for the treatment of acute methaemoglobinaemia requiring treatment. Congenital methaemogobinaemia can be treated long term with either oral methylene blue or ascorbic acid with partial effect. Adverse effects High doses may cause sleep disturbances, headaches and gut upsets. Ascorbic acid is eliminated partly in the urine unchanged and partly metabolised to oxalate. Doses above 4 g/day increase urinary oxalate concentration and there is a potential risk of renal oxalate stones with chronic ascorbic acid administration. Scurvy Deficiency of ascorbic acid leads to scurvy, which is characterised by petechial haemorrhages, haematomas, bleeding gums (if teeth are present) and anaemia. Vitamin D Vitamin D comprises a number of structurally related sterol compounds having similar biological properties (but different potencies) in that they prevent or cure the vitamin D-deficiency diseases, rickets and osteomalacia. It is also absorbed in the intestinal tract; however, few foods contain significant levels of vitamin D. Vitamin D2 (ergocalciferol) is made by ultraviolet irradiation of ergosterol in plants. There exist also a variety of synthetic vitamin D analogues, developed to treat vitamin D deficiency and hypoparathyroidism. The vitamin D derivative 1a-hydroxycolecalciferol (alfacalcidol) requires only hepatic hydroxylation to become calcitriol. In addition, a structural variant of vitamins D2 and Methaemoglobinaemia A reducing substance is needed to convert the methaemoglobin (ferric iron) back to oxyhaemoglobin (ferrous iron) whenever enough has formed seriously to impair the oxygen-carrying capacity of the blood. Ascorbic acid is nontoxic (it acts by direct reduction) but is less effective than methylene blue (methylthioninium chloride). Methaemoglobinaemia may be induced by oxidising drugs: sulphonamides, nitrites, nitrates (may also occur in drinking water), primaquine, -caine local anaesthetics, dapsone, nitrofurantoin, nitroprusside, vitamin K analogues, chlorates, aniline and nitrobenzene. Methylene blue turns the urine blue and high concentrations can irritate the urinary tract, so that fluid intake should be high when large doses are used. All are effective in renal failure as they bypass the defective renal hydroxylation stage. Pharmacokinetics Alfacalcidol and dihydrotachysterol have a fast onset and short duration of clinical effect (days) which renders them suitable for rapid adjustment of plasma calcium. Such factors are not relevant to the slower adjustment of plasma calcium (weeks) with vitamins D2 and D3 in the ordinary management of vitamin D deficiency. After a dose of D2 or D3 there is a lag of about 21 h before the intestinal effect begins; this is probably due to the time needed for its metabolic conversion to the more active forms. A large single dose of vitamin D has biological effects for as long as 6 months (because of metabolism and storage). Selecting the appropriate preparation requires a knowledge of the underlying aetiology. There is accumulating evidence that subclinical vitamin D deficiency has adverse effects on health. Vitamin D deficiency in pregnancy is a significant public health issue: babies born to mothers with low vitamin D levels are at increased risk of neonatal hypocalcaemia and other vitamin D deficiency-related symptoms. Vitamin D deficiency can be prevented in susceptible individuals by taking an oral supplement of ergocalciferol 20 micrograms (800 units) daily. For the treatment of simple nutritional vitamin D deficiency oral doses of either colecalciferol or ergocalciferol, 10 000 units daily or 60 000 units weekly, should be given for 12 weeks. Infants and children should receive between 1000 and 5000 units of vitamin D3 daily, depending on age (usually ergocalciferol), for 12 weeks. Alfacalcidol should not be given for the treatment of vitamin D deficiency as it does not replete vitamin D stores. Vitamin D deficiency resulting from intestinal malabsorption or chronic liver disease usually requires vitamin D in pharmacological doses. Vitamin D deficiency resulting from chronic renal failure is discussed below (see renal osteodystrophy). Epileptic patients taking enzyme-inducing drugs long term can develop osteomalacia (adults) or rickets (children). This may arise from the accelerated metabolism, increasing vitamin D breakdown and causing deficiency, or from inhibition of one of the hydroxylations that increase biological activity. Osteoporosis Calcitriol is licensed for the management of postmenopausal osteoporosis (see below). Ergocalciferol may be required in doses up to 100 000 units daily to achieve normocalcaemia, but the dose is difficult to titrate and hypercalcaemia from overdose may take weeks to resolve. Psoriasis Calcipotriol and tacalcitol are vitamin D analogues available as creams or ointments for the treatment of psoriasis (see p. An early sign is a tingling feeling in the mouth and of warmth spreading over the body. Serious effects are those on the heart, which mimic and synergise with digitalis, and it is advisable to avoid intravenous calcium administration in any patient taking a digitalis glycoside (except in severe symptomatic hypocalcaemia). The effect of calcium on the heart is antagonised by potassium, and similarly the toxic effects of hyperkalaemia in acute renal failure may be to an extent counteracted by calcium. Vitamin D toxicity has been reported in children accidentally overdosed on vitamin D supplements. Symptoms of overdosage are due mainly to an excessive increase in plasma calcium concentration and include anorexia, nausea and vomiting, diarrhoea, constipation, weight loss, polyuria and thirst. Other long-term effects include ectopic calcification almost anywhere in the body, renal damage and an increased calcium output in the urine; renal calculi may form. Recent research has suggested that the safe upper limit of vitamin D therapy be revised. It was previously considered dangerous to exceed 10 000 units daily of vitamin D in an adult for more than about 12 weeks; however, it has now become apparent that such doses are required to render a vitamin D-deficient individual replete. In general, use of vitamin D at pharmacological doses requires monitoring of plasma calcium. Hypercalcaemia Treatment of severe acute hypercalcaemia causing symptoms is needed whether or not the cause can be removed; generally a plasma concentration of 3. This should not be given at a faster rate because of the risk of cardiac arrhythmias and arrest. Correction of hypocalcaemia is temporary and this should be followed by a continuous intravenous infusion containing ten 10 mL ampoules of 10% calcium gluconate in 1 L of 0. Oral calcium therapy should be initiated meanwhile and the intravenous infusion stopped once the oral agents take effect. Avoid infusing with solutions containing bicarbonate or phosphate, which cause calcium to precipitate. Intramuscular injection is contraindicated as it is painful and causes tissue necrosis. Calcium glubionate (Calcium Sandoz) can be given by deep intramuscular injection in adults. Concurrent hypomagnesaemia should be corrected as hypocalcaemia is resistant to treatment without normal serum magnesium levels. Hypocalcaemia secondary to vitamin D deficiency should be treated with vitamin D as described above and there are preparations which combine calcium tablets with colecalciferol. The regimen requires careful attention to fluid and electrolyte balance, particularly in patients with renal insufficiency secondary to hypercalcaemia or heart failure who are unable to excrete excess sodium. Bisphosphonates are the agents of choice in moderate to severe hypercalcaemia, There are a number of Table 39. Zoledronic acid has the advantage of being more potent and it can be administered over a shorter time (4 mg over 15 min versus 2 h). When the hypercalcaemia is at least partly due to mobilisation from bone, calcitonin (4 units/kg) can be used to inhibit bone resorption, and may enhance urinary excretion of calcium. The effect develops in a few hours but responsiveness is lost over a few days owing to tachyphylaxis. Corticosteroid may be effective in the hypercalcaemia of malignancy where the disease itself is responsive. Dialysis is quick and effective and is likely to be needed in severe cases or in those with renal failure. Chapter 39 Hypercalciuria In renal stone formers, in addition to general measures (low calcium diet, high fluid intake), urinary calcium may be diminished by a thiazide diuretic (with or without citrate to bind calcium) and oral phosphate (see above). It acts on bone (inhibiting osteoclasts) to reduce the rate of bone turnover, and on the kidney to reduce reabsorption of calcium and phosphate. Antibodies develop particularly to pork calcitonin and neutralise its effect; synthetic salmon calcitonin (salcatonin) is therefore preferred for prolonged use; loss of effect may also be due to down-regulation of receptors. Longer-term treatment Sodium cellulose phosphate (Calcisorb) is an oral ion exchange substance with a particular affinity for calcium which is bound in the gut, and the complex eliminated in the faeces. It is effective for patients who over-absorb dietary calcium and develop hypercalciuria and renal stones. Adverse effects include allergy, nausea, flushing and tingling of the face and hands. It is of particular use for hypercalcaemia resulting from increased intestinal absorption of calcium. Bisphosphonates Bisphosphonates are synthetic, non-hydrolysable analogues of pyrophosphate (an inhibitor of bone mineralisation) in which the central oxygen atom of the -P-O-P- structure is replaced with a carbon atom to give the -P-C-P- group. There are two classes of bisphosphonates: nitrogen containing (alendronate, risedronate, ibandronate, pamidronate and zoledronate) and non-nitrogen containing (clodronate, etidronate and tiludronate). Repeated courses of intravenous bisphosphonates for treatment of hypercalcaemia of malignancy is associated with increased risk of osteonecrosis of the jaw in patients with metastatic bone disease or multiple myeloma. These compounds are effective calcium chelators that rapidly target exposed bone mineral surfaces, are imbibed by bone-resorbing osteoclasts, inhibit their function and cause osteoclast apoptosis. An additional action may be to stimulate bone formation by osteoblasts, but the therapeutic utility of bisphosphonates rests on their capacity to inhibit bone resorption. Bisphosphonate binding to hydroxyapatite crystals can, in high doses, inhibit bone mineralisation (potentially causing osteomalacia), an effect that is unrelated to their anti-resorptive efficacy. This disadvantageous effect, prominent with non-nitrogen containing bisphosphonates, is less with newer nitrogen containing members. Osteoporosis Osteoporosis is a disease characterised by increased skeletal fragility, low bone mineral density (less than 2. It occurs most commonly in post-menopausal women and patients taking long-term corticosteroid. Exclude underlying causes such as hyperthyroidism, hyperparathyroidism and hypogonadism (in both sexes) before treatment is initiated. Now, patients at risk of osteoporosis are advised to increase daily exercise, stop smoking and optimise diet to ensure sufficient calories and an adequate intake of calcium and vitamin D. The recommended daily calcium intake of 1500 mg can be achieved with calcium supplementation 1. Absorption is further impaired by food, drinks, and drugs containing calcium, magnesium, iron or aluminium salts. A proportion of bisphosphonate that is absorbed is rapidly incorporated into bone; the remaining fraction is excreted unchanged by the kidneys.

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Black cohosh (Cimicifuga racemosa) antiviral herpes medication purchase amantadine without prescription, taken for hot flushes and other menopausal symptoms (but no better than placebo in clinical trial) side effects of antiviral medication cheap amantadine 100mg, can cause serious liver disorder antiviral juicing purchase 100 mg amantadine free shipping. Herbal teas containing pyrrolizidine alkaloids (Senecio hiv infection rates decreasing 100 mg amantadine with mastercard, Crotalaria hiv infection stages pdf purchase generic amantadine on line, Heliotropium) cause serious hepatic veno-occlusive disease hiv infection french kissing buy 100mg amantadine free shipping. Comfrey (Symphytum) is similar but also causes hepatocellular tumours and haemangiomas. Other toxic natural remedies include lily of the valley (Convallaria) and horse chestnut (Aesculus). The Medicines and Healthcare products Regulatory Agency provides advice at. The following will suffice to give the flavour of homoeopathy, the principal complementary medicine system involving medicines, and the kind of criticism with which it has to contend. There remain extremists who contend that they understand scientific method, and reject it as invalid for what they do and believe. This is the position taken up by magic and religion where subordination of reason to faith is a virtue. Conventional practitioners may well feel uneasily that there has been and still is truth in this, that with the development of specialisation some doctors have been seduced by the enormous successes of medical science and technology and have become liable to look too narrowly at their patients where a much broader (holistic) approach is required. I was on the point of concluding that the whole art was vain and incapable of improvement. I gave myself up to solitary reflection, and resolved not to terminate my train of thought until I had arrived at a definite conclusion on the subject. The eternal, universal law of Nature, that every disease is destroyed and cured through the similar artificial disease which the appropriate remedy has the tendency to excite, rests on the following proposition: that only one disease can exist in the body at any one time. Use of the word to distinguish homoeopathy from conventional scientific medicine is clearly incorrect. Pharmacologists have felt, in the absence of conclusive evidence from empirical studies that homoeopathic medicines can reproducibly be shown to differ from placebo, that there is no point in discussing its hypotheses. A meta-analysis of 186 double-blind and/or randomised placebo-controlled trials of homoeopathic remedies found that 89 had adequate data for analysis. Conclusion There is a single fundamental issue between conventional scientific medicine and traditional, complementary and alternative medicine (although it is often obscured by detailed debates on individual practices); the issue is: what constitutes acceptable evidence. In the meantime, we depend on the accumulation of evidence from empirical studies to justify the allocation of resources for future research. Homoeopathic practitioners repeatedly express their irritation that critics give so much attention to dilution. They should not be surprised, considering the enormous implications of their claim. A report of an investigation into experiments with antibodies in solutions that contained no antibody molecules (as in some homoeopathic medicines). The editor of Nature took a three-person team (one of whom was a professional magician, included to detect any trickery) on a week-long visit to the laboratory that claimed positive results. Full reports in this issue of Nature (28 July 1988), including an acrimonious response by the original scientist, are highly recommended reading, both for scientific logic and for entertainment. Linde K, Clausius N, Melchart D et al 1997 Are the clinical effects of homoeopathy placebo effects Undue scepticism may prevent a drug from achieving its effect, and enthusiasm or confidence may potentiate the actions of drugs. They may be defined as substances that aspire to strengthen and increase the appetite of those so weakened by disease, misery, overindulgence in play or work, or by physical or mental inadequacy, that they cannot face the stresses of life. The essential feature of this weakness is the absence of any definite recognisable defect for which there is a known remedy. The deliberate use of drugs as placebos is a confession of therapeutic failure by the doctor. Failures, however, are sometimes inevitable and an absolute condemnation of the use of placebos on all occasions would be unrealistic. A placebo-reactor is an individual who reports changes of physical or mental state after taking a pharmacologically inert substance. The industry knows that it has to learn to live with restrictions of some kinds and one of the means of restriction is 45 Placebo-reactors are suggestible people who are likely to respond favourably to any treatment. Negative reactors, who develop adverse effects when given a placebo, exist but, fortunately, are fewer. Placebo reaction is an inconstant attribute: a person may respond at one time in one situation and not at another time under different conditions. In one study on medical students, psychological tests revealed that those who reacted to a placebo tended to be extroverted, sociable, less dominant, less self-confident, more appreciative of their teaching, more aware of their autonomic functions and more neurotic than their colleagues who did not react to a placebo under the particular conditions of the experiment. Modern brain-scanning techniques provide evidence that the placebo effect has a physiological basis. As the following account by a mountain rescue guide illustrates: `The incident involved a 15-year-old boy who sustained head injuries and a very badly broken leg. Helicopter assistance was unavailable and therefore we had to carry him by stretcher to the nearest landrover (several miles away) and then on to a waiting ambulance. During this long evacuation the boy was in considerable distress and we administered Entonox (a mixture of nitrous oxide and oxygen, 50% each) sparingly as we only had one small cylinder. He repeatedly remarked how much better he felt after each intake of Entonox (approximately every 20 minutes) and after 7 hours or so, we eventually got him safely into the ambulance and on his way to hospital. On going to replace the Extonox we discovered the cylinder was still full of gas due to the equipment being faulty. There was no doubt that the boy felt considerable pain relief because he thought he was receiving Entonox. Beer was a prescription item in hospitals until, decades later, an audit revealed that only 1 in 10 bottles reached a patient. More recently (1992): `There could be fewer Christmas puddings consumed this year. The puddings were recently struck off a bizarre list of items that doctors were able to prescribe for their patients. They were removed by Health Department officials without complaint from the medics, on the grounds they had "no therapeutic or clinical value". A formulary may list all nationally licensed medicines prescribable by health professionals, or list only preferred drugs. It may be restricted to what a third-party payer will reimburse, or to the range of formulations stocked in a hospital (and chosen by a local drugs and therapeutics committee, which all hospitals or groups of hospitals should have), or the range agreed by a partnership of general practitioners or primary care health centre. All restricted formularies are heavily motivated to keep costs down without impairing appropriate prescribing. There is a profusion of these from national sources, hospitals, group practices and specialty organisations (epilepsy, diabetes mellitus). Chapter 2 prescriber, and legal issues may be raised in the event of adverse therapeutic outcome. Under-prescribing can be just as harmful to the health of patients as over-prescribing. The pharmaceutical industry dislikes the concept of drugs classed as essential, as others, by implication, are therefore judged inessential. Reasons for under-prescribing include: lack of information or lack of the will to use available information (in economically privileged countries there is, if anything, a surplus of information); fear of being blamed for adverse reactions (affecting doctors who lack the confidence that a knowledge of pharmacological principles confers); fear of sanctions against over-costly prescribing. Prescription frequency and cost per prescription are lower for older than for younger doctors. There is no evidence that the patients of older doctors are worse off as a result. Taking a drug history the reasons for taking a drug history from patients are: Cost-containment Cost-containment in prescription drug therapy attracts increasing attention. Drugs can interact, producing a positive adverse effect or a negative adverse effect. Drugs available for independent patient self-medication are increasing in range and importance. Therapeutic substitution, where a drug of different chemical structure is substituted for the drug prescribed by the doctor. The substitute is of the same chemical class and is deemed to have similar pharmacological properties and to give similar therapeutic benefit. Patients now have access to a potentially confusing quantity of detail about the unwanted effects of drugs (information sheet, the internet, the media) but without the balancing influence of data on their frequency of occurrence. It would be prudent for doctors to draw attention at least to adverse effects that are common, serious (even if uncommon), or avoidable or mitigated if recognised. Continuing patients, especially the elderly, on courses of medicinal treatment over many months without proper review of their medication. Doctors may `prescribe brand-name drugs rather than cheaper generic equivalents, even where there is no conceivable therapeutic advantage in so doing. Many of the drugs on the market may not have been available when a general practitioner was at medical school. Twelve members of Parliament took evidence from up to 100 organisations and individuals orally and/or in writing. Just as engineers say that the only safe aeroplane is the one that stays on the ground in still air on a disused airfield or in a locked hangar, so the only safe drug is one that stays in its original package. If drugs are not safe then plainly patients are entitled to be warned of their hazards, which should be explained to them, as to probability, nature and severity. There is no formal legal or ethical obligation on doctors to warn all patients of all possible adverse consequences of treatment. It is their duty to adapt the information they give (not too little, and not so much as to cause confusion) so that the best interest of each patient is served. Courts of law will look critically at doctors who seek to justify under-information by saying that they feared to confuse or frighten the patient (or that they left it to the patient to ask, as one doctor did). Doctors should know what their patients have read (or not read, as is so often the case) when patients express dissatisfaction. Patient compliance Patient compliance is the extent to which the actual behaviour of the patient coincides with medical advice and instructions; it may be complete, partial, erratic, nil, or there may be over-compliance. To make a diagnosis and to prescribe evidence-based effective treatment is a satisfying experience for doctors, but too many assume that patients will gratefully or accurately do what they are told. Where lack of money to pay for the medicine is not the cause, this is due to lack of motivation or apprehension about drugs. Patient non-compliance or non-adherence is identified as a major factor in therapeutic failure in both routine practice and in scientific therapeutic trials; but, sad to say, doctors are too often non-compliant about remedying this. All patients are potential non-compliers;55 clinical criteria cannot reliably predict good compliance, but non-compliance often can be predicted. In addition to therapeutic failure, undetected noncompliance may lead to rejection of the best drug when it is effective, leading to substitution by second-rank medicines. Legal hazards for prescribers Doctors would be less than human if, as well as trying to help their patients, they were not also concerned to protect themselves from allegations of malpractice (negligence). Failure to provide appropriate information will usually be a breach of duty and if that breach leads to the patient suffering injury then the basis for a claim for compensation exists. At the very least, these should include records of warning about treatments that are potentially hazardous. The words adherence or concordance are preferred by some, the latter because it expresses the duality of drug prescribing (by the doctor) and taking (by the patient). We retain compliance, pointing out that it applies equally to those doctors who neither keep up to date, nor follow prescribing instructions, and to patients who fail, for whatever reason, to keep to a drug regimen. Unpleasant disease symptoms, particularly where these are recurrent and known by previous experience to be quickly relieved, provide the highest motivation. But particularly where the patient does not feel ill, adverse effects are immediate, and benefits are perceived to be remote. Doctors cannot be expected actually to like all their patients, but it is a great help (where liking does not come naturally) if they make a positive effort to understand how individual patients must feel about their illnesses and their treatments. This is not always easy, but its achievement is the action of the true professional, and indeed is part of their professional duty of care. Non-compliance may occur because: the patient has not understood the instructions, so cannot comply,56 or the patient understands the instructions, but fails to carry them out. Unintentional non-compliance, or forgetfulness,57 may be addressed by associating drug-taking with cues in daily life (breakfast, bedtime), by special packaging (e. This includes cognitive impairment and psychological problems, with depression being a particular problem. Oral instructions alone are not enough; one-third of patients are unable to recount instructions immediately on leaving the consulting room.

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Chemoprophylaxis the three common pathogens (below) are spread by respiratory secretions anti virus ware generic amantadine 100mg visa. Asymptomatic nasopharyngeal carriers seldom develop meningitis but may transmit the pathogens to close personal contacts hiv infection symptoms after 2 weeks cheap amantadine online master card. Initial parenteral therapy can be switched to oral once the patient has improved and susceptibility of the causative pathogen determined capside viral anti vca-igg generic 100 mg amantadine with visa. A longer period of treatment may be required for those who develop complications such as osteomyelitis or abscess hiv infection of oral cavity order amantadine 100mg online. A carrier state develops in a few individuals who have no symptoms of disease but who can infect others hiv eye infection pictures effective 100mg amantadine. Meningococcal meningitis often occurs in epidemics in closed communities antiviral immunity discount 100mg amantadine overnight delivery, but also in isolated cases. Patients and close personal contacts should receive rifampicin 600 mg 12-hourly by mouth for 2 days. Haemophilus influenzae type b has similar infectivity to that of the meningococcus; give rifampicin 600 mg by mouth daily for 4 days to unimmunised contacts. Pneumococcal meningitis tends to occur in isolated cases and contacts do not need chemoprophylaxis. Antimicrobial therapy should be reserved for specific conditions with identified pathogens where benefit has been shown; acute diarrhoea can be caused by bacterial toxins in food, dietary indiscretions, anxiety and by drugs as well as by infection. Even if diarrhoea is infective, it may be due to viruses; or, if bacterial, antimicrobial agents may not reduce the duration of symptoms and may aggravate the condition by permitting opportunistic infection and encouraging Clostridium difficile-associated diarrhoea. Prophylactic use of an antimicrobial is not usual but, should it be deemed necessary, a quinolone or rifaximin is effective. Death in cholera is due to electrolyte and fluid loss in the stools, and this may exceed 1 L/h. A single dose of doxycycline, given early, significantly reduces the amount and duration of diarrhoea and eliminates the organism from the faeces (thus lessening the contamination of the environment). Ciprofloxacin or a macrolide (clarithromycin or azithromycin) are alternatives for resistant organisms. Oral zinc acetate supplements have been shown modestly to reduce the volume and duration of cholera diarrhoea in combination with antibiotics, probably by improving gut mucosal integrity and function in malnourished patients. Suppression of bowel flora is thought by some to be useful in hepatic encephalopathy. Here, absorption of products of bacterial breakdown of protein (ammonium, amines) in the intestine leads to cerebral symptoms and even to coma. Mild disease requires no specific antimicrobial therapy but toxic shigellosis with high fever should be treated with ciprofloxacin or azithromycin by mouth for 5 days. Give an antimicrobial for severe salmonella gastroenteritis, or for bacteraemia or salmonella enteritis in an immunocompromised patient. The choice lies between ciprofloxacin, azithromycin or a parenteral cephalosporin: ciprofloxacin resistance is rising in incidence in salmonella (including in S. Drug treatment of urinary tract infection falls into several categories: Selective decontamination of the gut may reduce the risk of nosocomial infection from gut organisms (including fungi) in patients who are immunocompromised or receiving intensive care (notably mechanical ventilation). The commonest regimen involves combinations of topical non-absorbable (framycetin, colistin, nystatin and amphotericin) and. Alternatives include using the topical agents alone, or administering oral ciprofloxacin. Selective decontamination should be used with great care in hospitals with a high incidence of multiply resistant bacteria or Clostridium difficile diarrhoea. Lower urinary tract infection this is most commonly seen in young women with normal urinary tracts. Therapy should normally last for 3 days and may need to be altered once the results of bacterial sensitivity are known. Peritonitis is usually a mixed infection and antimicrobial choice must take account of coliforms and anaerobes, although the need to include cover for the other major component of the bowel flora, streptococci, is less certain. Piperacillin-tazobactam or a combination of gentamicin, benzylpenicillin plus metronidazole, or meropenem alone is usually appropriate, and can be stopped after the patient is clinically improved and their inflammatory markers (e. Surgical drainage of peritoneal collections and abscesses may need to be repeated. Upper urinary tract infection Acute pyelonephritis may be accompanied by septicaemia and is usually marked by fever and loin pain. If oral therapy is considered suitable, co-amoxiclav or ciprofloxacin is recommended for 2 weeks. This is an infection of the kidney substance and so needs adequate blood as well as urine concentrations, although a switch to an oral agent (guided by the results of susceptibility testing) to complete the course is recommended after the patient has clinically improved. Such bacteria are usually resistant also to ciprofloxacin, parenteral cephalosporins and gentamicin. Parenteral meropenem, ertapenem or amikacin, or oral pivmecillinam or fosfomycin may be effective. Identification of the causative organism and of its sensitivity to drugs is important because of the range of organisms and the prevalence of resistant strains. For infection of the lower urinary tract a low dose may be effective, as many antimicrobials are concentrated in the urine. Infections of the substance of the kidney require the doses needed for any systemic infection. A large urine Recurrent urinary tract infection Attacks following rapidly with the same organism may be relapses and indicate a failure to eliminate the original infection. Attacks with a longer interval between them and produced by differing bacterial types may be regarded as due to reinfection, most often by ascending infection from the perineal skin. There is some evidence that daily ingestion of cranberry juice may reduce the frequency of relapse in women, perhaps by sugars within the juice interfering with adhesion of bacteria to the urinary epithelium. Vesicoureteric reflux 199 Section 3 Infection and inflammation it has retained activity against a useful proportion of urinary tract coliforms that have acquired resistance to trimethoprim, oral b-lactams and quinolones. Excretion is reduced when there is renal insufficiency, rendering the drug both more toxic and less effective. Adverse effects include nausea and vomiting (much reduced with the macrocrystalline preparation) and diarrhoea. Peripheral neuropathy occurs especially in patients with significant renal impairment, in whom the drug is contraindicated. Allergic reactions include rashes, generalised urticaria and pulmonary infiltration with lung consolidation or pleural effusion. Nitrofurantoin is safe in pregnancy, except near to term (because it may cause neonatal haemolysis), and it must be avoided in patients with glucose-6-phosphate dehydrogenase deficiency (see p. Long-term oral antibiotic prophylaxis in such patients is modestly effective at reducing symptomatic infections. Amoxicillin or a cephalosporin is preferred in pregnancy, although nitrofurantoin may be used if imminent delivery is not likely (see below). Prostatitis the commonest pathogens here are Gram-negative aerobic bacilli, although chlamydia may also be involved. A quinolone such as ciprofloxacin is commonly used, although trimethoprim, doxycycline or erythromycin are also effective. Being lipid soluble, these drugs penetrate the prostate in adequate concentration; they may usefully be combined. Response to a single, short course is often good, but recurrence is common and a patient can be regarded as cured only if he has been symptom-free without resort to antimicrobials for a year. Tracing and screening of contacts plays a vital part in controlling spread and reducing re-infection. Recommended treatment regimens vary to some extent among countries, and this is in response to differences in antimicrobial susceptibility of the relevant pathogens and availability of antimicrobial agents. Chemoprophylaxis Chemoprophylaxis is sometimes undertaken in patients liable to recurrent attacks or acute exacerbations of ineradicable infection. It may prevent progressive renal damage in children who are found to have asymptomatic bacteriuria on routine screening. Gonorrhoea the problems of b-lactam and quinolone resistance in Neisseria gonorrhoeae infection are increasing (ciprofloxacin resistance rates rose from 2. Cefixime and ceftriaxone resistance on testing in vitro are increasing, but not yet to levels that compromise therapeutic efficacy. Effective treatment requires exposure of the organism briefly to a high concentration of the drug. The following schedules are effective: Tuberculosis of the genitourinary tract is treated on the principles described for pulmonary infection (see p. Special drugs for urinary tract infections General antimicrobials used for urinary tract infections are described elsewhere. A few agents find use solely for infection of the urinary tract: Nitrofurantoin, a synthetic antimicrobial, is active against the majority of urinary pathogens except pseudomonads, and has increased in importance recently because Uncomplicated anogenital infections. Chlamydia trachomatis is frequently present with Neisseria gonorrhoeae; tetracycline by mouth for 7 days or a single oral dose of azithromycin 1 g or ofloxacin 400 mg will treat the chlamydial urethritis. Presenting as pyrexia, it is common during the few hours after the first penicillin injection; other features include tachycardia, headache, myalgia and malaise, which last for up to a day. Prednisolone may prevent it and should probably be given if a reaction is specially to be feared. Non-gonococcal urethritis the vast majority of cases of urethritis with pus in which gonococci cannot be identified are due to sexually transmitted organisms, usually Chlamydia trachomatis (the most common bacterial sexually-transmitted infection worldwide) and sometimes Ureaplasma urealyticum. Chancroid the causal agent, Haemophilus ducreyi, normally responds to erythromycin for 7 days or a single dose of ceftriaxone or azithromycin. Granuloma inguinale Calymmatobacterium granulomatis infection responds to cotrimoxazole or doxycycline for 2 weeks or a single dose of azithromycin weekly for 4 weeks. Pelvic inflammatory disease Several pathogens are usually involved, including Chlamydia trachomatis, Neisseria gonorrhoeae and Mycoplasma hominis, and there may be superinfection with bowel and other urogenital tract bacteria. The condition is associated with overgrowth of several normal commensals of the vagina including Gardnerella vaginalis, Gram-negative curved bacilli and anaerobic organisms, the latter being responsible for the characteristic fishy odour of the vaginal discharge. The condition responds well to a single dose of metronidazole 2 g or 400 mg thrice daily for a week by mouth, with 7 days of topical clindamycin cream offering an alternative. Syphilis Primary and secondary syphilis are effectively treated by a single dose of 2. Doxycycline or erythromycin orally for 2 weeks may be used for penicillin-allergic patients, and a single oral dose of 2 g azithromycin appears to have equivalent efficacy. Treponema pallidum is invariably sensitive to penicillin but macrolide resistance has been reported worldwide rarely except in infections in men who have sex with men. Neurosyphilis requires higher serum concentrations for cure and should be treated with procaine penicillin 2. Congenital syphilis in the newborn should be treated with benzylpenicillin for 10 days at least. Some advocate that a pregnant woman with syphilis should be treated as for primary syphilis in each pregnancy, in order to avoid all danger to children. Therapy is best given between the third and sixth month, as there may be a risk of abortion if it is given earlier. Staphylococcus aureus is the commonest isolate in all patient groups, and Salmonella species in the tropics. Chronic osteomyelitis of the lower limbs (especially when underlying chronic skin infection in the elderly) frequently involves obligate anaerobes (such as Bacteroides spp. Definitive therapy is guided by the results of culture but commonly used regimens include co-amoxiclav (community-acquired cases in adults), flucloxacillin with or without fusidic acid (for Staphylococcus aureus), cefotaxime or co-amoxiclav (in children), and ciprofloxacin (for coliforms). Endemic trachoma in developing countries is usually caused by serotypes A, B and C. Staphylococcus aureus is the commonest pathogen, but a very wide range of bacteria may be involved including streptococci, coliforms and Neisseria spp. Aspiration of the joint allows specific microbiological diagnosis, differentiation from non-infectious causes such as crystal synovitis, and has therapeutic benefit. Infection of prosthetic joints may also involve a range of bacteria, but is most commonly staphylococcal. Debridement of the prosthesis and culture of adjacent bone biopsy samples fulfils both therapeutic and diagnostic needs, and prolonged antibiotic therapy guided by culture is successful (with retention of the prosthesis in situ) in 60% of cases or more as long as it is commenced within a few weeks of first presentation of the infection and the prosthesis is stable. Ciprofloxacin, ofloxacin, levofloxacin, gentamicin or tobramycin is used for Pseudomonas aeruginosa, and fusidic acid principally for Staphylococcus aureus. Preparations often contain hydrocortisone or prednisolone, but the steroid masks the progress of the infection, and should it be applied with an antimicrobial to which the organism is resistant (bacterium or virus) it may aggravate the disease by suppressing protective inflammation. Local chemoprophylaxis without corticosteroid is used to prevent secondary bacterial infection in viral conjunctivitis.

Marfan syndrome

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For instance hiv infection by swallowing blood cheap 100mg amantadine overnight delivery, lead inhibits the repair process in damaged endothelial cells (Fujiwara et al hiv infection rates us 2012 100 mg amantadine for sale. Mercury added to platelet-rich plasma causes a marked increase in platelet thromboxane B2 production and platelet responsiveness to arachidonic acid symptoms of primary hiv infection video best purchase amantadine. These actions have been associated with extravasation hiv infection rate switzerland cheap 100mg amantadine mastercard, transudation of plasma hiv infection life expectancy purchase amantadine 100 mg otc, and decreased intravascular volume antiviral vitamins for hpv purchase cheap amantadine line. A severe form of arteriosclerosis, blackfoot disease, in Taiwan has beens shown to be associated with high levels of arsenic in the soil and water. Blackfoot disease is an endemic peripheral vascular occlusive disease that exhibits arteriosclerosis obliterans and thromboangiitis. The ability of arsenic to induce these changes has been attributed to its effects on vascular endothelial cells. Aromatic Hydrocarbons Aromatic hydrocarbons, including polycyclic aromatic hydrocarbons and polychlorinated dibenzopdioxins, are persistent toxic environmental contaminants. Aromatic hydrocarbons have been identified as vascular toxins that can initiate and/or promote the atherogenic process in experimental animals (Ou and Ramos, 1992). However, studies have also shown that treatment with several polycylic hydrocarbons increases the size but not the frequency of atherosclerotic lesions (Albert et al. Although additional studies are required to define the "initiating" versus "promotional" actions of polycyclic aromatic hydrocarbons, their ability to readily associate with plasma lipoproteins may play a critical role in vascular toxicity. Importantly, these lesions lead to release or secretion of cytokines and chemokines, worsening cardiac complications. Bozkurt B: Cardiovascular toxicity with highly active antiretroviral therapy: Review of clinical studies. Relationship between altered ventricular myocyte contractility and ryanodine receptor function. Chacon E, Acosta D: Mitochondrial regulation of superoxide by Ca2+: An alternate mechanism for the cardiotoxicity of doxorubicin. De Simone G: Left ventricular geometry and hypotension in end-stage renal disease: a mechanical perspective. Depre C, Taegtmeyer H: Metabolic aspects of programmed cell survival and cell death in the heart. Fosslien E: Mitochondrial medicine-molecular pathology of defective oxidative phosphorylation. Gordon T, Reibman J: Cardiovascular toxicity of inhaled ambient particulate matter. Haunstetter A, Izumo S: Apoptosis: Basic mechanisms and implications for cardiovascular disease. Hino N, Ochi R, Yanagisawa T: Inhibition of the slow inward current and the time-dependent outward current of mammalian ventricular muscle by gentamicin. Maret W: the function of zinc metallothionein: A link between cellular zinc and redox state. Induction by P-hydrazinobenzoic acid hydrochloride of the cultivated mushroom Agaricus Bisporus. Nattel S: Experimental evidence for proarrhythmic mechanisms of antiarrhythmic drugs. Penn A, Snyder C: Arteriosclerotic plaque development is "promoted" by polynuclear aromatic hydrocarbons. Robbins J: Genetic modification of the heart: Exploring necessity and sufficiency in the past 10 years. Zakhari S: Cardiovascular toxicology of halogenated hydrocarbons and other solvents, in Acosta D (ed. Data from the Bureau of Labor Statistics indicate that in 2004, skin disease attributed to workplace exposures accounted for nearly 16% of the reported nonfatal occupational disease in private industry; incidence data indicate a rate of 4. Substantial reduction in the reported incidence has occurred in recent years thanks to workplace cleanup and better personal protective equipment. Nevertheless, improvements in prevention and management are needed for continued progress (Emmett, 2003). Skin conditions resulting from exposures to consumer products or occupational illnesses not resulting in work time loss are poorly recorded and tracked. The specific presentation depends on a variety of intrinsic and extrinsic factors including body site, duration of exposure, and other environmental conditions (Table 19-1). Skin Histology the skin consists of two major components: the outer epidermis and the underlying dermis, which are separated by a basement membrane. The junction ordinarily is not flat but has an undulating appearance (rete ridges). In addition, epidermal appendages (hair follicles, sebaceous glands, and eccrine glands) span the epidermis and are embedded in the dermis. In thickness, the dermis comprises approximately 90% of the skin and has mainly a supportive function. It has a high content of collagen and elastin secreted by scattered fibroblasts, thus providing the skin with elastic properties. Separating the dermis from the underlying tissues is a layer of adipocytes, whose accumulation of fat has a cushioning action. Capillaries also supply the bulbs of the hair follicles and the secretory cells of the eccrine (sweat) glands. The ducts from these glands carry a dilute salt solution to the surface of the skin, where its evaporation provides cooling. The interfollicular epidermis is a stratified squamous epithelium consisting primarily of keratinocytes. These cells are tightly attached to each other by desmosomes and to the basement membrane by hemidesmosomes. Melanocytes are interspersed among the basal cells and distributed in the papilla of hair follicles. In the epidermis, these cells are stimulated by ultraviolet light to produce melanin granules. The granules are extruded and taken up by the surrounding keratinocytes, which thereby become pigmented. Its biological sophistication allows it to perform a myriad of functions above and beyond that of a suit of armor. Physiologically, the skin participates directly in thermal, electrolyte, hormonal, metabolic, and immune regulation, without which a human would perish. Rather than merely repelling noxious physical agents, the skin may react to them with a variety of defensive mechanisms that prevent internal or widespread cutaneous damage. When a basal cell divides, one of the progeny detaches from the basal lamina and migrates outward. As cells move toward the skin surface, they undergo a remarkable program of terminal differentiation. They gradually express new protein markers and accumulate keratin proteins, from which the name of this cell type is derived. The keratins form insoluble intermediate filaments accounting for nearly 40% of the total cell protein in the spinous layer. At the granular layer, the cells undergo a striking morphological transformation, becoming flattened and increasing in volume by nearly 40-fold. Lipid granules fuse with the plasma membrane at the granular layer/stratum corneum interface, filling the intercellular spaces of the stratum corneum with lipid, as opposed to the aqueous intercellular solution in the viable epidermis. Meanwhile, the plasma membranes of these cells become permeable, resulting in the loss of their reducing environment and consequently in extensive disulfide bonding among keratin proteins. Cell organelles are degraded, while a protein envelope is synthesized immediately beneath the plasma membrane. The membrane is altered characteristically by the loss of phospholipid and the addition of sphingolipid. This program of terminal differentiation, beginning as keratinocytes leave the basal layer, produces the outermost layer of the skin, the stratum corneum. The process typically takes 2 weeks for basal cells to reach the stratum corneum and another 2 weeks to be shed from the surface. In the skin disease psoriasis, the migration of cells to the surface is nearly tenfold faster than normal, resulting in a stratum corneum populated by cells that are not completely mature. In instances in which the outer layer is deficient due to disease or physical or chemical trauma, the barrier to the environment that the skin provides is inferior to that provided by normal, healthy skin. Percutaneous Absorption Until a century ago, the skin was thought to provide an impervious barrier to exogenous substances. Gradually, the ability of substances to penetrate the skin, though this process generally is very slow, became appreciated. During the past 50 years, the stratum corneum has been recognized as the primary barrier (Scheuplein and Blank, 1971). The viable layer of epidermis provides a much less effective barrier, because hydrophilic chemicals readily diffuse into the intercellular water, while hydrophobic chemicals can partition into cell membranes, and each can diffuse readily to the blood supply in the rete ridges of the dermis. Probably the best-known biological membrane barrier for this purpose, the stratum corneum, prevents water loss from underlying tissues by evaporation. Its hydrophobic character reflects the lipid content of the intercellular space, 15% of the total volume (Elias, 1992). The lipids, a major component being sphingolipids, have a high content of long-chain ceramides, removal of which seriously compromises barrier function as measured by transepidermal water loss. The stratum corneum ordinarily is hydrated (typically 20% water) with the moisture residing in corneocyte protein; however, it can take up a great deal more water upon prolonged immersion, thereby reducing the effectiveness of the barrier to chemicals with a hydrophilic character. Indeed, occlusion of the skin with plastic wrap, permitting the retention of perspiration underneath, is a commonly employed technique to enhance uptake of chemicals applied to the skin surface. Although penetration from the air is generally too low to be of concern, protection from skin uptake may be advisable for some compounds (e. Finding the rate at which the uptake of chemicals through the skin occurs is important for estimating the consequences of exposure we encounter in the environment. Indeed, a regulatory strategy permitting bathing in water considered barely unfit for drinking was revised when it was realized that exposure from dermal/inhalation uptake during bathing could be comparable to that from drinking 2 L of the water (Brown et al. Uptake through the skin is now incorporated in pharmacokinetic modeling to estimate potential risks from exposures. The degree of uptake depends upon the details of exposure conditions, being proportional to solute concentration (assuming it is dilute), time, 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.

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It is characterised by severe dehydration hiv infection rate washington dc amantadine 100mg free shipping, a very high blood sugar level (> 33 mmol/L) hiv infection by country buy generic amantadine on line, and lack of ketosis and acidosis antiretroviral used for hiv effective 100 mg amantadine. Insulin requirements are less than in ketoacidosis hiv eye infection pictures buy 100 mg amantadine free shipping, where the acidosis causes resistance to the actions of insulin hiv infection rates in african countries purchase amantadine 100 mg free shipping, and should generally be half those shown in Table 36 hiv infection muscle pain purchase amantadine with american express. Patients may be profoundly dehydrated and liable to thrombosis so that prophylactic low molecular weight heparin should be considered. Note that fluid replacement itself causes a fall in blood glucose concentration both by dilution and also by restoring blood volume to perfuse skeletal muscle, a major insulin target tissue. Aggressive treatment of hypertension and hyperlipidaemia in addition to glycaemia is particularly important in patients with diabetes. Reduction of blood pressure in 758 patients to a mean of 144/82 mmHg achieved a 32% reduction in deaths related to diabetes and a 37% reduction in microvascular endpoints, compared with findings in 390 patients treated to a blood pressure of 154/87 mmHg. Similarly, aggressive targeting of lipids reduces cardiovascular complications in diabetes. In the Heart Protection Study, addition of simvastatin 40 mg daily to the treatment of 4000 patients with diabetes reduced cardiovascular complications by 30%. Some guidelines have suggested that aspirin may be worth using in primary prevention in diabetes. It is generally divided into two kinds: type 1 (previously, insulin dependent diabetes mellitus) and type 2 (previously, non-insulin dependent diabetes, essentially an umbrella term for a group of conditions which are non-type 1). Increasingly, insulin therapy is required in type 2 diabetes when glycaemic control is not optimised by oral drugs. Modern practice in type 1 diabetes is to educate patients in flexible insulin dosing which is adjusted for differing meals, activity levels, etc. Other monotherapy options include a sulfonylurea in the non-obese or a thiazolidinedione in patients intolerant of, or uncontrolled by, metformin or sulfonylurea. Many patients with type 2 diabetes will need treatment escalation with time to multiple combination therapy and/or insulin. Close attention to associated risk factors, especially hyperlipidaemia and hypertension, is important in reducing risk of macrovascular disease. Yusuf S, Sleight P, Pogue J et al 2000 Effects of an angiotensin converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. Obesity predisposes to several chronic diseases including hypertension, hyperlipidaemia, diabetes mellitus, cardiovascular disease and osteoarthritis, and aspects of these are discussed in the relevant sections of this book. Management of the condition involves a variety of approaches from nutritional advice to lifestyle alteration, drugs and, where available and appropriate, bariatric surgery. In general, drugs that have been used for obesity act either on the gastrointestinal tract, lowering nutrient absorption, or centrally, reducing food intake by decreasing appetite or increasing satiety (appetite suppressants). A number of pharmacological agents that have been marketed for obesity have been withdrawn because of concerns about safety. Adverse effects include flatulence and liquid, oily stools, leading to faecal urgency, abdominal and rectal pain. Orlistat is contraindicated where there is chronic intestinal malabsorption or cholestasis. Leptin the adipocyte-derived hormone leptin (Greek: leptos, thin) has a limited role in therapeutics for patients with rare genetic defects in the leptin or leptin receptor genes. Most obese patients have raised plasma leptin concentrations, to which they have become relatively resistant. A small number of patients are genuinely deficient in leptin and therapy with recombinant leptin has had dramatic beneficial effects. Leptin may also be of benefit in lipodystrophic patients, a rare group of conditions in which a generalised or partial lack of adipocytes leads to marked metabolic abnormalities and diabetes. Leptin acts to control satiety via the melanocortin system, predominantly in the basomedial hypothalamus, and a number of agents in development aim to target this. Orlistat Orlistat is a pentanoic acid ester that binds to and inhibits gastric and pancreatic lipases; the resulting inhibition of their activity prevents the absorption of about 30% of dietary fat compared with a normal 5% loss. Weight loss is due to calorie loss but drug-related adverse effects also contribute by diminishing food intake. The dose is 120 mg, taken immediately before, during or 1 h after each main meal, up to three times daily. Weighed against this is the challenge that certain pharmacologic therapies for diabetes, particularly sulfonylureas, thiazolidinediones and insulin, can promote weight gain. The patient and clinician may find themselves caught in a vicious cycle where dose escalation of these agents leads to weight gain, worsening glycaemic control, which in turn leads to further dose increments. As for patients without diabetes, diet and exercise are critical factors but diabetes treatment may need to be adjusted for this (for example insulin reductions to avoid hypoglycaemia with increased exercise or reduced carbohydrate intake). Ultimately, as for patients without diabetes, orlistat and/or bariatric surgery12 may be appropriate. Role of leptin in energy-deprivation states: normal human physiology and clinical implications for hypothalamic amenorrhoea and anorexia nervosa. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. The effect of oral antidiabetic agents on A1C levels: a systematic review and meta-analysis. These active thyroid hormones are stored in the gland within the molecule of thyroglobulin, a major component of the intrafollicular colloid. They are released into the circulation following reuptake of the colloid by the apical cells and proteolysis. Effects such as these would interfere with the assessment of the clinical significance of measurements of total thyroid hormone concentration but the availability of free thyroid hormone assay largely avoids such complicating factors. T4 and T3 are well absorbed from the gut, except in myxoedema coma when parenteral therapy is required. T4 is a less active precursor of T3, which is the major mediator of physiological effect. Physiology and pharmacokinetics Thyroid hormone synthesis requires oxidation of dietary iodine, followed by iodination of tyrosine to monoand di-iodotyrosine; coupling of iodotyrosines leads to T4 (levothyroxine). The usual replacement dose at steady state in patients with complete thyroid failure, is 1. Absorption is more complete and less variable if levothyroxine is taken at the same time every day, one hour before breakfast. Tablets containing physiological mixtures of levothyroxine and liothyronine are not sufficiently evaluated to recommend in preference to levothyroxine alone. Hypothyroid patients tend to be intolerant of drugs in general owing to slow metabolism. The adult requirement of hormone is remarkably constant, and dosage does not usually have to be altered once the optimum has been found. Early treatment of neonatal hypothyroidism (cretinism) (1 in 5000 births) is important if permanent mental defect is to be avoided. Hypothyroidism due to panhypopituitarism requires replacement with glucocorticoids as well as with thyroid hormone. It is not routine treatment for hypothyroidism because its rapid onset of effect can induce heart failure. A specialised use is during the withdrawal of levothyroxine replacement (to permit diagnostic radioiodine scanning) in patients with thyroid carcinoma. Myxoedema coma follows prolonged total hormone deficiency and constitutes an emergency. Intravenous hydrocortisone should be given to cover the possibility of coexisting adrenocortical insufficiency. Although termed subclinical, 25% of patients have symptoms of hypothyroidism and cognitive disturbance. Meta-analyses of population based studies show a higher incidence of ischaemic heart disease and mortality in subjects younger than 65 years. Treatment of hypothyroidism Levothyroxine tablets contain pure L-thyroxine sodium and should be used. In the old and patients with heart disease or multiple coronary risk factors, this level should be achieved gradually Adverse effects of thyroid hormone parallel the increase in metabolic rate. Symptoms of myocardial ischaemia, atrial fibrillation or heart failure are liable to be provoked by too vigorous therapy or in patients having serious ischaemic heart disease who may even be unable to tolerate optimal therapy. Should they occur, discontinue levothyroxine for 588 Thyroid hormones, antithyroid drugs at least a week, and recommence at lower dose. Only slight overdose may precipitate atrial fibrillation in patients aged over 60 years. Optimal replacement therapy is essential in the first trimester when the athyroid fetus is dependent on maternal supply to ensure normal neurointellectual development. An average 50% increase in dose of levothyroxine is required and ideally patients should anticipate this increase. Liver and other peripheral tissues Thyroxine Thionamides (thiourea derivatives) carbimazole, methimazole, propylthiouracil Mode of action. Maximum effect is delayed until existing hormone stores are exhausted (weeks, see below). The multiple effects of antithyroid drugs include inhibition of thyroid hormone synthesis and a reduction in both intrathyroid immune dysregulation and (in the case of propylthiouracil) the peripheral conversion of thyroxine to tri-iodothyronine. Immunosuppression In patients taking antithyroid drugs, serum concentrations of antithyrotropin receptor antibodies decrease with time, as do other immunologically important molecules, including intracellular adhesion molecule 1, and soluble interleukin-2 and interleukin-6 receptors. There is an increased number of circulating suppressor T cells and a decreased number of helper T cells. Patients must be given written warning to stop the drug and have a leucocyte count performed if symptoms of a sore throat, fever, bruising or mouth ulcers develop. Cross-allergy between the drugs sometimes occurs, but is not to be assumed for agranulocytosis. Treatment of agranulocytosis consists of drug withdrawal, admission to hospital, and administration of broad-spectrum antibimicrobials plus granulocyte colony-stimulating factor. If a pregnant woman has hyperthyroidism (2 per 1000 pregnancies), she should be treated with the smallest possible amount of these drugs because they cross the placenta; over-treatment causes fetal goitre. Failure to respond is likely to be due to the patient not taking the tablets or to wrong diagnosis. Control of antithyroid drug therapy the aim of drug therapy is to control the hyperthyroidism until a natural remission takes place. If hyperthyroidism recurs, there is little chance of a second course of thionamide achieving long-term remission. In such patients, indefinite low-dose antithyroid treatment is an alternative option to radioiodine or surgery. There is a higher risk of the dose-related adverse effects of carbimazole, and no compensatory reduction in the incidence of relapse. Symptoms and signs are, of course, less valuable as guides if the patient is also taking a b-adrenoceptor blocker, and reliance then rests on biochemical tests. Minor reactions include maculopapular or urticarial rash, pruritus, arthralgia, fever, anorexia, nausea, abnormalities of taste and smell. Major effects include agranulocytosis, aplastic anaemia, thrombocytopenia, acute hepatic necrosis, cholestatic hepatitis, lupus-like syndrome, vasculitis. Blood disorders (<3 per 10 000 patient-years) are most common in the first 2 months of treatment.

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