Robert J. McKenna, III, BS, MBS

• University of Southern California
• Marshall School of Business
• Tufts University, School of Medicine
• Staff Research Associate I
• Translation Oncology Research, Inc.
• University of California, Los Angeles
• School of Medicine
• Los Angeles, California

The risk of these was substantially increased by the use of long-term high doses of corticosteroids gastritis natural supplements buy cheap protonix. Low-dose corticosteroid regimens had been used successfully in Belfast gastritis and duodenitis buy 20 mg protonix with visa, Northern Ireland gastritis diet paleo cheap 20 mg protonix, in the 1970s (McGeown et al gastritis symptoms pregnancy order protonix 20 mg overnight delivery. In the early 1980s gastritis food to eat generic protonix 20mg online, randomized controlled trials of low-dose steroids versus conventional high-dose steroids were carried out in Oxford gastritis diet ��������� order 20mg protonix otc, United Kingdom, and elsewhere, confirming that low-dose corticosteroid regimens were just as effective in preventing rejection as those using high doses, but there was a dramatic reduction in the steroid-associated complications (Morris et al 1982). By 1980, most established transplant units reported cadaveric kidney graft survival of between 60% and 65% at 1 year with the use of azathioprine and steroids and patient mortality had reduced substantially, to around < 10% at 1 year. Combination immunosuppressive therapy the introduction of ciclosporin changed the practice of clinical transplantation. Physicians could no longer diagnose acute rejection easily, since it was more subtle than had been seen with previous immunosuppressive regimens. The nephrotoxic effect of ciclosporin meant an alternative diagnosis for declining renal function had to be considered. The diagnostic stakes were high, since the two most likely diagnoses-acute rejection and acute nephrotoxicity-required diametrically opposite actions, viz. The initial idea in the earlier part of the 1980s was simply to replace azathioprine with ciclosporin and argument revolved around whether, and if so at what dose, corticosteroids should be used. A surgeon in Portsmouth, United Kingdom-Maurice Slapak-introduced a new option when he presented the data from a pilot study of low-dose steroids, low-dose azathioprine (1. His argument was that reduced doses permitted reduced toxicity but the combination of all three agents provided synergic immunosuppression. Without the formal clinical trial proof that would be expected in later years, physicians and surgeons were given free rein to manage rejection Ciclosporin Ciclosporin was first isolated as part of a drug discovery programme run by the chemists at Sandoz (now Novartis) in Basel, Switzerland, who were looking for an antifungal agent from the fungi that had been collected on a field trip to a plateau above the Hardanger Fjord in Norway. This weakly antifungal molecule was shown to be immunosuppressive by Stahelin and his team at Sandoz and so rejected as an antifungal agent, but recognized by the immunologist in the Stahelin team, Jean Borel, for its potential in transplantation (see Morris, 2013). Borel gave a paper at the British Society of Immunology in 1975 on his experiments with the new agent in rat kidney transplants and within a year ciclosporin was tested in large animal kidney transplants by Roy Calne and David White in Cambridge. Within a very short time by current standards, ciclosporin was first used clinically by Roy Calne in organ transplantation (Calne et al. Translating the dose used in experimental studies to 25 mg/kg/day in the clinic rapidly led to the recognition of its nephrotoxic potential and, when used in combination with other immunosuppressive agents, to a 10% incidence of lymphoma (3/33 patients). By the early 1980s, ciclosporin was licensed as an immunosuppressive drug, first in Europe and then in the United States and globally during 1983 and 1984. The current era of immunosuppression reached its optimum with the addition of two additional approaches: induction agents and infection prophylaxis. The first was accelerated rejection and early graft loss from steroid unresponsive rejection. Hence induction immunosuppression using an antibody preparation could enhance outcomes especially in immunologically high-risk patients. Acute ciclosporin nephrotoxicity, especially in the context of ischaemic acute kidney injury or initial non-function, was the second concept driving adoption of a protocol of antibody induction in the first few days, changing to a consolidation immunosuppressive regimen beyond 10 or 14 days post transplant when the ischaemic injury had resolved. New opportunities for regular and prolonged use of prophylaxis were sought and found to complement the power of the chemical immunosuppression achievable at the start of the 1990s. Tacrolimus was clearly an effective immunosuppressant but also a cause of serious neurological and other sequelae, demanding formal randomized double-blinded clinical trials. In common with many immunosuppressive drugs, the doses and the blood concentration were high to avoid immunosuppressive failure, but risking adverse events. With time, the blood levels became trusted to reflect immunosuppressive potency and clinical experience with adverse events led to increased confidence in diagnosis of toxicity. The largest clinical trial to date in transplantation was designed and co-ordinated by Henrik Ekberg, a transplant surgeon from Malmo, Sweden. Mycophenolate mofetil Elion and Hitchings had identified the central importance of purine synthesis in activated lymphocyte function and had explored it successfully not only with the resultant use of azathioprine but also allopurinol for control of urate synthesis in gout. Transplantation in the mid 1990s had a problem created by the success of the therapy available at that time. Marketed as CellCept, it subsequently displaced the much cheaper azathioprine from clinical practice in almost all developed countries by the early 2000s. In 1985, a number of programmes had access to the agent for experimental transplantation and their data was presented at a symposium during the congress of the Transplantation Society in Helsinki in 1986. The outcome of that meeting was one of disappointment because of an unexpected dose-limiting adverse event of hepatotoxicity and small vessel inflammation in the dog model. Ochiai from Chiba University, Japan, examined efficacy in the rat, and his presentation convinced Starzl to obtain the molecule and study it in Pittsburgh, Pennsylvania. The first problem was not the level of in vitro cytotoxicity, since that could be managed by adjusting doses according to in vivo effect, but the cross-reactivity than came from impure inoculating preparations and from the multiple shared antigens between lymphocytes and other cells. Anaemia, thrombocytopaenia, and broad leucocyte depletion were just some of the problems encountered. Despite these problems it was often the dramatic efficacy in cases of severe rejection that ensured their continued use. Trends in the United States and European transplant programmes took different directions during the 1980s. Through the next 20 years it gradually fell from favour because of the severe adverse event profile and production was discontinued and supplies were exhausted by 2010. But it has also been used as an induction agent for prophylaxis of renal allograft rejection (Morgan et al. Produced by Genzyme which has recently been taken over by Sanofi-Aventis, alemtuzumab has now found a new indication in treatment of multiple sclerosis and the company has lost enthusiasm for its use in renal transplantation. Leaning on the haematology sector, renal transplant programmes have explored several other agents with haematological indications. The proteasome inhibitor bortezomib, and anti-terminal component complement inhibitor eculizumab, have also found favour amongst transplant programmes exploring methods of preventing graft loss from antibody-mediated rejection. Marketed as Myfortic, it provided competition for CellCept, until the expiry of the patent and advent of generic competition in most countries by 2012. Rapamycin Rapamycin was first identified by Suren Sehgal, an employee of the pharmaceutical company Ayerst, later Wyeth, and tested by Randall Morris in Stanford, California, and by Sir Roy Calne in Cambridge. It was found in soil samples from the beautiful Easter Island-Rapa Nui-the long-eared statues of which provided a symbol for many a lecture on the agent. Now named sirolimus, the active molecule was produced by Streptomyces hygroscopicus and was first identified as having not only antifungal properties but also antitumour and immunosuppressive actions (Sehgal, 2003). Wyeth brought the drug to market as Rapamune, and Novartis followed with a similar drug, everolimus. The two drugs, or their analogues, were developed directly as cancer chemotherapeutic drugs and have indications in renal cell carcinoma and tuberous sclerosis. It may find a role in patients with cancers or a high risk of developing cancer after transplantation (Campistol et al. Therapeutic antibodies the first clinical use of immunosuppressive antibodies in transplantation was in the 1960s as the role of the lymphocyte, in particular T lymphocytes, was understood. Injection of the target cells into a horse, goat, or rabbit led to production of anti-human lymphocyte serum which could then be injected into a patient depleting the target cells. Initially in competition with daclizumab made by Hoffman La Roche, basiliximab is widely used for induction. Used on days 0 and 4 after renal transplantation it reduces acute rejection rates and in meta-analyses improves graft survival rates. It is one of the few agents which have yet to have any adverse events described either in clinical trials or in extensive clinical practice (Webster et al. Organ preservation Development of sophisticated histocompatibility testing in the 1960s created a major problem for its implementation for cadaveric organ transplantation, in that a suitable method for organ preservation was required to provide the time for typing, recipient selection, and transport of the preserved organ to distant locations. Folkert Belzer had developed an effective preservation system for kidneys using a bulky perfusion machine in which the kidney was kept cool and constantly perfused with cryoprecipitated plasma (Belzer et al. This method was effective but too cumbersome to be helpful in achieving the above objective. To answer this challenge, the Waters company produced a portable version of the Belzer machine that could be used to transport kidneys, but it required an operator to accompany the machine, limiting its applicability. Geoff Collins was asked by Paul Terasaki to develop a simple cold storage technique for kidney preservation. So after establishing the lack of efficacy of extracellular compositions, Collins tried an intracellular solution. Working with a medical student, he formulated an intracellular solution, and added glucose as an additional osmotic agent to control cell swelling. He first tested this solution for 24-hour ice storage using dog kidneys and was amazed by the results. It turned out that there was an error in the magnesium concentration as a result of confusion between mM and mEq, and it was originally set at double the actual intracellular content accounting for reports of magnesium phosphate crystals in kidneys flushed with Collins solution. Improving an organ damaged by ischaemia and the cytokine storm unleashed by brain death may soon open dramatic new opportunities for organ donation. Failed drugs and the future transplant pipelines A large number of drugs have been tested for their role in transplantation. The pharmaceutical industry noted the transformation of Sandoz from a small to a large company based on the success of ciclosporin and sought to imitate their success. The early phase of this research in the 1980s and 1990s was the search for a non-nephrotoxic calcineurin inhibitor, a quest that remains active. A Canadian biotech company is today developing what they hope will replace tacrolimus. Greater understanding of the scientific basis of allograft rejection led to discovery pipelines of drugs with different mechanisms of action. The failures in those pipelines were many, dispiriting, and expensive, though not all were consigned to the filing cabinet and waste bin. The most recent drug to be brought to market with a transplantation indication is illustrative of the problem now faced by pharmaceutical companies. Belatacept is one of the drugs that emanated from knowledge of immunological mechanisms rather than a discovery programme designed to identify naturally occurring immunosuppressants (Vincenti et al. The drug is a designer molecule that targets co-stimulation receptors to block lymphocyte activation. Belatacept had an expensive development phase which lasted for at least 9 years before approvals were achieved. Marketed by Bristol Myer Squibb it has faced the reality that the price that could be sustained in the United States dropped markedly with the advent of generic standard of care drugs, despite the several advantages that a once-a-month injectable agent could bring, not least that it allowed minimization of calcineurin inhibitors and so better renal function. The sad reality is that today none of the major pharmaceutical companies have research and development groups orientated towards transplantation and there are essentially no active pipelines for investigation of new drugs in transplantation. Perhaps it will be in repackaging the more effective immunosuppressants registered for treatment of autoimmunity. A significant advance on plasmapheresis for removal of antibody was developed in Lund in Sweden, where specific immunoadsorption columns were placed into a dialysis circuit and depending upon the glycoprotein in the column, blood group antibodies were removed with greater efficiency than could be achieved by plasmapheresis. The other advantage of the columns was the lack of removal of other blood proteins such as clotting factors, making them safer to use in the context of the transplant operation. The Japanese experience, spearheaded by Tanabe in Tokyo, was successful in large numbers of patients (Tanabe et al. The critical elements of success were accurate measurement of the titre of anti-blood group antibody in the recipient and ensuring a low titre at the time of transplantation. It appears not to matter if the titre rises after the transplant has been in situ for a few weeks, implying some form of accommodation to the presence of antibody. Kidney donation the original studies of kidney transplants explored all three potential sources of viable kidneys-the living donor, the deceased donor, and an animal donor. These three sources remain viable options while a fourth-construction of a kidney through directed differentiation of stem cells-remains a source of grant funding but is not yet on the immediate horizon. Xenotransplantation, experimented on in man from the early 1900s to today, remains mired in two problems: full understanding and suppression of xenograft rejection, especially related to the presence of natural cytotoxic antibodies in man against all species except the higher order primates; and prevention of cross-infection from the selected animal species to man (McKenzie et al. The two sources of kidneys for clinical transplantation thus remain the deceased and living donor (see Chapter 277). There have been significant advances in the ability of communities to provide for the care of people with end-stage kidney failure such that the rate of transplantation has been unable to meet the needs of the population in almost all countries in the world. The mismatch between donor rate and recipients on waiting lists is often the introduction to many a lecture and grant proposal. Spain has led the way to maximizing the potential for donation from deceased donors, followed now by countries as diverse as Croatia, Portugal, Italy, Austria, United States, United Kingdom, and Australia where the lessons of Spain have been applied (Matesanz et al. The technical advances that have opened up the possibilities for related donors are several. Secondly, the procedure has advanced through development of the better accepted laparoscopic technique for donor nephrectomy (Ratner et al. The capacity of paired exchange programmes to avoid expensive and hazardous desensitization protocols has proved attractive to patients and transplant programmes and is now widely applied. The alternative explored in the United Kingdom in the 1980s and then implemented in the United States as more powerful immunosuppression became available, was to remove antibody by plasmapheresis and prevent recurrence through immunosuppression (Taube et al. The first universal prophylactic drug to be used from the late 1980s was also derived from the work of Hitchings and Elion-co-trimoxazole or combined sulphamethoxazole and trimethoprim. Reactivations and de novo infections in previously infected recipients, typically manifested at about 3 months after transplantation and caused less severe but still troubling disease. An intravenous drug treatment became available in the mid 1980s, ganciclovir, and a well absorbed oral version of aciclovir became a practical but still not very effective prophylactic alternative. All such strategies were resolved with the introduction of valganciclovir which provided the efficacy of ganciclovir and the bioavailability of the intravenous preparation (Kotton et al.

Melatonin seems to be important in controlling sleep cycles and plays a key role in bringing about the onset of sleep bile gastritis diet protonix 40 mg on-line. The potent sedative-hypnotic properties of these drugs have been recognized for some time diet chart for gastritis patient cheap protonix 40mg on line, and their status as the premier medication used to promote sleep went unchallenged for many years gastritis honey purchase protonix with amex. However gastritis diet ������ order protonix 20 mg without prescription, barbiturates are associated with a relatively small therapeutic index; approximately 10 times the therapeutic dose can often be fatal gastritis symptoms fatigue protonix 20mg for sale. These drugs are also very addictive gastritis during pregnancy protonix 40mg, and their prolonged use often leads to drug abuse. Consequently, the lack of safety of the barbiturates and their strong potential for addiction and abuse necessitated the development of alternative nonbarbiturate drugs such as the benzodiazepines. Still, some barbiturates are occasionally used for their hypnotic properties; these drugs are listed in Table 6-1. Despite their extensive use in the past, the exact mechanism of the barbiturates remains somewhat unclear. This drug may also have a lower risk of side effects, including a reduced incidence of next day "hangover" symptoms and less tolerance and physical dependence during long-term use. Other Nonbenzodiazepines Practitioners can prescribe several other nonbenzodiazepine compounds for their sedative-hypnotic properties. Cyclic ethers and alcohols (including ethanol) can be included in this category, but their use specifically as sedative-hypnotics is fairly limited at present. The recreational use of ethanol in alcoholic beverages is an important topic in terms of abuse and long-term effects. However, since this area is much too extensive to be addressed here, only their sedative-hypnotic effect is considered. Lastly, practitioners can prescribe many other sedation-causing drugs to facilitate sleep in specific situations. For example, certain antihistamines (see Chapter 26) can cause profound sedation, and these drugs are often used in over-the-counter products that are promoted as "sleep aids. Sedation, however, is usually a side effect of these other medications, and these drugs are not typically advocated for treating classic insomnia or chronic sleep problems. Pharmacokinetics Benzodiazepine and nonbenzodiazepine sedativehypnotics are usually highly lipid soluble (Table 6-2). Sedativehypnotics are metabolized primarily by the oxidative enzymes of the drug-metabolizing system in liver cells. However, when the drugs slowly leak out of their peripheral storage sites, they can be redistributed to the brain and can cause low levels of sedation. This occurrence may help explain the "hangover" frequently reported the day after taking sedative-hypnotic drugs. Finally, excretion of these drugs occurs through the kidney after their metabolism in the liver. As with most drug biotransformations, metabolism of sedative-hypnotics is essential in creating a polar metabolite that is readily excreted by the kidney. Problems and Adverse Effects of Sedative-Hypnotics Residual Effects the primary problem associated with sedativehypnotic use is the residual effects that can occur the day after administration. Residual effects can result in serious or catastrophic problems when the patient must react quickly the next morning while driving a car, avoiding a fall, or performing other activities that require rapid motor responses. Although usually a minor problem, this can become serious if the drug-induced amnesia exacerbates an already existing memory problem, as might occur in some elderly patients. The residual problems can be resolved somewhat by taking a smaller dose or by using a drug with a shorter half-life (see Table 6-2). Nonetheless, residual effects may continue to be a problem even with these milder nonbenzodiazepine drugs, and patients should still be careful about driving and performing other activities that require quick responses until the effects of these drugs have worn off. Tolerance and Physical Dependence Another potential problem with long-term sedativehypnotic drug use is that prolonged administration may cause tolerance and physical dependence. Although these problems were originally thought to be limited to barbiturates, benzodiazepines and other sedative-hypnotics are now recognized as also causing tolerance and dependence when taken continually for several weeks. These complex behaviors seem to be most prevalent with some of the nonbenzodiazepine drugs, especially zolpidem (Ambien). Hence, patients taking these drugs should be monitored as closely as possible to ensure that they do not engage in such behaviors, and evidence of any strange activities should be brought to the attention of the physician immediately. Anxiety disorders can also be classified in several clinical categories, including generalized anxiety disorder, social anxiety disorder, panic disorder, obsessive-compulsive disorder, and posttraumatic stress syndrome. Many drugs-including sedative-hypnotics-have the ability to decrease anxiety levels, but this is usually at the expense of an increase in sedation. Frequently, alleviating anxiety without producing excessive sedation is desirable so that the individual can function at home, on the job, and so on. Consequently, certain drugs are available that have significant anxiolytic properties at doses that produce minimal sedation. We discuss benzodiazepine drugs and other nonbenzodiazepine strategies for dealing with anxiety below. Benzodiazepines As discussed previously, because of their relative safety, the benzodiazepines are often the primary drugs used to treat many forms of anxiety. The extensive use of this drug in treating nervousness and apprehension has made the trade name of this compound virtually synonymous with a decrease in tension and anxiety. Cardiovascular and respiratory depression may also occur, but these problems are dose-related and are usually not significant, except in cases of overdose. The antianxiety properties of benzodiazepines involve a mechanism similar or identical to their sedative-hypnotic effects. Chapter 13 provides further discussion on the use of these drugs as skeletal muscle relaxants. Buspirone Buspirone (BuSpar) is an antianxiety agent (approved in 1986) used to treat general anxiety disorder. Buspirone may also be helpful in treating depression, in reducing the side effects of Parkinson treatment, and in helping decrease behavioral problems related to attention deficit disorder, dementia, and traumatic brain injury. Use of Antidepressants in Anxiety Many patients with anxiety also have symptoms of depression. Hence, patients with a combination of anxiety and depression often take a traditional antianxiety agent such as a benzodiazepine along with an antidepressant, especially if anxiety is resistant to treatment with only one agent. Although it is not clear exactly how these effects on serotonin and norepinephrine can help resolve anxiety disorders, there is ample evidence that these drugs are effective in many patients. Although benzodiazepines may take effect more quickly and are still often used to treat acute symptoms of anxiety, antidepressants tend to have fewer side effects and a lower risk of physical dependence and addiction. Future clinical research will continue to clarify how antidepressants can be used alone or in combination with other antianxiety drugs when managing the symptoms of specific anxiety disorders. Drugs such as meprobamate (Miltown) and barbiturates are not currently used to any great extent because they do not meet any of these criteria and are no more effective in reducing anxiety than benzodiazepines. Buspirone and certain antidepressants currently offer an effective and somewhat safer method of treating anxiety. Another option includes the beta-adrenergic antagonists (beta blockers, see Chapter 20), because these drugs can decrease situational anxiety without producing sedation. Beta blockers probably exert their antianxiety effects through their ability to decrease activity in the sympathetic nervous system-that is, through their sympatholytic effects. In any event, beta blockers may offer a suitable alternative to decrease the effects of nervousness without a concomitant decrease in levels of alertness or motivation. These drugs work in different ways to reduce excitation levels in the brain and may be helpful in patients who have not responded to more traditional antianxiety drugs. Problems and Adverse Effects of Anxiolytics Most of the problems that occur with benzodiazepine anxiolytic drugs are similar to those mentioned regarding the use of these agents as sedative-hypnotics. Sedation is still the most common side effect of anxiolytic benzodiazepines, even though this effect is not as pronounced as with their sedative-hypnotic counterparts. Antidepressants such as paroxetine and venlafaxine also produce several side effects (described in Chapter 7), depending on the specific agent. Nonetheless, these nonbenzodiazepine anxiolytics tend to produce less sedation, and their potential for addiction is lower compared to benzodiazepines. Consequently, nonbenzodiazepine drugs might be an attractive alternative, especially in patients who are prone to sedation. Special Concerns for Rehabilitation Patients Although sedative-hypnotic and antianxiety drugs are not used to directly influence the rehabilitation of musculoskeletal or other somatic disorders, the prevalence of their use in patient populations is high. Any time a patient is injured or hospitalized for treatment of a disorder, a substantial amount of apprehension and concern exists. The administration of sedative-hypnotic and antianxiety drugs has several direct implications for the rehabilitation session. Of course, this rationale will backfire if the drug produces significant hypnotic effects. Therapy sessions that require the patient to actively participate in activities such as gait training or therapeutic exercise will be essentially useless and even hazardous if the patient is extremely drowsy. Benzodiazepines and other drugs used to treat sleep disorders and anxiety are often associated with falls and subsequent trauma, including hip fractures, especially in older adults. Therapists can identify such people and intervene to help prevent this through balance training, environmental modifications. Finally, therapists can help plan and implement nonpharmacological interventions to help decrease anxiety and improve sleep. Interventions such as regular exercise, massage, relaxation techniques, yoga, and other complementary therapies may be very helpful in reducing stress levels, decreasing anxiety, and promoting normal sleep. He was admitted to an acute care facility, where a diagnosis of complete paraplegia was made at the T-12 spinal level. At the end of 1 month, he was transferred to a rehabilitation facility to begin an intensive program of physical therapy and occupational therapy. Flurazepam (Dalmane) was prescribed at a dosage of 30 mg administered orally each night at bedtime. These symptoms were present to a much greater extent than the normal slow start that occurs in some patients on wakening in the morning. Ramelteon in the treatment of chronic insomnia: systematic review and meta-analysis. Melatonergic drugs for therapeutic use in insomnia and sleep disturbances of mood disorders. As would be expected, many patients seen in a rehabilitation setting are taking these drugs. Benzodiazepines such as flurazepam and triazolam are commonly used to promote sleep because of their sedative-hypnotic effects. Although benzodiazepines are generally safer than their forerunners, they are not without their problems. Nonbenzodiazepine sedative-hypnotics such as zolpidem, zaleplon, eszopiclone, and ramelteon may also be effective in treating sleep disorders, and these agents may be somewhat safer than their benzodiazepine counterparts. Benzodiazepines such as diazepam (Valium) are also used frequently to reduce anxiety, but the introduction of newer drugs such as buspirone and specific antidepressants (paroxetine, venlafaxine) have provided an effective and somewhat safer alternative for treating anxiety. Because of the potential for physical and psychological dependence, sedative-hypnotic and antianxiety drugs should not be used indefinitely. These drugs should be prescribed judiciously as an adjunct to helping patients deal with the source of their problems. Sleep America: managing the crisis of adult chronic insomnia and associated conditions. Psychiatric disorders in patients with immune-mediated inflammatory diseases: prevalence, association with disease activity, and overall patient well-being. What is the role of sedating antidepressants, antipsychotics, and anticonvulsants in the management of insomnia Treatment options for insomnia-pharmacodynamics of zolpidem extended-release to benefit next-day performance. Zopiclone as positive control in studies examining the residual effects of hypnotic drugs on driving ability. Cognitive-behavioral therapy for the management of insomnia comorbid with mental disorders. Sleep in hospitalized medical patients, part 2: behavioral and pharmacological management of sleep disturbances. Zolpidem-induced sleepwalking, sleep related eating disorder, and sleep-driving: fluorine18-flourodeoxyglucose positron emission tomography analysis, and a literature review of other unexpected clinical effects of zolpidem. The anxiety spectrum and the reflex physiology of defense: from circumscribed fear to broad distress. The discovery of chlordiazepoxide and the clinical introduction of benzodiazepines: half a century of anxiolytic drugs. Propranolol use in the prevention and treatment of posttraumatic stress disorder in military veterans: forgetting therapy revisited. Sleep and cognition on everyday functioning in older adults: implications for nursing practice and research. Medication-related falls in the elderly: causative factors and preventive strategies. Potential impact of benzodiazepine use on the rate of hip fractures in five large European countries and the United States. Feasibility of exercise training for the short-term treatment of generalized anxiety disorder: a randomized controlled trial. Randomized controlled trial on the effects of a combined sleep hygiene education and behavioral approach program on sleep quality in workers with insomnia. Systematic review on the effectiveness of caffeine abstinence on the quality of sleep. Exercise training improves sleep quality in middle-aged and older adults with sleep problems: a systematic review. Because these forms of mental illness are relatively common, many rehabilitation specialists will work with patients who are receiving drug therapy for an affective disorder. Also, serious injury or illness may precipitate an episode of depression in the patient undergoing physical rehabilitation. Consequently, this chapter will discuss the pharmacological management of affective disorders and how antidepressant and antimanic drugs may influence the patient involved in physical therapy and occupational therapy. It is considered to be the most prevalent mental illness in the United States, with approximately 15 to 20 percent of adults experiencing major depression at some point in their lives.

If left untreated chronic gastritis operation order 40mg protonix with amex, the motor problems associated with this illness eventually lead to total incapacitation gastritis diet ��������� buy protonix 40mg otc. Parkinson disease is also associated with a wide variety of nonmotor symptoms such as depression chronic gastritis mayo best 40mg protonix, cognitive impairment curing gastritis with diet buy discount protonix 20 mg on line, memory loss gastritis kako se leci order protonix 40mg overnight delivery, sleep disorders gastritis diet 600 buy protonix 40 mg cheap, impulsiveness, fatigue, and chronic pain. Fortunately, the pharmacological management of Parkinson disease has evolved to where the symptoms associated with this disorder can be greatly diminished in many patients. The use of levodopa (l-dopa) alone or in combination with other drugs can improve motor function and general mobility well into the advanced stages of this disease. Drugs used in treating Parkinson disease do not cure this condition, and motor function often tends to slowly deteriorate regardless of when drug therapy is initiated. Antiparkinson drugs help improve motor function so that the patient can be actively involved in cardiovascular conditioning, balance training, fine motor tasks, and various other rehabilitation interventions. What follows is a brief discussion of the neurochemical changes and possible causative factors in Parkinson disease. The positive and negative aspects of specific drugs are then addressed, with the final part of this chapter lending some insight into future pharmacological and nonpharmacological treatments for Parkinson disease. One such nucleus, the substantia nigra, contains the cell bodies of neurons that project to other areas such as the putamen and caudate nucleus (known collectively as the corpus striatum). The primary neurochemical change in Parkinson disease is the degeneration of dopamine-producing cells in the substantia nigra, resulting in the eventual loss of dopaminergic input into the corpus striatum. The loss of dopamine influence is believed to then cause changes in neuronal activity within the basal ganglia, which causes changes in neuronal pathways that project from the basal ganglia to the thalamus and cortex. The references at the end of this chapter provide several sources for more detailed descriptions of the neurochemical basis for Parkinson disease. Dopamine released from these neurons binds to the dopamine type 1 (D1) receptor in the corpus striatum. These D1 receptors are excitatory, and they activate a direct pathway that inhibits other basal ganglia structures such as the globus pallidus interna and the substantia nigra pars reticulata. Outflow from these other structures would inhibit the ventroanterior and ventrolateral nuclei in the thalamus, which would result in less excitation of the cerebral cortex. Excitatory pathways are indicated by "+"; inhibitory pathways are indicated by "-". Increased activity in this indirect pathway increases inhibitory outflow from the globus pallidus interna and the substantia nigra pars reticulata, which inhibits the thalamus and reduces cortical excitation. But in Parkinson disease, decreased dopamine influence on striatal D1 and D2 receptors results in decreased activity in the direct and indirect pathways, respectively. Likewise, dopamine can no longer activate the D2 receptors that normally inhibit the indirect pathway, thereby allowing this pathway to excite the globus pallidus interna and the substantia nigra pars reticulata. The loss of dopamine influence in the corpus striatum results in a complex series of changes in other neuronal pathways that ultimately affect higher (cortical) brain function. The fact that several other neuronal pathways are involved in Parkinson disease suggests that neurotransmitters other than dopamine may also be affected by this disease. This idea is certainly true for neurotransmitters such as acetylcholine, because interneurons within the corpus striatum release acetylcholine that helps moderate the activity of the neuronal pathways described above. An imbalance between striatal dopamine and acetylcholine may therefore be responsible for some of the symptoms in Parkinson disease. Alterations in the release of, or receptor responses to , these amino acids have been implicated in the neurochemical changes seen in Parkinson disease. Drugs that help normalize dopamine activity in the basal ganglia will hopefully resolve the initial problem, thus allowing other neurochemical disruptions to return to normal levels. Likewise, some anti-Parkinson drugs may also directly affect acetylcholine or other neurotransmitters, thus helping to maintain the balance between dopamine and other neurotransmitters in motor pathways. Drugs that affect dopamine activity and the activity of other neurotransmitters are discussed later in this chapter. However, recent evidence suggests that genetic factors may interact with environmental factors to make certain individuals susceptible to the destruction of dopaminergic neurons in the substantia nigra. In this process, the free radical damages the cellular component, subsequently damaging the cell. Free radicals, for example, might initiate or accelerate the abnormal accumulation and aggregation of alpha-synuclein and other proteins within the neuron. Production of these free radicals appears to be increased in people with Parkinson disease, either in response to protein accumulation or because of a primary defect in the synthesis of free radicals by the mitochondria or by other enzymatic reactions within the cell. Environmental Factors the idea that environmental factors may play a role in Parkinson disease was discovered in an interesting way. In 1982, several young adults in their 20s and 30s developed permanent, severe parkinsonism. Upon close investigation, all of these individuals were found to have experimented with synthetic opioid-like drugs. These so-called designer drugs were manufactured by drug dealers in an attempt to create an illicit supply of narcotics for heroin addicts. The idea that toxins and free radicals may cause neuronal damage in Parkinson disease has also led to research in ways to delay or prevent the destructive effects of these chemicals. Such medications are often referred to as antioxidants because they may help control oxidative stress caused by the free radicals. This idea has encouraged the development and use of agents that might delay the neurodegenerative changes seen in Parkinson disease. Nonetheless, future research may continue to clarify the exact reason for the degeneration of substantia nigra neurons, and drugs that help prevent this degeneration could conceivably be developed to decrease or even eliminate the neuronal death that underlies the disease. Levodopa Levodopa has been the cornerstone of anti-Parkinson drugs for over 40 years. Administration of levodopa often dramatically improves all symptoms of parkinsonism, especially bradykinesia and rigidity. The decrease in symptoms and increase in function are remarkable in patients who respond well to the drug. As with any medication, there is a portion of the population who-for unknown reasons-do not respond well or simply cannot tolerate the drug. Also, prolonged use of levodopa is associated with some rather troublesome and frustrating side effects (see "Problems and Adverse Effects of Levodopa Therapy"). However, the use of levodopa has been the most significant advancement in the management of Parkinson disease, and it remains the most effective drug in the treatment of most patients with this disorder. Special Comments Still the best drug for resolving parkinsonian symptoms; long-term use limited by side effects and decreased efficacy. May produce fewer side effects (dyskinesias, fluctuations in response) than levodopa; early use may also delay the progression of Parkinson disease. Inhibits the enzyme that breaks down dopamine in the basal ganglia; enables dopamine to remain active for longer periods of time. Help prevent breakdown of dopamine in peripheral tissues; allows more levodopa to reach the brain. May be used alone during early/mild stages or added to drug regimen when levodopa loses effectiveness. May improve symptoms, especially in early stages of Parkinson disease; long-term use may be neuroprotective and delay disease progression. Useful as an adjunct to levodopa/carbidopa administration; may improve and prolong effects of levodopa. Dopa, or more specifically levodopa (the l-isomer of dopa), can cross the brain capillary endothelium through an active transport process that is specific for this molecule and other large amino acids. Dosages of levodopa are also minimized by administering it with a companion drug that inhibits premature levodopa breakdown. Levodopa dosages are progressively increased until a noticeable reduction in symptoms occurs or until side effects begin to be a problem. This enzyme is distributed extensively throughout the body and can be found in locations such as the liver, intestinal mucosa, kidneys, and skeletal muscle. Conversion of levodopa to dopamine in the periphery is rather extensive-less than 1 percent of the levodopa that is administered reaches the brain in that form. Any levodopa that is converted prematurely to dopamine in the periphery must remain there, becoming essentially useless in alleviating parkinsonism symptoms. The use of carbidopa dramatically decreases the amount of levodopa needed to achieve a desired effect. This ratio achieves a rapid and effective inhibition of the dopa decarboxylase enzyme. A 10:100- or 25:250-mg preparation of carbidopa to levodopa is usually started as the Parkinson symptoms become more pronounced and there is a need for larger relative amounts of levodopa. Average maintenance dosages of levodopa range between 600 and 700 mg/d, and the maximum dosage is often 800 mg/d; however, these dosages are highly variable from patient to patient. Problems and Adverse Effects of Levodopa Therapy Gastrointestinal Problems Levodopa is often associated with nausea and vomiting. These symptoms can be quite severe, especially during the first few days of drug use. However, the incidence of this problem is greatly reduced if levodopa is given in conjunction with a peripheral decarboxylase inhibitor such as carbidopa. The reduction in nausea and vomiting when levodopa peripheral decarboxylation to dopamine is inhibited suggests that these symptoms may be caused by excessive levels of peripherally circulating dopamine. Cardiovascular Problems Some problems with cardiac arrhythmias may arise in a patient taking levodopa. However, these problems are usually fairly minor unless the patient has a history of cardiac irregularity. Caution should be used in cardiac patients undergoing levodopa therapy, especially during exercise. Without carbidopa, most of the levodopa is converted to dopamine in the periphery, rendering it unable to cross the blood-brain barrier. Carbidopa inhibits the peripheral decarboxylase (D-Case) enzyme so that levodopa can cross the blood-brain barrier intact. Again, this side effect is usually diminished when peripheral decarboxylation is inhibited and peripheral dopamine levels are not allowed to increase excessively. Still, patients undergoing physical therapy or similar regimens should be carefully observed during changes in posture and should be instructed to avoid sudden postural adjustments. This factor is especially true in patients beginning or resuming levodopa therapy. Dyskinesias A more persistent and challenging problem is the appearance of various movement disorders in patients taking levodopa for prolonged periods. Approximately 80 percent of patients receiving chronic levodopa therapy begin to exhibit various dyskinesias such as choreoathetoid movements, ballismus, dystonia, myoclonus, and various tics and tremors. The onset of dyskinetic side effects is particularly frustrating since levodopa ameliorates one form of the movement disorder only to institute a different motor problem. The onset of dyskinesias usually occurs after the patient has been receiving levodopa therapy for periods ranging from 3 months to several years. In some patients, these abnormal movements may simply be caused by drug-induced overstimulation of dopaminergic pathways in the basal ganglia, and a decrease in the daily dosage should help. Because levodopa has a short half-life and erratic absorption, the drug may also cause dyskinesias due to its intermittent or pulsatile stimulation of dopamine receptors. For example, certain patients may exhibit dyskinesias when plasma levodopa levels are rising or falling or even when plasma levels are at a minimum. Dyskinesias may actually be the result of functional and structural adaptations of these neurons caused by periodic fluctuations in dopamine influence supplied from exogenous sources. Likewise, some of the parkinsonism symptoms may appear quite similar to the dyskinetic side effects, making it difficult to judge whether the levodopa dose is too high or too low. The physician, rehabilitation specialist, patient, and other individuals dealing with the patient should make careful observations to determine if adjustments in levodopa therapy are resulting in the desired effect. Behavioral Changes A variety of mental and behavioral side effects have been reported in patients taking levodopa. Psychotic symptoms seem especially prevalent, although depression, anxiety, confusion, impulsiveness, and other changes in behavior have also been noted. This may be caused by greater quantities of levodopa crossing the blood-brain barrier before being converted to dopamine, thus generating higher quantities of dopamine within the brain. This idea seems logical, considering that increased activity in certain dopamine pathways seems to be the underlying cause of psychosis (see Chapter 8). Treatment of these symptoms is often difficult because traditional antipsychotic medications tend to increase the symptoms of Parkinson disease. However, some of the newer "atypical" antipsychotics such as clozapine (Chapter 8) may help decrease psychotic symptoms without causing an increase in parkinsonism. When used continually for 3 to 4 years, the ability of levodopa to relieve parkinsonism symptoms often progressively diminishes to the point where the drug is no longer effective. These two theories have initiated a controversy as to whether levodopa therapy should be started early or late in the course of Parkinson disease (see "Clinical Course of Parkinson Disease: When to Use Specific Drugs"). Regardless of why this occurs, the loss of levodopa efficacy can be a devastating blow to the patient who had previously experienced excellent therapeutic results from this drug. Fluctuations in Response to Levodopa Several distinct fluctuations in the response to levodopa are fairly common in most patients. This condition is usually resolved by adjusting the quantity and timing of levodopa administration. A more bizarre and less understood fluctuation in response is the on-off phenomenon. Here, the effectiveness of levodopa may suddenly and spontaneously decrease, resulting in the abrupt worsening of parkinsonian symptoms (the "off" period). Remission of symptoms may then occur spontaneously or after taking a dose of levodopa (the "on" period). Although the exact reasons for this are unclear, the off periods are directly related to diminishing plasma levels of levodopa.

Currently there are limited data examining changes in these pathways in the critically ill gastritis supplements purchase discount protonix. Those manifesting higher filtration rates were generally postoperative or trauma admissions gastritis patient handout cheap 20 mg protonix, younger gastritis symptoms child purchase protonix 40mg with amex, with lower illness severity scores gastritis diet australia generic protonix 20mg otc, and higher diastolic blood pressures and urine outputs gastritis or anxiety purchase 20 mg protonix with visa. Burn victims will also commonly manifest elevated filtration rates for prolonged periods of time gastritis diet 5 meals order protonix canada, often associated with marked inflammation and protein catabolism (Loirat et al. Subarachnoid haemorrhage represents another neurosurgical cohort where vasopressors and aggressive fluid loading are regularly employed to prevent delayed cerebral ischaemia associated with vasospasm. Although data is currently lacking, similar changes in glomerular filtration and drug elimination are likely. Rectal administration is probably also unreliable but there is limited experience. Both are affected by altered kidney function and its frequently associated disorders. The capillary leak seen in sepsis can increase the extracellular water space by clinically significant amounts (Finn et al. For ascites, effusions, or oedema, additional aminoglycoside must be administered to achieve the target drug level (Etzel et al. Since aminoglycosides do not distribute into fat, an opposite approach must be taken in the obese. But fat is weighed and weight-based dosing including fat will lead to higher than expected levels, and may explain the increased aminoglycosides nephrotoxicity in the obese (Corcoran et al. Alternatively, an unappreciated increase in extracellular water may lead to under-dosing, contributing to the poorer prognosis in those with capillary leak (Schwenk et al. Uraemia and other organ dysfunction may affect tissue binding, manifesting as a change in the volume or distribution (Vd) and unexpected drug effect (enhanced or reduced). This may be a consequence of altered binding to membranes, receptors, or carrier proteins. Displacing substances could include retained solutes in uraemia or liver failure, as well as accumulated drugs that compete for albumin binding sites. However, application in the critically ill is not always straightforward, as these agents do not manifest easily titratable endpoints to guide therapy. Although outcome data is currently scarce concerning the use of such regimens (largely due to the heterogeneity of the populations under study), pharmacokinetic data supports such an approach in achieving optimal drug exposure (Roberts and Lipman, 2009). There is significant potential for suboptimal drug exposure, and treatment failure. Clinicians must be cognizant of such changes in kidney function and constantly adjust dosing regimens where appropriate. This may be secondary to induced enzymatic metabolism by the drug itself or retained solutes. Additionally, one must be aware that the duration of and speed of the loss of kidney function influences this effect (Macias et al. Even a solitary-kidney patient with nephrectomy for malignancy will experience changing metabolism as the body adapts to the anephric state. Absorption Gastrointestinal drug absorption may be altered by oedematous bowel (Sica, 2003), altered bowel perfusion, the use of acid-suppressant agents (antacids, proton pump inhibitors, or histamine blockers), the presence or absence of enteral nutrition, bowel motility, or fistulous losses. The lack of a reliable, rapidly determined measure of filtration or secretion hampers precise dosing recommendations based on kidney function (Steven et al. Adjustment of drug management for kidney replacement therapy We have mentioned the confounders affecting drug handling during changing kidney function. That dynamic situation precludes straightforward and precise guidelines on drug management (Vilay et al. Not only are these patients ill with kidney failure, but other organ systems are also still in dynamic (non-steady-state) conditions. Goals of therapy When a drug therapy has a specific goal that can be assessed clinically, dosing adjustments may be titrated more easily. A peak level must be drawn after the immediate distribution phase, typically an hour after administration. Shown here are post-haemodialysis samples at various times post dialysis, all of which could represent a trough level. This is highly relevant to drug removal since convective therapies are associated with a higher clearance of larger-molecular-weight species compared to diffusive therapies. Furthermore, this difference in size of removed molecules may affect intrinsic metabolism differently because of the selective removal of endogenous inhibitors or inducers of drug metabolism. Clearance through the circuit can never exceed Qb and equals Qb with 100% extraction. Qb depends on the nature of the access to the circulation which is almost always through dual-lumen catheters in central veins. Not all catheters are equal in delivering Qb due to location, vein pathologies, catheter luminal size, or catheter damage during placement. Blood is actively pumped from the vein in veno-venous access and if the vessel and catheter are functioning normally, the blood pump speed is the major controllable factor in Qb. The many variables involved are the reason this discussion has centred on physiology and operational characteristics. A comparison of estimates of glomerular filtration in critically ill patients with augmented renal clearance. Accuracy of short-duration creatinine clearance determinations in predicting 24-hour creatinine clearance in critically ill and injured patients. Variation in the pharmacokinetics of gentamicin and tobramycin in patients with pleural effusions and hypoalbuminemia. Indications, technical considerations, and strategies for renal replacement therapy in the intensive care unit. Drug removal during continuous arteriovenous hemofiltration: theory and clinical observations. Down regulation of hepatic P450 in chronic renal failure: role of uremic mediators. Antimicrobial dosing concepts and recommendations for critically ill adult patients receiving continuous renal replacement therapy or intermittent hemodialysis. The first international consensus conference on continuous renal replacement therapy. Dialysate flow rate or ultrafiltration rate In diffusion the transport driver is the concentration gradient between blood and dialysate. Dialysate can become saturated with solute under conditions of high Qb and low dialysate flow rate (Qd). This is often the case when dialysate needs to be sterile, since sterile dialysate is needed in peritoneal dialysis and some forms of haemodialysis. Enough substitution fluid must be administered to keep fluid balance in the specified range for that patient at that time. This is advantageous because dialysate does not need to be sterile with these membranes. These membranes mandate ultraclean or sterile dialysate to prevent the back transport of noxious agents from dialysate into blood (Golper and Leone, 1989). Bioelectrical impedance analysis predicts outcome in patients with suspected bacteremia. Influence of hemodialysis on gentamicin pharmacokinetics, removal during hemodialysis, and recommended dosing. Augmented renal clearance in the Intensive Care Unit: an illustrative case series. Augmented renal clearance: implications for antibacterial dosing in the critically ill. Increased glomerular filtration rate in patients with major burns and its effect on the pharmacokinetics of tobramycin. Vancomycin pharmacokinetics in acute renal failure; preservation of nonrenal clearance. Evaluation of noninvasive determinant for capillary leakage syndrome in septic shock patients. Administration of tobramycin in the beginning the hemodialysis session: a novel intradialytic dosing regimen. Harris Introduction Academic training programmes should provide both structured resources and a process of continual professional development in order to ensure that a physician can practise their chosen specialty independently and competently. In many countries around the world, nephrology training has evolved from the traditional apprenticeship model to a well-defined formal fellowship. In this way, nephrology training encompasses acquisition of knowledge and skills, broad clinical exposure, literature review, and research experience which collectively equip the trainee with the skills needed to safely manage patients with a comprehensive range of renal disorders. An ideal curriculum should also include epidemiological and population perspectives and be flexible in allowing modifications to add regionally relevant components in different parts of the world. Syllabus to set training targets Several published nephrology curricula are available (Kumar et al. Basic renal sciences: anatomy, growth and development, genetics, and physiology of renal function. Management of end-stage kidney disease with conservative therapy, dialysis, and renal transplantation. Miscellaneous: ethical issues, advocacy, public education, and economics of effective renal care. Goals of training Successful completion of postgraduate training in nephrology should make the trainee competent to provide independent, consultant-level, comprehensive care in nephrology. Perform a complete clinical history and physical examination of a patient presenting with renal disease and/or hypertension (to include digital rectal examination and fundoscopy). Integrate all clinical and investigative findings into a coherent diagnosis, with formulation of a differential diagnosis, management plan, and prognosis. Trainees are provided periodic feedback and are assessed in multiple ways such as direct observation, evaluation by peers, self-assessment, chart documentation review, in-training examination, and board certification examination. The basic guiding principles include a supportive learning environment, a learner-centred approach, and reflective practice. An educational framework is provided by two curricula, a Nephrology Advanced Training Curriculum and Professional Qualities Curriculum, and training is overseen by at least two individual supervisors. Perform a dipstick urinalysis, and fresh urine microscopy to detect cellular elements, crystals, and casts. Perform a percutaneous biopsy, under local anaesthetic, of a native and transplanted kidney. Place a Tenckhoff catheter (or equivalent) for commencing chronic ambulatory peritoneal dialysis [optional]. Interpret native and transplant kidney biopsies and urinary tract and dialysis access imaging [desirable]. Adequate exposure to permit satisfactory acquisition of these clinical skills may not be uniformly available. For example, in Australia, a recent increase in the number of nephrology trainees and reduced working hours has meant that exposure to skills for individual trainees is now substantially less than a decade ago (Amos et al. Competency assessment Traditionally, except for written tests, competency assessment in medical education has been subjective and dependent on individual faculty opinion and experience. This variable approach suffers in its inability to produce uniformly competent physicians (Kohn et al. Competency assessment is a fundamental component of nephrology training and ideally should be objective to ensure uniform training experience (Parker, 2010). Medical knowledge-demonstrated in the biomedical, clinical, epidemiological, and social-behavioural sciences. Practice-based learning and improvement-ability to investigate, appraise, assimilate scientific data, self-evaluate constantly, and engage in life-long learning. Interpersonal and communication skills-ability to effectively exchange information and collaborate with families and other health professionals. Professionalism-commitment to carrying out professional responsibilities and adhering to ethical principles. System-based practice-awareness of larger context of healthcare and effective use of available resources. In 1996, the minimum standards for training in nephrology were published by the European Union of Medical Specialists programme (Lappin et al. The programme outlines a minimum 2 years training in general medicine followed by a structured training of at least 3 years of supervised clinical practice in nephrology, and a final year in either nephrology, general medicine, a related specialty, or research. The nephrology training and learning includes similar components as outlined above involving a thorough understanding of pathophysiology and the physical and psychosocial impacts of various diseases affecting the kidneys, and eventually becoming an expert in the management of these disorders. Providing appraisals with ongoing feedback during the training years is considered an integral part of the curriculum. In 2010, the Joint Royal Colleges of Physicians Training Board of the United Kingdom developed a Specialty Training Curriculum for Renal Medicine and later updated it in August 2012 (Joint Royal Colleges of Physicians Training Board, 2012). The updates incorporated the importance of obesity and transition of care from adolescence to adult renal services. Specialty training in renal medicine in the United Kingdom requires completing 2 years of Core Medical Training followed by 3 years of training in renal medicine leading to a completion of training certificate award. The provision to complete the training with less than full-time training is a unique option available in the United Kingdom without compromising the competencies. The training covers domains including knowledge, skills and performance, safety and quality, communication, partnership, and teamwork. Methods of learning Traditional methods of learning and assessment In general, the overall philosophy of physician training is to empower the trainee to provide competent patient care under supervision, leading eventually to responsibility for independent decision-making. Participation in Journal Clubs or equivalent formats to maintain familiarity with current clinical trial evidence and new advances. Case presentations and discussions with supervisor and clinical department members.

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