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By: Vinay Kumar, MBBS, MD, FRCPath

  • Donald N. Pritzker Professor and Chairman, Department of Pathology, Biologic Sciences Division and Pritzker School of Medicine, The University of Chicago, Chicago, Illinois

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Those who started with diamorphine and subsequently switched to virus hitting us purchase darzitil with visa morphine terminated prematurely owing to antibiotic resistance biology order darzitil american express excessive histamine reactions antibiotics kill candida discount darzitil 625mg otc, all of which occurred during crossover to antibiotics for resistant sinus infection order 625mg darzitil amex morphine. Symptoms included severe pruritus, flushing, swelling, urticaria, severe headaches, nausea, general malaise, hypotension, and tachycardia. Only 44% of the original cohort finished the 6-week study (14 getting diamorphine at the end and three getting morphine). These results suggest that diamorphine produces fewer adverse effects than morphine and may be preferable for high-dose maintenance prescription. However, the study was very small and the subject selection was biased, as were the variables used to determine a successful outcome. The result was contrary to all the well-established pharmacological facts, and the authors did not mention the risks associated with high doses of short-acting opioids. In two separate open, randomized, controlled but unblinded trials, 549 patients were divided into five treatment groups. In the first study there were 375 patients in three groups methadone alone for 12 months (controls); methadone plus inhaled heroin for 12 months; methadone alone for 6 months followed by methadone plus inhaled heroin for 6 months. In the second study there were 174 patients in two similar experimental groups in whom injectable rather than inhaled heroin was used (5). A response to treatment was defined as at least a 40% improvement in physical, mental, or social domains of quality of life, if not accompanied by a substantial (over 20%) increase in the use of another illicit drug, such as cocaine or amphetamines. After 12 months those who took methadone and heroin (smoked or injected) had significantly better outcomes. The incidences of adverse effects (constipation and drowsiness) were similar in all the groups. However, owing to the limitations of the study and the complex nature of drug dependence, the therapeutic outcomes could not be justifiably and solely attributed to the specific drug(s). Organs and Systems Respiratory ``Chasing the dragon,' or inhaling heroin vapor through a straw, is a technique by which heroin users avoid the risks of injection. It can depress the respiratory center, release histamine (which can trigger asthma), result in septic emboli, and increase susceptibility to infectious diseases, such as tuberculosis and pneumonia. In 100 methadone maintenance users, lung function and shortness of breath were evaluated using spirometry and 58 Diamorphine Myelopathy has been reported after intranasal insufflation of diamorphine (15). Impaired lung function and shortness of breath correlated with chronic heroin smoking. There have been 27 reports of non-fatal heroin overdose associated with non-cardiogenic pulmonary edema (7). In a retrospective case-control study there were 23 heroin fatalities and 12 controls with sudden cardiac deaths (8). The authors tried to verify that defects of the alveolar capillary membranes and/or an acute anaphylactic reaction can lead to pulmonary congestion, edema, and hemorrhages. There were defects of the epithelial and endothelial basal laminae of the alveoli in both groups. The findings suggested that heroin-associated lung edema is generally not caused by an anaphylactic reaction. Bilateral pulmonary edema associated with heroin abuse has been reported several times (9). Bronchospasm has been noted following the use of street heroin, perhaps due to contaminants (10). In a retrospective study of the case notes of patients who had been admitted to hospital with acute attacks of asthma, there was a high prevalence of heroin use. However, they did not spend more time receiving mechanical ventilation or being in hospital. These findings suggest that heroin induced some degree of bronchoconstriction and respiratory depression, which worsened the initial presentation of asthma. A 52-year-old man with a history of diamorphine abuse presented with sudden paraplegia a few hours after intranasal insufflation. He had flaccid paralysis of both legs, acute urinary retention, and reduced rectal tone. This case of heroin myelopathy is similar to other reported cases, except that this case occurred with intranasal rather than intravenous use. The authors suggested that hypersensitivity and an immune-mediated attack on the spinal cord was the likely mechanism of injury. Reflex sympathetic dystrophy, in which there is an excessive or abnormal sympathetic nervous system response in a limb, has been associated with rhabdomyolysis secondary to heroin abuse (16). Nervous system Delayed onset oculogyric crisis and generalized dystonia occurred in a 19-year-old man after intranasal heroin use, possibly due to bilateral hypoxic infarction of the pallidum and pallidothalamic tracts (12). There has been one report of mixed transcortical aphasia attributed to heroin (13). A 41-year-old chronic diamorphine user developed an unsteady gait and dysarthria over 2 weeks, followed by severe cerebellar ataxia and moderate dysmetria of the arms and legs. A 37-year-old male heroin smoker developed teacolored urine and pain, swelling, and tenderness in both feet. He had acute renal insufficiency and rhabdomyolysis and was treated with hemodialysis. He also had persistent, burning pain in both feet, with cool, pale, thin skin on both legs, a mild reduction in sensation on the lateral aspects of the lower legs and diminished bilateral knee and ankle reflexes. His feet would swell and redden after a 5-meter walk, suggesting loss of sympathetic regulation. Nerve conduction velocity studies of the tibial, peroneal, and sural nerves were abnormal. Three-phase bone scintigraphy showed diffusely increased radiotracer accumulation over both feet in all three phases, as found in reflex sympathetic dystrophy. A follow-up three-phase bone scintigram showed less radiotracer uptake, consistent with a good response to calcitonin therapy. Substance-induced polyradiculopathy has been described in a 23-year-old Caucasian man after administration of high doses of heroin and cocaine into the left internal carotid artery (17). Four developed a plexopathy and two a symmetric distal axonal sensorimotor neuropathy. Diamorphine 59 Progressive spongiform leukoencephalopathy A rare consequence of inhaling heated heroin (``chasing the dragon') is a progressive spongiform leukoencephalopathy. The presentation includes apathy, bradyphrenia, motor restlessness, and progressive cerebellar ataxia. The three cases showed raised concentrations of intracerebral lactate (reflecting mitochondrial dysfunction), which suggests a conversion of aerobic to anaerobic metabolism seen in hypoxic-ischemic conditions, including stroke. Thus, the authors recommended that although the role of antioxidant therapy in this condition is unclear, it may be prudent to administer oral coenzyme Q supplemented with vitamins C and E to patients with this syndrome. Spongiform leukoencephalopathy has been described in a 26-year-old after inhalation of heroin (20). Toxicology was negative, but was done some time after the report of substance use. Although the findings suggested the possibility of heroin toxicity due to inhalation, sparing of the cerebellum and brain stem, frontal predominance of degeneration, and the more prominent axonal involvement are not typical of heroin toxicity, throwing speculation on an unidentified impurity. Four patients developed acute toxic spongiform leukoencephalopathy after inhaling heroin vapor (23,24). Intravenous administration of pure heroin did not cause a leukoencephalopathy in a patient in whom inhalation had caused it (25), and toxicity in these cases may have been due to the heating of the heroin. A 46-year-old man with a 26-year history of heroin abuse developed a slowly progressive gait disorder with paresthesia in the legs after he had bought heroin from a different illicit heroin dealer (21). Prolonged multivitamin supplementation and subsequent high-dose prednisone for 10 days did not improve the symptoms. A 23-year-old pregnant woman at 39 weeks of gestation developed tonic-clonic seizures and hypothermia after taking excessive heroin intravenously (26). She developed Cheyne-Stokes respiration needing intubation and a cesarean section was performed, after which she developed inappropriate secretion of antidiuretic hormone and acute renal insufficiency. Other cases of possible toxic leukoencephalopathy following probable inhalation of heroin vapor have been reported (22). A 55-year-old man developed confusion, behavioral change, aggression, poor attention, disorientation in time, and impaired short term memory. He had full ocular movements with no nystagmus, brisk deep tendon reflexes, and bilateral extensor plantar responses.

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Penicillamine withdrawn and the breast enlargement regressed over 3 months; the bra cup size reverted to antibiotic used for kidney infection discount generic darzitil uk B virus 68 in michigan buy 625 mg darzitil amex. After she started to antibiotic resistance ncbi discount darzitil on line use an oral contraceptive dead infection purchase 625mg darzitil with visa, her breasts enlarged rapidly and she experienced cyclic mastodynia; in addition, gingival hyperplasia developed. All symptoms improved on withdrawal of penicillamine, but additional mammoplasty was needed. In one case breast enlargement was accompanied by systemic lupus erythematosus (363). A 37-year-old woman with a 7-year history of rheumatoid arthritis had taken penicillamine for about 1­2 years (dose not specified). When she presented at the Cambridge Breast Unit she had had rapidly increasing painful enlargement of the breasts for 7 months. There were several palpable masses; mammography showed no evidence of malignancy and an ultrasound scan showed large hypo-echoic nodules with engorged vessels. Immunologic Several experimental studies in humoral and cellmediated immune systems have demonstrated numerous effects of penicillamine on the immune system; these findings are in keeping with a reduction in the overactivity of helper T lymphocyte that is found in rheumatoid arthritis (2,364). There is a fall in the numbers of immunoglobulin-secreting cells, and cultured mononuclear cells produce less IgA, IgG, and IgM. There is suppression of the autologous mixed lymphocyte reaction (365) and reduced hydroxyl radical generation from polymorphonuclear leukocytes (366). Penicillamine reduces the clearance of immune complexes and inhibits the complement cascade (367). Penicillamine is uniquely likely among therapeutic drugs to cause autoimmune reactions (see Table 3). Clinically and pathologically these variants of autoimmune disorders are closely similar to or indistinguishable from the spontaneous diseases. A major difference is that the patients usually recover when penicillamine is withdrawn. During penicillamine treatment autoantibodies develop in a high proportion of patients without clinical disease (368). For example, penicillamine can be associated with the development of anticentromere antibodies (369,370). Although these are usually a marker of serious autoimmune diseases, in association with penicillamine, the phenomenon was not accompanied by clinical symptoms and disappeared after stopping the drug. In the serum of three patients with acute hypersensitivity reactions to penicillamine, complement-binding antibodies against penicillamine were detected (371). An unusual case report showed that low back pain can be a manifestation of drug hypersensitivity (268). Anaphylaxis Although hypersensitivity reactions are frequent, systemic anaphylaxis has only been reported rarely (373). Effects vary from only biochemical abnormalities, through moderate muscular weakness, to severe polymyositis with myolysis and sometimes myocarditis. There can be dysrhythmias, heart block, and Adams­Stokes attacks (384) and deaths have occurred (106). The clinical, pathological, and electromyographic features are similar to those of idiopathic polymyositis. Antinuclear antibodies are found in about 90% of cases of penicillamine-induced polymyositis, a finding that may be helpful in distinguishing this condition from true polymyositis (379). In one patient anti-Jo-1 antibodies were found, which was thought to be an epiphenomenon and not pathogenic (86). Of interest is the report of a patient with penicillamine-associated polymyositis who had a relapse after administration of ampicillin (380). In penicillamine-induced polymyositis, weakness can be the presenting symptom and it may at first be mistaken for myasthenia (64). The diagnostic pitfalls of penicillamine-induced polymyositis have been reviewed in the light of a report of a patient in whom postural changes were at first mistaken for possible ankylosing spondylitis (387). The findings illustrate that this type of vasculitis is a predominantly drug-induced disorder. The most frequently implicated drug was hydralazine (10 cases); the rest involved propylthiouracil (three cases), penicillamine (two cases), allopurinol (two cases), and sulfasalazine. A 49-year-old woman with systemic sclerosis, taking penicillamine 750 mg/day, developed a vasculitis, with an orbital pseudotumor and, 2 months later, fatal alveolar hemorrhage. These patients had been taking penicillamine for rheumatoid arthritis in daily doses of 100, 200, and 300 mg for 32, 42, and 39 months respectively. All three had proteinuria, hematuria, anemia, and rapidly progressive renal insufficiency. Histological examination showed crescentic glomerulonephritis with granular deposits of IgG, IgM, IgA, C1q, and C3 in the mesangium. Penicillamine was withdrawn and the patients were given steroid pulse therapy, warfarin, and in two cases cyclophosphamide. Renal function gradually improved and the antineutrophil cytoplasmic antibodies disappeared. IgA deficiency IgA deficiency is a rare penicillamine-induced immune disorder, which can be accompanied by recurrent upper respiratory tract infections (75,76,390). IgA deficiency is more likely to develop when there is improved rheumatic disease activity, together with other adverse effects (for example rash, thrombocytopenia, proteinuria). Churg­Strauss syndrome the Churg­Strauss syndrome is a rare disease, with eosinophilia, vasculitis, and granulomas, involving many organ systems (skin, lungs, kidneys, gastrointestinal tract, joints, heart, and central nervous system); rhinitis and asthma are often early manifestations. In one of two patients with the syndrome, penicillamine might have triggered its development (72); however, withdrawing the drug had no effect on the course of the disease and the relation was therefore uncertain. Lupus-like syndrome Serological features of systemic lupus erythematosus develop in about 7% of patients taking penicillamine (184,240,264­266,391). The disorder usually improves in a few weeks or months after stopping penicillamine, but serological tests may remain abnormal for a longer period. Penicillamine rheumatoid arthritis, in particular because of lack of effect and the possibility of inducing a lupus-like syndrome (392). She improved with prednisolone, and penicillamine was continued in a lower dosage. After the withdrawal of penicillamine there was rapid improvement of pemphigus and myasthenia. However, polymyositis was progressive, required high doses of corticosteroids for about 18 months, and improved only slowly. Desensitization the National Taiwan University Hospital has reported successful desensitization with prednisolone in a patient with hypersensitivity to penicillamine (399). In one study, reference was made to a patient Ё with a Henoch­Schonlein-like syndrome as a suspected adverse reaction to penicillamine, but no details were given (396). Multiple autoimmune reactions Penicillamine often elicits multiple adverse reactions in the same patient, illustrating its immunomodulatory actions. In a long-term prospective study of 69 patients taking penicillamine (750 mg/day) for progressive systemic sclerosis, 27 had adverse effects requiring either temporary reduction or complete withdrawal of therapy. He was given penicillamine in an initial dose of 300 mg/ day, which was increased to 600 mg/day in increments of 150 mg over 3 days and subsequently to 900 mg/day. Prednisolone was gradually discontinued over a 4-week interval, and penicillamine was increased to 1. Infection risk In a nested case-control study in Mexican patients with rheumatoid arthritis encompassing 1274 patient years, the risk factors were determined for acquiring infectious diseases (400). In addition to the cumulative doses of methotrexate and the duration of corticosteroids use, the mean daily dose of penicillamine was a risk factor. A 47-year-old woman developed concurrent pemphigus and myasthenia gravis (with ptosis and diplopia), apparently induced by penicillamine (500 mg/day for rheumatoid arthritis; 398). In another patient, pemphigus, polymyositis, myasthenia gravis developed simultaneously (121). A 67-year-old patient with rheumatoid arthritis had taken penicillamine 600 mg/day for 15 months when a skin eruption developed. Although no intercellular substance or basement membrane antibodies were found, a biopsy showed characteristic intraepidermal blistering. Direct immunofluorescence showed anti-IgG and antiC3 antibodies, and desmoglein immunolabelling Table 4 Examples of simultaneous multiple reactions reported with penicillamine Pulmonary alveolitis, pancytopenia, cholestatic hepatitis, stomatitis, proctitis, skin rash, proteinuria, renal insufficiency (60) Cholestatic hepatitis with allergic pneumonitis (199) Pemphigus and nephrosis (minimal change nephropathy) (397) Pemphigus and myasthenia gravis (398) Thyroiditis and myasthenia gravis (135) Polyradiculopathy and nephrosis (78) Aplastic anemia and cholestatic hepatitis (174) Gingival hyperplasia, acne, hirsutism, breast gigantism (270) Agranulocytosis and toxic epidermal necrolysis (179) Є 2010 Elsevier B. This case was found as part of a case-control study of 24 696 mothers of malformed infants. However, cleft lip has not previously been observed in association with maternal use of penicillamine, and there is little reason for suspecting the drug.

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Table 3 Frequency of adverse effects of modified-release naltrexone Adverse event Nausea Headache Fatigue Discontinuation because of adverse events Dose 190 mg 380 mg 190 mg 380 mg 190 mg 380 mg Placebo 190 mg 380 mg Frequency (n) 25% (53) 33% (68) 16% (33) 22% (45) 16% (34) 20% (41) 6 oral antibiotics for dogs hot spots buy discount darzitil 625 mg on line. The status of naltrexone in the treatment of alcohol dependence: specific effects on heavy drinking treatment for glaucoma dogs purchase darzitil 1000 mg without prescription. Balldin J antimicrobial for dogs order darzitil with amex, Berglund M antibiotics not helping uti cheap darzitil 375 mg otc, Borg S, Mansson M, Berndtsen P, Franck J, Gustafsson L, Halidin J, Nilsson L-H, Stolt G, Willender A. A 6-month controlled naltrexone study: combined effect with cognitive behavioural therapy in outpatient treatment of alcohol dependence. Initial and maintenance naltrexone treatment for alcohol dependence using primary care vs speciality care. Kiefer F, Jahn H, Tarnaske T, Helwig H, Briken P, Holzbach R, Kampf P, Stracke R, Baehr M, Naber D, Wiedermons K. Comparing and combining naltrexone and acamprosate in relapse prevention of alcoholism. Dose-ranging kinetics and behavioural pharmacology of naltrexone and acamprosate, both alone and combined, in alcohol-dependent subjects. Naltrexone effects on alcohol consumption in a clinical laboratory paradigm: temporal effects of drining. A pilot evaluation of the safety and tolerability of repeat dose administration of long-acting injectable naltrexone (VivitrexТ) in patients with alcohol dependence. Naltrexone depot for treatment of alcohol dependence: a multi-centre, randomized, placebo-controlled clinical trial. Naltrexone augmentation of neuroleptic treatment in alcohol abusing patients with schizophrenia. Naltrexone, a relapse prevention maintenance treatment of alcohol dependence: a meta-analysis of randomized controlled trials. Naltrexone versus acamprosate: one year follow-up of alcohol dependence treatment. Slattery J, Chick J, Cochrane M, Craig J, Godfrey C, Macpherson K, Parrott S, Quinn S, Tochel C, Watson H. Prevention of relapse in alcohol dependenceGlasgow: Health Technology Board for Scotland;. Guardia J, Caso C, Arias F, Gual A, Sanahuja J, Ramirez M, Mengual I, Gonzalvo B, Segura L, Trujols J, Casas M. A double-blind, placebo-controlled study of naltrexone in the treatment of alcohol-dependence disorder: results from a multicenter clinical trial. Effects on smoking cessation: naltrexone combined with cognitive behavioural treatment based on the community reinforcement approach. Efficacy of naltrexone in smoking cessation: a preliminary study and an examination of sex differences. A systematic review of the effectiveness of naltrexone in the maintenance treatment of opioid and alcohol dependence. Naltrexone therapy of apnea in children with elevated cerebrospinal fluid beta-endorphin. Efficacy and safety of naltrexone use in pediatric patients with autistic disorder. Induction of withdrawal-like symptoms in a small randomized, controlled trial of opioid blockade in frequent tanners. Naltrexone in the treatment of heroin dependence: relationship with depression and risk of overdose. Naltrexone-induced nausea in patients treated for alcohol dependence: clinical predictors and evidence for opioidmediated effects. Florid opioid withdrawal-like reaction precipitated by naltrexone in a patient with chronic cholestasis. Acute opioid withdrawal in the emergency department: inadvertent naltrexone abuse? Naltrexone and disulfiram in patients with alcohol dependence and comorbid psychiatric disorders. Plasma concentrations during naltrexone implant treatment of opiate-dependent patients. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence. Naltrexone implants-duration, tolerability and clinical usefulness: a pilot study. Complications of ultrarapid opioid detoxification with subcutaneous naltrexone pellets. Drug studies Pain relief the postoperative analgesic effects of intravenous ketamine 10 mg and oxycodone 2 mg have been compared in a randomized, double-blind study in 40 tonsillectomized men (1). Oxycodone also caused a significantly lower respiratory rate with lower oxygen saturation throughout the recovery period and increased sedation throughout the study. The effects of modified-release oxycodone in osteoarthritic pain have been evaluated in a placebo-controlled, double-blind trial in 133 patients (2). Oxycodone was effective, and although opioid-related adverse effects were frequent they were considered acceptable by the authors. In a double-blind, randomized, crossover comparison of the efficacy and safety of modified-release oxycodone bd and immediate-release oxycodone qds in 57 patients with intervertebral disc disease or osteoarthritis, eleven patients withdrew: eight with nausea and constipation while taking modified-release oxycodone and three (one with migraine and two with nausea, vomiting, and headaches) while taking immediate-release oxycodone (3). There were no statistically significant differences in the adverse effects profiles between the two formulations. The overall incidence of adverse effects fell over the three phases of the study: from 89% (51/57 patients) during titration to 77% (36/47 patients) in stage 1 and 62% (29/47 patients) in stage 2. The most common adverse effects were constipation, nausea, pruritus, somnolence, and dizziness, the frequency of which fell with time; the incidence of constipation remained constant. In a randomized, double-blind, crossover study, previous findings on the adverse effects of oxycodone among sufferers of postherpetic neuralgia were confirmed (4). Oxycodone was analgesic in this group, although 76% of the sample reported adverse effects compared with 49% of the placebo group. Constipation, nausea, and sedation were the most frequently reported adverse effects. In the first, modified-release and immediate-release oxycodone were compared (5) in a multicenter, double-blind trial in 180 patients who were given either modified-release oxycodone, mean dose 114 mg bd, or immediate-release oxycodone 127 mg qds, four times a day for cancer-related pain. Oxycodone A 5-day comparison showed no significant difference in the analgesic effects of the two formulations, both of which provided effective relief of pain. However, of the 160 patients who received at least one dose of medication, 104 reported a total of 295 adverse events, significantly fewer being reported with modified-release oxycodone (109) than immediate-release oxycodone (186). Reported adverse effects included: nausea (18 versus 26%), vomiting (11 versus 23%), and constipation (9 versus 17%). With immediate-release oxycodone headache was reported by 7% and anxiety by 5%; neither was reported with modified-release oxycodone. Altogether, 7% of the modified-release group and 11% of the immediate-release group discontinued medication because of adverse effects. It is suggested that the equianalgesic effect is likely to be a factor of the rapid initial release of the modified-release formulation, allowing adequate drug concentrations to establish sufficient receptor activation, followed by a slower release of the remaining drug, which may be responsible for the reduction in adverse effects. Alternatively the peaks achieved with each administration of medication may account for the observed difference in the rates of adverse effects between the two formulations. The second study was a randomized, double-blind, crossover comparison of the safety and efficacy of oral modified-release oxycodone with modified-release morphine in 32 patients with cancer pain, nine of whom completed the trial (6). There were no significant differences in the degrees of sedation, nausea, or pain intensity experienced by the subjects on the different regimens and the results suggested that oxycodone may be used as an alternative to morphine. Drug withdrawal A patient with atypical oxycodone withdrawal had restlessness and delusions (11). Susceptibility Factors Genetic A 60-year-old man, who was taking rifampicin, had negative urine drug screens for oxycodone, despite using a combination of immediate- and modified-release oxycodone for chronic pain (12). Each case was evaluated to determine the role of oxycodone and especially the controlledrelease formulation. Of the other cases 96-97% were multiple drug deaths in which there was at least one other contributory drug in addition to oxycodone. The drugs that were most commonly combined with oxycodone were a benzodiazepine (8), alcohol, cocaine, other opioids (9), cannabinoids, or antidepressants. This highlights the increased risk of oxycodone abuse and its contribution to either drug-induced or drug-related deaths. Drug Administration Drug formulations Modified-release oxycodone has been reviewed comprehensively in relation to its pharmacokinetics and pharmacodynamics, impact on health economics, addiction potential, and use in palliative care (13).

As the data from this meta-analysis were subject to antibiotics for acne birth control order darzitil master card many potential biases ear infection 8 month old buy darzitil with visa, the same authors reanalysed their results virus barrier order darzitil online now, taking into account only randomized bacteria mod purchase darzitil toronto, prospective studies (290). The incidence of adverse effects was higher with Sandimmune in open-label studies (840 patients) and higher with Neoral in blinded studies (3006 patients). In accordance with other investigators, these authors concluded that de novo immunosuppression with Neoral is beneficial, without significant differences in the incidence of adverse effects, whereas conversion from Sandimmune to Neoral in previously stable patients is associated with significantly more adverse effects with Neoral. Drug dosage regimens Several authors were unable to find convincing evidence that ciclosporin specifically increases the risk of tumors in transplant patients compared with previously used immunosuppressive regimens, and some even suggested a possibly lower incidence in ciclosporin-treated patients Є 2010 Elsevier B. Ciclosporin 437 whom one died after severe metabolic acidosis and renal insufficiency. Subchronic ciclosporin overdose over 8 days did not appear to cause any additional risk (301). Taken together, the available data suggest that the acute toxicity of ciclosporin is low in adults, but that more severe intoxication could be expected in neonates. However, two reports, including one fatal case, have shown that accidental intoxication sometimes produces severe complications in adults (302,303). Aminoglycoside antibiotics Severe nephrotoxicity has been reported in three renal transplant patients who received ciclosporin and gentamicin, and in others receiving both drugs before surgical procedures, even though toxic serum concentrations of either drug were not reached (308). Angiotensin receptor blockers In an analysis of changes in ciclosporin clearance and systemic availability obtained from the medical records of 100 transplant patients, losartan and valsartan altered ciclosporin pharmacokinetics (305). Antiretroviral drugs Reduced clearance of ciclosporin has been attributed to antiretroviral drugs (310). A 29-year-old man received a double lung transplantation for end-stage cystic fibrosis. After uneventful surgery, he was accidentally given ten times the intended dose of ciclosporin (30 instead of 3 mg/kg) and 18 hours later became anuric. A renal biopsy 7 weeks later showed typical features of acute tubular necrosis and lesions that resembled chronic nephrotoxicity. Renal function was still abnormal when he died from another cause 14 weeks after the accidental overdose. A 51-year-old man underwent double lung transplantation for pulmonary fibrosis, accidentally received an infusion of ciclosporin 30 mg/hour instead of 3 mg/ hour, and 3 hours later had bilateral reactive mydriasis and absence of tendon reflexes. He died 5 hours later from brainstem compression, and pathological examination showed diffuse cerebral edema with neuronal necrosis. The first of these cases suggested that acute renal dysfunction secondary to acute overdose can lead to renal sequelae. In the second patient, an isolated neurotoxic effect of ciclosporin was suggested because no predisposing factor except overdose was identified. Drug­Drug Interactions Acetazolamide the interaction of ciclosporin with acetazolamide was previously supported by a single case report only. In three further patients, the addition of acetazolamide produced a near seven-fold increase in ciclosporin blood concentrations within 3 days (304). Aciclovir In an analysis of changes in ciclosporin clearance and systemic availability obtained from the medical records of 100 transplant patients, aciclovir altered ciclosporin pharmacokinetics (305). The coadministration of ciclosporin with drugs with nephrotoxic effects carries a risk of increased renal dysfunction. Although a possible enhancement of nephrotoxicity has been suggested in patients also taking aciclovir (306), there were no such findings in a retrospective analysis of a double-blind study (307). A 45-year-old man taking lamivudine, tenofovir, enfuvirtide, and amprenavir boosted with ritonavir was stable and underwent orthotopic liver transplantation from a cadaveric donor. The dosage of ciclosporin was 200­350 mg bd with ciclosporin blood concentrations of 200­300 ng/ml. Antiretroviral therapy was restarted and the ciclosporin trough concentration rose to more than 1000 ng/ml. Immunosuppression was started using ciclosporin 250­350 mg bd to maintain blood concentrations at 300­400 ng/ml. The authors concluded that the combination of amprenavir + ritonavir had a greater effect on ciclosporin clearance than fosamprenavir. In a retrospective study of 221 renal transplant patients, five of 10 patients who took both drugs developed acute or chronic proximal myopathy, whereas none of the 30 controls matched for age, sex, transplant duration, ciclosporin use, and cumulative dose of glucocorticoids had similar symptoms (318). Multiorgan failure has been described in cases of colchicine poisoning and in patients after taking usual doses of colchicine during ciclosporin therapy after kidney transplantation. Bisphosphonates In an analysis of changes in ciclosporin clearance and systemic availability obtained from the medical records of 100 transplant patients, alendronic acid altered ciclosporin pharmacokinetics (305). Calcium channel blockers A large amount of data has accumulated on the effects of various calcium channel blockers on ciclosporin metabolism or a possible renal protective effect. Diltiazem, nicardipine, or verapamil inhibit ciclosporin metabolism, and this has been investigated as a potential beneficial combination for ciclosporin-sparing effects, particularly for diltiazem or verapamil (312,313). Any change in the formulation of calcium channel blockers in patients previously stabilized should be undertaken cautiously because unpredictable changes in ciclosporin concentrations can occur (314). Co-administration of calcium channel blockers is also regarded as a valuable option in the treatment of ciclosporin-induced hypertension, or to prevent ciclosporin nephrotoxicity. There are conflicting results from studies on the protective role of calcium channel blockers in patients taking ciclosporin in regard to blood pressure and preservation of renal graft function. In a multicenter, randomized, placebo-controlled study in 131 de novo recipients of cadaveric renal allografts, lacidipine improved graft function from 1 year onwards, but had no effect on acute rejection rate, trough blood ciclosporin concentrations, blood pressure, number of antihypertensive drugs, hospitalization rate, or rate of adverse events (315). A renal transplant recipient developed multiorgan failure after taking appropriate doses of colchicine in combination with ciclosporin (319). An interaction between colchicine and ciclosporin was postulated, but ciclosporin toxicity was excluded because of low ciclosporin blood trough concentrations before and throughout the episode, in the presence of relatively stable renal function. Cytotoxic drugs High-dose chemotherapy with cyclophosphamide, vincristine, prednisolone, and intrathecal methotrexate given for post-transplant lymphoproliferative disease was suggested to have favored the occurrence of acute ciclosporin neurotoxicity (headache, fever, seizures, and visual agnosia) in a 9-year-old cardiac transplant patient (320). Ciclosporin serum concentrations were normal and a further similar episode occurred on ciclosporin readministration. There was a dramatic increase in the systemic availability of paclitaxel when ciclosporin was administered concomitantly (322) and in a phase I study of the pharmacokinetics of twice-daily oral paclitaxel 60­160 mg/m2 in 15 patients in combination with ciclosporin (15 mg/kg) there was a sevenfold increase in the systemic exposure to paclitaxel; the plasma concentration increased from negligible to therapeutic concentrations (323). The inhibitory effect of ciclosporin on the gastrointestinal multidrug transporter P-glycoprotein was suggested to account for these interactions. Digoxin In an analysis of changes in ciclosporin clearance and systemic availability obtained from the medical records of 100 transplant patients, digoxin increased ciclosporin systemic availability (305). Chloramphenicol Chloramphenicol was suspected of causing a dramatic increase in ciclosporin blood concentrations in a single patient (316). However, multiple concomitant confounding factors made this interaction purely speculative. Clindamycin In two lung-transplant patients aged 39 and 48 years, blood ciclosporin concentrations fell after the addition of oral clindamycin (1. Ciclosporin 439 Etoposide Ciclosporin inhibits P glycoprotein and increases the cytotoxicity of some anticancer drugs, including etoposide. In rats, ciclosporin caused higher tissue concentrations of etoposide as a direct consequence of higher plasma concentrations resulting from a reduced clearance of etoposide rather than as a consequence of changes in the tissue distribution of etoposide (326). Fluoroquinolones Although ciprofloxacin was initially thought to increase ciclosporin blood concentrations and enhance ciclosporin nephrotoxicity, no definite evidence to support this interaction has been found (327). A norfloxacin-induced increase in ciclosporin blood concentrations has been reported in children (5,248), while ofloxacin did not appear to alter ciclosporin metabolism (329). Foscarnet Foscarnet (330), but not ganciclovir (331), has also been involved in reversible renal insufficiency after concomitant use with ciclosporin. However, this has been strongly criticized and considered hazardous because of large interindividual variability and the commercial availability of different formulations of grapefruit juice with potentially different effects on ciclosporin pharmacokinetics (332). Histamine H2 receptor antagonists the available data on a possible interaction between histamine H2 receptor antagonists and ciclosporin are inconclusive. Whereas neither cimetidine nor ranitidine significantly altered ciclosporin pharmacokinetics, there was an increase in serum creatinine concentration in patients taking both ciclosporin and cimetidine, but not ranitidine. The clinical significance of this interaction is probably limited, and it has been attributed to competition of cimetidine with creatinine for tubular secretion (333). Among 110 ciclosporin-treated patients with heart transplants, four of 18 patients taking simvastatin 20 mg/day developed rhabdomyolysis, whereas none of the patients taking simvastatin 10 mg/day (26 patients) or pravastatin 20 mg/day (66 patients) had similar symptoms (334). The addition of atorvastatin (10 mg/day) to a multidrug regimen including ciclosporin in a 40-year-old patient with a renal transplant resulted in rhabdomyolysis within 2 months (336). Pharmacokinetic interactions Plasma concentrations of lovastatin- or simvastatin-active metabolites were increased in several patients and in a pharmacokinetic study, suggesting that ciclosporin can inhibit their metabolism (337­339).

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