Medication Blood Levels Research Articles

Evaluating non‐adherence to immunosuppressant medications in pediatric liver transplant recipients

Non-adherence with recommended immunosuppressant medications is common post-pediatric liver transplant and is the most important reason for organ rejection in long-term survivors. However, there is currently no validated, standard method to measure adherence, with a well-defined threshold, making it extremely difficult to evaluate interventions to improve adherence. Previous studies have suggested that the degree of fluctuation of medication blood levels over time can provide an idea about how regularly the medication is being taken. The present study, conducted at UCLA medical center, sought to identify a specific threshold value of the s.d. of individual tacrolimus blood levels in pediatric liver transplant recipients which would be associated with rejection episodes in these patients. A threshold of 3.0 has been identified in other studies, and was supported by the analysis of retrospective data from 96 subjects. However, further analysis found that a s.d. of 2.5 appeared to have a better fit with the data. These findings suggest the utility of monitoring the s.d. of routine tacrolimus blood levels in pediatric liver transplant recipients for detecting non-adherence to immunosuppressant medication prior to clinical rejection, allowing earlier interventions.

Childhood Abuse, Nonadherence, and Medical Outcome in Pediatric Liver Transplant Recipients

The study assessed the relationship between a history of child abuse, nonadherence to medications, and medical outcome in children who had a liver transplant. Abuse history for children and adolescents ages 8 to 21 who underwent a liver transplantation at Mount Sinai Medical Center in New York was obtained in interviews in 2002. Adherence to tacrolimus was assessed from January 1 to December 31, 2003 by computing the SD of a series of medication blood levels for each patient. Biopsy-proven rejection episodes, degree of fluctuation of alanine aminotransferase (ALT), and maximal ALT levels were recorded as indicators of medical outcome. Of 72 eligible patients, 56 were evaluated. Five had documented abuse. Abused children were less adherent to their medication regimen (p = .02; 95% confidence interval [CI] -2.66 to -0.24), had poor disease control (higher maximal ALT, p <.01; 95% CI -613.72 to -249.55), had greater fluctuation in ALT levels (p <.01; 95% CI -151.19 to -65.91), and suffered more biopsy-proven rejection episodes (two episodes in the abused cohort versus none in the rest) in 2003. A history of child abuse is a significant risk factor for poor outcome posttransplantation and should be evaluated routinely. Adherence to medications can be a target for intervention in patients with a history of abuse.

Tabac et schizophrénie : aspects thérapeutiques

Although patients with have low motivations to quit smoking, smoking cessation treatment can be effective for these patients. Patients schizophrenia who achieve significant smoking reduction during a treatment intervention can at least maintain that level of reduction at 2 years. Cigarette smoking by patients with frequently goes unaddressed, contributing to excess mortality in this population. Behavioural interventions improve smoking cessation in schizophrenia patients. Nicotine replacement can substantially reduce withdrawal symptoms. Bupropion enhances smoking abstinence rates. Bupropion is well-tolerated and safe for use in schizophrenia patients: bupropion does not worsen clinical symptoms of schizophrenia. Atypical antipsychotics may reduce smoking consumption in schizophrenia patients, in particular clozapine. Atypical antipsychotic medication, in combination with the nicotine transdermal patch, significantly enhance the rate of smoking cessation. Interactions between smoking and antipsychotic medication - Smoking increases the metabolism of the antipsychotic medications by inducing the cytochrome P450 1A2 isoform. Smoking lowers the blood levels of typical or atypical antipsychotic medication, in particular haloperidol, chlorpromazine, olanzapine and clozapine. -Abstinence can increase many psychotropics' blood levels. Accordingly, smoking appears to reduce neuroleptic-induced parkinsonism. In contrast, smoking is a risk factor for tardive dyskinesia, independent of neuroleptic exposure.

Non‐adherence to medications following pediatric liver transplantation

Non-adherence to medications is a leading cause of organ loss and morbidity in children and adolescents who had a liver transplant. Yet there are very few published studies about ways to detect whether patients are taking their medications or not, and about treatment options to improve adherence. The Pediatric Liver/Liver Transplant Program at Mount Sinai developed clinical and research programs that evaluate adherence. We review initial results from these programs. Clinic patients participate in an adherence-monitoring program that involves standardized assessments by patients, parents, clinicians, and routine examinations of medication blood levels. A research program adds an electronic monitoring device (MEMS-caps, AARDEX/APREX, Switzerland) and examines the use of azathioprine metabolites as predictors for non-adherence. Patients receive a thorough psychosocial evaluation to identify potential risk factors for non-adherence. Preliminary results indicate that an objective adherence detection method has to be incorporated into practice if non-adherence is to be reliably detected (clinicians' impressions and patients' reports are not sufficient). A risk factor for non-adherence, post-traumatic stress disorder, emerges as a potential target for intervention. It is possible to integrate a formal mechanism to assess adherence into the work of a liver/liver transplant clinic. We hope that the presented program will inspire clinicians in the community and other programs to regard the assessment and improvement of adherence to medications as an important goal in the management of children who had a transplant.

Sirolimus and Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation.

Sirolimus (SRL) is a novel immunosuppressive agent that has been demonstrated to reduce GVHD and minimize morbidity after allogeneic stem cell transplantation (alloSCT). We have described a syndrome of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolysis, thrombocytopenia, and renal dysfunction, whose incidence is increased when SRL is used in association with calcineurin inhibitors (CIs) but not with SRL monotherapy. To determine if SRL use potentiates the effects of CIs on TMA incidence and risk factors, we performed a retrospective cohort analysis of subjects who underwent alloSCT between 1997 and 2003.Methods: Subjects who received a SRL-containing GVHD prophylaxis after a myeloablative preparative regimen were compared with a cohort who received a non-SRL regimen. All subjects received CIs. Diagnosis of TMA required the simultaneous occurrence of: (1) creatinine elevation >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) elevated LDH, and (4) no laboratory evidence of disseminated intravascular coagulopathy.Results: 111 patients who received SRL were compared with 216 patients who received no SRL during the first 100 days after alloSCT. The two groups of patients were balanced for demographic parameters; however, more patients in the SRL group received peripheral blood stem cells (50.5 vs. 18.1%, p<0.01) and had unrelated donors (58.6 vs. 42.6%, p<0.01). The incidence of TMA in the SRL group was 10.8% in comparison with an incidence of 4.2% in the non-SRL group (OR 2.57, p=0.03). Patients who received SRL developed TMA earlier than those who did not receive SRL (median 25 vs. 58 days, p=0.04). At the time of TMA diagnosis, median blood levels of immunosuppressive medications were in their respective therapeutic ranges: SRL (study group) 6.1 ng/ml, tacrolimus (study group) 9.9 ng/ml, tacrolimus (control group) 9.1 ng/ml; cyclosporine (control group) 418 ng/ml. In a multivariable logistic regression model, only the use of SRL (Adjusted Exact OR 3.49, p =0.02) and grade II-IV acute GVHD (Adjusted Exact OR 6.60, p = 0.0002) predicted the occurrence of TMA. Treatment of TMA consisted of discontinuation or dose adjustment of CIs. SRL was discontinued or dosed according to serum level. Two subjects in each group required temporary hemodialysis, and 3 subjects (1 SRL, 2 non-SRL) underwent plasmapheresis. 78% of surviving SRL-treated subjects regained normal renal function. No subject had a TMA recurrence if SRL was reintroduced. Overall survival after TMA diagnosis was better for SRL patients than non-SRL patients (58.3 vs. 11.1%, log rank p=0.02).Conclusion: SRL use is associated with an increased risk of TMA after alloSCT and may act by potentiating the effects of CIs. TMA associated with SRL appears reversible and does not affect overall survival after alloSCT. A careful monitoring strategy for TMA should be employed as part of a SRL-containing GVHD prophylaxis regimen.

Drug Interactions Casebook: The Cytochrome P450 System and Beyond

Drug Interactions Casebook: The Cytochrome P450 System and Beyond

Medication adherence in pediatric and adolescent liver transplant recipients.

Nonadherence to medications is a leading cause of morbidity in children and adolescents who have had a transplant, yet there are no published data about the use of different methods for detecting whether these children are taking their medications. There are also no published data about the age of transition at which a child assumes responsibility over taking the medications. This information is important if interventions to improve adherence are contemplated. We present an analysis of data obtained in the first year of the implementation of an adherence assessment protocol at a pediatric liver transplant clinic in a tertiary medical care center. Data were obtained for children and adolescents who had a liver transplant at least 1 year before the assessments took place. We used 5 adherence detection methods. The 4 subjective methods were self-reported, scaled questionnaires answered by nurses, physicians, caregivers, and patients. For the objective method, a standard deviation (SD) was calculated for tacrolimus blood levels obtained from each patient over time. A higher SD suggests increased variation among patients' blood levels and hence more erratic medication taking. We also asked the patients and caregivers who is responsible for taking the medications and what are the reasons for not taking them. The medical outcome measures were biopsy-proven rejection episodes, number of biopsies regardless of the results, number of hospital admissions, and number of in-patient days. An analysis of 81 cases (258 assessments) revealed that the only method that predicted the medical outcome variables (biopsy-proven rejection and number of biopsies) was the SD of medication blood levels. Patients', clinicians', and caregivers' reports were not predictive. Clinicians' ratings of adherence were not correlated with patients' or caregivers'. The transition of responsibility for medication taking occurred approximately at the age of 12 years. Forgetfulness was cited as the most common reason for nonadherence by patients and caregivers; medication side effects were not frequently cited. Our results indicate that clinical impression is not sufficient to determine whether children and adolescents are taking their medications after they have had a liver transplant. An objective assessment method should be used. Interventions targeting adherence should address the child's increasing role beginning in early adolescence. A clinical protocol incorporating objective assessments of adherence could potentially be implemented in other settings. It could form the basis for the evaluation of efficacy of interventions seeking to improve adherence to medications.

Treatment of mood-congruent psychotic depression with imipramine

Background: Most studies report a poor response of psychotic depressed patients to treatment with a tricyclic antidepressant alone compared to combined treatment with an antipsychotic preparation and compared to non-psychotic depressed patients. However, the issue of optimal treatment of psychotic depressed patients has not been resolved as yet. Previously, we reported a significant difference in response to mirtazapine compared to imipramine in a randomised, double-blind, fixed-blood-level study with in-patients with major depression. In the current study we focus on the treatment response to imipramine in a group of patients with psychotic depression and compare this to patients who manifest no psychotic features. Our aim in presenting these findings was to contribute to the discussion on the optimal treatment of psychotic depressed patients. Methods: Fifty-two patients with a unipolar major depression (DSM-IIIR), comprising 15 patients with mood-congruent psychotic features and 37 patients with no psychotic features, were commenced on treatment with imipramine after a drug-free and placebo-washout period of 7 days. The dose of imipramine was adjusted for all patients to a predetermined blood level. The Hamilton (HRSD) and Montgomery–Asberg (MADRS) Depression Rating Scales were used to evaluate treatment response. Results: Of the 45 patients who completed the study, nine of the 13 psychotic patients (69.2%) and 14 of the 32 non-psychotic patients (43.8%) responded to treatment. The patients with psychotic features demonstrated a lower mean final HRSD score, together with a greater fall in MADRS score over time, compared to the non-psychotic group. Both these findings remained statistically significant after controlling for a number of possible confounding factors. Conclusions: These results demonstrate that, in this group of patients with mood-congruent psychotic depression, imipramine used on its own together with strict control of serum drug levels produced a high treatment response rate of 70%. Clinical implications: If replicated, these findings suggest that imipramine with control of blood levels of medication may be a useful first-line treatment for depressed patients with mood-congruent psychotic features. Limitations: Our sample size was modest. This fact may caution against generalisation of the results.

Chapter 36 EEG in neonates. What does the neonatal EEG tell about prognosis?

Publisher Summary The prognosis of the child in the neonatal intensive care unit (NICU) is of paramount importance in the decision to continue or stop treatment. Reliable measures of psychomotor development in the far future are indispensable in such decisions. The electroencephalography (EEG) has the advantage that most technicians can easily apply the method, even in small children. EEG gives not only prognostic features but, in contrast to evoked potentials, gives information on epileptic discharges as well. This chapter discusses a study to evaluate neonatal EEG criteria that are widely used for the prediction of outcome. The study was performed in a large group of children born around term in which follow-up was sufficiently long to give insight into the final performance of the patients. EEGs were recorded on day 2 or 3 of life. Only in very exceptional cases was the EEG made in the first 24 hours of life. This was done only in those patients for whom (suspicion of) epileptic seizures urged early registration. Many children needed drug treatment, in particular anti-epileptic drugs. Blood levels of medication that might have sedative effects were measured. The follow-up of all patients was at least two years and up to six years. The children were regularly seen by a senior pediatrician or a child neurologist for at least the first two years of life. The psychomotor performance of the children was assessed.

Smoking and persistent mental illness: an exploratory study.

The rate of smoking is alarmingly high among persons with persistent mental illness and they are no less susceptible to the harmful effects of smoking. Nicotine is a potent, addictive drug which affects neurotransmitters. Smoking can affect psychiatric symptoms as well as blood levels of psychotropic and other medications. Most persons with mental illness are aware of the detrimental health risks of smoking and many are interested in quitting. Poor physical health is associated with efforts to quit. Personal commitment is important to successfully quitting.

Variations in Smoking Policies on Psychiatric Units

BACKGROUND: The high prevalence of smoking among clients with psychiatric disorders and the effect of smoking on metabolism of psychiatric medications has been documented. Implementation of inpatient smoking policies that alter smoking patterns may affect symptom presentation and medication metabolism. OBJECTIVE: Variations in how smoking policies are implemented on psychiatric units are described. DESIGN: A telephone survey of nurses working on 32 psychiatric units was used to collect information about how smoking policies were implemented. RESULTS: Most (n = 23) units allowed smoking only in designated areas outside the facility. Smoking frequency varied widely, ranging from twice a day to anytime, and some units placed restrictions on the number of cigarettes that could be smoked at each opportunity. CONCLUSION: The large variation in how smoking policies are implemented warrants further research. Smoking policies may alter smoking practices that affect psychotropic medication blood levels, side effects, and symptom presentation.

Variations in smoking policies on psychiatric units

Abstract Background : The high prevalence of smoking among clients with psychiatric disorders and the effect of smoking on metabolism of psychiatric medications has been documented. Implementation of inpatient smoking policies that alter smoking patterns may affect symptom presentation and medication metabolism. Objective : Variations in how smoking policies are implemented on psychiatric units are described. Design : A telephone survey of nurses working on 32 psychiatric units was used to collect information about how smoking policies were implemented. Results : Most (n = 23) units allowed smoking only in designated areas outside the facility. Smoking frequency varied widely, ranging from twice a day to anytime, and some units placed restrictions on the number of cigarettes that could be smoked at each opportunity. Conclusion : The large variation in how smoking policies are implemented warrants further research. Smoking policies may alter smoking practices that affect psychotropic medication blood levels, side effects, and symptom presentation.

Schizophrenia and nicotine use: report of a pilot smoking cessation program and review of neurobiological and clinical issues.

Nicotine use is a major public health problem that increases medical morbidity and mortality. Nicotine's action and the pathobiology of schizophrenic disorders have common neurobiological substrates. Tobacco smoking alters medication blood levels and effectiveness, modifies psychiatric symptoms, and is a clue for other substance abuse. This article presents an evaluation of a smoking cessation program for 24 smokers with schizophrenia. Fifty percent completed the program, 40 percent decreased use by 50 percent, and 13 percent remained abstinent (carbon monoxide verified) for 6 months. Nicotine replacement, motivational enhancement therapy, and relapse prevention behavioral therapy were important components of treatment. Pharmacotherapy strategies of a higher-dose nicotine patch, combining nicotine gum and a patch, and augmentation medication to nicotine replacement should be evaluated in future studies in this population.

Occurrence of seizures related to psychotropic medication among psychiatric inpatients

Seizures associated with psychotropic medication are serious and reportable adverse drug reactions. This study examined the occurrence of seizures associated with psychotropic medication during psychiatric hospitalization. Among 10,994 admissions to a psychiatric teaching hospital over a 30-month period between 1990 and 1993, 29 patients were identified by a specially trained quality assurance nurse as having seizures that were probably related to psychotropic medication. These cases were verified by a clinical pharmacist and a psychopharmacologist. Two patients were excluded, and the records of 27 patients were reviewed in detail. Nineteen of the 27 patients (70 percent) whose seizures were related to psychotropic medication had a preexisting seizure disorder, and eight had new-onset seizures. Psychotropic medications were primarily implicated as being associated with seizures in the cases of three of the 19 patients with preexisting seizure disorders (15.8 percent) and five of the eight patients with new-onset seizures (62.5 percent). In the group with preexisting seizure disorders, six patients (32 percent) had subtherapeutic blood levels of antiseizure medication, and four (21 percent) experienced pseudoseizures. Seizures among inpatients on psychotropic medication were infrequent (.3 percent of psychiatric admissions); the majority (70 percent) occurred in patients with preexisting seizure disorders. Seizures were directly attributed to psychotropic medications in less than .1 percent of admissions.

ERPs in schizophrenia: Effects of antipsychotic medication

Thirty unmedicated schizophrenics were compared to 29 age-matched controls on auditory and visual event-related brain potential (ERP) paradigms. Twenty-one of these patients were tested again after 1 week on placebo and after 4 weeks on antipsychotic medication. Before treatment, N1, N2, and P3 components of the auditory ERP were smaller in the schizophrenics than in the controls. Although visual N2 was smaller in schizophrenics, visual P3 was not. In spite of significant clinical improvement with antipsychotic treatment, amplitudes of auditory and visual N1, N2 and P3 were not significantly changed. Higher blood levels of antipsychotic medication were related to reductions in auditory P3 latency, however. In addition, higher levels of cerebrospinal fluid (CSF) MHPG (methoxyhydroxyphenylglycol) were associated with larger auditory N1s and larger auditory and visual P3s, suggesting an influence of arousal on these components in schizophrenics. In spite of this influence, reduction of the auditory P3 in schizophrenia is an enduring trait of the disease, which is not affected by antipsychotic medication or clinical improvement.

Driving and Epilepsy: The Effects of Medication-Reply

In Reply.— The issue Dr Novak raises, the potential for antiepileptic medications to impair driving ability, has not received much attention in the medical literature. Antiepileptic medications at therapeutic doses would be unlikely to pose serious hazards for driving. Still, as with any medication, there is the potential for toxic side effects. Consequently, it seems wise for physicians to inform drivers with epilepsy of such potential problems, particularly when changes in treatment are made. In specific instances when an individual's driving ability is questioned, a driving performance test or a test of reaction time may be useful to determine whether a license should be issued. The risk of toxic effects may be minimized by attention to correct prescribing practices for antiepileptic drugs. In particular, we recommend regularly monitoring blood levels of antiepileptic medications, preferentially prescribing a nonsedating antiepileptic medication, and treating with a single antiepileptic medication whenever possible. As Dr

Effect of Cardiopulmonary Bypass on Plasma Levels of Nifedipine

Blood levels of many medications are acutely lowered by cardiopulmonary bypass (CPB). Because nifedipine is often used to provide protection from coronary ischemia, a determination of the effect of CPB on plasma nifedipine levels might help to determine the potential clinical benefit of nifedipine during and after bypass. Four samples of blood were drawn from each of eight patients undergoing cardiac surgery: one before, two during, and one after CPB. Although plasma levels of nifedipine declined during and after bypass (P less than 0.05, analysis of variance), the time-course and slope of the decline indicate that this was an effect of normal metabolism of the drug rather than an effect of physiologic changes occurring during CPB. An important additional finding was that the majority of patients had subtherapeutic levels of nifedipine before bypass, suggesting that additional nifedipine given during and after surgery might be of benefit. The effect of the CPB circuit itself was also examined in vitro by mixing nifedipine into a pump prime solution that was then recirculated with 2 U of outdated blood while levels of nifedipine were measured for 3 h. Plasma levels did not change in either a CPB circuit exposed to light or kept in a darkened room.

Geropharmacology treatment: behavioral problems extend nursing responsibility.

1. Assessment of older adults with behavior problems considers factors contributing to the behavior; potential psychosocial interventions; patient characteristics influencing medication action; and medication characteristics influencing therapeutic and adverse effects. 2. Anxiety, agitation, and other behavioral problems in demented patients might arise from their inability to verbally express complaints such as pain and discomfort. 3. Although constant blood levels of medication are most effective for ongoing management of behavior problems, as needed doses can be used to establish the optimal dosing schedule. 4. Medications in low doses can be used to improve the patient's response to psychosocial interventions for behaviors such as anxiety, agitation, depression, and sleep disorders; but they should not be used as the only intervention.

Management of Chronic Pain

To the Editor. — While nalbuphine may be worthy of consideration as an appropriate analgesic for certain patients, Dr Defalque's1discussion of the use of that drug in injectable form for chronic, intractable nonmalignant pain in the QUESTIONS AND ANSWERS section was inadequate. Presuming that the patient indeed has tissue damage and can respond to the agent pharmacologically is not enough. Dr Leveque must be asked whether other medical, psychological, social, and behavioral factors exist that serve to perpetuate this patient's pain. Behavioral factors are particularly important given the perceived lack of alternatives to injectable medication and the dosing interval of nalbuphine. While nalbuphine may have low potential for abuse, the patient may be psychologically dependent on the injections themselves. Injections cause a rapid increase in blood levels of medication and resultant analgesia. If they are not spaced closely enough together so as to maintain near-constant blood levels of

Sudden epilepsy deaths and the forensic pathologist.

Sudden unexpected deaths in epileptic persons are not rare events, most commonly encountered by the forensic pathologist rather than the clinician. Such deaths may represent 1-1.5% of all "natural" deaths certified by the medical examiner or coroner. The typical victim is a black male about 30 years of age who tends to abuse alcohol, with a history of generalized epilepsy for more than 1 year and likely for more than 10 years. There are a lack of obvious anatomic causes for the death at autopsy, but 60-70% of cases will have a lesion in the brain (most commonly old trauma) to explain the epilepsy. Most victims have no blood levels of anticonvulsant medications at the time of death. We have evolved a form for use by medical examiner/coroner's investigators at the scene to collect relevant information which will be of assistance to the pathologist in interpreting the case. Estimated prevalence of sudden epilepsy death, mechanisms, and other features of such cases are reviewed briefly.