Adverse Effects Of Long-term Use Research Articles

Efficacy and safety of tegoprazan in the treatment of gastroesophageal reflux disease: A protocol for meta-analysis and systematic review.

The incidence of gastroesophageal reflux disease (GERD) is increasing year by year, the clinical manifestations are complex and diverse, and the adverse effects of long-term use of proton pump inhibitors and gastrointestinal motility drugs have been of great concern in recent years. The effectiveness of tegoprazan in the treatment of GERD is still controversial. This protocol describes a systematic review and meta-analysis to evaluate the efficacy and safety of tegoprazan in the treatment of gastroesophageal reflux disease. PubMed, Embase, Cochrane Library and Web of Science will be searched from the database inception to 1 March 2023. All randomized controlled trials related to tegoprazan for GERD will be included. Extracted data will include publication details, basic information, demographic data, intervention details and patient outcomes. The primary outcome will be complete resolution of major symptoms, complete resolution of heartburn, proportion of heartburn-free days, chronic cough, hoarseness, and adverse events. Risk of bias will be assessed using the Cochrane Collaboration's tool for assessing risk of bias. Article selection, data extraction and risk of bias assessment will be performed in duplicate by two independent reviewers. If the meta-analysis is precluded, we will conduct a descriptive synthesis using a best-evidence synthesis approach. The results of this study will provide reliable evidence to evaluate the efficacy and safety of tegoprazan in the treatment of GERD and help patients, physicians and clinical investigators choose the most appropriate treatment.

Long-term Use of Proton Pump Inhibitors is Associated With An Increased Risk of Nonalcoholic Fatty Liver Disease.

The adverse effects of long-term use of proton pump inhibitors (PPIs) have led to growing concern. The association between PPIs use and the risks of nonalcoholic fatty liver disease (NAFLD) remains controversial. The aim of this study was to investigate the association between PPIs use and the risks of NAFLD among the general adult population in the United States. We performed a cross-sectional study by extracting data from the National Health and Nutrition Examination Survey of 2017 to 2018. The association between PPIs use and NAFLD risks was analyzed by weighted multivariate logistic regression. Among the 4238 participants included in this study, 2167 were diagnosed with NAFLD. In the multivariate logistic regression model, PPIs use was associated with increased risks of NAFLD [odds ratio (OR): 1.318, 95% CI: 1.044-1.663; P=0.020]. This association was nonsignificant in participants taking PPIs for ˂5 years (OR: 0.846, 95% CI: 0.579-1.238; P=0.390), whereas it remained significant in participants taking PPIs for more than 5 years (OR: 2.016, 95% CI: 1.366-2.975; P=0.031). Further analysis showed that the use of PPIs was positively associated with risks of severe hepatic steatosis (OR: 1.451, 95% CI: 1.034-2.036; P=0.031) but not with mild-to-moderate steatosis (OR: 1.242, 95% CI: 0.886-1.741; P=0.208). This study indicated that taking PPIs was associated with increased risks of NAFLD, especially severe hepatic steatosis. Awareness should be raised regarding the potential risks of NAFLD when prescribing PPIs.

Proton pump inhibitors affect sperm parameters by regulating aquaporins

Proton pump inhibitors (PPIs) were one of the most commonly used drugs in daily life. The adverse effects of long-term use of PPIs have aroused widespread controversy. It was of great significance to explore the molecular mechanism of sperm abnormality caused by PPIs. The PPI group was given omeprazole by gavage for 28 days. After the omeprazole intervention, the caudal epididymis was dissected to obtain sperms, and the sperm was counted through the microscope, as the acrosomal integrity was observed through PNA-FITC staining. The expression of aquaporins were detected by immunofluorescence and western blot in the testis, epididymis and spermatozoa. The liver cytochrome enzyme was evaluated by immunohistochemistry and western blot. We detected the serum estrogen level by ELISA, and the level of alanine transaminase (ALT) were detected through microplate method. The sperm count in PPI group was less than control group (p < 0.05), and the sperm acrosin integrity in PPI group was lower than control group (p < 0.05). In the testis, the expression of aquaporin 3 and aquaporin 8 in PPI group was higher than control group (p < 0.05), while the expression of aquaporin 7 was lower than control group (p < 0.05). In the epididymal and sperm, the expression of aquaporin 3 and aquaporin 7 in PPI group was higher than control group (p < 0.05), while the expression of aquaporin 8 in PPI group was lower than control group (p < 0.05). Meanwhile, the liver cytochrome enzyme in PPI group were lower than control group (p < 0.05), and estrogen and ALT in PPI group were higher than control group (p < 0.05). PPI may lead to the up-regulation of estrogen by inhibiting the activity of cytochrome enzyme, and then lead to the dysfunction of sperm parameters and acrosin integrity by affecting aquaporins function.

A masked, placebo-controlled, randomized clinical trial evaluating safety and the effect on cardiac function of low-dose rapamycin in 17 healthy client-owned dogs.

Geroscience studies of low-dose rapamycin in laboratory species have identified numerous benefits, including reversing age-related cardiac dysfunction. Cardiovascular benefits have been observed in dogs with 10 weeks of treatment, raising questions about possible benefits and adverse effects of long-term use of low-dose rapamycin. The objectives of this study were to assess the impact of 6 months of low-dose rapamycin on echocardiographic indices of cardiac function in healthy dogs and to document the occurrence of adverse events. Seventeen client-owned dogs aged 6-10 years, weighing 18-36 kg, and without significant systemic disease were included in a prospective, randomized, placebo-controlled, masked clinical trial. Low-dose rapamycin (0.025 mg/kg) or placebo was administered three times per week for 6 months. Baseline, 6-month, and 12-month evaluation included physical examination, cardiology examination, and clinicopathology. Three-month evaluation included physical examination and clinicopathology. Owners completed online questionnaires every 2 weeks. There were no statistically significant differences in echocardiographic parameters between rapamycin and placebo groups at 6 or 12 months. No clinically significant adverse events occurred. In 26.8% of the bi-weekly surveys owners whose dogs received rapamycin reported perceived positive changes in behavior or health, compared to 8.1% in the placebo group (p = 0.04). While no clinically significant change in cardiac function was observed in dogs treated with low-dose rapamycin, the drug was well-tolerated with no significant adverse events.

Use of antiseizure medications after traumatic brain injury

Background: Post-traumatic seizures and epilepsy are major complications that increase the mortality rate among patients with traumatic brain injury (TBI) and hinder functional recovery. It is important to establish prophylaxis and treatment strategies for high-risk patients. The use of antiseizure medications may not only adversely affect the cognitive function following TBI but also may be associated with a worse rehabilitation outcome.Current Concepts: The level of evidence in the current international guidelines related to the prophylaxis and management of post-traumatic seizure is not robust. Furthermore, the use of antiseizure medications after TBI remains unclear, indicating substantial variations in clinical practice.Discussion and Conclusion: Prophylactic antiseizure medications can reduce the risk of early seizures and partially prevent the secondary injury process of TBI; however, they do not seem to inhibit epileptogenesis. Therefore, if the benefits of preventing early seizures outweigh the potential risks associated with antiseizure medication, it is recommended to use them for a short period of about one week after the injury. Then, it is not recommended to continue using them routinely without considering the individual risk of seizure recurrence and potential adverse effects of long-term use. The treatment duration of anticonvulsant in patients with post-traumatic epilepsy should also be determined based on the individual risk of seizure recurrence, and the decision should take into account the opinions of both the patient and the caregiver, while considering not only the potential benefits but also the risks associated with long-term use.

Voriconazole induced periostitis

Voriconazole is a second generation broad spectrum triazole antifungal agent which is commonly used for prophylaxis and treatment of invasive aspergillosis, especially in patients with solid organ and hematopoietic stem cell transplants. One of the rare, adverse effects of long-term use is periostitis which is caused by increased circulating levels of fluoride from voriconazole metabolism with clinical findings similar to skeletal fluorosis. Given the increased use of voriconazole, it is essential to recognize periostitis as an adverse effect with prompt discontinuation of the medication improving patient outcomes and quality of life.

Insights into the Use of Peripherally Acting μ-Opioid Receptor Antagonists (PAMORAs) in Oncologic Patients: from Scientific Evidence to Real Clinical Practice.

Management of chronic pain is crucial to improve the quality of life of cancer and palliative care patients. Opioid-based treatments used to control pain can be prolonged over time. Unfortunately, constipation is one of the most disturbing adverse effects of long-term use of opioids. Opioid-induced constipation (OIC) occurs when opioids bind to the specific receptors present in the gastrointestinal (GI) tract, and can affect any patients receiving chronic opioid therapy, including cancer patients. The limited efficacy of laxatives to treat OIC symptoms prompted the search for new therapeutic strategies. Peripherally acting μ-opioid receptor antagonists (PAMORAs) have recently emerged as new effective drugs for OIC management due to their specific binding to enteric μ-receptors. Little information is available on the use of PAMORAs in real-life practice for OIC treatment in cancer patients. In this paper, a panel of experts specializing in cancer and palliative care pools their clinical experience with PAMORAs in cancer patients presenting OIC and highlights the importance of timing and choice of therapy in achieving prompt OIC management and benefitting patients.

Community-dwelling older adults\u2019 awareness of the inappropriate use of proton pump inhibitors

BackgroundProton pump inhibitors (PPIs) are effective in treating gastroesophageal reflux, peptic ulcers, and esophagitis. However, the long-term use of PPIs by older adults is associated with adverse health outcomes. There is limited evidence about older adults’ awareness of long-term PPI use and its associated adverse effects. This study aimed to assess older adults’ awareness of the adverse effects of the long-term use of PPIs, and their willingness to stop PPI use given of the risks and benefits of PPI use.Methodsthis cross-sectional study was conducted on a convenience sample of 120 older adults from three local healthcare centers located in Irbid, Jordan. Older adults’ awareness of PPI use was measured using the Patients’ Perceptions of Proton Pump Inhibitor Risks and Attempts at Discontinuation Survey.Resultsthe majority of the participating older adults were not familiar with any reports linking long-term PPI use with adverse effects, reported no concerns related to the chronic use of PPIs, and reported that they had not discussed the benefits and risks of PPI use with their primary care providers (PCPs). Although the majority of the participants had not previously attempted to stop using PPIs, the majority expressed a willingness to stop PPIs due to their adverse effects, especially if advised to do so by a PCP. The factors associated with the long-term use of PPIs included age, indications for gastrointestinal reflux disease (GERD), improvement of GERD symptoms, and the willingness to reduce or stop PPIs. Being advised by a PCP to stop PPIs (p = 0.049) and having increased concerns about the adverse effects of long-term PPI use (p < 0.0001) were the only two statistically significant predictors of previous attempts to stop PPIs.Conclusionsconcerns regarding the adverse effects of long-term PPI use were associated with attempts to stop PPIs, especially in cases where this was recommended by a PCP. Discussions between PCPs and patients regarding the risks and benefits of PPIs are necessary in order to ensure that patients do not make inappropriate decisions regarding ongoing PPI therapy. Careful evaluation of the long-term use of PPIs among older adults is required.

Immunosuppression in Liver Transplantation: State of the Art and Future Perspectives.

Novel drugs and combinations for immunosuppression (IS) after liver transplantation is one main reason for improved graft and patient survival seen in the last decades. The backbone of IS is still steroids and calcineurin inhibitors, although novel drugs are being introduced, such as the mammalian target of rapamycin inhibitors (mTOR inhibitor). The challenge today, along with increased patient survival, is the adverse effects of long-term use of immunosuppressive drugs, mainly nephrotoxicity and other serious adverse effects. Concepts: The ultimate outcome after liver transplantation would be achieving tolerance, a state where all IS can be withdrawn. In the meantime, different approaches to reduce and withdraw IS have been tested out in different clinical trials with the aim to reduce the adverse effects of steroids and calcineurin inhibitors. This has formed the basis of today's clinical practice. The different combinations of immunosuppressive drugs have included mTOR inhibitor such as everolimus and different induction drugs such as anti-interleukin 2 receptor antibodies. Regarding induction drugs, lymphocyte depleting (alemtuzumab and ATG) and non-depleting agents, such as basiliximab, have shown advantageous effects. Alongside steroid and calcineurin inhibitors reduction or elimination, current strategies for post-liver transplantation immunosuppression explore combinations of novel agents. The gauge (or yardstick) here is the fine balance between the adverse effects of IS drugs and the risk of rejection. Long-term maintenance IS regimens, development of tolerance and antibody-mediated rejection are also discussed in this review.

Perspective of Plant Medicine in Therapy of Rheumatoid Arthritis

Rheumatoid Arthritis is a systemic autoimmune disease characterized by chronic, inflammatory condition. The adverse effects of long-term use of presently available anti-arthritic or non-steroidal anti-inflammatory drugs are gastrointestinal symptoms, cardiovascular complications, renal impairment, myelosuppression etc. and this requires continuous monitoring and eventually increasing the cost of treatment. Thus complementary and alternative medicines may fulfill the demand for patients suffering from this disease. Moreover, herbal therapy has been safe and effective enough to treat rheumatoid arthritis. With these backgrounds, the present review includes different 37 plants reported for anti-arthritic or anti-inflammatory effect. Also enlisted 37 bioactive principals reported for anti-arthritic effect with their source, mechanism of action and commercial herbal products available in the market for treatment of rheumatoid arthritis. The compiled information regarding plants and their role in the treatment of rheumatoid arthritis will help to justify the use of plant-derived medicine in the therapy of rheumatoid arthritis in future.

Potential risks of rare serious adverse effects related to long-term use of bisphosphonates: An overview of systematic reviews.

There have been concerns about a potential link between long-term use of bisphosphonates (BPs) for the treatment of osteoporosis and rare serious adverse effects, such as atypical femoral fractures. However, many reviews exist with conflicting conclusions about this issue. The aim of this overview of reviews was to systematically evaluate the risk of rare serious adverse effects of long-term use of BPs for the treatment of osteoporosis. We identified systematic reviews with meta-analyses of randomized controlled trials (RCTs) and (or) observational studies published in English or Chinese that evaluated the safety of BPs through to December 2018. The Cochrane library, PubMed, Web of Science and hand-searching of reference lists and clinical practice guidelines were electronically searched for data sources. Carcinogenicity, atypical fracture, osteonecrosis of jaw (ONJ) and fracture union time were specified as the primary outcomes. The methodological quality of each systematic review was assessed by two reviewers using the Assessment of Multiple Systematic Reviews (AMSTAR) tool, and the quality of evidence for key outcomes was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach. In total, 1376 potentially relevant citations were identified, of which only 8 systematic reviews with meta-analyses met the eligibility criteria. All the included reviews were published between 2012 and 2015 and documented the pooled estimates of effect size (relative risk [RR], odds ratio [OR] or hazard ratio [HR] and their 95% confidence intervals [95% CI]) for the incidence of adverse events. All included systematic reviews were of moderate or high quality. The median AMSTAR score was 7.5 (interquartile range, 5-10). However, evidence of the key outcomes was mainly of very low or moderate quality. BP treatment only increased the risk of atypical fracture and ONJ, and prolonged union time compared with placebo or other anti-osteoporosis drugs (P＜.05). This study indicated that long-term use of BPs could increase the risk of rare serious adverse effects, but the relationship between long-term use of BPs and carcinogenicity was often uncertain. Therefore, high-quality research and more complete inclusion criteria are needed.

A review on some medicinal plants with hepatoprotective effects

Liver diseases have become a major global health challenge and may be triggered by several toxic chemicals, which include chemotherapeutic agents, thioacetamide, carbon tetrachloride, certain antibiotics, excessive alcohol consumption, and pathogenic microbes. Hence, safeguarding a healthy liver is vital for good health and well-being. Despite advances in pharmacology, the demerits associated with synthetic drugs have outshone the merits. Treatment of liver diseases based on modern medical principles is becoming ineffective and also associated with adverse effects of long-term use, in addition to prohibitive costs in developing countries. Thus, exploring medicinal plants which are easily available and cheap and do not involve strenuous pharmaceutical production processes appears to have gained worldwide attention as alternative therapeutic agents for the diseases. Consequently, emphasis has been placed on folkloric herbs with high efficacy, low toxicity, and cost-effectiveness. In this paper, literature search was conducted using various databases such as Google Scholar, ISI Web of Knowledge, and PubMed; we carried out a comprehensive review on existing information on some medicinal plants around the world with hepatoprotective prospects. Phytochemical compounds with hepatoprotective effects were also discussed, and finally, the future work in the field was also highlighted.

Phosphodiesterase Inhibitors (PDE Inhibitors) and Male Reproduction.

The nonspecific PDE inhibitors, particularly the methylxanthines: caffeine, pentoxifylline (PTX), and theophylline, are known to stimulate sperm motility in vitro and have been used to treat sperm prior to insemination. The in vivo effects are less dramatic. A beneficial effect of caffeine, which is a constituent of some medications, remains controversial. Very high doses of caffeine do have negative effects on fertility endpoints in men and experimental species. The specific PDE5 inhibitors, particularly sildenafil and tadalafil, are prescribed for erectile dysfunction, as well as pulmonary hypertension, lower urinary tract symptoms, and premature ejaculation. PDE5 is expressed throughout the contractile tissues of the male reproductive tract, generally increasing contractility. Some PDE5 inhibitors tend to increase circulating testosterone levels somewhat. For short-term exposure consistent with use prior to intercourse, there appears to be minimal effects on semen quality. Several large, randomized controlled trials (RCTs) in healthy men have not found adverse effects of long-term use of these drugs on semen quality. RCTs in infertile men have demonstrated a modest increase in semen quality. Animal studies at human equivalent doses (HED) have produced similar results in young males, but a study in aging male rats found progressive decreases in epididymal sperm quality accompanied by consistent degeneration of the seminal tubules suggesting that studies in older men might be warranted. A concerning study in mice found lower fertilization rates in males treated with HED of sildenafil and mated the next day to untreated females than for control males. Fertility studies in humans are needed.

Association between drug-induced hyperprolactinemia related adverse events on women schizophrenia patients with DRD2 Taq1 polymorphism

ObjectivesTo observe the association between adverse effects of long-term use of antipsychotic drugs in female schizophrenic patients and dopamine D2 receptor (DRD2), cytochrome P450 (CYP) 2D6, estrogen receptor-α gene (ESR1).MethodThe subjects were 89 female schizophrenic patients (age range from 18 to 40) who had been taking the same medication for more than 3 months. The adverse effects with regard to hyperprolactinemia were studied through the blood collection at one point of the subjects. Furthermore, the effect of DRD2, CYP2D6, ESR1 on serum prolactin level and amenorrhea was analyzed.ResultsThere was a lower concentration of E2 in patients with amenorrhea. In addition, an inverse correlation was found between prolactin level and E2 level. Hyperprolactinemia (HPRL) was commonly found in patients who had been using risperidone, amisulpride and paliperidone; in contrast, HPRL was found less in those who had been taking aripiprazole, olanzapine, ziprasidone, clozapine and quetiapine. Moreover, female schizophrenic patients who had DRD2 Taq1 A1 allele had twice the chance of developing amenorrhea than those who did not have A1 allele. Female schizophrenic patients who had Taq1 A1 allele also had 48% higher concentration level of prolactin than those who did not have A1 allele. There was no association found between prolactin and CYP2D6 or ESR1.ConclusionFemale schizophrenic patients who had DRD2 Taq1 A1 allele showed high prolactin level and high-frequency of HPRL. Therefore, reducing the use of prolactin-elevating antipsychotics for female schizophrenic patients with DRD2 Taq1 A1 allele would be one method minimizing the adverse effects of drug-induced hyperprolactinemia.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Severe Hypomagnesemia with Long-Term Use of a Proton Pump Inhibitor: A Case Report

Hypomagnesemia is a rare, though likely under-recognized, adverse effect of long-term use of proton pump inhibitors (PPIs), one of the most commonly prescribed classes of medications in North America. Hypomagnesemia can cause potentially life-threatening neurologic abnormalities, cardiac arrhythmias, and secondary electrolyte disorders. In this manuscript we present the case of a long-term PPI user who presented with an episode of decreased level of consciousness. He was found to have severe hypomagnesemia with avid renal retention of magnesium, secondary hypocalcemia with an inappropriately normal parathyroid hormone level, and hypokalemia. His serum magnesium and other electrolyte abnormalities rapidly corrected with cessation of PPI use and electrolyte supplementation. Given the propensity for patients with hypomagnesemia associated with PPI use to go unrecognized until they present with severe symptomatic hypomagnesemia, we recommend that patients being started on a PPI for an intended long-term course have baseline testing of serum magnesium and monitoring of magnesium on an annual basis, or sooner, if they develop symptoms.

Severe Hypomagnesemia with Long-Term Use of a Proton Pump Inhibitor: A Case Report

Hypomagnesemia is a rare, though likely under-recognized, adverse effect of long-term use of proton pump inhibitors (PPIs), one of the most commonly prescribed classes of medications in North America. Hypomagnesemia can cause potentially life-threatening neurologic abnormalities, cardiac arrhythmias, and secondary electrolyte disorders. In this manuscript we present the case of a long-term PPI user who presented with an episode of decreased level of consciousness. He was found to have severe hypomagnesemia with avid renal retention of magnesium, secondary hypocalcemia with an inappropriately normal parathyroid hormone level, and hypokalemia. His serum magnesium and other electrolyte abnormalities rapidly corrected with cessation of PPI use and electrolyte supplementation. Given the propensity for patients with hypomagnesemia associated with PPI use to go unrecognized until they present with severe symptomatic hypomagnesemia, we recommend that patients being started on a PPI for an intended long-term course have baseline testing of serum magnesium and monitoring of magnesium on an annual basis, or sooner, if they develop symptoms.

Evaluation of costs accrued through inadvertent continuation of hospital-initiated proton pump inhibitor therapy for stress ulcer prophylaxis beyond hospital discharge: a retrospective chart review.

BackgroundStress ulcers and related upper gastrointestinal bleeding are well-known complications in intensive care unit (ICU) patients. Proton pump inhibitor (PPI)-based stress ulcer prophylaxis (SUP) has been widely prescribed in noncritically ill patients who are at low risk for clinically significant bleeding, which is then injudiciously continued after hospital discharge. This study aimed to evaluate the incidence of inappropriate prescribing of PPI-based preventative therapy in ICU versus non-ICU patients that subsequently continued postdischarge, and to estimate the costs incurred by the unwarranted outpatient continuation of PPI therapy.MethodsA retrospective review of patient data at a major teaching hospital in Korea was performed. During the 4-year study period, adult patients who were newly initiated on PPI-based SUP during hospital admission and subsequently discharged on a PPI without a medical indication for such therapy were captured for data analysis. The incidence rates of inappropriate prescribing of PPIs were compared between ICU and non-ICU patients, and the costs associated with such therapy were also examined.ResultsA total of 4,410 patients, more than half of the inpatient-initiated PPI users, were deemed to have been inadvertently prescribed a PPI at discharge in the absence of a medical need for acid suppression. The incidence of inappropriate outpatient continuation of the prophylaxis was higher among ICU patients compared with non-ICU patients (57.7% versus 52.2%, respectively; P=0.001). The total expenditure accrued through the continuation of nonindicated PPI therapy was approximately US$40,175.ConclusionThis study confirmed that excess usage of PPIs for SUP has spread to low-risk, non-ICU patients. The overuse of unwarranted PPI therapy can incur large health care expenditure, as well as clinical complications with minimal therapeutic benefits. Educating clinicians regarding SUP guidelines and the adverse effects of long-term use of acid suppression can improve the cost effectiveness of PPI therapy.

Pharmacogenomics: personalizing pediatric heart transplantation.

In recent years, outcomes for pediatric cardiac transplantation (PCTx) have steadily improved, with current 5-year overall survival rates estimated at 83%.1 This progress may be attributed to improvements in pretransplantation management, selection of donor hearts, surgical technique, prevention and treatment of rejection, and minimization of treatment-related adverse events. Despite these advances, children who receive cardiac transplants experience significant morbidity and mortality, and there is considerable variability in outcomes, much of which cannot be explained by known clinical risk factors. One source of interindividual variability is genetic variation in the host. There is growing evidence that genomic variation leads to differences in immune response, response to therapies, and susceptibility to adverse outcomes such as malignancy and infection.2–4 This review will focus on the effect of variation in genes that encode enzymes, transporters, and drug target molecules that influence drug response. After review of the foundational principles of pharmacogenomics, evidence for the pharmacogenomic effects on cyclosporine, tacrolimus, azathioprine, mycophenolate mofetil (MMF), and the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus will be reviewed and clinical implications of these findings discussed. Given the limited nature of evidence from studies of PCTx patients, support will also be drawn from non-PCTx research and pediatric renal transplantation. Genetic studies of nonpharmacogenes such as those in immunomodulatory pathways and variation in the donor genotype may contribute to risk prediction but are beyond the scope of this review. ### Genetic Variation DNA variation can alter biological function through several mechanisms (Figure 1). Variation within the coding sequence or in intron/exon borders can change the protein product through changes in start codons, stop codons, splice sites, or within the coding sequence, leading to nonsense-mediated decay or altered protein function. Other variants associated with pharmacogenomic outcomes are not predicted to change the encoded protein. These synonymous and …

Rationale for the potential use of mesenchymal stromal cells in liver transplantation.

Mesenchymal stromal cells (MSCs) are multipotent and self-renewing cells that reside essentially in the bone marrow as a non-hematopoietic cell population, but may also be isolated from the connective tissues of most organs. MSCs represent a heterogeneous population of adult, fibroblast-like cells characterized by their ability to differentiate into tissues of mesodermal lineages including adipocytes, chondrocytes and osteocytes. For several years now, MSCs have been evaluated for their in vivo and in vitro immunomodulatory and 'tissue reconstruction' properties, which could make them interesting in various clinical settings, and particularly in organ transplantation. This paper aims to review current knowledge on the properties of MSCs and their use in pre-clinical and clinical studies in solid organ transplantation, and particularly in the field of liver transplantation. The first available clinical data seem to show that MSCs are safe to use, at least in the medium-term, but more time is needed to evaluate the potential adverse effects of long-term use. Many issues must be resolved on the correct use of MSCs. Intensive in vitro and pre-clinical research are the keys to a better understanding of the way that MSCs act, and to eventually lead to clinical success.

A case of intentional asenapine overdose.

To the Editor: Asenapine, marketed as Saphris, is a relatively new psychopharmaceutical agent approved in 2009 for the treatment of acute mania or mixed episodes in the context of bipolar I disorder as well as schizophrenia.1 Asenapine has a unique receptor profile and has been shown to be effective and well tolerated by patients experiencing an acute manic episode.2,3 Adverse effects of long-term use are not yet known, but the incidence of cardiovascular disease and diabetes is expected to be substantially lower than with older neuroleptic agents.4 Here we present the first published case of asenapine overdose of known quantity and route. Case report. Mr A, a 49-year-old man, presented to the emergency department (ED) after having ingested 74 tablets of asenapine in the ED parking lot several minutes previously. He was currently undergoing a course of electroconvulsive therapy (ECT), having been diagnosed with bipolar disorder with mixed episodes and borderline personality disorder (both according to DSM-IV-TR criteria) and was 1 day postdischarge from the inpatient psychiatry unit. The quantity of ingested tablets was confirmed by the patient’s mental health outreach worker after examination of packages in the patient’s car. Mr A had made previous suicide attempts using ibuprofen and clonazepam in overdose. Because the ED physician was unfamiliar with asenapine toxicity, the patient was admitted to the intensive care unit (ICU) for observation. Examination in the ED and ICU revealed a drowsy, yet easily rousable man who was unwilling to answer questions. Blood pressure was maintained at 149/88 mm Hg, pulse was 99 bpm, respiratory rate was 19/min, oxygen saturation was 98% on room air. Findings of cardiac, respiratory, and abdominal examinations were unremarkable. Urine drug screen was positive for amphetamines, marijuana, opiates, and benzodiazepines. There was no nausea or vomiting, and activated charcoal was not administered. Electrolytes, troponin I, international normalized ratio, complete blood cell count, and creatinine were all within normal laboratory values. Electrocardiogram showed only normal sinus rhythm. Mr A was determined to be medically stable by the ICU physician, and care was transferred to the psychiatric unit approximately 24 hours later. This patient’s bilateral ECT course was continued for a total of 10 treatments with good therapeutic effect and minimal side effects. He was subsequently discharged and has been followed by the outpatient psychiatry service, has received cognitive-behavioral therapy to address coping skills, and is doing well as of last contact. Here we present the first documented case of asenapine overdose with a known quantity and route of administration. Six previous cases of asenapine overdose have been noted at doses up to 400 mg, but the exact dose and route were not known.4 Similar to those cases, no specific adverse drug effects were observed. Notably, the bioavailability of asenapine is less than 2% when administered orally, compared to approximately 35% when given sublingually; this patient did not administer his overdose sublingually.4 Thus, despite ingesting 740 mg of asenapine, he was exposed to only the equivalent of 4 sublingual doses. Despite the large number of tablets and considerable concern from the ED, asenapine appears to be safe in overdose situations, likely due to its pharmacokinetic profile.