Dose-related Phenomenon Research Articles

New Genetic Link May Identify Mechanism Behind Clozapine Agranulocytosis

Back to table of contents Previous article Next article Clinical and Research NewsFull AccessNew Genetic Link May Identify Mechanism Behind Clozapine AgranulocytosisNick ZagorskiNick ZagorskiSearch for more papers by this authorPublished Online:18 Aug 2016https://doi.org/10.1176/appi.pn.2016.8a29AbstractA genome-wide scan of over 5,000 schizophrenia patients identifies a potential role for a liver transporter linked with a similar white blood cell problem induced by the chemotherapy drug docetaxel.Agranulocytosis is a rare but potentially fatal problem in which the levels of white blood cells in the blood drop rapidly. Unfortunately, agranulocytosis is one of the potential side effects of taking clozapine, which has limited the use of the antipsychotic despite its proven benefits. Two years ago, an analysis of the genetic data from over 160 people who experienced clozapine-induced agranulocytosis (CIAG) by an international research consortium revealed two genes associated with an increased risk of this adverse effect—a finding that could one day help to develop a predictive screen for the disorder (Psychiatric News, October 3, 2014).Researchers in the United Kingdom recently analyzed the genomes of nearly 5,500 schizophrenia patients taking clozapine, which included 66 patients whose blood cell counts dropped below normal levels. This analysis also identified several potential genetic variants linked with an increased risk of white blood cell loss following clozapine use, including one near HLA-DBQ—a critical immune-related gene that was identified in the 2014 study. The findings were published July 12 in Molecular Psychiatry.Fred Jarskog, M.D., a professor of psychiatry at the University of North Carolina School of Medicine and one of the members of the consortium behind the 2014 study, told Psychiatric News that these latest findings validate the association between HLA-DBQ and CIAG. “In some ways, though, the more exciting news emerged after the U.K. group reached out to our team [led by Patrick Sullivan, M.D., the director of UNC’s Psychiatric Genetics program] to discuss pooling our respective data,” Jarskog said. When all 239 cases were compared with controls, a new variant associated with clozapine-associated white blood cell loss emerged, in between a pair of genes called SLCO1B1 and SLCO1B3. Both these genes encode transport proteins that help the liver absorb a wide variety of compounds, including drugs, for subsequent metabolism. While neither of these genes has previously been linked with clozapine responses, they both have strong connections to adverse events brought on by other medications; SLCO1B1 variants are associated with the risk of muscle problems in statin users, while SLCO1B3 variants are interestingly linked to the loss of white blood cells in patients taking the chemotherapy drug docetaxel.“In the case of docetaxel, the evidence points to a dose-related phenomenon, where higher drug concentrations in the blood lead to worse cell loss,” Jarskog told Psychiatric News. Jarskog said it would be worthwhile to see whether a similar dose-dependent profile exists for CIAG, thus confirming some metabolic influence on this disorder. However, he noted that determining whether such a relationship exists could prove challenging given the rarity of CIAG compared with docetaxel-induced white blood cell loss.“For our samples, we have the information on the clozapine dosage for each patient, but not how the drug was being metabolized in the body,” he said. “It took a major international effort to reach the point of having data for over 200 cases of this disorder,” he continued. “For the time being we have to work with what we got.”The fact that clozapine-associated white blood cell loss is relatively rare also means that even with this new genetic information, it will likely be some time before researchers achieve the ultimate clinical goal of developing a screen that can identify patients who are susceptible to this side effect of the medication. The authors of the Molecular Psychiatry report calculated that a genomic test incorporating the HLA and SLCO1B variants would be about only 10 percent accurate at detecting whether a person might develop significant white blood cell loss while taking clozapine, as a majority of people who develop this side effect do not carry any of the currently identified risk alleles.This study was funded by grants from the Medical Research Council. ■“Genome-Wide Common and Rare Variant Analysis Provides Novel Insights Into Clozapine-Associated Neutropenia” can be accessed here. ISSUES NewArchived

Antipsychotic-induced akathisia in delirium: A systematic review.

Akathisia is a neuropsychiatric syndrome characterized by subjective and objective restlessness. It is a common side effect in patients taking antipsychotics and other psychotropics. Patients with delirium are frequently treated with antipsychotic medications that are well known to induce akathisia as a side effect. However, the prevalence, phenomenology, and management of akathisia in patients with delirium remain largely unknown. The purpose of this review was to examine the medical literature in order to establish the current state of knowledge regarding the prevalence of antipsychotic-induced akathisia in patients with delirium. A systematic review of the literature was conducted using the EMBASE, MEDLINE, PsycINFO, and CINAHL databases. Ten studies addressing the incidence of akathisia in patients taking antipsychotic medication for delirium were identified and included in our review. The included studies reported a variable prevalence of antipsychotic-induced akathisia. A higher prevalence was found in patients taking haloperidol. Among atypical antipsychotics, paliperidone and ziprasidone were associated with a higher risk of akathisia. The risk for akathisia appeared to be a dose-related phenomenon. Studies using specific scales for evaluation of akathisia in delirium are lacking. Some populations, such as patients with cancer or terminally ill patients in palliative care settings taking antipsychotics for the treatment of delirium, could be at higher risk for development of akathisia as a side effect.

Thresholds in chemical respiratory sensitisation

There is a continuing interest in determining whether it is possible to identify thresholds for chemical allergy. Here allergic sensitisation of the respiratory tract by chemicals is considered in this context. This is an important occupational health problem, being associated with rhinitis and asthma, and in addition provides toxicologists and risk assessors with a number of challenges. In common with all forms of allergic disease chemical respiratory allergy develops in two phases. In the first (induction) phase exposure to a chemical allergen (by an appropriate route of exposure) causes immunological priming and sensitisation of the respiratory tract. The second (elicitation) phase is triggered if a sensitised subject is exposed subsequently to the same chemical allergen via inhalation. A secondary immune response will be provoked in the respiratory tract resulting in inflammation and the signs and symptoms of a respiratory hypersensitivity reaction. In this article attention has focused on the identification of threshold values during the acquisition of sensitisation. Current mechanistic understanding of allergy is such that it can be assumed that the development of sensitisation (and also the elicitation of an allergic reaction) is a threshold phenomenon; there will be levels of exposure below which sensitisation will not be acquired. That is, all immune responses, including allergic sensitisation, have threshold requirement for the availability of antigen/allergen, below which a response will fail to develop. The issue addressed here is whether there are methods available or clinical/epidemiological data that permit the identification of such thresholds. This document reviews briefly relevant human studies of occupational asthma, and experimental models that have been developed (or are being developed) for the identification and characterisation of chemical respiratory allergens. The main conclusion drawn is that although there is evidence that the acquisition of sensitisation to chemical respiratory allergens is a dose-related phenomenon, and that thresholds exist, it is frequently difficult to define accurate numerical values for threshold exposure levels. Nevertheless, based on occupational exposure data it may sometimes be possible to derive levels of exposure in the workplace, which are safe. An additional observation is the lack currently of suitable experimental methods for both routine hazard characterisation and the measurement of thresholds, and that such methods are still some way off. Given the current trajectory of toxicology, and the move towards the use of non-animal in vitro and/or in silico) methods, there is a need to consider the development of alternative approaches for the identification and characterisation of respiratory sensitisation hazards, and for risk assessment.

Acceptably aware during general anaesthesia: 'dysanaesthesia'--the uncoupling of perception from sensory inputs.

This review makes the case for 'dysanaesthesia', a term encompassing states of mind that can arise in the course of anaesthesia during surgery, characterised by an uncoupling of sensation and perceptual experience. This is reflected in a macroscopic, functional model of anaesthetically-relevant consciousness. Patients in this state can be aware of events but in a neutral way, not in pain, sometimes personally dissociated from the experiences. This makes events associated with surgery peripheral to their whole experience, such that recall is less likely and if it exists, makes any spontaneous report of awareness unlikely. This state of perception-sensation uncoupling is therefore broadly acceptable (a minimum requirement for acceptable anaesthesia) but since it is likely a dose-related phenomenon, may also represent a precursor for awareness with adverse recall. This hypothesis uniquely explains the often inconsistent responses seen during the experimental paradigm of the 'isolated forearm technique', wherein apparently anaesthetised patients exhibit a positive motor response to verbal command, but no spontaneous movement to surgery. The hypothesis can also explain the relatively high incidence of positive response to relatively direct questions for recall (e.g., using the Brice questionnaire; ∼1:500; the vast majority of these being neutral reports) versus the very low incidence of spontaneous reports of awareness (∼1:15,000; a higher proportion of these being adverse recollections). The hypothesis is consistent with relevant notions from philosophical discussions of consciousness, and neuroscientific evidence. Dysanaesthesia has important implications for research and also for the development of appropriate monitoring.

Post-kala-Azar dermal leishmaniasis: A diagnostic dilemma in a nonendemic area.

Post-kala-Azar dermal leishmaniasis: A diagnostic dilemma in a nonendemic area.

Hypomania Associated With Adjunctive Aripiprazole in an Elder Female With Recurrent Major Depressive Disorder

Hypomania Associated With Adjunctive Aripiprazole in an Elder Female With Recurrent Major Depressive Disorder

Probable Psychosis Associated With Levetiracetam: A Case Report

Probable Psychosis Associated With Levetiracetam: A Case Report

Bupropion-Induced Mania and Hypomania: A Report of Two Cases

Bupropion-Induced Mania and Hypomania: A Report of Two Cases

Melamine and its Effect on Coagulation System

A recent emerging health problem is the tainted milk from China. The contamination of melamine in milk was reported to relate to death of several infants exposed to the problematic product [1]. The renal pathology is the main manifestation in intoxicated case. Here, the author focuses the interest on the effect of melamine on coagulation system. First, biochemically, it is well accepted that melamine can affect the coagulation system. Although there is no direct evidence that melamine can deteriorate the vascular structure or coagulation factor, suppressive to the blood platelet aggregation can be seen [2]. Second, the melamine can be directly absorbed into blood stream before passed to the nephron for excreted out. There is a chance for interaction between melamine and platelet in the blood stream. This might lead to the conclusion that melamine might cause the bleeding problem due to disturbance on coagulation system. However, this must be the dose related phenomenon. Only cases with large dose exposure can present the symptoms. This hypothesis might be a good explanation for observation on hematuria in exposed case that has no renal glomerular pathology or urolithiasis [3].

Opiate-Induced Nausea and Vomiting: What Is the Challenge?

Opiate-Induced Nausea and Vomiting: What Is the Challenge?

Hepatotoxicity in acute iron poisoning

Although liver injury is a recognized consequence of acute iron poisoning, its description is limited to several case reports. It appears to be dose-related, however, there are published reports of severe iron poisoning without liver injury. The purpose of this study is to examine the hypothesis that this is a dose-related phenomenon and to identify the serum iron concentration of risk for this outcome. The design of this study is a retrospective review of our hospital's experience over 20 years. Extracted data included demographics, time of ingestion, highest serum iron concentration and highest hepatic transaminase activity. Iron poisoning was defined as a serum iron concentration >300 microg/dL (55 micromol/L) within 12 hours of ingestion. Hepatotoxicity was defined as a serum transaminase (either ALT or AST) >150 U/L. Severe hepatotoxicity was defined >1000U/L. Seventy-three patients (1-48 years old) participated in the study and of these patients 60 (47 female) did not have hepatotoxicity. Their serum iron concentrations were 300-704 microg/dL (55-128 micromol/L). Thirteen patients had hepatotoxicity and of these patients, nine had severe liver injury. Severe injury was associated with serum iron concentrations well in excess of 1000 microg/dL (182 micromol/L). Our data support hepatotoxicity due to iron poisoning as a dose-related phenomenon with clinically important cases unlikely with a serum iron concentration of < 700 microg/dL (128 micromol/L) within the first 12 hours. Clinically important hepatotoxicity occurs with values in excess of 1000 microg/dL (182 micromol/L).

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Dopamine agonists and sleep in Parkinson's disease.

Dopaminergic therapy is increasingly recognized as a cause of excessive daytime sleepiness in patients with PD. This adverse effect may be a dose-related phenomenon that is somewhat more likely to occur with dopamine agonists than with levodopa, although all dopaminergic drugs can be sedating. However, medication effect is only one of several causes of somnolence in PD. Other factors include age-related changes in sleep quality, nocturnal motor disturbances, primary sleep disorders such as sleep apnea, medication-induced sleep disruption, and concurrent medical illnesses. There is also increasing evidence that the disease process itself may affect the control of the sleep-wake cycle. Although we have characterized the sleep disturbances in PD, further investigation is needed to define their prevalence and etiology, particularly with respect to the role of dopamine and dopaminergic agents. Clinicians should be alert to the complaint of excessive sleepiness in their patients and should attempt to identify and treat the underlying causes.

Dose discrepancies between the Physicians' Desk Reference and the medical literature, and their possible role in the high incidence of dose-related adverse drug events.

Adverse drug events (ADEs) are a major cause of morbidity and mortality, and even minor ADEs may adversely affect patients' compliance with treatment. Because most ADEs are dose-related phenomena, adjusting drug dosages to account for individual patients' needs and tolerances is fundamental to good therapeutics. To determine whether the Physicians' Desk Reference (PDR), the leading source of drug information for physicians, provides the full range of effective drug doses, especially the lowest, least ADE-prone doses of medications, for physicians to consider in treating patients. Review of dosage guidelines and dose-response information in the PDR. Comparison with dose-response data obtained from articles listed in MEDLINE from 1966 to 2000. For many types of medications, physicians are frequently advised to use the lowest effective doses of drugs, especially initially. Yet, effective low doses determined in prerelease studies or in postrelease work are often omitted from the PDR, even when they have been recommended by expert panels. Optimal therapeutics depends on the availability of comprehensive information. However, the PDR contains only the limited dose information from package inserts. Because the PDR was originally developed as a promotional device, there is no mechanism by which all clinically relevant dose-response data or important postrelease discoveries are regularly and rapidly incorporated into it. Thus, a gap exists in the availability of current and comprehensive dose information for physicians. This article provides information on lower, effective doses for 48 major medications, with an extensive reference list-a compilation of low-dose information not previously published, to our knowledge, in the medical literature. Physicians must have a readily accessible source of current and complete dose-response information to individualize drug therapy and minimize the risks of ADEs.

Hepatotoxicity in acute iron poisoning.

Although hepatotoxicity is a known sequela of acute iron poisoning, the literature describing it is confined to sporadic reports. Key issues such as prognosis and whether this is a dose-related phenomenon are not addressed. Review of this literature and of experimental animal studies demonstrates that it occurs early in the clinical course and has a relatively high mortality. The lowest acute serum iron concentration associated with hepatotoxicity was 1700 microg/dL (304 micromol/L). Since this greatly exceeds the reference range of 50-150 microg/dL (9-27 micromol/L), it supports a dose-related etiology. Unlike most other hepatotoxins, the periportal areas of the hepatic lobule are the primary sites of injury. As this is the principle sitefor hepatic regeneration, this accountsfor the relatively high mortality rate. An understanding of the pathogenesis of the hepatotoxicity of acute iron poisoning is central to the identification of rational and effective interventions. From the clinical perspective, the relatively high mortality rate of iron poisoning-induced hepatotoxicity requires vigilance for its onset and earlier consideration of liver transplantation.

ADR Monitoring in Children; Pancytopenia and Valproic Acid: A Dose-Related Phenomenon; Asterixis with Lithium Therapy?; Splenic Rupture Due to Subcutaneous Heparin; EPS on Clozapine?

The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), to discuss methods of prevention, and to promote reporting of ADRs to the FDA's medWatch program (1-800-FDA-1088). If you have reported an interesting preventable ADR to medWatch, please consider sharing the account with our readers.

Mania with Bupropion: A Dose-Related Phenomenon?

Mania with Bupropion: A Dose-Related Phenomenon?

Awareness during anesthesia.

MEMORY is not a single entity. Current classification distinguishes between two types: explicit, or conscious memory, and implicit, or unconscious memory. Explicit memory refers to the conscious recollection of previous experiences. Implicit memory, by contrast, refers to changes in performance or behavior that are produced by previous experiences but without any conscious recollection of those experiences. 1 Explicit memory is equivalent to remembering (e.g., can you remember what you did last Tuesday evening?). In the case of an anesthetized patient, one might ask the patient in the postoperative period can you remember hearing any words or sounds during your operation? (i.e., a recall test) or which of the following words were played to you during surgery? (a recognition test). As an example of implicit memory, consider the following scenario. Patients were exposed during anesthesia to a list of words containing the word pension.' Postoperatively, when they were presented with the three-letter word stem PEN and were asked to supply the first word that came to their minds beginning with those letters, they gave the word pension more often than pencil or peninsula or others. The term awareness' will be used to describe explicit memory during anesthesia.

Transforming growth factor-beta differentially inhibits epithelial ovarian carcinoma cells from primary and metastatic isolates without up-regulation of p21WAF1.

Transforming growth factor-beta (TGF-beta) is known to inhibit primary epithelial ovarian carcinoma cells. The mechanism by which this inhibitory response is achieved is poorly understood. Furthermore, whether this response is consistent in cells from metastatic sites compared with the primary site cells is unknown. The authors wanted to determine whether TGF-beta differentially inhibited ovarian carcinoma cells from primary tumor sites compared with metastatic sites and to establish whether this response was associated with up-regulation of p21WAF1 or overexpression of p53. Tumor cells were purified from primary and metastatic sites in five patients with advanced epithelial ovarian carcinoma. TGF-beta effect at concentrations of 10, 1, and 0.1 ng/mL was determined by tritiated thymidine incorporation assay. Expression of p21WAF1 was determined by Northern and slot blot analysis. p53 was detected by immunocytochemistry. Metastatic tumor isolates were more responsive to the inhibitory effect of TGF-beta compared with their corresponding primary tumor isolates at 0.1 ng/mL. Increasing TGF-beta concentration conferred no additional inhibitory effect on the metastatic isolates; however, a dose-related phenomenon was observed in primary tumor isolates. p21WAF1 mRNA was up-regulated in only 2 of 10 primary and metastatic isolates. There was no correlation between TGF-beta responsiveness, p21WAF1 up-regulation, and p53 overexpression. Differential inhibition was observed between primary and metastatic tumor isolates. p21WAF1 up-regulation and p53 overexpression were not major modulators in TGF-beta regulation of primary and metastatic tumor growth in early passaged ovarian carcinoma cells.

Comparative safety of teicoplanin and vancomycin

Teicoplanin have different safety profiles which can affect choice. Nephrotoxicity is significantly less likely to occur during treatment with teicoplanin than vancomycin when an aminoglycoside is being given concurrently. ‘Red man’ syndrome is a troublesome effect of vancomycin infusion which is extremely uncommon with teicoplanin use. Rash and fever can be dose-related phenomena but patients reacting to one glycopeptide may not react to both. Although thrombocytopenia is more frequent with teicoplanin, it is reversible and seldom seen at standard doses.