HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Pollak, P. T. Articles by Shafer, S. L. Search for Related Content PubMed PubMed Citation Articles by Pollak, P. T. Articles by Shafer, S. L. Social Bookmarking                   What's this?

Teaching Application of Clinical Pharmacology Skills Using Unusual Observations from Clozapine Overdoses

From the Department of Medicine, Queen Elizabeth II HSC, Dalhousie University, Halifax, Nova Scotia, Canada (Dr. Pollak); Department of Anesthesiology, Stanford University, Palo Alto, California (Dr. Shafer); and Department of Biopharmaceutical Science, University of California at San Francisco, Anesthesiology Service, Palo Alto VA Health Care System, Palo Alto, California (Dr. Shafer).

Address for reprints: P. Timothy Pollak, Suite 406 Bethune Building, Queen Elizabeth II HSC, Victoria General Site, 1278 Tower Road, Halifax, Nova Scotia, Canada B3H 2Y9.

	ABSTRACT

TOP ABSTRACT CASE METHODS DISCUSSION APPENDIX ACKNOWLEDGEMENTS REFERENCES

 
Massive drug overdoses provide a unique opportunity to observe human pharmacokinetic data not otherwise ethically available. They can also provide practical examples for teaching thoughtful application of the principles of clinical pharmacology. Following a case of clozapine overdose in which onset of toxicity was delayed by 72 hours, a probable explanation was found in an exploration of three cases with unusual concentration-time profiles and revealed unexpected implications for the management of clozapine overdoses. The authors systematically addressed the possible mechanisms proposed in the literature for an unusual plateau in concentrations observed in three clozapine overdoses. The effects that the most commonly suggested explanations (i.e., delayed absorption and saturated or impaired metabolism) would have on both clozapine and norclozapine concentrations were then modeled using the data available from those three cases to provide an objective illustration for comparison. This exercise was then used as a teaching seminar, leading students through the steps required to reach a logical explanation for the observed delayed toxicity and to consider the implications for therapy. Delayed absorption best predicted the sustained serum clozapine and norclozapine concentrations observed in three cases, and modeling suggests that much of the drug remains in the gut, available for absorption for days following an overdose. As a seminar, the exercise provides students with a practical example of the value of systematically ruling out possible explanations by considering what effects various pharmacokinetic alterations would have on observed data. Absorption following massive clozapine overdose appears fundamentally different from that with conventional dosing. This suggests a potential for delayed or prolonged toxicity, extending well beyond the time frame predicted by its half-life, unless aggressive and sustained efforts are applied to remove clozapine from the gut. Data from drug overdoses provide opportunities to explore unusual aspects of pharmacokinetics, better understand future overdoses of the same agent, and present excellent material for teaching. A seminar illustrating the role that thoughtful application of pharmacologic principles had in addressing this case is now used to introduce the clinical aspects of pharmacology to students at our institutions.

Key Words: Clozapine • pharmacokinetics • safety • overdose

Clozapine (Clozaril®), a tricyclic dibenzothiazepine, is considered an atypical antipsychotic agent because it produces minimal extrapyramidal side effects, no tardive dyskinesia, and no prolactin elevation.1 It is highly effective in controlling schizophrenia and would be more widely used except for a 2% occurrence of serious agranulocytosis.2,3 Data on its pharmacokinetics are limited. In chronic schizophrenic patients, mean half-life was 10.5 hours, and volume of distribution was 7 L/kg.4 First-pass hepatic metabolism reduces systemic bioavailability by 50%, and it is highly protein bound.5 Metabolism is chiefly via the hepatic cytochrome P450 isozymes—CYP3A4, CYP2C19, and CYP2D6—to norclozapine (N-desmethylclozapine) and inactive N-oxide clozapine.6 Clozapine has less binding to muscarinic receptors than traditional antipsychotic agents, but anticholinergic effects are still seen at high doses.1,7 Typical symptoms of overdose include sedation, tachycardia, hypersalivation, and hypothermia.8 Reduced gastrointestinal motility would also be an expected adverse effect of clozapine overdose.

To understand the possible mechanism for the delayed onset of toxicity in a case of clozapine overdose, we analyzed data available to us from three cases in which prolonged toxicities were observed.9-11 The concentration-time plots of clozapine and norclozapine for the three cases (Figure 1) all demonstrated sustained plateaus lasting up to 4 days. The process of addressing these unusual observations provided both unexpected mechanistic implications that could affect the way clozapine overdoses are managed and a practical teaching example of a thoughtful application of the principles of clinical pharmacology.

View larger version (18K): [in this window] [in a new window]   Figure 1. Concentration-time profiles for clozapine (upper graph) and norclozapine concentrations (lower graph) from cases of overdose reported by British (, ——), Canadian (,---), and Swedish (,....) investigators.

	CASE

TOP ABSTRACT CASE METHODS DISCUSSION APPENDIX ACKNOWLEDGEMENTS REFERENCES

 
A 33-year-old Caucasian woman was admitted to the emergency department following a witnessed clozapine overdose. She had a history of more than 30 presentations for self-inflicted harm, and a year earlier, she had been diagnosed with schizoaffective and borderline personality disorders. Following an argument with her boyfriend, she had taken 20 clozapine 100-mg tablets in his presence. He immediately called emergency medical services, and she arrived at the emergency department within 20 minutes of the ingestion, fully conscious, with a Glasgow Coma Scale of 15. Blood pressure was 145/85 mmHg, pulse 105 bpm, temperature 37°C, and weight 68 kg. Blood counts were normal, with a white cell count of 5.6 10⁹/L, hemoglobin of 145 g/L, and platelets of 219 10⁹/L. Serum electrolytes were normal, with a potassium of 3.5 mmol/L and creatinine of 71 µmol/L. EKG demonstrated sinus tachycardia. Urine screen was negative for tricyclic antidepressants, benzodiazepines, barbiturates, opiates, amphetamines, cannabinoids, cocaine, and phencyclidine, and blood analysis did not detect acetaminophen, acetylsalicylic acid, or ethanol. A single 200-mL bottle of premixed activated charcoal 50 g/sorbitol 180 g was administered orally, an IV was established, and normal saline with KCl 10 meq/L was administered at 150 mL/h. Because her vital signs were stable, it was elected not to intubate or lavage her. Following an uneventful overnight observation, the patient was transferred to the psychiatric hospital for further assessment because she was fully conscious, with a heart rate of 80 bpm and a blood pressure of 120/80 mmHg. However, 72 hours after admission, the psychiatric staff sought medical help because she had become noncommunicative and obtunded and developed hypersalivation. Heart rate rose to 120 bpm, with a blood pressure of 108/68 mmHg, and temperature fell to 35.9C. She slowly recovered over the next 24 hours without further intervention. Although serum clozapine concentrations would have been very helpful in determining the cause of this episode, they were not ordered during the initial presentation because of her seemingly benign presentation and were not ordered during the deterioration in her condition because it was assumed that the incident could not be connected to an overdose 3 days previous.

	METHODS

TOP ABSTRACT CASE METHODS DISCUSSION APPENDIX ACKNOWLEDGEMENTS REFERENCES

 
In the course of reviewing possible explanations for this case, we accessed data from three cases of clozapine overdose that had shown unexpected delays in the reduction of serum parent and metabolite concentrations. To ascertain the meaning of these unusual concentration-time observations, we followed a stepwise approach in answering the following questions:

1. Were these observations factitious? We examined the possibility of lab error at our center11 by reviewing the liquid chromatography assay procedure12 with the director of the laboratory. Quality control measures on the days of the assay showed no evidence of errors.
   
2. Were the observations internally consistent? No dramatic fluctuations in consecutive data points for either the parent or metabolite concentrations were identified that might have indicated outliers or measurement errors in the cases.
   
3. Was the observed plateau externally consistent (i.e., was the sustained elevation observed in the case that was reported at our center a random or unique observation)? A search of Medline for other reports of clozapine overdose in which serial serum concentrations were documented had revealed only two other cases.9,10 The data from these cases were kindly provided by the respective authors. The characteristics of the overdoses observed in Britain, Canada, and Sweden, respectively, are listed in Table I, and their concentration-time curves are illustrated in Figure 1. These data provided reasonable confirmation that sustained concentrations following clozapine overdose represent a real phenomenon.
   
4. Could the observed period of sustained concentrations be explained by a plausible change in pharmacokinetic parameters that is related to the extreme conditions developed in overdose? Possible mechanisms mentioned in the literature included nonlinearity of kinetics, enterohepatic recirculation, delayed absorption, and limitation or inhibition of elimination.
   

These steps are retraced in presenting this case as a teaching seminar. The students are reminded of the importance of considering the validity of the data. Then, the initial graphical exploration of the data from the three reports (Figure 1) is presented. Faced with an unusual observation that could not be explained as data error, the students are then asked to discuss plausible pharmacokinetic explanations and describe what features of the data support their ideas. With several explanations under consideration, the pattern of concentration change is discussed. It can be seen that in each case, there was an initial and a terminal period of decline in concentrations that was consistent with the published rate of elimination. Since the unexpected observations occurred only in the middle period, nonlinearity can be discarded, as this would have most affected the initial rate of decline when concentrations were highest. Enterohepatic recirculation could also be discarded because it would have been expected to produce a normal slope of decline, with superimposed undulations in concentrations related to emptying of the gall bladder rather than a prolonged plateau. This leaves the two mechanisms most commonly proposed by the students: delayed absorption and saturated or impaired metabolism. The latter is usually more attractive to the students and has been suggested as resulting from drug interaction or self-inhibition of metabolism in the literature. To facilitate discussion of these mechanisms, we used models developed in NONMEM13 to produce Figures 2 and 3. These models demonstrate how well each of the proposed mechanisms could explain the observed concentrations in each of the cases in which data were available. In addition, the input and output rates required to approximate the observed concentrations using each of the mechanisms can be illustrated from the model outputs. The students do not have to understand the mechanics of nonlinear mixed-effects modeling to be able to appreciate the implications of the results. For those interested in the assumptions used to construct the models, they are made available after class and are included in the appendix of this article.

View larger version (16K): [in this window] [in a new window]   Figure 2. A variable absorption model of clozapine overdose. In the upper graph, the observed data for both parent () and metabolite concentrations () are seen to be well described by the lines fit from the variable absorption model. The lower graphs show the pattern of absorption necessary to explain the observed concentrations, an early rapid absorption of clozapine, a subsequent decline in absorption rate, and then a prolonged period of relatively constant delayed absorption.

View larger version (16K): [in this window] [in a new window]   Figure 3. A variable elimination model of clozapine overdose. In the upper graph, the observed data for both parent () and metabolite concentrations () are seen to be less successfully described by the lines fit from the variable elimination model than from the variable absorption model. The lower graphs show the pattern of elimination necessary to approximate the observed concentrations, an abrupt drop in clozapine metabolism followed by an abrupt return to normal metabolism, and then a return to normal elimination during the terminal portion of the observations.

Figures 2 and 3 provide a basis for objective discussion of the two competing hypotheses that might explain a delayed elevation of clozapine concentrations. Figure 2 shows the clear superiority of the variable absorption model in predicting the observed concentrations. In addition to describing the sustained plateau of both clozapine and norclozapine concentrations in each case, the absorption rate function, depicted in the lower plot, could be reasonably explained as drug retained in the gut. In contrast, Figure 3 shows that the variable elimination model performed poorly at predicting the parent and metabolite concentrations for the Canadian and Swedish data. It did better for the British patient who had a short plateau, more closely approximating a steady decline in concentrations. The rates of elimination, depicted in the lower graphs of Figure 3, show that the variable elimination model would require a profound depression of metabolism followed by an almost instantaneous recovery to normal elimination, a pattern for which a physiological correlate would be difficult to postulate.

To demonstrate that the models presented to the students were a reasonable approximation of the actual pharmacokinetics of the cases, the ingested doses were estimated for the British, Canadian, and Swedish cases. Based on the assumption of 100% absorption from the gut and a volume of distribution of 490 L,4 these estimates were 3070, 1780, and 4990 mg for the variable absorption model and 2459, 1114, and 1008 mg for the variable elimination model. All estimates were within the same magnitude as the reported ingestions of 4000, 3500, and 2500 mg. Elimination rate constants estimated by the model ranged from 0.035 to 0.040 h^-1,corresponding to half-lives between 17 and 20 hours, values within the range found with therapeutic clozapine use.4,14

	DISCUSSION

TOP ABSTRACT CASE METHODS DISCUSSION APPENDIX ACKNOWLEDGEMENTS REFERENCES

 
Clozapine overdose is an infrequent occurrence, and therefore many aspects of its management are incompletely understood. However, application of clinical pharmacology skills to data from three previous clozapine overdoses provided a probable explanation for the delayed onset of toxicity in this clozapine overdose. The stepwise analysis demonstrating that delayed absorption of clozapine from the gut was the most plausible explanation of delayed toxicity also proves to be a useful student seminar. While modeling tools were used to demonstrate effects of varying pharmacokinetic input and output parameters, students do not need to understand the details of the modeling process to appreciate the arguments being illustrated by them.

A seminar based on this analysis coaxes students to follow a methodical approach to interpreting data and illustrates the pitfalls of not examining both the validity of the data and all possible explanations in turn. The effect of time-varying changes in each parameter in the disposition of the drug and metabolite is discussed. For example, in these data, nonlinear pharmacokinetics and enterohepatic recirculation could be eliminated as explanations by inspecting the concentration-time profiles. Changes in volume of distribution could not logically account for a 4-day plateau in serum concentrations, as this would require a continuous change in volume at a rate exactly inverse to the amount of drug leaving the system. This leaves for consideration only factors influencing the amount of drug in the system: dose, absorption, metabolism, and elimination. These can loosely be grouped into input and output factors and compared in the models supplied to the students.

For these models, dose was permitted to vary as a scaling parameter since, aside from being obviously large, little is known with certainty about a suicidal dose. The amount of drug available for absorption may also be confounded by gastric lavage and charcoal administration if done soon enough or often enough. Two other points were also addressed. First, whatever the pharmacokinetic abnormality, it had affected both the parent and the metabolite in a like manner. Second, as already concluded by Hagg et al9 and Renwick et al,10 the cause of the plateau clearly involved changes in either absorption or elimination over time. Given Occam's razor, favoring the simplest explanation, we elected not to permit simultaneous alterations of both absorption and elimination in our models. This provided us with two models clearly illustrating the pure effects of changing absorption with changing elimination over time.

As demonstrated in Figure 2, the model of time-varying absorption proved best at predicting the observed concentrations. The obvious implication is that drug absorption must persist beyond the normally expected period after the overdose. The absorption rate function for this model (Figure 2) showed a dramatic decrease for several hours after drug administration, the time during which drug may have been retained in the upper gastrointestinal tract with little absorption. This was followed by a relatively steady input of drug consistent with both parent and metabolite serum concentrations being maintained in a steady-state plateau. Since the atropinic affects of clozapine may well limit its own movement through the gastrointestinal system,1 a concretion of tablets with a limited surface area could be slowed in transiting the gastrointestinal tract. The resultant rate-limited absorption could logically be the physiologic explanation for availability of drug long after the normal period of absorption and an approximate zero-order input of drug producing the plateau period days after the overdose.

Students examining Figure 3 can see, in contrast, that the time-varying elimination model was unable to fit parallel concentrations of parent and metabolite. Since greatly reducing the metabolism of the parent drug would have caused a dramatic fall in metabolite concentrations, the model was not free to shut off production of norclozapine to fit a sustained plateau in the parent drug concentrations. Thus, the model objectively demonstrates that the parallel nature of the parent and metabolite concentrations ultimately precludes time-varying metabolism as a logical explanation for these unusual observations.

While the unusual nature of the concentration-time data from these cases provides an interesting teaching example that focuses on the pharmacokinetic aspects of overdose, pharmacodynamic considerations relative to these cases could also be discussed in another seminar. Central to the explanation put forward in this seminar is the concept of prolonged gastrointestinal transit time and the existence of a conglomeration of tablets with a surface area that would limit rapid uptake of the drug. Many medical conditions, such as hypothyroidism, can affect gastrointestinal motility and therefore drug absorption both in regular therapy and in overdose. Patients receiving other classes of drugs that reduce gastrointestinal motility, including opioids, catechol-O-methyltransferase inhibitors, calcium channel blockers, and nonsteroidal antiestrogens (e.g., toremifene), might also have altered absorption during an overdose. Adverse effects have always complicated the treatment of schizophrenia with antipsychotic agents. The Parkinsonian effects related to the antidopaminergic activity of these agents often result in therapy with anticholinergic agents such as benztropine. Although such agents were not involved in the cases analyzed, they could potentially complicate an overdose situation by reducing gastrointestinal motility.15 Unfortunately, there is no simple way of predicting the degree of reduced gastrointestinal motility associated with various antipsychotic agents. Some classical older agents, such as haloperidol, have trivial anticholinergic effects, while others, such as chlorpromazine, are quite potent.16 Some newer, atypical agents, such as quetiapine, have low anticholinergic potential, while olanzapine and clozapine are both quite anticholinergic.1 Therefore, in any overdose of antipsychotic agents, it is important to look up the specific pharmacological profile for the drug involved. The effects of clozapine and norclozapine on the gastrointestinal motility in a given patient must therefore reflect a complex interaction between their intrinsic anticholinergic effects and gastrointestinal effects of any other medications or medical conditions affecting them. However, none of these factors played a role in the overdose cases examined for this seminar.

Drug overdose presents unique challenges for pharmacokinetic analysis that are related to the magnitude of the administered dose, the uncertainty surrounding dose administration, and the sparse numbers of subjects (often 1) and data points. However, the exercise of analyzing data from a massive overdose, as outlined here, does provide students with a practical demonstration of the value of clinical pharmacology skills. While the data from any given case of overdose would not be available to aid acute therapy, systematic consideration of the available concentration-time data could have clear implications for the future management of overdoses. In this example, it suggests that delayed or prolonged toxicity should always be considered as a potential problem with clozapine overdose. Therefore, concerted efforts at effective gastric lavage and limitation of drug absorption would be useful in these cases if they could be done safely. Unfortunately, whole-bowel irrigation and multi-dose-activated charcoal administration are not without risk, and their application remains a controversy in the emergency medicine literature.11,17,18 As methods for reducing the availability of excessive drug from the gastrointestinal tract become safer and more reliable, they would certainly be of benefit in reducing the kind of delayed toxicity observed in this case and avoiding the prolonged hospitalization seen in the three cases from which concentration data were analyzed. At present, the decision to proceed with gut decontamination protocols will remain a difficult risk-benefit decision faced by the emergency room physician, but there is a strong indication of a benefit to be gained, even many hours after ingestion. Once admitted, the possibility of delayed toxicity should also not be forgotten.

	APPENDIX

TOP ABSTRACT CASE METHODS DISCUSSION APPENDIX ACKNOWLEDGEMENTS REFERENCES

 
Description of NONMEM Models
The task of to constructing illustrations to comparing the ability of delayed absorption versus delayed excretion to predict the observed concentration-time curves was accomplished by models that used the following assumptions:

1. Independent estimation of the total dose, systemic bioavailability (f), and the systemically delivered dose (total dose x f) would not be possible from the available data.
   
2. If all of the dose left in the gut was eventually absorbed into the portal system, it is possible to estimate f and ingested dose from a model of both the parent and metabolite. It was unlikely that drug was lost from the gut as these patients often do not have bowel movements for many days after the overdose.11
   
3. Systemic bioavailability, f, is assumed to equal 1 - ER, with ER being the hepatic extraction ratio, calculated from the estimated clearance/liver blood flow (90 L/h).
   
4. The volume of distribution (7 L/kg) was fixed at 490 L for the model.4
   
5. The shape of the concentration versus time curve for both the parent drug (clozapine) and the metabolite (norclozapine) reflects the balance between absorption, first-pass metabolism, and elimination of the parent and metabolite. The magnitude of the observations in similarly shaped curves reflects the relative size of the ingested dose.
   
6. The rate of metabolite formation minus the input from first-pass metabolism of the parent cannot exceed the rate of parent drug elimination (i.e., mass balance will be respected).
   
7. The metabolites are lost from the system through bile and urine and are not further metabolized by a process that could be inhibited metabolically.
   
8. Within the resolution of the available blood samples, the pharmacokinetic properties of clozapine are adequately described by a simple one-compartment system having one input rate constant and one elimination rate constant. A compartment representing the drug depot in the gut completes the model.
   
9. The pharmacokinetics of norclozapine can be adequately described by linking the above clozapine model to a one-compartment model of norclozapine formation and elimination.
   

Two variations on the model were explored: one in which absorption was variable (e.g., saturable absorption, persistence of a concretion of tablets, reduced peristalsis) and one in which elimination was variable (e.g., saturable metabolism, drug interaction, or self-inhibition). The structure of the models is shown in Figure 4 and described as follows.

View larger version (21K): [in this window] [in a new window]   Appendix Figure 1. The compartmental model of clozapine and norclozapine pharmacokinetics used to compare the effects of delayed absorption to delayed elimination. A depot (compartment 1) functions as the input to a one-compartment model of clozapine (compartment 2), which serves as an input to a one-compartment model of norclozapine metabolite concentrations (compartment 3) along with the contribution from first-pass metabolism. ER is the extraction ratio, and the subscripted constants (k) describe intercompartmental rate constants.

Variable Absorption Model
The absorption rate constant, k_a, was allowed to vary from zero to infinity for each interval between observations, while the elimination rate constant, k₂₀, was estimated and fixed over time. The changes to amounts in three compartments—A₁, A₂, A₃—were modeled with the following equations.

Compartment 1 (gut depot):

A₁ at time 0 = dose (allowed to float as required to fit the data).

Compartment 2 (serum clozapine):

Compartment 3 (serum norclozapine):

where represents norclozapine formed during first-pass metabolism, is the fraction of norclozapine formation to total metabolite formation, and k₂₃ < k₂₀, as required for mass balance.

where

k_a,i = the absorption rate constant over the ith interval. Once the observed clozapine concentrations began to decrease in a log-linear manner (e.g., after 114 h for the Canadian patient), the absorption rate constant was constrained to be the same from interval to interval.

k₂₀ = the clozapine elimination rate constant from the serum, determined directly from the terminal slope of the log(clozapine) versus time graphs.

k₂₃ = the rate constant for the formation of norclozapine from clozapine. As norclozapine cannot be formed any faster than clozapine is eliminated, k₂₃ was constrained to be less than or equal to k₂₀ to preserve mass balance.

k₃₀ = the elimination rate constant for norclozapine.

V_metab = the norclozapine distribution volume.

Variable Elimination Model
The elimination rate constant, k₂₀, was allowed to vary from zero to infinity for each interval between observations, while the absorption rate constant, k_a, was estimated and held constant over time. The changes to amounts in three compartments—A₁, A₂, A₃—were modeled with the following equations.

Compartment 1 (gut depot):

A₁ at time 0 = dose (allowed to float as required to fit the data).

Compartment 2 (serum clozapine):

Compartment 3 (serum norclozapine):

where

k_a = the absorption rate constant.

k_{20, i} = the clozapine elimination rate constant over the ith interval. Once the clozapine concentrations entered the terminal log-linear phase (e.g., after 114 h for the Canadian patient), k₂₀ was constrained to equal the terminal slope estimated from the log(clozapine) versus time graphs.

k₂₃, k₃₀, and V_metab are defined as for the variable absorption model above.

The parameters of the two models were estimated using NONMEM.13 The residual error was modeled using a "constant coefficient of variation" model. The two models had an identical number of parameters. Thus, an apparent improvement in the fit of either model over the other could not be attributed to increased numbers of parameters.

	ACKNOWLEDGEMENTS

TOP ABSTRACT CASE METHODS DISCUSSION APPENDIX ACKNOWLEDGEMENTS REFERENCES

 
The authors wish to thank Dr. Albert D. Fraser, head of the Drug Monitoring Laboratory, QEII Health Sciences Centre (Halifax, Canada), for his consultation regarding the analysis of clozapine in the Canadian overdose case. They also thank Drs. Staffan Hägg, Olav Spigset, Hakan Edwardsson, and Henrik Bjork of Sweden and Drs. Amanada Renwick, Andrew Renwick, Robert Flanagan, and Robin Ferner of England for graciously allowing them access to the concentration-time data from their respective acute overdoses.

	FOOTNOTES

 
Dr. Pollak is supported by the Dalhousie Clinical Scholarship.

DOI: 10.1177/0091270003262106

Submitted for publication June 4, 2003; Revised version accepted November 30, 2003.

	REFERENCES

TOP ABSTRACT CASE METHODS DISCUSSION APPENDIX ACKNOWLEDGEMENTS REFERENCES

 

1. Richelson E: Receptor pharmacology of neuroleptics: relation to clinical effects. J Clin Psychiatry 1999;10: 5-14.

2. Anderman B, Griffith RW: Clozapine-induced agranulocytosis: a situation report up to August 1976. Eur J Clin Pharmacol 1977;11: 199-201.[CrossRef][Medline] [Order article via Infotrieve]

3. Kinon BJ, Lieberman JA: Mechanisms of action of atypical antipsychotic drugs: a critical analysis. Psychopharmacology (Berl) 1996;124: 2-34.[CrossRef][Medline] [Order article via Infotrieve]

4. Guitton C, Kinowski JM, Abbar M, Chabrand P, Bressolle F: Clozapine and metabolite concentrations during treatment of patients with chronic schizophrenia. J Clin Pharmacol 1999;39: 721-728.[Abstract]

5. Baldessarini RJ, Frankenburg FR: Clozapine: a novel antipsychotic agent. N Engl J Med 1991;324: 746-754.[Web of Science][Medline] [Order article via Infotrieve]

6. Linnet K, Olesen OV: Metabolism of clozapine by cDNA-expressed human cytochrome P450 enzymes. Drug Metab Dispos 1997;25: 1379-1382.[Abstract/Free Full Text]

7. Jann MW: Clozapine. Pharmacotherapy 1991;11: 179-195.[Medline] [Order article via Infotrieve]

8. Le Blaye I, Donatini B, Hall M, Krupp P: Acute overdosage with clozapine: a review of the available clinical experience. Pharm Med 1992;6: 169-178.

9. Hagg S, Spigset O, Edwardsson H, Bjork H: Prolonged sedation and slowly decreasing clozapine serum concentrations after an overdose [letter]. J Clin Psychopharmacol 1999;19: 282-284.[Medline] [Order article via Infotrieve]

10. Renwick AC, Renwick AG, Flanagan RJ, Ferner RE: Monitoring of clozapine and norclozapine plasma concentration-time curves in acute overdose. J Toxicol Clin Toxicol 2000;38: 325-328.[Medline] [Order article via Infotrieve]

11. Thomas L, Pollak PT: Delayed recovery associated with persistent serum concentrations after clozapine overdose. J Emerg Med 2003;25: 61-6.[Medline] [Order article via Infotrieve]

12. Avenoso A, Facciola G, Campo GM, Fazio A, Spina E: Determination of clozapine, desmethylclozapine and clozapine N-oxide in human plasma by reversed-phase high-performance liquid chromatography with ultraviolet detection. J Chromatogr B Biomed Sci Appl 1998;714: 299-308.[Medline] [Order article via Infotrieve]

13. Sheiner LB, Beal SL: Evaluation of methods for estimating population pharmacokinetic parameters: III. Monoexponential model: routine clinical pharmacokinetic data. J Pharmacokinet Biopharm 1983;11: 303-319.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

14. Byerly MJ, DeVane CL: Pharmacokinetics of clozapine and risperidone: a review of recent literature. J Clin Psychopharmacol 1996;16: 177-187.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]

15. Grace RF: Benztropine abuse and overdose—case report and review. Adverse Drug React Toxicol Rev 1997;16: 103-112.[Medline] [Order article via Infotrieve]

16. Sneader W: The 50th anniversary of chlorpromazine. Drug News Perspect 2002;15: 466-471.[Medline] [Order article via Infotrieve]

17. Tenenbein M: Position statement: whole bowel irrigation. American Academy of Clinical Toxicology; European Association of Poisons Centres and Clinical Toxicologists. J Toxicol Clin Toxicol 1997;35: 753-762.[Web of Science][Medline] [Order article via Infotrieve]

18. Chyka PA: Multiple-dose activated charcoal and enhancement of systemic drug clearance: summary of studies in animals and human volunteers. J Toxicol Clin Toxicol 1995;33: 399-405.[Web of Science][Medline] [Order article via Infotrieve]
CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Request Reprints Citing Articles Citing Articles via ISI Web of Science (2) Citing Articles via Google Scholar Google Scholar Articles by Pollak, P. T. Articles by Shafer, S. L. Search for Related Content PubMed PubMed Citation Articles by Pollak, P. T. Articles by Shafer, S. L. Social Bookmarking                   What's this?