Travel-Acquired Leptospirosis Androula Pavli , MD, FRACGP * and Helena C. Maltezou , MD, PhD † * Ofﬁ ce for Travel Medicine and † Department for Interventions in Health-Care Facilities, Hellenic Center for Disease Control and Prevention, Athens, Greece International travel is rapidly growing worldwide. Microbiology It has been estimated that international travels Leptospi
Bardzo tanie apteki z dostawą w całej Polsce kupic levitra i ogromny wybór pigułek.
Urine drug screening: practical guide for cliniciansUrine Drug Screening:
Practical Guide for Clinicians
KAREN E. MOELLER, PHARMD, BCPP; KELLY C. LEE, PHARMD, BCPP; AND JULIE C. KISSACK, PHARMD, BCPP Drug testing, commonly used in health care, workplace, and Our goal is to provide clinically relevant information criminal settings, has become widespread during the past decade.
that can be used to interpret urine drug screens (UDSs) for Urine drug screens have been the most common method foranalysis because of ease of sampling. The simplicity of use and commonly abused drugs (ie, alcohol, amphetamines, ben- access to rapid results have increased demand for and use of zodiazepines, opioids, marijuana, cocaine, phencyclidine immunoassays; however, these assays are not perfect. False- [PCP], and tricyclic antidepressants [TCAs]). Proper positive results of immunoassays can lead to serious medical orsocial consequences if results are not confirmed by secondary evaluation of urine specimens, including detection times, analysis, such as gas chromatography–mass spectrometry. The are discussed, as well as false-positive results and potential Department of Health and Human Services’ guidelines for the false-negative results. Interpretation of tests for perfor- workplace require testing for the following 5 substances: amphet-amines, cannabinoids, cocaine, opiates, and phencyclidine. This mance-enhancing drugs is beyond the scope of this article article discusses potential false-positive results and false-nega- tive results that occur with immunoassays of these substancesand with alcohol, benzodiazepines, and tricyclic antidepressants.
Other pitfalls, such as adulteration, substitution, and dilution of urine samples, are discussed. Pragmatic concepts summarized inthis article should minimize the potential risks of misinterpreting Urine, blood, hair, saliva, sweat, and nails (toenails and fingernails) are some biological specimens used to perform laboratory drug testing, and they provide different levels ofspecificity, sensitivity, and accuracy. Urine is most often 6-MAM = monoacetylmorphine; BAC = blood alcohol concentration;DHHS = Department of Health and Human Services; EMIT = enzyme- the preferred test substance because of ease of collection.
multiplied immunoassay technique; FPIA = fluorescence polarization Concentrations of drugs and metabolites also tend to be immunoassay; GC-MS = gas chromatography–mass spectrometry;MDMA = methylenedioxy-methylamphetamine; NSAID = nonsteroidal high in the urine, allowing longer detection times than anti-inflammatory drug; PCC = pyridinium chlorochromate; PCP = phen- cyclidine; RIA = radioimmunoassay; TCA = tricyclic antidepressant;THC = tetrahydrocannabinol; UAC = urine alcohol concentration; UDS = Two types of UDSs are typically used, immunoassay and gas chromatography–mass spectrometry (GC-MS).
Immunoassays, which use antibodies to detect the presenceof specific drugs or metabolites, are the most common Drug testing beyond the health care and criminal method for the initial screening process. Advantages of justice systems has increased throughout the past de- immunoassays include large-scale screening through au- cade. Common areas for drug testing include the workplace tomation and rapid detection.2 Forms of immunoassay (eg, preemployment and random testing), the military, ath- techniques include cloned enzyme donor immunoassay; letics, legal and criminal situations (eg, postaccident testing, enzyme-multiplied immunoassay technique (EMIT), a rehabilitation testing of ex-convicts), and health care (eg, form of enzyme immunoassay; fluorescence polarization treatment, compliance monitoring, cause of death). Misinter- immunoassay (FPIA); immunoturbidimetric assay; and ra- pretation of drug tests can have serious consequences, such dioimmunoassay (RIA). In addition, immunoassay tech- as unjust termination from a job, risk of prison sentence, niques are used in many home-testing kits or point-of-care inappropriate exclusion from a sporting event, and possibly inappropriate medical treatment in emergencies.
The main disadvantage of immunoassays is obtaining false-positive results when detection of a drug in the sameclass requires a second test for confirmation. Results of From the Pharmacy School, University of Kansas Medical Center, Kansas City,KS (K.E.M.); Department of Clinical Pharmacy, UCSD Skaggs School of immunoassays are always considered presumptive until Pharmacy and Pharmaceutical Sciences, La Jolla, CA (K.C.L.); and Depart- confirmed by a laboratory-based test for the specific drug ment of Pharmacy Practice, Mercer University, College of Pharmacy andHealth Sciences, Atlanta, GA (J.C.K.).
(eg, GC-MS or high-performance liquid chromatogra- Address reprint requests and correspondence to Karen E. Moeller, PharmD, phy). Yet even GC-MS can fail to identify a positive spec- BCPP, Clinical Assistant Professor, University of Kansas Medical Center, imen (eg, hydromorphone, fentanyl) if the column is de- Mailstop 4047, Room B440, 3901 Rainbow Blvd, Kansas City, KS 66160-7231 ([email protected]).
signed to detect only certain substances (eg, morphine, 2008 Mayo Foundation for Medical Education and Research
Mayo Clin Proc. • January 2008;83(1):66-76 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. TABLE 1. Federal Workplace Cutoff Valuesa Gas chromatography–mass spectrometry is considered the criterion standard for confirmatory testing. The method is able to detect small quantities of a substance and confirm the presence of a specific drug (eg, morphine in an opiate screen). It is the most accurate, sensitive, and reliable method of testing; however, the test is time-consuming, requires a high level of expertise to perform, and is costly.
For these reasons, GC-MS is usually performed only after a positive result is obtained from immunoassay.
a GC-MS = gas chromatography–mass spectrometry.
In postmortem analyses, lactate dehydrogenase and lac- b Delta-9-tetrahydrocannabinol-9-carboxylic acid.
tate were found to interfere with assays for commonly abused substances (amphetamine, barbiturates, benzodiaz- Specimen must also contain amphetamine at a concentration greater than epines, opiates, and propoxyphene).4 Additional confirma- tory testing is advised for patients who have illnesses thatincrease the risk of lactic acidosis, such as diabetes melli-tus, liver disease, and toxin ingestion (eg, ethanol, metha- The first step in evaluating a urine sample is documenta- tion of the appearance and color. Urine specimens shouldbe shaken to determine whether such substances as soaphave been added to the urine. Excessive bubble formation that is long lasting can indicate an attempt to adulterate the The Department of Health and Human Services (DHHS) specimen.13 Liquid drain cleaner, chlorine bleach, liquid has established specific cutoff levels that define a positive soap, ammonia, hydrogen peroxide, lemon juice, and result for the workplace (Table 15). These values were eyedrops have been used to manipulate the urine. Other developed to help eliminate false-positive results (eg, commercial products containing glutaraldehyde, sodium or poppy seeds causing positive opium results). Values below potassium nitrate, peroxide and peroxidase, and pyridinium the cutoff levels are reported as negative, which can lead to chlorochromate (PCC) are being sold to falsify urine speci- false-negative results. These values from the DHHS were mens.14 Tetrahydrocannabinol (THC) assays tend to be the established for the workplace only, and the role of thesethreshold levels in clinical settings (eg, health care, sub-stance abuse programs) remains controversial because of TABLE 2. Length of Time Drugs of Abuse Can Be the potential for false-negative results. Cutoff levels were developed for adults, and values might need to be lowered for children because their urine is more dilute than that of adults.6 All laboratories should evaluate cutoff values for Several factors need to be considered to determine the length of time a drug or substance can be detected in the urine.
Pharmacokinetics, presence of metabolites, patient variabil- ity (eg, body mass), short-term vs long-term use of a drug, pH of the urine, and time of last ingestion are some factors that influence detection times. Table 27-12 reports usual detec- tion times for drugs of abuse discussed in this article.
Adulterating, substituting, and diluting urine samples are common practices used to avoid detection of drug use.
Understanding specific characteristics of a urine specimencan help in identifying false-negative results.
Mayo Clin Proc. • January 2008;83(1):66-76 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. most sensitive for adulterants causing false-negative re- the specific substance for which the person is being tested.
sults.15 Normally, urine specimens range from pale yellow Several studies have evaluated the risk of false-positive to clear depending on concentration.16 Urine specimens results and have found high positive predictive values for collected in the early morning are the most concentrated cocaine (92.1; 97.8)82,83 and THC (92.2; 100)82,83 in contrast and often provide the most reliable information.10 Unusual to low positive predictive values for opiates (71.2)82 and colors in urine samples can be due to medications, foods, or diseases and should be noted on documentation that ac-companies the specimen for evaluation.17 The urine specimen temperature should be recorded Alcohol, a substance legal for adults in the United States to within 4 minutes of collection; the temperature should be ingest, is the most widely used substance of intoxication in 32°C to 38°C initially and can remain warmer than 33°C the world.7 It is rapidly metabolized in the human body.
for up to 15 minutes.16 Temperatures outside this range can Approximately 90% to 95% is oxidized in the liver by indicate that a substituted urine sample was used. The pH alcohol and aldehyde dehydrogenase and the microsomal for normal urine fluctuates throughout the day but usually ethanol-oxidizing system before elimination in the urine.84 is in the range of 4.5 to 8.0. Specimen contamination Only 1% to 2% of ingested alcohol is excreted unchanged should be suspected if the pH level is less than 3 or greater in the urine.85 Urine alcohol concentration (UAC) follows a than 11 or if the specific gravity is less than 1.002 or greater variable pattern when compared with blood alcohol con- than 1.020.16 Creatinine concentrations in normal human centrations (BACs). During alcohol ingestion (ie, the early urine should be greater than 20 mg/dL. Urinary creatinine absorptive phase), the UAC is less than the BAC. A 1.0 to concentrations of less than 20 mg/dL are considered dilute, 1.2 ratio of UAC to BAC is noted during the late absorptive whereas concentrations of less than 5 mg/dL are inconsis- phase (ie, >60 minutes after intake). The UAC in the tent with human urine.10 Urinary nitrite levels should be postabsorptive phase is always greater than the BAC. Thus, less than 500 µg/mL.16 If adulteration is suspected or re- the UAC result from the postabsorptive phase should be sults fall outside these ranges, another specimen should be divided by 1.3 to extrapolate a BAC value from the urine collected under direct, observed supervision.
sample.85 This calculated value is useful in estimating the Devices such as the Intect 7 (Branan Medical Corp, BAC at the time of specimen collection but cannot be used Irvine, CA), Mask Ultra Screen (Kacey, Asheville, NC), to estimate impairment after alcohol ingestion. Factors AdultaCheck 4, and AdultaCheck 6 (both from Chimera to be considered when evaluating the results of a UAC Research and Chemical Inc, Tampa, FL) have been devel- include the quantity of alcohol ingested, time between oped to assess the integrity of urine samples.14 These tests collection and last alcohol intake, and concentration of all detect validity parameters, such as creatinine and pH, urine. In addition to urine screens, several other physi- but vary in their detection of adulterants, such as bleach, ologic biomarkers (ie, aspartate aminotransferase, alanine glutaraldehyde, PCC, nitrites, and oxidants. Two recent aminotransferase, γ-glutamyl transpepsidase, carbohy- studies have shown the Intect 7 to be the most sensitive for drate-deficient transferrin, ethyl glucuronide) are used to adulterations because it can detect bleach, PCC, and vin- assess alcohol intake, but these tests entail laboratory egar.18,19 These devices are often used in conjunction with analysis of blood.86 In clinical settings, urine alcohol screens are used far less frequently than breath or bloodtests.15 The DHHS guidelines for workplace urine testing include 5 Amphetamines are among the 5 drug assays required by the mandated drugs of abuse (amphetamines, cannabinoids, DHHS. Amphetamines and methamphetamines are avail- cocaine, opiates, and PCP); however, several other sub- able by prescription for therapeutic use; however, amphet- stances can be abused (eg, benzodiazepines), warranting amines are commonly abused for their stimulant and eu- screening for more than the 5 mandated drugs of abuse.
phoric effects. Most amphetamine assays are designed to Urine drug screens for alcohol, benzodiazepines, metha- detect amphetamine, racemic compounds (eg, dextro- done, and TCAs could be of interest to clinicians in various amphetamine, methamphetamine), and illicit analogues settings and are also discussed in this article. Table 31,8,16,20-81 (methylenedioxyethylamphetamine, methylenedioxyam- summarizes false-positive results sometimes seen with these phetamine, and methylenedioxymethylamphetamine abused substances. Overall risk of having a false-positive [MDMA]). Unfortunately, other stimulants, anorexiants, result due to cross-reactivity on immunoassays depends and chemically related compounds (eg, pseudoephedrine), largely on the specific test (eg, EMIT, FPIA, RIA) used and have been shown to produce false-positive results, making Mayo Clin Proc. • January 2008;83(1):66-76 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. TABLE 3. Summary of Agents Contributing to Positive Results by Immunoassaya Coca leaf teaTopical anesthetics containing cocaine l-Methamphetamine (Vick’s inhaler)d a MDMA = methylenedioxymethylamphetamine, NSAID = nonsteroidal anti-inflammatory drug.
b Approved in Mexico. Not approved in the United States.
c Converts to l-methamphetamine and l-amphetamine.
d Newer immunoassays have corrected the false-positive result for Vick’s inhaler.
e Diphenhydramine and verapamil (including metabolites) have been shown to cause positive results in methadone assays only.
f Reports of false-positive results occurred with serum only.
the amphetamine assay one of the most difficult tests to been reported to interfere with immunoassays. Most of interpret. The Figure illustrates common medications with these reports attribute the cross-reactivity to metabolites structures similar to amphetamines that can produce false- of these agents, which typically are not assessed in manu- facturers’ evaluations of immunoassays for interference.
Interpretation of amphetamine assays requires a detailed Other unique agents found to cross-react with the am- medication history that includes over-the-counter, pre- phetamine immunoassay include labetalol,23 isometh- scription, and herbal medications. Pseudoephedrine, ephed- eptene,27 ranitidine,24,26,35 ritodrine,32 and trimethobenza- rine, phenylephrine, and decongestants common in over- mide.22,25 Structural similarities are the main reasons for the-counter cold medicines are known to cross-react with the amphetamine assay.39 Results of amphetamine assays Another confounding factor for the amphetamine im- are often positive among patients taking prescription munoassay is the inability to distinguish between the 2 stimulants for attention deficit and hyperactivity disorder, isomers of methamphetamine, d-methamphetamine and l- for narcolepsy, and as anorexiants because many of these methamphetamine (l-desoxyephedrine). The d-isomer is stimulants contain amphetamines (Table 3). Many psycho- responsible for the central nervous system stimulant ef- tropic medications, such as bupropion,33,40 phenothiazines fects, whereas the l-isomer mainly works peripherally and (eg, chlorpromazine, promethazine, and thioridazine),29,34 does not possess euphoric effects.15 Vicks nasal inhaler trazodone,37 and TCAs (desipramine and doxepin),30,31 have contains l-methamphetamine and did cross-react with older Mayo Clin Proc. • January 2008;83(1):66-76 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. cologic properties: (1) sedative-hypnotic, (2) anxiolytic, (3) antiepileptic, and (4) muscle relaxant activities.90 Ben- zodiazepines cause sedation, impaired memory, cognitive impairment, and disinhibition. They have also been associ- ated with paradoxical effects (such as increased agitation and insomnia), especially in pediatric and elderly pa- tients.91 Although all benzodiazepines can be abused,agents that have the shortest half-life with the highest po- tency (eg, alprazolam, triazolam) and greatest lipophilia (eg, diazepam) tend to have the most abuse potential.92 Benzodiazepines are often abused for their euphoric effects (along with other abused substances, such as alcohol).
The widespread use of benzodiazepines makes it diffi- cult to distinguish between pharmacologic use vs abuse ofthese substances with a UDS. In addition, detection of FIGURE. Agents that can cause positive results on amphetamine benzodiazepines on assays will not establish single use vs immunoassay. Adapted from ChemIDplus Lite. US National Library of long-standing use, abuse, or dependence. Anxiolytic Medicine, National Institutes of Health. Available from: http://sis.nlm.nih.gov/chemical.html. Accessed December 7, 2007.
agents, such as lorazepam, are often used in emergencydepartments for sedation and control of acute agitation; immunoassay tests when used in large quantities. Newer therefore, a thorough medication history is warranted to EMIT tests have shown no positive results with the Vicks prevent misinterpretation of a positive benzodiazepine re- nasal inhaler when used up to twice the recommended sult. Detection of benzodiazepines in the urine by commer- dose.36 Additionally, selegiline and deprenyl, agents used cially available assays is primarily based on detection of for the treatment of Parkinson disease and depression, pro- oxazepam and nordiazepam, the primary metabolites of duce l-amphetamine and l-methamphetamine metabolites, many of the benzodiazepine drugs.93,94 Yet assays are un- which give a positive result on immunoassays.38 Unfortu- able to distinguish between individual benzodiazepines.
nately, routine GC-MS also does not distinguish between The standard cutoff levels of benzodiazepines are set by the 2 isomers and requires chiral chromatography to differ- DHHS and are listed in Table 1.5 After ingestion, highly entiate between the d- and l- forms.21 lipophilic agents (eg, diazepam) are detected within min- An added problem of amphetamine immunoassays is utes in serum and within 36 hours in the urine.95 Agents that their low sensitivity for detection of MDMA.87 Common are extensively metabolized with long half-lives (eg, diaz- monoclonal amphetamine and methamphetamine immu- epam, chlordiazepoxide) can be detected in the urine up to noassays (eg, EMIT, FPIA, and RIA) can detect MDMA 30 days after ingestion. As noted previously, extensively because of cross-reactivity; however, sensitivity for metabolized drugs are detected in the urine as their metabo- MDMA is approximately 50% less than for amphetamine and methamphetamine.88,89 High concentrations of MDMA Recently, several published reports described the use of in the urine are needed to elicit positive results on amphet- hair and urine samples for detection of benzodiazepine amine immunoassays. However, specific tests have been drugs in forensic cases (eg, drug-facilitated sexual as- designed to incorporate 3 monoclonal antibodies specific sault)96-98; therefore, clinicians need to become more famil- for amphetamine, methamphetamine, and MDMA, result- iar with interpreting results from screening tests.
ing in greater sensitivity for detection of MDMA.87 These Few reports assess agents that produce false-positive or tests should be considered if MDMA use is suspected.
false-negative results on benzodiazepine screens. Ser-traline and oxaprozin have been identified as agents that have cross-reactivity with benzodiazepines. Oxaprozin is a Benzodiazepines belong to a class of prescribed drugs that nonsteroidal anti-inflammatory drug (NSAID) marketed are widely used for a variety of medical and psychiatric for treatment of rheumatic arthritis and osteoarthritis.42 conditions. Benzodiazepines bind to the benzodiazepine Plasma concentrations of the drug are found within 3 to 6 site at the γ-aminobutyric acid type A receptor, which is the hours after ingestion.41 In one report, 2 patients tested main inhibitory neurotransmitter in the central nervous positive for diazepam after taking oxaprozin. Both patients system. Benzodiazepines, which are structurally similar had a negative urine panel after discontinuing oxaprozin with differences primarily in pharmacokinetic parameters (4-7 days after cessation of the drug).42 In follow-up docu- (eg, onset of effect, half-life, metabolites), have 4 pharma- mentation, 1200 mg of oxaprozin for 1 day produced a Mayo Clin Proc. • January 2008;83(1):66-76 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. positive result on the benzodiazepine panel, although 600 THC. Some speculate that the metabolite of efavirenz mg of ibuprofen twice daily and 500 mg of naproxen twice leads to interference with the antibody complexes in the daily did not produce positive results. Oxaprozin is not structurally related to benzodiazepines,41 and whether other Several studies have evaluated the possibility of testing NSAIDs can also produce similar positive results is un- positive for THC via passive inhalation. Perez-Reyes et known.99 Recently, the prescribing information for oxapro- al105 evaluated 3 separate scenarios involving UDS and zin was revised to state that false-positive tests for benzo- passive exposure to THC. Methods included (1) placing diazepines have been reported in patients who take the nonsmokers in a room with participants actively smoking NSAID. The effect can last up to 10 days after drug discon- marijuana cigarettes for 1 hour (2.5% THC), (2) placing tinuation, and confirmatory testing by GC-MS is recom- nonsmokers in a medium-sized station wagon for 1 hour mended. Some evidence suggests that compounds with after 4 participants smoked marijuana cigarettes (2.8% various differences in chemical structure, such as midazo- THC), and (3) placing nonsmokers in a room with 4 smokers lam, chlordiazepoxide, and flunitrazepam, are not detected who smoked only 1 marijuana cigarette each. Of the 80 in many assays. Detection tends to be manufacturer- and urine samples collected from 12 nonsmokers in the 24 hours after exposure to marijuana, only 2 had THC concen-trations greater than 20 ng/mL. No samples met the re- quired 50 ng/mL cutoff concentration mandated by the Cannabis (hemp plant), also referred to as marijuana, was DHHS; thus, it is highly unlikely for an individual to test the most commonly used illicit drug in 2005.102 Cannab- positive (50 ng/mL) for THC by urine immunoassay inoids refers to a unique subset of chemicals found in a cannabis plant believed to have mental and physical effects Researchers have evaluated whether hemp-containing on users. Delta-9-tetrahydrocannabinol is the most psycho- foods (eg, hemp-seed tea, hemp-seed oil) can produce posi- active chemical in the cannabis plant. Urine drug screens tive results from UDSs for marijuana. A study evaluating are designed to detect 11-nor-delta-9-tetrahydrocannab- the consumption of a single drink of hemp-seed tea (12-24 inol-9-carboxylic acid (9-carboxy-THC) and other metabo- oz; to convert to milliliters, multiply by 30) resulted in trace amounts of cannabinoids in the urine; however, none of the The substance THC has high lipid solubility, resulting in urine concentrations met the cutoff concentrations for both extensive storage of the drug in the lipid compartments of the EMIT and GC-MS tests.48 Several case reports have shown body. This lipid solubility is associated with slow excretion positive results for cannabinoids with the consumption of of the drug and its metabolites into the urine. A single use of hemp-seed oil. One study found positive results on RIA after marijuana can result in positive urine tests up to 1 week after a daily THC dose of 0.6 mg via hemp-seed oil; however, this administration, whereas long-term use can produce positive specimen did not meet the cutoff value for GC-MS.45 results in the urine up to 46 days after cessation.103 People using THC often attempt to manipulate the urine Nonsteroidal anti-inflammatory drugs have been re- to produce negative results. Addition of Visine eyedrops to ported to interfere and cause false-positive results for mari- urine samples has been shown to cause false-negative re- juana in EMIT and other assay systems, although conflict- sults for THC.106 Chemical analysis of Visine eyedrops has ing results have been reported among studies. Rollins et al46 shown that the ingredients, benzalkonium chloride and the tested 510 urine samples from patients who received borate buffer, can directly decrease the concentration of 9- ibuprofen, naproxen, or fenoprofen at therapeutic dosing carboxy-THC in the urine with no effects on the antibodies regimens (one-time and long-term ingestion). Two false- in the immunoassay. However, these ingredients do not positive results were found in this study, 1 during the short- chemically alter 9-carboxy-THC, which will still be de- term ingestion of ibuprofen (1200 mg for 1 day) and the other after long-term use of naproxen. In contrast, Joseph etal104 tested 14 different NSAIDs and found no interference with the cannabinoid assay. Rollins et al46 speculate that Cocaine and amphetamines stimulate the central nervous NSAIDs interfere with the enzyme on the EMIT tests, system and are abused primarily for their euphoric effect.
In addition, they are frequently used to increase attention Other agents that have been shown to cross-react with and decrease appetite and sleep time. Immunoassay screens cannabinoid immunoassays include efavirenz 44,47 and are most commonly used in clinical practice to detect co- proton pump inhibitors.43 Efavirenz, a nonnucleoside re- verse transcriptase inhibitor, has been extensively re- Urine drug screens used to evaluate cocaine ingestion ported in the literature to cause false-positive results for assess the presence or absence of cocaine’s main metabo- Mayo Clin Proc. • January 2008;83(1):66-76 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. prescribed opiates, such as sedation, miosis, nausea or vomiting, and decreased blood pressure, heart rate, andrespiratory rate. Although detection of actual heroin would be ideal, it is difficult to accomplish because heroin is Heroin, hydrocodone, hydromorphone, oxycodone rapidly metabolized to 6-monoacetylmorphine (6-MAM), Methadone, propoxyphene, meperidine, fentanyl morphine, and morphine glucuronide. Heroin can be de- tected in the serum 3 to 5 minutes after administration, andthe metabolite, morphine, can be detected 2 to 4 days after lite, benzoylecgonine. Cross-reactivity between this screen heroin use. Confirmation by GC-MS is necessary for sus- and substances other than cocaine are nearly nonexist- pected heroin use, and the presence of 6-MAM is confirma- ent.15,107 Urine screens for cocaine are very accurate in tory for heroin. The 6-MAM metabolite is a product of detecting recent cocaine ingestion. Consumption of tea and heroin, not morphine or codeine, which makes it ideal for other natural products created with coca plant leaves pro- confirmatory testing of heroin. Unfortunately, the metabo- duces positive cocaine screen results.50,51 Foodstuffs ob- lite has a short half-life of 36 minutes and is detected in the tained through the Internet and other sources, and adulter- urine only up to 8 hours after heroin use.109,110 A potential ated natural products, could also produce a positive result problem can arise when street heroin is contaminated with from a cocaine screen even when the person tested denies acetylcodeine, which is further metabolized to codeine.20 It use of cocaine. In addition, children exposed to cocaine can be difficult to differentiate between heroin, codeine, or smoke in heavily contaminated environments can have morphine use among patients with low morphine and co- positive cocaine screen results even if they had not in- deine concentrations.111 Ingestion of products that contain codeine, such as cough medicines and medications fordiarrhea, must also be ruled out before determining abuse.
Opiate screening cutoff levels for DHHS were changed Opioids are a class of drugs comprising both prescribed from 300 ng/mL to 2000 ng/mL of morphine in December and illicit agents. Morphine and codeine are naturally oc- 1998 to avoid false-positive results from poppy-seed inges- curring alkaloids from the opium poppy seed, Papaver tion. However, the sensitivity for detecting true opiate use somniferum. Table 47 categorizes opioid compounds ac- can be a concern,112 and most clinical laboratories continue cording to sources of derivation. Opioids can have varying to use the lower cutoff.53 Positive results for heroin abuse therapeutic effects, such as analgesic, antitussive, and an- are caused by use of prescribed opiates, such as codeine and hydrocodone; however, ingestion of modest amounts Urinalysis testing for opiates, whether prescribed or of poppy seeds has been known to cause a positive result illicit, generally detects the metabolite of heroin and co- from urinalysis. Ingestion of poppy-seed cookies (contain- deine, namely morphine. Morphine is further metabolized ing about 1 teaspoon of poppy-seed filling available com- to 2 main substances, 3-morphine-glucuronide and 6-mor- mercially in the United States for baking) produced posi- phine-glucuronide. The 3-morphine-glucuronide metabo- tive results for opiates within 2 hours of ingestion among 5 lite accounts for 50% of the morphine that is excreted patients.62 Codeine was also found in a concentration of 20 renally and can produce hyperalgesia and neurotoxicity.
ng/mL in 2 samples 2 hours after ingestion. Urine samples Fentanyl is usually not detected in urine screens because of analyzed after 24 hours were negative for opiates. Similar lack of metabolites, and oxycodone is not usually detected results were seen in another analysis in which consumption because of its derivation from thebaine (a compound that is of poppy-seed bagels produced positive results for codeine not detected in the urine).108 Codeine is extensively me- and morphine up to 25 hours after ingestion.60 A single tabolized, and 10% to 15% of the dose is converted to bagel was estimated to contain 1.5 mg of morphine and 0.1 morphine and norcodeine. All 3 compounds are detected in mg of codeine. Similar results were observed in other analyses with slight variations ranging from 1 hour for Whereas prescribed opiates have indications for pain earliest detection of morphine to 60 hours for the latest management, illicit agents or semisynthetic derivatives of morphine are not used for therapeutic effects because of Rifampin and rifampicin have also been known to inter- their high abuse potential. Heroin (diacetylmorphine) is a fere with opiate immunoassays.55-57,61 In one case report semisynthetic derivative of morphine that is more potent involving 3 patients, the 1-step chromatographic assay pro- than morphine with rapid onset of action. Heroin also binds duced false-positive results when urine samples were to the opioid receptor as an agonist (µ, κ, δ) and inhibits tested 1 hour after rifampin administration. All 3 samples substance P. Further, heroin has effects similar to those of were negative by urinalysis using the competitive binding Mayo Clin Proc. • January 2008;83(1):66-76 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. immunoassays and GC-MS. The interference occurred in of 0.025%. Some speculated that, despite the low cross- concentrations as low as 0.05 mg/L. Rifampicin was shown reactivity, the combined concentrations of the parent drug to cause false-positive results in 2 reports56,57 and has 12% and metabolite could have contributed to the false-positive cross-reactivity. A single oral dose of 600 mg of rifampicin has been detected within 18 hours after ingestion (about 24 Phencyclidine is not structurally related to venlafaxine; hours among patients with renal dysfunction or dehydra- however, on the basis of other false-positive results with tion).56 The color of the drug was not shown to interfere drugs of equally dissimilar structure, the potential risk must with the reaction. Quinolones also have been known to be considered. This finding was confirmed by another re- cause false-positive results on urine screens for opiates.53,59 port, in which a false-positive result for PCP was detected Methadone is a long-acting opioid that is used as substi- in a developmentally disabled patient who received 75 mg/d tution treatment for opioid dependence and chronic pain.
of venlafaxine XR.66 In another report, venlafaxine overdose Assays for methadone are specific and detect the parent resulted in a false-positive result for PCP.65 Other cross- compound because about a third of the drug is excreted reactivities for PCP are listed in Table 3.
unchanged. In patients with maintenance doses of metha-done, the urine concentrations for methadone and its me- tabolite (2-ethylene-1,5-dimethyl-3,3-diphenylpyrrolidine) Although assays for drugs of abuse do not routinely test for range from 1 to 50 mg/L.54 A confirmatory testing for TCAs, rapid screening for TCA in the urine is often valu- methadone use, if suspected, is recommended. Although able in emergency situations, such as intentional overdose many urinalysis panels do not routinely screen for metha- or toxicity. Results of urine screening for TCA have an done, verapamil metabolites that contribute to false-posi- important role in determining early management of pa- tive results for methadone have been reported.58 tients; however, many commonly prescribed and over-the-counter medications can lead to false-positive results from Phencyclidine is an anesthetic that is abused for its halluci- The 3-ring nucleus of TCAs is the characteristic struc- nogenic properties and is often referred to as angel dust.
ture of this class of antidepressants. Several structurally This noncompetitive N-methyl-D-aspartic acid antagonist related medications (ie, 3-ringed structures) have been inhibits the reuptake of dopamine. Its short-term effects shown to cross-react with TCAs in either serum or urine can range from dissociation, euphoria, sensory deprivation, immunoassays. Antihistamine agents (eg, cyprohepta- decreased inhibition, increased blood pressure and tem- dine,80,81 carbamazepine,72,74,75 cyclobenzaprine,79 and quetia- perature, and agitation to loss of appetite. In overdose pine71,76,77) have often been reported to interfere with the situations, PCP ingestion can result in combativeness or serum immunoassay for TCAs because of their 3-ringed convulsions and can even lead to coma. The psychedelic structures. Although structurally dissimilar to TCAs, the effects are seen for approximately 1 hour after ingestion, antihistamines diphenhydramine,78 hydroxyzine,73 and and long-term use can lead to symptoms resembling psy- cetirizine73 (hydroxyzine’s metabolite) have also been chotic disorders, such as schizophrenia. The detection time shown to interfere with serum TCA immunoassay in over- after smoking PCP is 5 to 15 minutes in the serum20 and dose situations. Unfortunately, these case reports did not approximately 8 days in the urine.67 Blood concentrations test for interference in the urine immunoassay, except for ranging from 20 to 30 ng/mL can produce excitation, and seizures and death can occur at levels above 100 ng/mL.3Detection of true PCP use is rare because the drug is no longer widely available in the United States.
In one case report of 3 patients, venlafaxine resulted in Urine drug screens are valuable tools in health care, the false-positive results from urine assays for PCP.70 The workplace, and other settings. Accurate interpretation of urine samples were collected from 3 patients in the emer- the validity and reliability of these tools is critical for gency department, none of whom had a history of PCP use.
making decisions that will ultimately have social and Venlafaxine was the only medication ingested by all 3 legal ramifications. Understanding how to evaluate UDSs patients. On repeated testing with gas chromatography, the for adulterations, substitutions, and potential false-posi- samples produced negative results for PCP. Pure samples tive results is complex but vital to interpret these results.
of venlafaxine and the metabolite O-desmethylvenlafaxine A detailed medication history, including prescription, were tested using the emergency department’s urine assay nonprescription, and herbal medications, and proper test, and again, a positive PCP result was observed. The knowledge of medications that cross-react with UDSs are drug had a cross-reactivity of 0.0125% and the metabolite Mayo Clin Proc. • January 2008;83(1):66-76 • www.mayoclinicproceedings.com For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings. Clinicians need to be aware that the preliminary tests 19. Peace MR, Tarnai LD. Performance evaluation of three on-site adulter-
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Ketogene Diät Eine Hilfe für epilepsiekranke Kinder ? D.Fritzenschaft SHG Eltern anfallskranker Kinder Mannheim 1999 Die ketogene Diät (KD) ist eine Ernährungsweise bei der es einer fettreichen und kohlenhydratarmen Kost bedarf. Ziel dieser Diätform ist es eine kontrollierte Ketonurie herbeizuführen. In der Praxis wird diese Diät jedoch nur sehr selten versucht. Hauptindikati