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P Kintz

Publications and source records attributed to P Kintz.

At least 19 recordsLinked to original sources
PubMed2006

Quantitative determination of taxine B in body fluids by LC-MS-MS.

A new specific and sensitive LC-MS-MS method for the detection of taxine B and isotaxine B, the main toxic pseudo-alkaloids from yew (Taxus sp.), in biological samples (blood, urine, gastric content) was developed. Biological samples were prepared for LC-MS-MS by means of solid-phase extraction (SPE) procedure and yielded a recovery of 86%. Chromatographic separation was achieved using an RP(18) column. Detection of taxine B and isotaxine B was performed using multiple reaction monitoring with m/z 584.2 as precursor ion, i.e. [M+H](+), of both isomers and m/z 194.3 and m/z 107.1 as product ions after collision-induced dissociation. Docetaxel was applied as internal standard. The method was fully validated for the analysis of blood samples. Linearity was proven in the range from 0.1-500 ng/g. The limit of detection and the limit of quantitation are 0.4 and 2 ng/g, respectively. The method was applied to the determination of taxine B and isotaxine B in four fatal cases (two humans, two horses) with suspected yew intoxication. Blood levels were 105, 168, 174 and 212 ng/g.

Adult↗
PubMed2005

Use of drugs of abuse in less than 30-year-old drivers killed in a road crash in France: a spectacular increase for cannabis, cocaine and amphetamines.

A collaborative study was conducted in France in order to determine the prevalence of cannabinoids, opiates, cocaine metabolites and amphetamines in blood samples from drivers killed in road accidents in 2003 and 2004 and to compare these values with those of a previous study performed during the period 2000-2001 involving 900 drivers. Blood samples were provided from 2003 under 30-year-old drivers, killed in a traffic accident. Drugs of abuse were determined by gas chromatography-mass spectrometry using the same analytical procedures in all the 12 laboratories. The most frequently observed compounds were by far cannabinoids, that tested positive in 39.6% of the total number of samples. Delta9 tetrahydrocannabinol (THC), the most active of the principle constituents in marijuana (cannabis sativa), was detected in the blood of 28.9% drivers and was the single drug of abuse in 80.2% of the positive cases. It was associated with amphetamines in 7.4% and with opiates and cocaine in 1.9 and 4.8%, respectively. Amphetamines were present in 3.1% of the total number of samples, cocaine metabolites in 3.0% and opiates in 3.5%. When comparing these results with those of a previous study performed 3 years before, a significant increase is observed for THC (28.9% versus 16.9%), cocaine metabolites (3.0% versus 0.2%) and amphetamines (3.1% versus 1.4%). This study demonstrates the critical necessity of implementing in France as soon as possible systematical roadside testing for drugs of abuse.

Accidents, Traffic↗
PubMed2005

Evidence of addiction by anesthesiologists as documented by hair analysis.

Chemical dependency is a disease that can affect all professions. Among the health care professionals, anesthesiologists represent a specific group. Numerous factors have been proposed to explain the high incidence of drug abuse among anesthesiologists. These include: easy access to potent drugs, particularly narcotics, highly addictive potential of agents with which they are in contact, and easy diversion of these agents since only small doses will initially provide an effect desired by the abuser. Opioids are the drugs of choice for anesthesiologists, and among them fentanyl and sufentanil are the most commonly used. Alcohol is mostly abused by older anesthesiologists. Propofol, ketamine, thiopental and midazolam are also abused. In fact, all but quaternary ammonium drugs can be observed. Signs and symptoms of addiction in the hospital workplace include: unusual changes in behavior, desire to work alone, refusal of lunch relief or breaks, volunteer for extra cases, call, come in early and leave late, frequent restroom breaks, weight loss and pale skin, malpractice, behind on charts .... Toxicological investigations are difficult, as the drugs of interest are difficult to test for. In most cases, half-lives of the compounds are short, and the circulating concentrations weak. It is, therefore, necessary to develop tandem mass spectrometry procedures to satisfy the criteria of identification and quantitation. In most cases, blood and/or urine analyses are not useful to document impairment, as these specimens are collected at inadequate moments. Hair analysis appears, therefore, as the unique choice to evidence chronic exposure. Depending the length of the hair shaft, it is possible to establish an historical record, associated to the pattern of drug use, considering a growth rate of about 1cm/month. An original procedure was developed to test for fentanyl derivatives. After decontamination with methylene chloride, drugs are extracted from the hair by liquid/liquid extraction after incubation in pH 8.4 phosphate buffer. Fentanyl derivatives are analyzed by GC-MS/MS. The following cases are included in this paper: Case 1: 50-year-old anesthetist, positive for fentanyl (644 pg/mg); Case 2: 42-year-old anesthetist, positive for fentanyl (101 pg/mg) and sufentanil (2 pg/mg); Case 3: 40-year-old anesthetist, positive for codeine (210 pg/mg), alfentanil (30 pg/mg) and midazolam (160 pg/mg); Case 4: 46-year-old nurse, found dead, positive for alfentanil (2 pg/mg) and fentanyl (8 pg/mg). In these cases, the combination of an alternative specimen (hair) and hyphenated analytical techniques (tandem mass spectrometry) appears to be a pre-requisite.

Adult↗
PubMed2005

Dioxins and furans determination in postmortem blood by gas chromatography--high-resolution mass spectrometry.

Dioxins and related compounds (furans) are persistent environmental contaminants that cause adverse biological effects. Their influence on humans is still unclear, except for accidental high-dose exposure. However, chronic exposure to these compounds seems to be involved in cancer, endocrine disruption, and neurobehavioral effects. For several years, a large concern about the potential health risks of dioxins is emerging in Europe and United States. Dioxin levels in biological specimens are extremely low and require very sensitive and specific methods of analysis. In this study, gas chromatography coupled to high-resolution mass spectrometry was used to evaluate dioxin body burden of two women deceased from generalized cancer. Fat fraction of blood specimens was obtained after precipitation with ethanol and extraction of both liquid and solid phases spiked with labeled 13C12-dioxin analogues. Organic phases were grouped, washed, and evaporated to weigh the lipid content. Lipids were dissolved in hexane, hydrolyzed with concentrated sulfuric acid, and discarded during water washes. Dioxins purification was achieved using three successive columns: silica, alumina/sodium sulfate, and carbon/Celite. Finally, the toluene eluent was evaporated and the extract injected in the analytical system. After chromatographic separation, detection was achieved in single ion monitoring mode using a high-resolution mass spectrometer operating in electron impact ionization mode (40 eV, minimal resolution of 10,000). Dioxin levels were expressed in pg TEQ/g of fat as defined by the World Health Organization. Quantification limits for each dioxin congener ranged from 2.5 to 12.0 pg/g fat with a relative extraction recovery always higher than 60%. Dioxin concentrations in the blood of the two deceased women were 35.0 and 42.7 pg TEQ/g fat, respectively. These concentrations are largely lower than those observed after accidental releases, but in the range of those observed in the general European population. Therefore, it was not possible to correlate dioxin body burden of the two women as a potential contributor of their cancer pathology. Nevertheless, knowledge of dioxin body burden in the French population would be of interest for an accurate interpretation of these results.

Aged↗
PubMed2004

Identification of alprazolam in hair in two cases of drug-facilitated incidents.

The use of a drug to modify a person's behaviour for criminal gain is not a recent phenomenon. However, the recent increase in reports of drug-facilitated crimes (sexual assault, robbery) has caused alarm by the general public. Among the drugs that can be used, alprazolam (Xanax), an anxiolytic benzodiazepine, has been seldom observed. To document two cases involving this drug, we have developed an approach based on hair testing by LC-MS/MS. After pH 8.4 buffer incubation and extraction with methylene chloride/diethyl ether (80/20, v/v), hair extracts were separated on a XTerra MS C18 column using a gradient of acetonitrile and formate buffer. Alprazolam and diazepam-d5, used as internal standard, were detected by electrospray tandem mass spectrometry. In the first criminal case, alprazolam tested positive in two consecutive 2 cm hair segments at 4.9 and 2.4 pg/mg, from a 12-year-old girl, assaulted by her father who had sedated her three or four times. In the other case, alprazolam was detected in four consecutive 1cm hair segments at 3.1-0.4 pg/mg, obtained from an adolescent who had been forced to prostitute herself.

Adolescent↗
PubMed2004

Testing for zopiclone in hair application to drug-facilitated crimes.

The use of a drug to modify a person's behaviour for criminal gain is not a recent phenomenon. However, the recent increase in reports of drug-facilitated crimes (sexual assault, robbery) has caused alarm in the general public. The drugs involved can be difficult to detect due to low dosages or chemical instability. They possess amnesic properties and can be quickly cleared from the body fluids. In these situations, blood or even urine can be of poor interest. This is the reason why this laboratory developed an original approach based on hair testing by LC-MS/MS. Zopiclone (Imovane), due to its short half-life associated with rapid hypnotic activity, is considered as a compound of choice to sedate victims. To document the detection of zopiclone in hair, we first tested specimens obtained from two volunteers who had ingested a single 7.5 mg Imovane tablet, and from repetitive consumers of zopiclone. After pH 8.4 buffer incubation and extraction with methylene chloride/diethyl ether (80/20 (v/v)), hair extracts were separated on a Xterra MS C18 column using a gradient of acetonitrile and formate buffer. Zopiclone and diazepam-d5, used as internal standard, were detected by tandem mass spectrometry. A single exposure to zopiclone was detectable in the first hair segment of two volunteers at concentration of 5.4 and 9.0 pg/mg, respectively. Hair from repetitive consumers tested positive for zopiclone at concentrations of 37 and 66 pg/mg. Hair analysis was applied to two authentic criminal cases. In the first one, zopiclone tested positive in the corresponding hair segment at 4.2 pg/mg, in accordance with a single exposure to the drug. In the other expertise, zopiclone was detected in the two segments analyzed, at 21.3 and 21.5 pg/mg, making unlikely the hypothetical single exposure to zopiclone.

Adolescent↗
PubMed2004

Evaluation of the One-Step ELISA kit for the detection of buprenorphine in urine, blood, and hair specimens.

A solid-phase enzyme immunoassay involving microtiter plates was recently proposed by International Diagnostic Systems corporation (IDS) to screen for buprenorphine in human serum. The performance of the kit led us to investigate its applicability in other biological matrices such as urine or blood, and also hair specimens. Low concentrations of buprenorphine were detected with the ELISA test and confirmed by HPLC/MS (buprenorphine concentrations measured by HPLC/MS: 0.3 ng/mL in urine, 0.2 ng/mL in blood, and 40 pg/mg in hair). The intra-assay precision values were 8.7% at 1 ng/mL of urine (n = 8), 11.5% at 2 ng/mL in serum (n = 8), and 11.5% at 250 pg/mg of hair (n = 8), respectively. The immunoassay had no cross-reactivity with dihydrocodeine, ethylmorphine, 6-monoacetylmorphine, pholcodine, propoxyphene, dextromoramide, dextrometorphan at 1 and 10 mg/L, or codeine, morphine, methadone, and its metabolite EDDP. A 1% cross-reactivity was measured for a norbuprenorphine concentration of 50 ng/mL. Finally, the immunoassay was validated by comparing authentic specimens results with those of a validated HPLC/MS method. From the 136 urine samples tested, 93 were positive (68.4%) after the ELISA screening test (cutoff: 0.5 ng/mL) and confirmed by HPLC/MS (buprenorphine concentrations: 0.3-2036 ng/mL). From the 108 blood or serum samples screened, 27 were positive (25%) after the ELISA test with a cutoff value of 0.5 ng/mL (buprenorphine concentrations: 0.2-13.3 ng/mL). Eighteen hair specimens were positive (72%) after the screening (cutoff: 10 pg/mg) and confirmed by LC/MS (buprenorphine concentrations: 40-360 pg/mg). The ELISA method produced false positive results in less than 21% of the cases, but no false negative results were observed with the immunological test. Four potential adulterants (hypochloride 50 mL/L, sodium nitrite 50 g/L, liquid soap 50 mL/L, and sodium chloride 50 g/L) that were added to 10 positive urine specimens (buprenorphine concentrations in the range 5.3-15.6 ng/mL), did not cause a false negative response by the immunoassay.

Buprenorphine↗
PubMed2004

Windows of detection of zolpidem in urine and hair: application to two drug facilitated sexual assaults.

A LC-MS/MS method for the detection of zolpidem in hair was developed to detect this drug after a single dose in possible drug facilitated sexual assaults. To determine the window of detection of zolpidem in both urine and hair, three volunteers received a 10 mg dose. Urine specimens were collected each 12 h for 144 h. Hair was sampled 3-5 weeks after exposure. Hair and urine extracts were separated on a Xterra MS C18 column using a gradient of acetonitrile and formate buffer. For each compound, detection was related to two daughter ions. Zolpidem was detected for up to 60 h in urine with peak concentrations obtained at 12 h. A single exposure to zolpidem was detected in hair at concentrations ranging from 1.8 to 9.8 pg/mg. Hair analysis was applied to two possible criminal cases. In the first case, zolpidem tested positive in the corresponding hair segment at 4.4 pg/mg. In the other case, zolpidem was detected in all the segments analyzed, demonstrating likely previous drug use in addition to recent exposure associated with a positive blood result.

Adult↗
PubMed2004

Entomotoxicology for the forensic toxicologist: much ado about nothing?

We present a series of 29 necropsies in which organic compounds (including benzodiazepines, barbiturates, antidepressants, phenothiazine, opiates, cannabinoids, meprobamate, digoxin and nefopam) were detected in arthropod larvae sampled on human corpses. No correlation was observed between drug concentrations in the larvae versus human samples. When tested, inter-larvae and inter-site variations of drug concentrations (i.e., within larvae when analyzed separately, and within anatomic sites when larvae were grouped according to their site of sampling) were enormous and not reproducible from one case to another, confirming that arthropod larvae are unreliable for quantitative toxicological analysis. Since drugs identified in maggots are always detectable in the cadaver too, we conclude that larvae analysis is of almost no interest for practical forensic casework.

Animals↗
PubMed2004

Fatal overdosage with cisplatin.

This paper presents a case of fatal overdosage due to an accidental massive administration (750 mg instead of 170 mg) of cisplatin, an anticancer agent, to a 63-year-old patient suffering from lymphoma. Platinum was measured in various postmortem samples by means of inductively coupled plasma mass spectrometry. Heart and peripheral blood concentrations of platinum were 1515 and 1253 micro g/L, respectively. Concentrations in urine and bile were 1038 and 501 micro g/L, respectively. Renal dialysis was started immediately after the end of cisplatin perfusion, when the mistake was noticed, but the patient deceased at day 16, presenting renal and hepatic insufficiency, ototoxicity, and pancytopenia.

Accidents↗
PubMed2003

Testing for kavain in human hair using gas chromatography-tandem mass spectrometry.

A sensitive, specific and reproducible method for the quantitative determination of kavain in human hair has been developed. The sample preparation involved a decontamination step of the hair with methylene chloride. The hair sample (about 50 mg) was incubated in 1 ml of methanol for 1 h, in an ultrasonic bath, in presence of 20 ng of methaqualone-d7 used as internal standard. The methanolic solution was evaporated to dryness, and the residue reconstituted by adding 30 microl of methanol. A 2 microl aliquot of the extract was injected onto the column (Optima5-MS capillary column, 5% phenyl-95% methylsiloxane, 30 m x 0.25 mm i.d. x 0.25 mm film thickness) of a Hewlett-Packard (Palo Alto, CA) gas chromatograph (5890). Kavain was detected by its parent ion at m/z 230 and daughter ions at m/z 111 and 202 through a Finnigan TSQ 700 MS/MS system. The assay was capable of detecting 30 pg/mg of kavain (limit of detection (LOD)). Linearity was observed for kavain concentrations ranging from 100 to 2000 pg/mg with a correlation coefficient of 0.998. Intra-day precision at 400 pg/mg was 13.7%. The analysis of a segment of hair, obtained from an occasional consumer, revealed the presence of kavain at the concentration of 418 pg/mg. A higher concentration (1708 pg/mg) was detected in the corresponding pubic hair.

Calibration↗
PubMed2003

Determination of heroin after embalmment.

A 30-year-old male died in Thailand after a scuffle. The corpse was embalmed and repatriated to France where an autopsy was performed. As usual in cases of embalmment, fluids such as blood and urine were unavailable and the toxicological analyses was performed on the bile and the liver. An overdose of heroin was determined as the cause of death. A review of the literature indicates that several drugs can be detected in fluids and tissues that contain formaldehyde. This case demonstrates that in embalmed corpses, toxicological assessment is still possible, e.g. after heroin fatalities.

Adult↗
PubMed2003

Screening procedure for eight quaternary nitrogen muscle relaxants in blood by high-performance liquid chromatography-electrospray ionization mass spectrometry.

A screening procedure was developed for the identification and the quantification of eight quaternary nitrogen muscle relaxants, including d-tubocurarine, alcuronium, pancuronium, vecuronium, atracurium, mivacurium, rocuronium and mebezonium, in blood samples. The procedure involves ion-pair extraction with methylene chloride at pH 5.4, reversed-phase HPLC separation and electrospray ionization mass spectrometry detection. The procedure was validated in terms of linearity (0.929 5 for all the target compounds at 0.1 mg/l). The screening test was found satisfactory and applied in two fatal deaths. In the first case, toxicological investigations on biological fluids collected during the autopsy revealed the presence of vecuronium (1.2 and 0.6 mg/l in blood and urine, respectively) and its desacetylated metabolite, 3-hydroxy-vecuronium (4.4 and 0.7 mg vecuronium equivalent/l in blood and urine, respectively). In the second forensic case, blood analysis showed high levels of mebezonium (6.5 mg/l). The developed procedure was found suitable for forensic investigations.

Adult↗
PubMed2003

Comparison of the prevalence of alcohol, cannabis and other drugs between 900 injured drivers and 900 control subjects: results of a French collaborative study.

A collaborative case-control study was conducted in France in order to determine the prevalence of alcohol, cannabinoids, opiates, cocaine metabolites, amphetamines and therapeutic psychoactive drugs in blood samples from drivers injured in road accidents and to compare these values with those of a control population. Recruitment was performed in emergency departments of six university or general hospitals and comprised 900 drivers involved in a non-fatal accident and 900 patients (controls) who attended the same emergency units for a non-traumatic reason. Drivers and controls were matched by sex and age. Alcohol was determined by flame ionization-gas chromatography, drugs of abuse (DOA) by gas chromatography-mass spectrometry with the same analytical procedures in the six laboratories, and medicines by high performance liquid chromatography with diode array detection. Blood alcohol concentration exceeding 0.5 g/l (i.e. the legal French threshold) was found in 26% of drivers and 9% of controls. In the 18-27 years age range, alcohol was the only toxic found in blood samples of 17% drivers and 5% controls, leading to an odds-ratio (OR) of 3.8. A significant relationship was found between alcohol blood concentrations and OR values. All age groups confounded, the main active substance of cannabis, Delta(9) tetrahydrocannabinol (THC), was found in 10% of drivers and 5% of controls. In the less than 27 years old, THC (>1 ng/ml) was detected alone in the blood of 15.3% drivers and of 6.7% controls, giving OR=2.5, whereas there was no link between THC blood concentrations and OR value. THC was found alone in 60% of cases and associated with alcohol in 32%, with OR=4.6 between drivers and controls for this association. The difference in morphine prevalence between drivers (2.7%) and controls (0.03%) was highly significant (P<0.001), with OR=8.2. The number of positive cases for amphetamines and cocaine metabolites was too low for reaching any interpretation. The most frequently observed psychoactive therapeutic drugs were by far benzodiazepines, that were found alone in 9.4% of drivers and 5.8% of controls, which led to OR=1.7 (P<0.01). This study demonstrates a higher prevalence of opiates, alcohol, cannabinoids and the combination of these last two compounds in blood samples from drivers involved in road accidents than in those from controls, which suggests a causal role for these compounds in road crashes.

Accidents, Traffic↗
PubMed2003

Enzyme immunoassay validation for the detection of buprenorphine in urine.

A solid-phase enzyme immunoassay involving microtiter plates was proposed by Microgenics to screen buprenorphine in urine. The intra-assay precision at 10 ng/mL was 7.7% (coefficient of variation). The immunoassay was determined to have no cross-reactivity with codeine, dihydrocodeine, morphine, ethylmorphine, 6-monoacetylmorphine, methadone, pholcodine, propoxyphene, dextromoramide, and dextromethorphan at 1 and 10 mg/L. A low cross-reactivity (3% at 1 ng/mL) was observed at low concentrations of norbuprenorphine. After comparing this new immunological test (Singlestep ELISA) for 76 urine specimens with our validated high-performance liquid chromatography-electrospray mass spectrometry (HPLC-ES-MS) procedure, an optimum cutoff concentration of 2 ng/mL was determined for the kit. At this cutoff, the screening assay was able to determine more than 90% of true results with 43.4% true positives and 48.7% true negatives. Four positive urines (5.3%) were not confirmed by HPLC-ES-MS. In only one case, the negative urine test was confirmed as positive by HPLC-ES-MS (buprenorphine: 62.5 ng/mL). Buprenorphine concentrations determined by HPLC-ES-MS ranged from 1.2 to 1052 ng/mL. Of the four potential adulterants (hypochloride 50 mL/L, sodium nitrite 50 g/L, liquid soap 50 mL/L, and sodium chloride 50 g/L) that might be added to a positive urine specimen, none were able to cause a false-negative response by the immunoassay. The results of this study support the concept that the Singlestep ELISA for buprenorphine determination in urine should be considered as a new, valided screening procedure.

Buprenorphine↗
PubMed2003

HPLC/MS findings in a fatality involving sustained-release verapamil.

A fatality involving verapamil, a calcium channel blocker agent, is presented. A 51-year old male ingested 7200 mg of sustained-release (SR) verapamil at T0 and died 40 hours later of refractory, mixed shock and multiorgan failure. The symptoms displayed during hospitalization were quite typical and involved altered consciousness, hypotension, bradycardia, atrioventricular block, metabolic acidosis and renal failure. Verapamil and its primary metabolite, norverapamil, were assayed on eight plasma and two urine samples, successively taken between the admission to the ICU (T0 + 4 hours) and time of death, using an original high-performance liquid chromatography/mass spectrometry (HPLC/MS) procedure with verapamil-d3 as internal standard. Plasma verapamil and norverapamil levels on admission were 0.94 and 1.36 microg/mL, respectively, then verapamil remained practically unchanged throughout the hospitalization (0.85 microg/mL at T0 + 40 hours). The discussion focuses on the detrimental role of SR formulations in overdose, with special emphasis on the risk of pharma-cobezoar development already reported with SR-verapamil. To our knowledge, this is the first report of a verapamil fatality documented by repeated plasma measurements of the drug during the antemortem period.

Calcium Channel Blockers↗
PubMed2002

Last performance with VIAGRA: post-mortem identification of sildenafil and its metabolites in biological specimens including hair sample.

A 43-year-old man was found dead in a hotel room during a sexual relation with a colleague.He was treated both for cardiovascular disease and for erectile dysfunction with VIAGRA. A pillbox was found in the room with several tablets of verapamil (Isoptine), trimetazidine (Vastarel), yohimbine and bromazepam (Lexomil). A box of VIAGRA 25mg was found in his raincoat and two tablets were missing. His wife declared during the investigation that he was also treated by trinitrine. Autopsy revealed severe coronary artery sclerosis as well as signs of previous myocardial infarctions. Blood, urine, bile, gastric content and hair and representative tissues for histology were collected for toxicological analysis. Sildenafil and yohimbine were screened with liquid chromatography/mass spectrometry (LC/MS) and trinitrine with headspace injection (HS)/GC/MS. Verapamil and trimetazidine were identified and quantified with LC/diode array detection (DAD). Sildenafil was identified in blood, urine, bile and gastric content at 105, 246, 1206 and 754ng/ml, respectively. Hair concentration was 177pg/mg. The desmethyl metabolite was quantified in urine at 143ng/ml. Blood concentrations of verapamil and trimetazidine were measured at 659 and 2133ng/ml, respectively and were above therapeutic ranges. Trinitrine and yohimbine were not identified. These results confirm the absorption of sildenafil, verapamil and trimetazidine before the death and hair analysis indicates the chronic use of sildenafil. To the author's knowledge, this is the first report of a fatal sildenafil-verapamil association, probably by hypotension and cardiac dysrhythmia.

Adult↗