Treatment of methanol and isopropanol poisoning with intravenous fomepizole.

CASE REPORT: We report a case of mixed methanol and isopropanol poisoning in a patient who refused dialysis but agreed to treatment with intravenous fomepizole. The patient was asymptomatic on arrival, with initial blood methanol and isopropanol concentrations of 146 mg/dL and 39 mg/dL, respectively. Blood ethanol was undetectable. The patient was treated with fomepizole twice daily intravenously until blood methanol was undetectable. No side effects of therapy, other than transient eosinophilia, were observed. The evolution was uneventful and no metabolites of either alcohol were detected at any time during the hospitalization. The decay of plasma methanol and isopropanol under fomepizole treatment were well described by first-order kinetics. The plasma elimination half-lives of methanol and isopropanol were 47.6 hours and 27.7 hours, respectively. Fomepizole appears to have been effective in blocking the toxic metabolism of both methanol and isopropanol and was associated with a favorable outcome.

Acute decreases in cerebrospinal fluid glutathione levels after intracerebroventricular morphine for cancer pain.

UNLABELLED: Intracerebroventricular (ICV) morphine administration is effective for the management of refractory cancer pain. Recent preclinical observations of acute depletion of the major endogenous intracellular antioxidant glutathione (GSH) in brain and peripheral organs after ICV morphine in rodents led us to apply microchemical methods to profile the neurochemical effects of ICV morphine in three patients treated for intractable cancer pain. Assessment of morphine, morphine-6-glucuronide, and a panel of endogenous compounds and metabolites in ventricular and cisternal cerebrospinal fluid (CSF) demonstrated transient, postdose increases in morphine and morphine-6-glucuronide in ventricular and cistemal CSF, accompanied by acute decreases in CSF GSH levels. Significant changes were also observed in the CSF levels of 4-hydroxybenzoic acid, homovanillic acid, 5-hydroxyphenyllactic acid, and uric acid. These pilot clinical observations of acute central GSH depletion after ICV morphine suggest a novel mechanism for neuropsychiatric toxicity or preclinical findings, such as hyperalgesia or increased motoric activity observed in nonhuman species after central morphine administration. Because ICV morphine is a mainstay of treatment for refractory cancer pain, elucidation of a mechanism's (or mechanisms') mediating a potential pro-oxidant state in the central nervous system induced by ICV morphine is important. IMPLICATIONS: We observed acute decreases in glutathione levels in cerebrospinal fluid sampled from patients after intracerebroventricular doses of morphine for intractable cancer pain. Such doses may, by depleting the antioxidant glutathione, render the central nervous system vulnerable to damage from oxidative stress.

Elevated concentrations of morphine 6-beta-D-glucuronide in brain extracellular fluid despite low blood-brain barrier permeability.

1 This study was done to find out how morphine 6-beta-D-glucuronide (M6G) induces more potent central analgesia than morphine, despite its poor blood-brain barrier (BBB) permeability. The brain uptake and disposition of these compounds were investigated in plasma and in various brain compartments: extracellular fluid (ECF), intracellular space (ICS) and cerebrospinal fluid (CSF). 2 Morphine or M6G was given to rats at 10 mg kg(-1) s.c. Transcortical microdialysis was used to assess their distributions in the brain ECF. Conventional tissue homogenization was used to determine the distribution in the cortex and whole brain. These two procedures were combined to estimate drug distribution in the brain ICS. The blood and CSF pharmacokinetics were also determined. 3 Plasma concentration data for M6G were much higher than those of morphine, with Cmax and AUC 4-5 times more higher, Tmax shorter, and VZf-1 (volume of distribution) and CL f(-1) (clearance) 4-6 times lower. The concentrations of the compounds in various brain compartments also differed: AUC values for M6G were lower than those of morphine in tissue and CSF and higher in brain ECF. AUC values in brain show that morphine levels were four times higher in ICS than in ECF, whereas M6G levels were 125 higher in ECF than in ICS. 4 Morphine entered brain cells, whereas M6G was almost exclusively extracellular. This high extracellular concentration, coupled with extremely slow diffusion into the CSF, indicates that M6G was predominantly trapped in the extracellular fluid and therefore durably available to bind at opioid receptors.

Single- and repeated-dose pharmacokinetics of intramuscular thiocolchicoside in healthy volunteers.

OBJECTIVE: The aim of this study was to investigate the pharmacokinetics and the accumulation and stationarity of thiocolchicoside after repeated intramuscular administration. METHOD: The pharmacokinetics of thiocolchicoside were studied in 6 healthy male volunteers after one single dose and repeated intramuscular doses of 4 mg twice a day for seven days. Plasma and urine samples were assayed for thiocolchicoside levels by a radioimmunoassay (RIA) using a cross-reacting colchicine-specific polyclonal antibody. The pharmacokinetic parameters between the first and the last days were compared using Student's t-test. RESULTS: Thiocolchicoside pharmacokinetic parameters, calculated after the single dose using non-compartmental analysis, were in good agreement with those obtained in previous studies. Following the repeated-dose regimen, the terminal half-life was not significantly different (2.7 (0.3) h) from that predicted from a single-dose (2.8 (0.2) h). The accumulation ratio, based on the repeated-dose/single-dose ratio of AUCtau was approximately 1.25. A decrease of CLT/f was found between day 1 (24.1 (5.2) l/h) and day 7 (19.9 (3.4) l/h), suggesting that moderate time-related alterations occur in the pharmacokinetics of thiocolchicoside, which may be due to a change in its CL(NR) (CL(R) was constant) or to the extent of bioavailability, explained by enterohepatic recirculation. CONCLUSION: Serum thiocolchicoside concentrations accumulated to steady-state when the drug was given twice a day for seven days and the pharmacokinetics were modified. But no adjustments of dose or dosing interval were necessary because the accumulation did not lead to marked change in the plasma levels.

Rapid determination of valaciclovir and acyclovir in human biological fluids by high-performance liquid chromatography using isocratic elution.

A rapid high-performance liquid chromatographic assay with isocratic elution is developed for the simultaneous quantification of valaciclovir (VACV) prodrug and its active converted compound, acyclovir (ACV), in biological fluids of treated patients. For serum, the samples are deproteinized with perchloric acid in presence of 1-methylguanosine as the internal standard (IS). For urine and dialysis liquid, the samples are diluted with a mobile phase containing the IS, then filtered. VACV, ACV and the IS are separated on a SymmetryShield RP-8 column with acetonitrile-ammonium phosphate buffer as the mobile phase and detected at 254 nm. The chromatographic time is about 12 min. The relative standard deviations (RSD) of VACV and ACV standards are between 0.5 and 3.5%. Most endogenous nucleosides and their metabolites, psychotropic drugs and drugs of abuse are shown not to interfere with this technique. The method has been applied to study the pharmacokinetics of VACV and ACV in serum, dialysis liquid and urine of renal failure patients on continuous ambulatory peritoneal dialysis (CAPD) under oral treatment of VACV.

Effect of social isolation on the metabolism of morphine and its passage through the blood-brain barrier and on consumption of sucrose solutions.

RATIONALE: We have previously shown that place preference conditioning to morphine was observed in social mice at the dose of 8 mg/kg, whereas 4 weeks of isolation impairs the place preference conditioning to morphine (8-100 mg/kg). OBJECTIVE: The present study, aimed at explaining this phenomenon, tested three hypotheses: firstly, a reduced sensitivity to reinforcers induced by isolation; secondly, a difference in morphine disposition in isolated and social mice; thirdly, an altered blood-brain barrier transport of morphine in isolated mice. METHODS: In the sucrose experiments, mice had the choice (for 24 h) between a bottle containing tap water and a bottle containing a sucrose solution. Three sucrose concentrations were used: 0.5, 1 and 2% (weight/weight). In the morphine disposition experiments, the plasma levels of morphine and of morphine-3-glucuronide (M3G) were measured for 240 min. The brain concentrations of morphine was measured at 15 and 30 min. The passage of morphine through the blood-brain barrier was measured using a method modified from that of Takasato (1984). RESULTS: The preference for the sucrose solutions was significantly greater in isolated than in social mice for the concentration of 2%. Isolation reduced the plasma levels of morphine and of M3G, but did not alter the brain concentration of morphine. The passage of morphine through the blood-brain barrier was altered by isolation in neither of the eight structures examined. CONCLUSIONS: We conclude that the behavioural effect of isolation observed in the conditioned place preference to morphine may depend on changes both in morphine disposition and in the sensitivity to reinforcers in isolated mice.

Bioavailability of morphine after administration of a new bioadhesive buccal tablet.

A new bioadhesive buccal morphine tablet was developed for controlled release delivery of drug and improved bioavailability compared with oral controlled release tablet. In order to characterize the pharmacokinetic properties of this bioadhesive buccal formulation, a bioavailability study was performed in 12 healthy volunteers who received: a 30 mg oral controlled release tablet (A); a 20 mg aqueous solution retained in the mouth for 10 min (B); and the 60 mg bioadhesive buccal tablet placed between the lower gum and lip for 6 h (C). The mean amount of morphine absorbed from the solution was very low, only 2 mg of the 20 mg dose. After administration of forms A and C, plasma levels exhibit typical sustained release concentration-time curves. The mean amount of drug recovered from the residual bioadhesive buccal tablet after 6 h indicated that approximately 50% of the dose was released from the bioadhesive buccal tablet. The relative bioavailability of the buccal tablet (corrected for residual unabsorbed dose) compared with the controlled-release tablet was 98% based on the morphine AUC values. Good correlations between the AUC and the Cmax of the bioadhesive tablet for the drug and metabolite plotted versus the amount of morphine absorbed were found.

Intestinal absorption and stability of morphine 6-glucuronide in different physiological compartments of the rat.

Morphine 6-glucuronide (M6G) is an active metabolite of morphine that could be used as a drug, but its hydrolysis into morphine remains controversial. We investigated the acidic hydrolysis of M6G and found that the recovery of morphine did not exceed 5%. The stability of M6G was studied in different physiological compartments of male Sprague-Dawley rats. The formation of morphine after M6G incubation in feces was under 2% in the small intestine, whereas the formation of morphine in colon feces represented 85.6 +/- 12.9% of the initial concentration of M6G. The stability of M6G was also determined ex vivo using the isolated perfused rat liver. The hepatic extraction ratio of M6G was very low (0.04 +/- 0.02), but 88. 7 +/- 11.2% of the dose was excreted in bile. The elimination half-life of M6G in the perfusate (66.4 +/- 20.6 min) was higher than the elimination half-life in bile (18.6 +/- 2.5 min). The hydrolysis of M6G was low, with only 7.7% and 0.03% of morphine in the perfusate and bile, respectively. The perfusate level of morphine 3-glucuronide (M3G) resulting from morphine conjugation was 4.9 +/- 3.6%. An in vivo experiment demonstrated that after oral administration, M6G was absorbed per se in the proximal intestine, and the process was prolonged over the 24-hr experiment due to its reabsorption following enterohepatic recirculation. Finally, 10.5 +/- 4.3% of morphine and 12.9 +/- 5.1% of M3G compared with M6G AUCs were found in plasma. These results show that M6G is weakly converted into morphine when orally absorbed, with a kinetic profile similar to a slow release formulation.

Influence of a dietary alpha-linolenic acid deficiency on learning in the Morris water maze and on the effects of morphine.

Female OF1 mice were fed on a diet deficient in alpha-linolenic acid or on a control diet 3 weeks before mating and throughout pregnancy and lactation. Pups fed on the same diet as their mothers were used for experiments. The effects of dietary alpha-linolenic acid deficiency were studied in a model of learning, the Morris water maze, and on the following effects of morphine: increase in locomotor activity, modifications of rectal temperature and analgesia. In the place and in the cue versions of the Morris water maze, learning occurred at the same speed in the two diet groups; however, in the place version of the test, the level of the performance was significantly lower in the deficient mice. The probe trial and the extinction procedure did not show any difference between the two diet groups. The morphine-induced increase in locomotor activity occurred significantly earlier and was greater in the deficient diet group. Morphine induced an early hypothermia followed by a late hyperthermia; the hypothermia was significantly greater and the hyperthermia significantly smaller in the deficient mice. The pain thresholds and the morphine-induced analgesia were unmodified by the dietary deficiency. The plasma levels of morphine were similar in the two diet groups.

Pharmacokinetics of hydroxocobalamin in smoke inhalation victims.

OBJECTIVE: Hydroxocobalamin has been proposed as a cyanide antidote. Little is known, however, about its pharmacokinetics in human cyanide poisoning. METHODS: We prospectively studied the pharmacokinetics of hydroxocobalamin in 11 smoke inhalation victims of whom all but one had objective evidence of cyanide exposure. Serum hydroxocobalamin levels were followed from just before drug administration to six days after a single 5 g dose of hydroxocobalamin. RESULTS: The results (mean +/- standard error) suggest a two compartment model. Distribution half-life is on the order of 1.86 +/- 0.34 h and the elimination half-life 26.2 +/- 2.7 h. The apparent volume of distribution is 0.45 +/- 0.03 L/kg. Renal and total body clearance are 0.31 +/- 0.06 and 0.83 +/- 0.07 L/h, respectively. CONCLUSION: The apparent volume of distribution suggests a predominantly extracellular partitioning of the antidote, even in the presence of cyanide, an important factor in terms of its antidotal effect. Hydroxocobalamin's elimination half-life in these cyanide-exposed patients far exceeds those found in previous studies of dogs and minimally-exposed humans. If confirmed, this half-life suggests that a single dose of hydroxocobalamin, sufficiently large enough to bind the cyanide present, should be adequate.

Pharmacokinetics of thiocolchicoside in humans using a specific radioimmunoassay.

The myorelaxant thiocolchicoside (TC), an analogue of colchicine (COL), was assayed in plasma and urine by a radioimmunoassay (RIA) using a cross-reacting COL-specific polyclonal antibody. Cross-reactivity was 56% for TC, giving a limit of quantification of 0.5 ng/ml and a linear response from 0.5 to 100 ng/ml. Specificity was checked by cross-reactivity studies with COL analogues and by using liquid chromatography and RIA in tandem on urine samples. Two immunoreactive peaks were detected, but the nonspecific peak represented < 2% of the total urine concentration of TC. Pharmacokinetics of TC following infusion of 4 mg in two subjects revealed a moderate distribution (Vss from 31 to 35 L) and mainly extrarenal elimination (75% of the total body clearance). Terminal half-lives ranged from 2.4 to 2.7 h in plasma and from 3.2 to 3.7 h in urine.

Analgesic response and plasma and brain extracellular fluid pharmacokinetics of morphine and morphine-6-beta-D-glucuronide in the rat.

The analgesic effects of subcutaneously administered morphine and morphine-6-beta-D-glucuronide (M6G) were determined in male Sprague-Dawley rats. Morphine produced a dose-dependent (2.5 to 10.0 mg/kg) analgesic response as measured by the tail-flick test. M6G in the same doses as morphine produced a greater degree of analgesia with longer duration of action. The concentrations of M6G and morphine were determined in plasma as the protein unbound form after the use of an equilibrium dialysis technique and in BECF after administration of the drugs (10.0 mg/kg s.c.). The concentrations of morphine and M6G in BECF were determined by using microdialysis. The concentration of M6G in plasma and BECF at each time interval after its administration was much higher than morphine. The maximal concentrations in plasma and AUC0-infinity values for M6G were, thus, significantly higher for M6G than for morphine in plasma and BECF. In BECF, the Tmax value for M6G was lower than for morphine, but the t1/2 beta values did not differ. In plasma, Tmax and T1/2 values for M6G and morphine did not differ, but volume of distribution and total clearance values for M6G were lower than for morphine. It is concluded that per milligram, M6G has a much higher analgesic potency than morphine in the rat and these differences may be related, in part, to the higher levels of M6G in comparison to morphine in plasma and BECF.

Elemental mercury vapour toxicity: treatment and levels in plasma and urine.

1. We report two cases of acute mercury vapour intoxication in humans. The mercury vapour was released from smelting alloys (gold-mercury amalgam). The alloy was apparently contaminated with an unknown amount of mercury. 2. Within half an hour of the incident, the victims began having moderate headache, nausea, lumbar pain and shortness of breath at rest. The patients were treated with BAL (2,3 dimercaptopropanol), followed by DMSA (2,3 dimercaptosuccinic acid). 3. Serial measurements of mercury metal in plasma and in urine were made for ten days. 4. The results suggest that in spite of the treatment, relatively high concentrations of mercury remain in the plasma for a very long time, and this could be explained by the progressive release of mercury from red blood cells and tissues after oxidation. However, BAL and DMSA did not seem to be the most efficient antidotes. They reduce the plasma inorganic mercury uptake at concentrations of < 50 micrograms I-1.

Morphine disposition in opiate-intoxicated patients: relevance of nonspecific opiate immunoassays.

The use of routine nonspecific immunoassays to detect or quantitate opiates in biological fluids raises the question of the relevance of such immunoassays in the investigation of opiate overdose disposition. We investigated the plasma disposition of morphine in 13 patients intoxicated by the intravascular (i.v.) (n = 5) or oral routes (n = 8) using both a highly morphine-specific antibody radioimmunoassay (RIA) and a nonspecific morphine RIA. Both RIAs showed a first-order elimination rate after i.v. intoxication (apparent plasma terminal half-life ranged from 2.9 to 4.7 hours for unchanged morphine and from 3.2 to 4.9 hours for total opiates) and a persistent opiate concentration with rebound after oral ingestion, suggesting a slow release of opiates from the gastrointestinal tract, in dealers and bodypackers. Moreover, i.v. and oral kinetic data were similar for the two RIAs, except for the ratio between total and unchanged morphine concentrations. The nonspecific morphine assay gave a threefold to 16-fold higher concentration than the specific morphine assay but with parallel kinetics for all patients. We conclude that the current, routine nonspecific morphine immunoassays could be a valuable analytical tool for investigating opiate toxicokinetics.

Plasma and cerebrospinal fluid concentrations of morphine and morphine glucuronides after oral morphine. The influence of renal failure.

BACKGROUND: In patients with renal failure, morphine may cause prolonged narcosis and respiratory depression. Accumulation of the pharmacologically active metabolite morphine-6-glucuronide (M-6G) may explain this effect of morphine in patients with renal failure. After a single oral dose, morphine and its conjugates were measured in the plasma and the cerebrospinal fluid (CSF) in patients with renal failure. METHODS: Eight patients with normal renal function and six patients with renal failure requiring dialysis were studied after operation under spinal anesthesia. Plasma and CSF concentrations of morphine, morphine-3-glucuronide (M-3G), and M-6G were measured by high-pressure liquid chromatography every 4 h for 24 h after an oral dose of 30 mg morphine. RESULTS: The area under morphine plasma concentration-time curve from 0 to 24 h increased from 38 +/- 4 ng.ml-1 x h in patients with normal renal function to 110 ng.ml-1 x h in those with renal failure (P < 0.01). In patients with renal failure, plasma concentrations of M-3G and M-6G were higher at 4 h and remained at an increased level until the end of the study. The peak CSF concentration of morphine at 8 h was similar in those with renal failure or normal renal function, 1.8 +/- 0.4 and 2.0 +/- 0.6 ng.ml-1 respectively. M-3G and M-6G in CSF reached a maximum at 12 h in patients with normal renal function, whereas in those with renal failure the concentrations gradually increased so that the highest concentrations were observed at 24 h. At 24 h, CSF M-6G concentration was 15 times greater in patients with renal failure than in those with normal renal function. CONCLUSIONS: We conclude that M-3G and M-6G readily cross the blood-brain barrier in patients with normal renal function or with renal failure. In patients with renal failure, the retention of plasma M-6G induces a progressive accumulation of this active metabolite in CSF; this accumulation may explain the increased susceptibility to morphine in patients with renal failure.

Pharmacokinetics of hydroxocobalamin in dogs.

Hydroxocobalamin is a powerful cyanide antidote that prevents sodium nitroprusside-induced cyanide toxicity. The pharmacokinetics of an i.v. bolus of hydroxocobalamin (70 and 140 mg/kg) were studied in conscious dogs (n = 6). Plasma hydroxocobalamin concentrations were measured using derivative spectrophotometry. The pharmacokinetics were compatible with a two-compartment model with a first-order distribution and elimination rate, and pharmacokinetic parameters were not different between the two doses, except for the elimination half-life. At 70 mg/kg, which is the recommended dose in acute cyanide poisoning, the elimination half-life was 7.36 +/- 0.79 h, the volume of distribution was 0.49 +/- 0.10 L/kg, and the total clearance 0.58 +/- 0.11 L/h. At high doses, hydroxocobalamin has a short elimination half-life and a limited volume of distribution that exceeds blood volume. These results could be useful in elaborating guidelines for the administration of hydroxocobalamin, when repetitive bolus and/or continuous infusion is required.

Morphine and morphine metabolite kinetics in the rat brain as assessed by transcortical microdialysis.

Morphine (M), morphine 3-glucuronide (M3G) and morphine 6-glucuronide (M6G) were subcutaneously administered at 10 mg/kg in three groups of six awake rats. A transverse microdialysis probe was implanted in the brain cortex and dialysates were collected every 30 minutes for a period of 4 hours. Dialysates were measured by two different opiate radioimmunoassays. Maximum brain opiate concentrations, 41 +/- 10 ng/ml (M), 147 +/- 27 ng/ml (M3G), 177 +/- 43 ng/ml (M6G), were reached at the same Tmax, 0.75 h, and elimination half-lives ranged from 0.99 to 0.81 h for the 3 compounds. Kinetic parameters confirmed that penetration and elimination rates in the extracellular space of the rat brain cortex for the 2 hydrophilic M metabolites were similar to those of M. These results indicate for the first time that, in spite of their structural differences, glucuronide metabolites of M are capable of crossing the blood-brain-barrier (BBB) at the same rate as morphine does, but in higher amount.

Single-dose bioavailability of oral and intramuscular thiocolchicoside in healthy volunteers.

A single dose of 8 mg of thiocolchicoside was administered to 12 healthy volunteers according to a Latin square design, either as tablets (reference), oral solution, or intramuscular injection. Serum thiocolchicoside concentrations showed an absorption phase followed by a biexponential decay with a terminal half-life (t1/2 beta) of approximately 5 h, similar for the three formulations. The relative bioavailability of both oral formulations was approximately 25%, compared to the intramuscular formulation. There was a trend for the oral solution to have a slightly larger AUC and Cmax, as well as a slightly shorter Tmax, than the tablet formulation. However, the comparison of the two oral forms did not show statistically significant differences in the pharmacokinetic parameters Cmax, Tmax, and AUC, suggesting that the Coltramyl tablets have an adequate in vivo dissolution profile.

Uptake, 3-, and 6-glucuronidation of morphine in isolated cells from stomach, intestine, colon, and liver of the guinea pig.

Orally administered morphine undergoes a considerable first-pass glucuronidation in animals and humans. However, the respective contribution of the gastrointestinal tract and the liver to the formation of the analgetically highly potent morphine-6-glucuronide (M6G) and the inactive morphine-3-glucuronide (M3G) is still debated. In this study, morphine uptake and biotransformation to M3G and M6G were compared in isolated cells from stomach, intestine, colon, and liver of the guinea pig. Morphine was taken up by all cell types in a time-dependent manner. There was evidence for a carrier-mediated accumulation in liver cells, but not in the other cell types. Morphine was glucuronidated to M3G by gastric, intestinal, colonic, and liver cells, and to M6G by all cell types excepted gastric cells. The M3G/M6G ratio averaged 3.5, 4.7, and 5.4 for colonic, intestinal, and liver cells, respectively. At low (1 microM) morphine concentration, glucuronidation rates for M3G and M6G in intestinal cells (88 and 20 pmol x mg protein-1 x hr-1, respectively) were similar to those in liver cells (133 and 12 pmol x mg protein-1 x hr-1, respectively). At high concentration (100 microM), rates of M3G and M6G formation in liver cells exceeded by 5- to 10-fold those of intestinal or colonic cells. In conclusion, the epithelium of the small and large intestine contributes with the liver to the formation of the active M6G; at the same time, the gastric, intestinal, and colonic epithelia are involved in the inactivation of morphine to M3G.

Monoclonal antibodies in hapten immunoassays.

This review deals with the potency of monoclonal antibodies (MAbs) to haptens in immunoassays. Specificity and affinity of MAbs to haptens are the major determinants to be considered. Specificity of MAbs depends on the selection of the hapten coupling site to the carrier protein and the antigen used for the screening of MAbs. Nevertheless, cross-reactivity can occur with compounds related to the hapten. This polyspecificity may be circumvented with the use of many MAbs, as has been demonstrated for MAbs to cyclosporine. Affinity of MAbs to haptens is often lower than that of corresponding polyclonal antibodies (PAbs), thereby limiting assay sensitivity. Low affinity is more frequently observed with low molecular weight (100-300) haptens than with larger haptens, such as digoxin or cyclosporine. Affinity enhancement by increasing resemblance to the immunogen can be effective in resolving the lack of sensitivity. With suitable selection strategies. MAbs exhibit real advantages over classical PAbs to haptens because large amounts of worldwide standardized reagents can be prepared.