Human Sensory LTP Predicts Memory Performance and Is Modulated by the BDNF Val66Met Polymorphism.

Background: Long-term potentiation (LTP) is recognised as a core neuronal process underlying long-term memory. However, a direct relationship between LTP and human memory performance is yet to be demonstrated. The first aim of the current study was thus to assess the relationship between LTP and human long-term memory performance. With this also comes an opportunity to explore factors thought to mediate the relationship between LTP and long-term memory. The second aim of the current study was to explore the relationship between LTP and memory in groups differing with respect to brain-derived neurotrophic factor (BDNF) Val66Met; a single-nucleotide polymorphism (SNP) implicated in memory function. Methods: Participants were split into three genotype groups (Val/Val, Val/Met, Met/Met) and were presented with both an EEG paradigm for inducing LTP-like enhancements of the visually-evoked response, and a test of visual memory. Results: The magnitude of LTP 40 min after induction was predictive of long-term memory performance. Additionally, the BDNF Met allele was associated with both reduced LTP and reduced memory performance. Conclusions: The current study not only presents the first evidence for a relationship between sensory LTP and human memory performance, but also demonstrates how targeting this relationship can provide insight into factors implicated in variation in human memory performance. It is anticipated that this will be of utility to future clinical studies of disrupted memory function.

Pharmaceutical quality of "party pills" raises additional safety concerns in the use of illicit recreational drugs.

AIM: To determine the content and release kinetics of 1-benzylpiperazine (BZP) and 1-(3-trifluoromethyl-phenyl)piperazine (TFMPP) from "party pill" formulations. From these data, the possible impact of pharmaceutical quality upon the safety of such illicit formulations may be inferred. METHODS: The amount of BZP and TFMPP in party pill formulations was determined using a validated HPLC method. The in-vitro release kinetics of selected party pill brands were determined using a USP dissolution apparatus (75 rpm, 37.5 degrees Celsius). The release data were then fitted to a first order release model using PLOT software and the time taken to achieve 90% release reported. RESULTS: Many of the tested party pill brands contained amounts of BZP and TFMPP that varied considerably from that stated on the packaging; including considerable TFMPP content in some brands not labelled to contain this drug. Dissolution studies revealed that there was considerable variability in the release kinetics between brands; in one case 90% release required >30 minutes. CONCLUSION: Lack of quality control in party pill manufacture may have led to the toxic effects reported by users unaware of the true content and release of drug from pills. More stringent regulation in the manufacture and quality control of "new generation party pills" is essential to the harm reduction campaign.

Validation of an LC-MS method for the detection and quantification of BZP and TFMPP and their hydroxylated metabolites in human plasma and its application to the pharmacokinetic study of TFMPP in humans.

An LC-MS method was developed for benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP), constituents of "party pills" or "legal herbal highs," and their metabolites in human blood plasma. Compounds were resolved using a mixture of ammonium formate (pH 4.5, 0.01 M) and acetonitrile (flow rate of 1.0 mL/min) with a C18 column. Calibration curves were linear from 1 to 50 ng/mL (R(2) > 0.99); the lower limit of quantification (LLOQ) was 5 ng/mL; the accuracy was >90%; the intra- and interday relative standard deviations (R.S.D) were <5% and <10%, respectively. Human plasma concentrations of TFMPP were measured in blood samples taken from healthy adults (n = 6) over 24 h following a 60-mg oral dose of TFMPP: these peaked at 24.10 ng/mL (±1.8 ng/mL) (C(max) ) after 90 min (T(max)). Plasma concentrations of 1-(3-trifluoromethyl-4-hydroxyphenyl) piperazine peaked at 20.2 ng/mL (±4.6 ng/mL) after 90 min. TFMPP had two disposition phases (t(½) = 2.04 h (±0.19 h) and 5.95 h (±1.63 h). Apparent clearance (Cl/F) was 384 L/h (±45 L/h).

In vivo interactions between BZP and TFMPP (party pill drugs).

AIM: This study explores potential drug-drug interactions between BZP and TFMPP. This was achieved by comparing the metabolism and pharmacokinetics of BZP and TFMPP when taken together with previously published data on their individual metabolism and pharmacokinetics. METHOD: Blood and urine samples were collected from seven participants given a combined dose of BZP (100 mg) and TFMPP (30 mg) and analysed by LC-MS in order to quantify the concentrations of BZP, TFMPP, and their major hydroxylated metabolites 3-OH BZP, 4-OH BZP, and 4-OH TFMPP. RESULTS: The metabolic profiles of both drugs were altered when co-administered. Both BZP and TFMPP lost one metabolite, 3-OH BZP and 4-OH TFMPP, respectively. Some differences in the pharmacokinetic properties of TFMPP were also noted. CONCLUSION: Metabolic interactions between BZP and TFMPP are clearly observed in this study along with some changes to the pharmacokinetics of TFMPP. As these drugs are often co-administered, the interactions between them are both relevant and concerning. Awareness of these interactions can assist clinicians in understanding toxicities relating to the co-administration of BZP and TFMPP or other party pill drugs.

Metabolic interactions with piperazine-based 'party pill' drugs.

OBJECTIVES: 'Party pills' have found use worldwide as a substitute for amphetamine-derived designer drugs. Whilst some information exists about the metabolism of these drugs, there is little information about their ability to inhibit the metabolism of co-administered drugs. This study aimed to determine whether predictions can be made about global interactions between 'party pills' constituents and other drugs metabolised by the same cytochrome P450 (CYP) isoenzymes. METHODS: The inhibitory effects of seven benzyl and phenyl piperazines were measured in microsomal incubation assays of probe substrates for five major CYP isoenzymes. In addition, the metabolism of benzylpiperazine and trifluoromethylphenylpiperazine, the two most commonly used constituents of 'party pills', was investigated using human liver microsomes assays and known inhibitors of CYP isoenzymes. KEY FINDINGS: All piperazine analogues tested showed significant inhibitory activity against most, if not all, isoenzymes tested. The metabolism of benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP) involved CYP2D6, CYP1A2 and CYP3A4. Furthermore, BZP and TFMPP inhibited each other's metabolism. CONCLUSIONS: Fluorophenylpiperazine, methoxyphenylpiperazine, chlorophenylpiperazine, methylbenzylpiperazine and methylenedioxybenzylpiperazine had significant inhibitory effects on CYP2D6, CYP1A2, CYP3A4, CYP2C19 and CYP2C9 isoenzymes but each piperazine had a different inhibitory profile. The metabolic interaction between BZP and TFMPP may have clinical implications, as these agents are often combined in 'party pills'.

Party pills and drug-drug interactions.

AIM: This study aimed to explore the potential for drug-drug interactions involving benzylpiperazine (BZP) and trifluoromethylphenylpiperazine (TFMPP). This was achieved by determining the effects of BZP and TFMPP on the metabolism of drugs commonly found in the clinical setting by using pooled human liver microsomes. METHOD: Incubations consisted of a probe substrate (drug of interest), a potential inhibitor (BZP or TFMPP), a suitable enzyme co-factor (NADPH), and pooled human liver microsomes. Loss of substrate was determined by analysing pre- and post-incubation concentrations in the samples by using HPLC/UV analysis. RESULTS: Both TFMPP and BZP were found to inhibit the metabolism of dextromethorphan, caffeine, and ethinyloestradiol. These are reported substrates of CYP2D6, CYP1A2, and CYP3A4 respectively. Greater enzyme inhibition was observed in TFMPP microsomal assays in comparison to those using BZP. The metabolism of omeprazole was not affected, suggesting that BZP and TFMPP do not have a significant inhibitory effect on CYP2C19. CONCLUSION: The inhibitory effects of BZP and TFMPP observed in this study are of potential significance to clinical practice because CYP2D6, CYP1A2, and CYP3A4 are involved in the metabolism of many commonly used drugs. Knowledge about the observed inhibitory effects will be a useful aid in preventing toxicity when drugs metabolised by these isoenzymes are taken with party pills.