Chemical profiling: a tool to decipher the structure and organisation of illicit drugs markets: an 8-year study in Western Switzerland

Illicit drug analyses usually focus on the identification and quantitation of questioned material to support the judicial process. In parallel, more and more laboratories develop physical and chemical profiling methods in a forensic intelligence perspective. The analysis of large databases resulting from this approach enables not only to draw tactical and operational intelligence, but may also contribute to the strategic overview of drugs markets. In Western Switzerland, the chemical analysis of illicit drug seizures is centralised in a laboratory hosted by the University of Lausanne. For over 8 years, this laboratory has analysed 5875 cocaine and 2728 heroin specimens, coming from respectively 1138 and 614 seizures operated by police and border guards or customs. Chemical (major and minor alkaloids, purity, cutting agents, chemical class), physical (packaging and appearance) as well as circumstantial (criminal case number, mass of drug seized, date and place of seizure) information are collated in a dedicated database for each specimen. The study capitalises on this extended database and defines several indicators to characterise the structure of drugs markets, to follow-up on their evolution and to compare cocaine and heroin markets. Relational, spatial, temporal and quantitative analyses of data reveal the emergence and importance of distribution networks. They enable to evaluate the cross-jurisdictional character of drug trafficking and the observation time of drug batches, as well as the quantity of drugs entering the market every year. Results highlight the stable nature of drugs markets over the years despite the very dynamic flows of distribution and consumption. This research work illustrates how the systematic analysis of forensic data may elicit knowledge on criminal activities at a strategic level. In combination with information from other sources, such knowledge can help to devise intelligence-based preventive and repressive measures and to discuss the impact of countermeasures.

Effects of Cytochrome P450 Enzyme Inhibitors on the Pharmacokinetics of Nonsteroidal Anti-inflammatory Drugs and Venlafaxine

Cytochrome P450 (CYP) enzymes play a pivotal role in the metabolism of many drugs. Inhibition of CYP enzymes usually increases the plasma concentrations of their substrate drugs and can thus alter the safety and efficacy of these drugs. The metabolism of many widely used nonsteroidal antiinflammatory drugs (NSAIDs) as well as the metabolism of the antidepressant venlafaxine is nown to be catalyzed by CYP enzymes. In the present studies, the effect of CYP inhibition on the armacokinetics and pharmacodynamics of NSAIDs and venlafaxine was studied in clinical trials with healthy volunteers and with a crossover design, by using different antifungal agents as CYP inhibitors. The results of these studies demonstrate that the inhibition of CYP enzymes leads to increased concentrations of NSAIDs. In most cases, the exposure to ibuprofen, diclofenac, etoricoxib, and meloxicam was increased 1.5to 2 fold when they were used concomitantly with antifungal agents. CYP2D6 inhibitor, terbinafine, substantially increased the concentration of parent venlafaxine, whereas the concentration of active moiety of venlafaxine (parent drug plus active metabolite) was only slightly increased. Voriconazole, an inhibitor of the minor metabolic pathway of venlafaxine, produced only minor changes in the pharmacokinetics of venlafaxine. These studies show that an evident increase in the concentrations of NSAIDs may be expected, if they are used concomitantly with CYP inhibitors. However, as NSAIDs are generally well tolerated, use of single doses of NSAIDs concomitantly with CYP inhibitors is not likely to adversely affect patient safety, whereas clinical relevance of longterm concomitant use of NSAIDs with CYP inhibitors needs further investigation. CYP2D6 inhibitors considerably affect the pharmacokinetics of venlafaxine, but the clinical significance of this interaction remains unclear.

Synthesis of angiotensin-converting enzyme (ACE) inhibitors: an important class of antihypertensive drugs

This report outlines the discovery, the design and development of new compounds, and, structure-activity relationships for this drug category. Updated approaches to planned syntheses of new worthy ACE-inhibitors are also exploited.

Role of Membrane Transporters, P-Glycoprotein and Mrp1, in The Placental Transfer of Drugs With Special Reference to Saquinavir and Quetiapine

Drug transporting membrane proteins are expressed in various human tissues and blood-tissue barriers, regulating the transfer of drugs, toxins and endogenous compounds into or out of the cells. Various in vitro and animal experiments suggest that P-glycoprotein (P-gp) forms a functional barrier between maternal and fetal blood circulation in the placenta thereby protecting the fetus from exposure to xenobiotics during pregnancy. The multidrug resistance-associated protein 1 (MRP1) is a relatively less studied transporter protein in the human placenta. The aim of this study series was to study the role of placental transporters, apical P-gp and basal MRP1, using saquinavir as a probe drug, and to study transfer of quetiapine and the role of P-gp in its transfer in the dually perfused human placenta/cotyledon. Furthermore, two ABCB1 (encoding P-gp) polymorphisms (c.3435C>T, p.Ile1145Ile and c.2677G>T/A, p.Ala893Ser/Thr) were studied to determine their impact on P-gp protein expression level and on the transfer of the study drugs. Also, the influence of the P-gp protein expression level on the transfer of the study drugs was addressed. Because P-gp and MRP1 are ATP-dependent drug-efflux pumps, it was studied whether exogenous ATP is needed for the function of ATP-dependent transporter in the present experimental model. The present results indicated that the addition of exogenous ATP was not necessary for transporter function in the perfused human placental cotyledon. Saquinavir and quetiapine were both found to cross the human placenta; transplacental transfer (TPTAUC %) for saquinavir was <0.5% and for quetiapine 3.7%. Pharmacologic blocking of P-gp led to disruption of the blood-placental barrier (BPB) and increased the placental transfer of P-gp substrate, saquinavir, into the fetal circulation by 6- to 8-fold. In reversed perfusions P-gp, MRP1 and possibly OATP2B1 had a negligible role in the fetal-to-maternal transfer of saquinavir. The TPTAUC % of saquinavir was about 100-fold greater from the fetal side to the maternal side compared with the maternal-to-fetal transfer. P-gp activity is not likely to modify the placental transfer of quetiapine. Higher P-gp protein expression levels were associated with the variant allele 3435T, but no correlation was found between the TPTAUC % of saquinavir and placental P-gp protein expression. The present results indicate that P-gp activity drastically affects the fetal exposure to saquinavir, and suggest that pharmacological blockade of the P-gp activity during pregnancy may pose an increased risk for adverse fetal outcome. The blockade of P-gp activity could be used in purpose to obtain higher drug concentration to the fetal side, for example, in prevention (to decrease virus transfer to fetal side) or in treating sick fetus.

The natural hallucinogen 5-MeO-DMT, component of Ayahuasca, disrupts cortical function in rats: reversal by antipsychotic drugs

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a natural hallucinogen component of Ayahuasca, an Amazonian beverage traditionally used for ritual, religious and healing purposes that is being increasingly used for recreational purposes in US and Europe. 5MeO-DMT is of potential interest for schizophrenia research owing to its hallucinogenic properties. Two other psychotomimetic agents, phencyclidine and 2,5-dimethoxy-4-iodo-phenylisopropylamine (DOI), markedly disrupt neuronal activity and reduce the power of low frequency cortical oscillations (<4 Hz, LFCO) in rodent medial prefrontal cortex (mPFC). Here we examined the effect of 5-MeO-DMT on cortical function and its potential reversal by antipsychotic drugs. Moreover, regional brain activity was assessed by blood-oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI). 5-MeO-DMT disrupted mPFC activity, increasing and decreasing the discharge of 51 and 35% of the recorded pyramidal neurons, and reducing (−31%) the power of LFCO. The latter effect depended on 5-HT1A and 5-HT2A receptor activation and was reversed by haloperidol, clozapine, risperidone, and the mGlu2/3 agonist LY379268. Likewise, 5-MeO-DMT decreased BOLD responses in visual cortex (V1) and mPFC. The disruption of cortical activity induced by 5-MeO-DMT resembles that produced by phencyclidine and DOI. This, together with the reversal by antipsychotic drugs, suggests that the observed cortical alterations are related to the psychotomimetic action of 5-MeO-DMT. Overall, the present model may help to understand the neurobiological basis of hallucinations and to identify new targets in antipsychotic drug development.

Non conventional biological treatment based on Trametes versicolor for the elimination of recalcitrant anticancer drugs in hospital wastewater

This work presents a study about the elimination of anticancer drugs, a group of pollutants considered recalcitrant during conventional activated sludge wastewater treatment, using a biological treatment based on the fungus Trametes versicolor. A 10-L fluidized bed bioreactor inoculated with this fungus was set up in order to evaluate the removal of 10 selected anticancer drugs in real hospital wastewater. Almost all the tested anticancer drugs were completely removed from the wastewater at the end of the batch experiment (8 d) with the exception of Ifosfamide and Tamoxifen. These two recalcitrant compounds, together with Cyclophosphamide, were selected for further studies to test their degradability by T. versicolor under optimal growth conditions. Cyclophosphamide and Ifosfamide were inalterable during batch experiments both at high and low concentration, whereas Tamoxifen exhibited a decrease in its concentration along the treatment. Two positional isomers of a hydroxylated form of Tamoxifen were identified during this experiment using a high resolution mass spectrometry based on ultra-high performance chromatography coupled to an Orbitrap detector (LTQ-Velos Orbitrap). Finally the identified transformation products of Tamoxifen were monitored in the bioreactor run with real hospital wastewater

Branding and Marketing Communications of Lifestyle Prescription Drugs in a Strict Legislative Environment

This thesis discusses the different possibilities to brand and promote a patented prescription lifestyle drug through different marketing communications practices. This thesis aims in explaining how branding procedures can be built in circumstances, where the legislative environment is strickt and furthermore, the environment consists of both B-to-B and B-to-C market characteristics simultaneously.

Flow analysis-hydride generation-gas phase derivative molecular absorption spectrophotometric determination of antimony in antileishmanial drugs

In the present work, the development of a method based on the coupling of flow analysis (FA), hydride generation (HG), and derivative molecular absorption spectrophotometry (D-EAM) in gas phase (GP), is described in order to determine total antimony in antileishmanial products. Second derivative order (D²224nm) of the absorption spectrum (190 - 300 nm) is utilized as measurement criterion. Each one of the parameters involved in the development of the proposed method was examined and optimized. The utilization of the EAM in GP as detection system in a continuous mode instead of atomic absorption spectrometry represents the great potential of the analytic proposal.

Reaction mixtures formed by nitrite and selected sulfa-drugs showed mutagenicity in acidic medium

Nitrite, which is present in preserved meat and can be produced in the oral cavity by reduction of nitrate taken from vegetables, could react in stomach with nitrosatable drugs, giving genotoxic-carcinogenic N-nitroso compounds (NOC). The mutagenicity of reaction mixtures formed by sodium nitrite and selected sulfa-drugs (sulfathiazole, HST; phtalylsulfathiazole, PhST; complex Co(II)-sulfathiazole, Co(II)-ST) in acidic medium was evaluated using the Salmonella typhimurium reverse mutation assay (Ames test), with TA98 and TA 100 strains. The reactions were carried out at room temperature, with a mole ratio [nitrite]/[sulfa-drug] > 1. The three reaction mixtures showed mutagenic effects in the considered range.

Sustainable drugs and global health care

Each day, Earth's finite resources are being depleted for energy, for material goods, for transportation, for housing, and for drugs. As we evolve scientifically and technologically, and as the population of the world rapidly approaches 7 billion and beyond, among the many issues with which we are faced is the continued availability of drugs for future global health care. Medicinal agents are primarily derived from two sources, synthetic and natural, or in some cases, as semi-synthetic compounds, a mixture of the two. For the developed world, efforts have been initiated to make drug production "greener", with milder reagents, shorter reaction times, and more efficient processing, thereby using less energy, and reactions which are more atom efficient, and generate fewer by-products. However, most of the world's population uses plants, in either crude or extract form, for their primary health care. There is relatively little discussion as yet, about the long term effects of the current, non-sustainable harvesting methods for medicinal plants from the wild, which are depleting these critical resources without concurrent initiatives to commercialize their cultivation. To meet future public health care needs, a paradigm shift is required in order to adopt new approaches using contemporary technology which will result in drugs being regarded as a sustainable commodity, irrespective of their source. In this presentation, several approaches to enhancing and sustaining the availability of drugs, both synthetic and natural, will be discussed, including the use of vegetables as chemical reagents, and the deployment of integrated strategies involving information systems, biotechnology, nanotechnology, and detection techniques for the development of medicinal plants with enhanced levels of bioactive agents.

Spectrophotometric and spectrofluorimetric determination of some drugs containing secondary amino group in bulk drug and dosage forms via derivatization with 7-Chloro-4-Nitrobenzofurazon

Sensitive and selective spectrophotometric and spectrofluorimetric methods have been developed for determination of some drugs such as Pramipexole, Nebivolol, Carvedilol, and Eletriptan, which commonly contain secondary amino group. The subject methods were developed via derivatization of the secondary amino groups with 7-Chloro-4-Nitrobenzofurazon in borate buffer where a yellow colored reaction product was obtained and measured spectrophotometrically or spectrofluorimetrically. Concentration ranges were found as 2.0 to 250 μg mL-1 and 0.1 to 3.0 μg mL-1, for spectrophotometric and spectrofluorimetric study, respectively. The described methods can be easily applied by the quality control laboratories in routine analyses of these drugs in pharmaceutical preparations.

Liquid-phase microextraction for simultaneous chromatographic analysis of three antidepressant drugs in plasma

A method using Liquid Phase Microextraction for simultaneous detection of citalopram (CIT), paroxetine (PAR) and fluoxetine (FLU), using venlafaxine as internal standard, in plasma by high performance liquid chromatography with fluorescence detection was developed. The linearity was evaluated between 5.0 and 500 ng mL-1 (r > 0.99) and the limit of quantification was 2.0, 3.0 and 5.0 ng mL-1 for CIT, PAR and FLU, respectively. Therefore, it can be applied to therapeutic drug monitoring, pharmacokinetics or bioavailability studies and its advantages are that it necessary relatively inexpensive equipment and sample preparation techniques.

Designer drugs: aspectos analíticos e biológicos

In the recent years, analytical toxicologists have been facing difficulties in detecting designer drugs due to the chemical modifications on the existing structures and the speed in which they are released into the market, requiring the development and improvement of specific and appropriate analytical methods. This work is a review of the literature which summarizes the characteristics of the drugs and the analytical validated methods using conventional and unconventional matrices currently used for correct identification and quantification of the following classes of emerging drugs of abuse: derivatives of opiates, amphetamines, tryptamines, piperazines and cannabinoids.

Simultaneous determination of non-steroidal anti-inflammatory drugs in pharmaceutical formulations and human serum by reversed phase high performance liquid chromatography

A rapid and sensitive method using high performance liquid chromatography has been developed and validated for the simultaneous determination of non-steroidal anti-inflammatory drugs (NSAIDs) in pharmaceutical formulations and human serum. Six NSAIDs including: naproxen sodium, diclofenac sodium, meloxicam, flurbiprofen, tiaprofenic and mefenamic acid were analyzed simultaneously in presence of ibuprofen as internal standard on Mediterranea C18 (5 µm, 250 x 0.46 mm) column. Mobile phase comprised of methanol: acetonitrile: H2O (60:20:20, v/v; pH 3.35) and pumped at a flow rate of 1 mL min-1 using 265 nm UV detection. The method was linear over a concentration range of 0.25-50 µg mL-1 (r² = 0.9999).

Quantification of beta-lactam antibiotics in veterinary drugs: amoxicillin and ampicillin determination by high performance liquid chromatography

This work focused on the development and validation of an RP-HPLC-UV method for quantification of beta-lactam antibiotics in three pharmaceutical samples. Active principles analyzed were amoxicillin and ampicillin, in 3 veterinary drugs. Mobile phase comprised 5 mmol L-1 phosphoric acid solution at pH 2.00, acetonitrile with gradient elution mode and detection wavelength at 220 nm. The method was validated according to the Brazilian National Health Surveillance regulation, where linear range and linearity, selectivity, precision, accuracy and ruggedness were evaluated. Inter day precision and accuracy for pharmaceutical samples 1, 2 and 3 were: 1.43 and 1.43%; 4.71 and 3.74%; 2.72 and 1.72%, respectively, while regression coefficients for analytical curves exceeded 0.99. The method had acceptable merit figure values, indicating reliable quantification. Analyzed samples had active principle concentrations varying from -12 to +21% compared to manufacturer label claims, rendering the medicine unsafe for administration to animals.