Pharmacodynamic Effects Of Drugs Research Articles

Transcranial magnetic stimulation as biomarker of excitability in drug development: A randomized, double-blind, placebo-controlled, cross-over study.

AimsThe purpose of this study was to investigate pharmacodynamic effects of drugs targeting cortical excitability using transcranial magnetic stimulation (TMS) combined with electromyography (EMG) and electroencephalography (EEG) in healthy subjects, to further develop TMS outcomes as biomarkers for proof‐of‐mechanism in early‐phase clinical drug development. Antiepileptic drugs presumably modulate cortical excitability. Therefore, we studied effects of levetiracetam, valproic acid and lorazepam on cortical excitability in a double‐blind, placebo‐controlled, 4‐way cross‐over study.MethodsIn 16 healthy male subjects, single‐ and paired‐pulse TMS‐EMG–EEG measurements were performed predose and 1.5, 7 and 24 hours postdose. Treatment effects on motor‐evoked potential, short and long intracortical inhibition and TMS‐evoked potential amplitudes, were analysed using a mixed model ANCOVA and cluster‐based permutation analysis.ResultsWe show that motor‐evoked potential amplitudes decreased after administration of levetiracetam (estimated difference [ED] −378.4 μV; 95%CI: −644.3, −112.5 μV; P < .01), valproic acid (ED −268.8 μV; 95%CI: −532.9, −4.6 μV; P = .047) and lorazepam (ED −330.7 μV; 95%CI: −595.6, −65.8 μV; P = .02) when compared with placebo. Long intracortical inhibition was enhanced by levetiracetam (ED −60.3%; 95%CI: −87.1%, −33.5%; P < .001) and lorazepam (ED −68.2%; 95%CI: −94.7%, −41.7%; P < .001) at a 50‐ms interstimulus interval. Levetiracetam increased TMS‐evoked potential component N45 (P = .004) in a central cluster and decreased N100 (P < .001) in a contralateral cluster.ConclusionThis study shows that levetiracetam, valproic acid and lorazepam decrease cortical excitability, which can be detected using TMS‐EMG–EEG in healthy subjects. These findings provide support for the use of TMS excitability measures as biomarkers to demonstrate pharmacodynamic effects of drugs that influence cortical excitability.

Impact of smoking on metabolic changes and effectiveness of drugs used for lung cancer.

This article reviews the published studies dealing with the influence of cigarette smoking on metabolic changes and effectiveness of drugs used in the systemic chemotherapy of the lung cancer. The literature search of interactions between cigarette smoking and drugs used for lung cancer was carried out. The abstracted data mostly involved some induction of key drug-metabolizing enzymes of cytochrome CYP1A1/2, CYP2D6, CYP3A4 and isoforms of UDP-glucuronosyltransferase. Metabolic changes are important both in the non-chemotherapy and for the drugs used in the chemotherapy. They can change pharmacokinetic and pharmacodynamic effects of drugs. Primarily, we addressed potential differences in drug effects on smokers and non-smokers. The increased clearance of erlotinib and irinotecan may have impact on effectiveness of the lung cancer therapy. The effects of taxanes and gemcitabine are more complex. The evaluated studies show that continued smoking after lung cancer diagnosis is related to poor prognosis, reduced survival, risk of second primary malignancies, and increased cancer recurrence. Of particular importance is the deterioration in the quality of life and an increased incidence of the adverse drug reactions in smokers. The patient's cigarette smoking history should be considered carefully and smoking cessation must be taken into account.

Pharmacodynamic dose effects of oral cannabis ingestion in healthy adults who infrequently use cannabis

BackgroundPrior controlled cannabis research has mostly focused on smoked cannabis and predominantly included frequent cannabis users. Oral cannabis products (“edibles”) make up a large and growing segment of the retail cannabis market. This study sought to characterize the pharmacodynamic effects of oral cannabis among infrequent cannabis users. MethodsSeventeen healthy adults who had not used cannabis for at least 60 days completed four experimental sessions in which they consumed a cannabis-infused brownie that contained 0, 10, 25, or 50 mg THC. Subjective effects, vital signs, cognitive/psychomotor performance, and blood THC concentrations were assessed before and for 8 h after dosing. ResultsRelative to placebo, the 10 mg THC dose produced discriminable subjective drug effects and elevated heart rate but did not alter cognitive/psychomotor performance. The 25 and 50 mg THC doses elicited pronounced subjective effects and markedly impaired cognitive and psychomotor functioning compared with placebo. For all active doses, pharmacodynamic effects did not manifest until 30−60 min after ingestion, and peak effects occurred 1.5−3 h post-administration. Blood THC levels were significantly correlated with some pharmacodynamic drug effects, but were substantially lower than what is typically observed after cannabis inhalation. ConclusionIngestion of oral cannabis dose-dependently altered subjective drug effects and impaired cognitive performance. Unlike inhaled forms of cannabis for which acute effects occur almost immediately, effects of oral cannabis were considerably delayed. In an era of legalization, education about the time course of drug effects for cannabis edibles is needed to facilitate dose titration and reduce acute overdose incidents.

STatistically Assigned Response Criteria in Solid Tumors (STARCIST).

BackgroundSeveral reproducibility studies have established good test-retest reliability of FDG-PET in various oncology settings. However, these studies are based on relatively short inter-scan periods of 1–3 days while, in contrast, response assessments based on FDG-PET in early phase drug trials are typically made over an interval of 2–3 weeks during the first treatment cycle. With focus on longer, on-treatment scan intervals, we develop a data-driven approach to calculate baseline-specific cutoff values to determine patient-level changes in glucose uptake that are unlikely to be explained by random variability. Our method takes into account the statistical nature of natural fluctuations in SUV as well as potential bias effects.MethodsTo assess variability in SUV over clinically relevant scan intervals for clinical trials, we analyzed baseline and follow-up FDG-PET scans with a median scan interval of 21 days from 53 advanced stage cancer patients enrolled in a Phase 1 trial. The 53 patients received a sub-pharmacologic drug dose and the trial data is treated as a ’test-retest’ data set. A simulation-based tool is presented which takes as input baseline lesion SUVmax values, the variance of spurious changes in SUVmax between scans, the desired Type I error rate, and outputs lesion and patient based cut-off values. Bias corrections are included to account for variations in tracer uptake time.ResultsIn the training data, changes in SUVmax follow an approximately zero-mean Gaussian distribution with constant variance across levels of the baseline measurements. Because of constant variance, the coefficient of variation is a decreasing function of the magnitude of baseline SUVmax. This finding is consistent with published results, but our data shows greater variability. Application of our method to NSCLC patients treated with erlotinib produces results distinct from those based on the EORTC criteria. Based on data presented here as well as previous repeatability studies, the proposed method has greater statistical power to detect a significant %-decrease on SUVmax compared to published criteria relying on symmetric thresholds.ConclusionsDefining patient-specific, baseline dependent cut-off values based on the (null) distribution of naturally occurring fluctuations in glucose uptake enable identification of statistically significant changes in SUVmax. For lower baseline values, the produced cutoff values are notably asymmetric with relatively large changes (e.g. >50 %) required for statistical significance. For use with prospectively defined endpoints, the developed method enables the use of one-armed trials to detect pharmacodynamic drug effects based on FDG-PET. The clinical importance of changes in SUVmax is likely to remain dependent on both tumor biology and the type of treatment.

Pharmacological MRI response to a selective dopamine transporter inhibitor, GBR12909, in awake and anesthetized rats.

Pharmacological magnetic resonance imaging (phMRI) is a powerful tool for imaging the effects of drugs on brain activity. In preclinical phMRI studies, general anesthesia used for minimizing head movements is thought to influence the phMRI responses to drugs. In this study we investigated the phMRI responses to a selective dopamine transporter (DAT) inhibitor, GBR12909, and a dopamine (DA) releaser, d-amphetamine (AMPH), in the isoflurane anesthetized and awake rats using a relative cerebral blood volume (rCBV) method. AMPH (1 mg/kg i.p.) caused an increase in rCBV in the dopaminergic circuitry in the both anesthetized and awake rats. The striatal rCBV change was correlated with the change of the striatal DA concentration induced by AMPH in the both anesthetized and awake rats. GBR12909 (10 mg/kg i.p.) caused a positive rCBV response and showed a similar regional pattern of rCBV response to AMPH in the awake rats, and the correlation between the change of the striatal rCBV and the striatal DA concentration was observed. However, in the anesthetized rats, GBR12909 induced a widespread negative rCBV response, whereas an increase in striatal DA concentration was observed. These findings indicate that phMRI responses to activation of DA neurotransmission by GBR12909 or AMPH are overall identical in the awake state, while the phMRI response to a DAT inhibitor, GBR12909 but not to AMPH was changed by isoflurane anesthesia. For the evaluation of neuroactive drugs using phMRI, isoflurane anesthesia might be complicated the interpretation of pharmacodynamic effects of drugs in preclinical studies.

Injection Route and TLR9 Agonist Addition Significantly Impact Heroin Vaccine Efficacy

Active immunization is an effective means of blocking the pharmacodynamic effects of drugs and holds promise as a treatment for heroin addiction. Previously, we demonstrated the efficacy of our first-generation vaccine in blocking heroin self-administration in rats, however, many vaccine components can be modified to further improve performance. Herein we examine the effects of varying heroin vaccine injection route and adjuvant formulation. Mice immunized via subcutaneous (sc) injection exhibited inferior anti-heroin titers compared to intraperitoneal (ip) and sc/ip coadministration injection routes. Addition of TLR9 agonist cytosine-guanine oligodeoxynucleotide 1826 (CpG ODN 1826) to the original alum adjuvant elicited superior antibody titers and opioid affinities compared to alum alone. To thoroughly assess vaccine efficacy, full dose–response curves were generated for heroin-induced analgesia in both hot plate and tail immersion tests. Mice treated with CpG ODN 1826 exhibited greatly shifted dose–response curves (10–13-fold vs unvaccinated controls) while non-CpG ODN vaccine groups did not exhibit the same robust effect (2–7-fold shift for ip and combo, 2–3-fold shift for sc). Our results suggest that CpG ODN 1826 is a highly potent adjuvant, and injection routes should be considered for development of small molecule–protein conjugate vaccines. Lastly, this study has established a new standard for assessing drugs of abuse vaccines, wherein a full dose–response curve should be performed in an appropriate behavioral task.

Cerebrospinal fluid biomarkers for pathological processes in Alzheimer's disease

To review the rationale behind and the use of cerebrospinal fluid (CSF) biomarkers in Alzheimer's disease (AD). Established as well as new candidate biomarkers will be covered. AD is a complex disorder and the AD brain is characterized by multiple pathological processes, in addition to well-described plaque and tangle diseases. Recent studies have tried to address this by evaluating biomarkers related to features such as neuroinflammation, oxidative stress, microglial activation and synaptic degeneration, with some positive results. The CSF biomarkers total tau, phosphorylated-tau and the 42 amino acid isoform of amyloid beta reflect core elements of AD, that is, axonal degeneration, tangle disease and senile plaques, have been thoroughly tested and provide high diagnostic accuracy in the discrimination of patients with AD as compared with cognitively normal controls. They are also highly predictive of AD with dementia in patients with mild cognitive impairment, and have been included in new diagnostic criteria. New biomarkers may add to their diagnostic performance. Other potential fields of use include the monitoring of disease progression or pharmacodynamic drug effects. A common denominator for the candidate biomarkers is the need for validation in further studies to clarify their potential.

Factors related to biopsy willingness in patients with advanced cancer in a phase 1 clinic for molecularly targeted therapy.

Tumor biopsies are critical for delineating pharmacodynamic effects of drugs and for optimal patient selection during oncology clinical trials of molecular targeted therapies. The purpose of this study was to identify factors related to patients' willingness to provide study-related tumor biopsies in phase 1 clinical trials of molecularly targeted therapy. An investigator-designed survey, that assessed biopsy willingness, demographic and clinical factors, was completed anonymously by patients with advanced cancer in a phase 1 clinic for targeted therapy. Data were analyzed using multivariate logistic regression models with odds ratios (OR) and 95 % confidence intervals (CI). Three hundred and sixty-two patients with advanced cancer (50 % male, 56 % aged ≤ 60 years) participated. In univariate analyses, willingness to provide study-related biopsy was associated with male gender, white race, higher income, using the Internet for cancer-related information, and having had a biopsy previously (p < 0.05). In multivariate analyses, male gender (OR 2.41, 95 % CI 1.54, 3.78) and having had a biopsy (OR 3.71, 95 % CI 1.68, 8.15) were associated with willingness to have one biopsy; male gender (OR 1.97, 95 % CI 1.30, 3.00) and relying on the Internet as a source of information (OR 1.87, 95 % CI 1.21, 2.89) were associated with willingness to have more than one biopsy. The results suggest that male gender is associated with greater stated willingness to undergo biopsy. Also, the Internet is an important source of information for patients with cancer and may strongly influence their decisions about whether to consent to biopsies in early clinical trials.

Miotic and subject-rated effects of therapeutic doses of tapentadol, tramadol, and hydromorphone in occasional opioid users

Tapentadol is a novel analgesic that activates mu-opioid receptors and blocks norepinephrine reuptake. There is very little information available regarding the non-analgesic pharmacodynamic effects of tapentadol. This outpatient study evaluated the physiological, subject-rated, and performance effects of therapeutic doses of tapentadol compared to two control drugs in humans. This double-blind, within-subject study examined the effects of oral placebo, tapentadol (25, 50, and 75 mg), tramadol (50, 100, and 150 mg), and hydromorphone (2, 4, and 6 mg). Nine occasional opioid users completed the study. Pharmacodynamic drug effects were measured before and for 6 h after drug administration. All three doses of the tested drugs produced comparable, time-dependent decreases in pupil diameter, but the effects were generally not dose dependent. The high dose of tapentadol, as well as all three doses of tramadol and hydromorphone, increased positive subject-rated effects (e.g., "Good Effects" and "Like the Drug") as a function of time. Only tramadol increased negative subject-rated effects (e.g., "Bad Effects" and "Nauseous"); however, these were of low magnitude. The highest tested dose of tapentadol produced a profile of positive effects comparable to that of hydromorphone, whereas tramadol produced positive and negative subject-rated effects. The mixed findings for tramadol are consistent with previous findings indicating that it has a distinct profile of effects relative to prototypic opioids. Future research should examine the effects of higher tapentadol doses, as well as the factors contributing to the different subject-rated profile of effects observed for tramadol relative to tapentadol and hydromorphone.

Assay validation of phosphorylated S6 ribosomal protein for a pharmacodynamic monitoring of mTOR‐inhibitors in peripheral human blood

Therapeutic drug monitoring (TDM) of immunosuppressive drugs after organ transplantation is based on measuring blood levels alone, which often results in under- or over-immunosuppression. Previous studies have shown the potential of measuring pharmacodynamic drug effects for TDM, but assessment of biomarkers for individual drugs is still not clinical routine. Therefore, we validated a specific assay to measure the pharmacodynamic effects of mammalian target of rapamycin (mTOR)-inhibitors on phosphorylated S6 ribosomal protein (p-S6RP), a downstream target of mTOR. Clinical relevant concentrations of sirolimus (SRL, 0.9-91.4 μg/L), cyclosporine A (CsA, 75.1-1202 μg/L), mycophenolate acid (MPA, 0.08-3.2 mg/L), or dexamethasone (DEX, 0.5-200 ng/mL) were added to whole-blood from healthy volunteers. Activated whole-blood was analyzed by phospho-flow cytometry to measure p-S6RP in T cells. Phospho-flow analysis revealed that SRL suppressed p-S6RP in human T cells in a dose-dependent manner with a half-maximal inhibitory concentration (IC(50)) at 19.8 nM and a maximal inhibitory effect (I(max) %) at 91.9%. Neither CsA, MPA, nor DEX inhibited mTOR-related S6RP-phosphorylation. Coefficient of variations from 0.03 to 0.05, 0.12 to 0.25, and 0.14 to 0.38 for intra-, interassay, and interindividual variability respectively, showed robustness of our assay. Furthermore, samples can be stored at RT or 4°C up to 2 h after withdrawal. We validated a robust whole-blood assay that allows the specific measurement of SRL- and everolimus-induced inhibition of T cells' function through detection of p-S6RP. Future studies in organ transplanted recipients will show if this assay has the potential to enhance a TDM for mTOR-inhibitor drugs in combination therapies.

S.27.03 Catecholamines and fronto-striatal circuitry in ADHD: human studies and translational models

Attention deficit hyperactivity disorder (ADHD) is a common childhood psychiatric condition that is effectively treated by catecholaminergic drugs with a variety of different mechanisms and the SH rat is frequently used as a model of this disorder. In vivo microdialysis in freely-moving rats has been employed extensively to provide a better understanding of the pharmacodynamics of drugs at their sites of action. In this review, these three topics are brought together to explore the contribution of in vivo microdialysis studies in spontaneously hypertensive (SH) rats to our understanding of the neurochemical deficits in this rat strain and the actions of ADHD drugs on catecholaminergic function in the prefrontocortex (PFC), striatum and nucleus accumbens. What is revealed is that basal efflux of norepinephrine in the PFC is attenuated, whilst striatal and mesolimbic dopaminergic neurotransmission is hyperfunctional; the latter observation fits closely with the hyperactive phenotype of the SH rat. Furthermore, experiments performed with the enantiomers of amphetamine and threo-methylphenidate demonstrate that pharmacodynamic effects of drugs reported from experiments in outbred rat strains, e.g. Sprague–Dawleys, do not necessarily translate to the SH rat. When the findings are compared with the clinical efficacy of drugs used in treating ADHD, they indicate that the most efficacious drugs powerfully increase both norepinephrinergic and dopaminergic neurotransmission.

Part 3: Pharmacogenetic Variability in Phase II Anticancer Drug Metabolism

Equivalent drug doses may lead to wide interpatient variability in drug response to anticancer therapy. Known determinants that may affect the pharmacological response to a drug are, among others, nongenetic factors, including age, gender, use of comedication, and liver and renal function. Nonetheless, these covariates do not explain all the observed interpatient variability. Differences in genetic constitution among patients have been identified to be important factors that contribute to differences in drug response. Because genetic polymorphism may affect the expression and activity of proteins encoded, it is a key covariate that is responsible for variability in drug metabolism, drug transport, and pharmacodynamic drug effects. We present a series of four reviews about pharmacogenetic variability. This third part in the series of reviews is focused on genetic variability in phase II drug-metabolizing enzymes (glutathione S-transferases, uridine diphosphoglucuronosyl transferases, methyltransferases, sulfotransferases, and N-acetyltransferases) and discusses the effects of genetic polymorphism within the genes encoding these enzymes on anticancer drug therapy outcome. Based on the literature reviewed, opportunities for patient-tailored anticancer therapy are proposed.

Part 1: Background, Methodology, and Clinical Adoption of Pharmacogenetics

Equivalent drug doses may lead to wide interpatient variability with regard to drug response, reflected by differences in drug activity and normal tissue toxicity. A major factor responsible for this variability is variation among patients in their genetic constitution. Genetic polymorphism may affect the activity of proteins encoded, which in turn may lead to changes in the pharmacokinetic and pharmacodynamic behavior of a drug, observed as differences in drug transport, drug metabolism, and pharmacodynamic drug effects. Recent insights into the functional effect of polymorphism in genes that are involved in the pharmacokinetics and pharmacodynamics of anticancer drugs have provided opportunities for patient-tailored therapy in oncology. Individualized pharmacotherapy based on genotype will help to increase treatment efficacy while reducing unnecessary toxicity, especially of drugs characterized by a narrow therapeutic window, such as anticancer drugs. We provide a series of four reviews aimed at implementing pharmacogenetic-based drug and dose prescription in the daily clinical setting for the practicing oncologist. This first part in the series describes the functional impact of genetic polymorphism and provides a general background to and insight into possible clinical consequences of pharmacogenetic variability. It also discusses different methodologies for clinical pharmacogenetic studies and provides a concise overview about the different laboratory technologies for genetic mutation analysis that are currently widely applied. Subsequently, pharmacogenetic association studies in anticancer drug transport, phase I and II drug metabolism, and pharmacodynamic drug effects are discussed in the rest of the series. Opportunities for patient-tailored pharmacotherapy are highlighted.

145 Novel Immunoassay for Therapeutic Drug Monitoring of mTOR-Inhibitors after Heart and Lung Transplantation

Therapeutic drug monitoring (TDM) of immunosuppressive drugs after transplantation like the mTOR-inhibitors sirolimus (SRL) or everolimus (ERL) is based on measuring blood levels alone. But this often results in under- or over-immunosuppression leading to rejection or infection, respectively. Earlier studies have shown the potential value of measuring pharmacodynamic drug effects for TDM. Therefore we developed an assay to measure drug effects on the mTOR-pathway.

A novel flow cytometry based assay for therapeutic monitoring of mTOR-inhibitor induced immunosuppression after heart transplantation

Objective: Therapeutic drug monitoring (TDM) of immunosuppressive drugs after transplantation (Tx) like the mTOR-inhibitors sirolimus (SRL) or everolimus (ERL) is based on measuring blood levels alone. But this often results in under- or over-immunosuppression leading to rejection or infection, respectively. Earlier studies have shown the potential value of measuring pharmacodynamic drug effects for TDM. Therefore we developed an assay to measure drug effects on the mTOR-pathway.

Drug metabolizing enzymes and transporters at the blood-brain barrier

Event Abstract Back to Event Drug metabolizing enzymes and transporters at the blood-brain barrier Jaime Kapitulnik1* 1 The Hebrew University of Jerusalem, Department of Pharmacology, Israel The blood–brain barrier (BBB) is a physical and functional barrier that prevents the entrance of many drugs and chemicals into brain cells regardless of their molecular size. Carrier-mediated transport systems in the BBB, that are active in efflux of drugs, include the P-glycoprotein pump (Pgp/MDR1/ABCB1) and non-Pgp multidrug-resistance proteins (MRPs). The human MDR1-Pgp is located at the luminal site of BBB endothelial cells. It is an amphipatic cationic efflux pump, and limits the influx and diffusion of many drugs and chemicals, thus protecting the brain from the toxic effects of high concentrations of these compounds. Very importantly, Pgp handles also the efflux of endogenous compounds, as is the case with bilirubin (BR), a neurotoxic catabolite of heme. Thus, BR–drug competition for the Pgp in the BBB may affect the entrance of both BR and drugs into the brain. Since Pgp is expressed only after birth, newborn infants are very sensitive to this endogenous neurotoxin, which can diffuse into the brain and precipitate in discrete areas such as the basal ganglia (kernicterus). Pgp can have a pronounced influence on the pharmacodynamic effects of drugs in the brain. Many CNS-active drugs are Pgp substrates (e.g., morphine, phenytoin, anti-brain-cancer drugs, anti-HIV agents, etc.), and consequently inhibition of Pgp at the BBB increases the therapeutic effects of these drugs by increasing their concentrations in the brain. However, in vivo drug–drug interactions at the BBB Pgp can also lead to side effects (e.g., for diltiazem and tacrolimus) and even to CNS toxicity. The MRPs are non-Pgp, amphipatic anion efflux pumps that can also transport cations and neutral compounds (co-transported with GSH). Several of the identified members of the MRP family are expressed at the BBB. Several drug metabolizing enzymes, including cytochrome P450, UDP-glucuronosyltransferase and glutathione transferase, were identified in discrete areas of the brain in which they may perform important functions in the synthesis and elimination of compounds vital to the brain. These enzymes may also participate in the elimination of drugs and toxicants, thus offering an additional protective mechanism for the CNS. Drug-drug and drug-endogenous compound interactions, as well as the 'cross-talk' between enzymes and transporters, will be discussed. Keywords: Blood-Brain Barrier, transporters, drug metabolizing enzymes, P-glycoprotein pump (Pgp), multidrug-resistance proteins (MRPs) Conference: 8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010, Thessaloniki, Greece, 1 Oct - 5 Oct, 2010. Presentation Type: Invited speaker Topic: Drug transport Citation: Kapitulnik J (2010). Drug metabolizing enzymes and transporters at the blood-brain barrier. Front. Pharmacol. Conference Abstract: 8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010. doi: 10.3389/conf.fphar.2010.60.00135 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Oct 2010; Published Online: 04 Nov 2010. * Correspondence: Dr. Jaime Kapitulnik, The Hebrew University of Jerusalem, Department of Pharmacology, Jerusalem, 91120, Israel, jaimek@savion.huji.ac.il Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jaime Kapitulnik Google Jaime Kapitulnik Google Scholar Jaime Kapitulnik PubMed Jaime Kapitulnik Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Pharmacogenetics of Phase I and Phase II Drug Metabolism

Genetic variation in the receptors and other intracellular targets that mediate the pharmacodynamic effects of drugs can affect therapeutic outcomes. However, at present greater knowledge is available concerning the extent of gene variation in drug metabolizing enzymes that determine drug pharmacokinetics and, in turn, drug efficacy and toxicity. Information on the incidence of polymorphisms in the cytochrome P450 (CYP) genes that mediate phase I biotransformation is increasing, although the level of detail in the case of phase II conjugation enzymes, such as the UDP-glucuronosyltransferases (UGTs) and N-acetyltransferases (NATs), is not as extensive. It is now apparent that defective alleles that encode variant CYPs, UGTs, NATs and other biotransformation enzymes can influence the outcome of therapy. Diminished rates of drug clearance can increase the incidence of toxicity from many drugs, but may also enhance efficacy, as in the case of the proton-pump inhibitor omeprazole, that maintains therapeutic serum concentrations in individuals that carry null alleles for CYP2C19. Variant alleles of UGT1A1 are less capable of conjugating and eliminating SN-38, the active form of the topoisomerase inhibitor irinotecan, and defective alleles for NAT2 are responsible for the well-described acetylation polymorphism that leads to impaired clearance of isoniazid and other agents. This review focuses on reports that relate pharmacogenetic variation in phase I and phase II enzymes to the safety and toxicity of drug therapy and highlights a number of themes that have emerged recently that may be developed to streamline therapy for individuals.

Pharmaceutical forms in Antidotarium Nicolai

Pharmaceutical forms are equally important as pharmacodynamic effect of drug for expression of therapeutic effect. Antidotarium Nicolai was the first pharmacopoeia written in the beginning of the 12th century by Nicolaus Salernitanus. Pharmaceutical forms were not described clearly in terms of type, structure, technological process and application. Salerno’s pharmacotherapy, as it can be seen from the Antidotarium, was based on “sugar-honey pharmacy” and the only difference between pharmaceutical forms was viscosity of forms. The following forms are described in the Antidotarium: electuaria, morsuli, pillules, trochisci, sirupi, emplastra, unguenta and olea. Antidotarium Nicolai is of unique importance since it is the first attempt of systematisation of pharmaceutical forms. Although today’s criteria differ significantly from Nicolaus’s, this book still has a great value as it represents the basis for all further pharmacopoeias written many years after Antidotarium Nicolai.

Translational studies for target-based drugs

The biological background for the clinical and prognostic heterogeneity among tumors within the same histological subgroup is due to individual variations in the biology of tumors. The number of investigations looking at the application of novel technologies within the setting of clinical trials is increasing. The most promising way to improve cancer treatment is to build clinical research strategies on intricate biological evidence. New genomic technologies have been developed over recent years. These techniques are able to analyze thousands of genes and their expression profiles simultaneously. The purpose of this approach is to discover new cancer biomarkers, to improve diagnosis, predict clinical outcomes of disease and response to treatment, and to select new targets for novel agents with innovative mechanisms of action. Gene expression profiles are also used to assist in selecting biomarkers of pharmacodynamic effects of drugs in the clinical setting. Biomarker monitoring in surrogate tissues may allow researchers to assess "proof of principle" of new treatments. Clinical studies of biomarkers monitoring toxicity profiles have also been done. Such pharmacodynamic markers usually respond to treatment earlier than clinical response, and as such may be useful predictors of efficacy. Epidermal growth factor receptor (EGFR) mutation in lung cancer tissues is a strong predictive biomarker for EGFR-targeted protein tyrosine kinase inhibitors. Monitoring of EGFR mutation has been broadly performed in retrospective and prospective clinical studies. However, global standardization for the assay system is essential for such molecular correlative studies. A more sensitive assay for EGFR mutation is now under evaluation for small biopsy samples. Microdissection for tumor samples is also useful for the sensitive detection of EGFR mutation. Novel approaches for the detection of EGFR mutation in other clinical samples such as cytology, pleural effusion and circulating tumor cells are ongoing.

Baseline Plasma GABA: Its Relationship to the Adverse Effects of Acute Lorazepam Administration on Cognition in the Elderly

The GABA system is an active target for drugs to treat a variety of disorders and the availability of an indirect measure of central GABA activity would not only enhance psychiatric research, but also permit assessment of the pharmacodynamic effects of drugs designed to act on this system. The relationships between plasma baseline pre-drug GABA concentrations and cognitive impairments induced by an acute oral dose of lorazepam (0.5 and 1.0 mg) were investigated in 22 healthy elderly individuals. Partial correlations controlling for plasma lorazepam concentrations revealed no significant relationship between baseline plasma GABA levels and lorazepam-induced impairments on tests of cognitive functioning. Plasma GABA concentration does not appear to be a useful marker of susceptibility to benzodiazepine-induced cognitive toxicity in the elderly. Other approaches to estimating central GABA activity should be pursued.