PQLI Engineering Controls and Automation Strategy

This paper discusses the development of engineering controls and automation strategy required to practically implement a Control Strategy within a Quality by Design environment. It describes the relationship to the ISPE PQLI Control Strategy model, and covers operating philosophy, record keeping, data management, and alarm strategy. Engineering and automation controls may include measurement technologies for equipment parameters (off-line, at-line, in-line or on-line), univariate or multivariate process models and control models, engineering or plant procedural controls and automation systems. Concepts from ANSI/ISA S95 standards are applied.

PQLI Definition of Criticality

This paper describes progress made by the Criticality Task Team within the ISPE PQLI initiative. It aims to provide a concise, coherent, and universal approach for determining criticality for parameters, material attributes, conditions, and quality attributes. The work also clarifies the risk based distinctions governing the assignment of criticality to provide consistency and facilitate the adoption and implementation of Quality by Design (QbD) principles in the development of pharmaceutical manufacturing processes. The application of the concept of criticality presented in this paper aligns with the principles of ICH Q8, Q9 and Q10 guidelines.

Lack of sedative effects after vespertine intake of oxazepam as hypnotic in healthy volunteers

Aims  An objective physiological test was used to investigate the hangover effect, its time course and dose relationship compared to placebo and an herbal relaxant. Methods  Pupillographic Sleepiness Test as an objective measurement, Stanford Sleepiness Scale (SSS) and visual analogue scales (VAS) were used. Study design included: (a) randomised, double-blind, double-dummy, placebo-controlled crossover trial; (b) double-blind, placebo-controlled, randomised study. Primary end point was the Pupillary Unrest Index (lnPUI). Results  Oxazepam 10 mg did not increase PUI. In the VAS and SSS, there was no increase in sleepiness after the three treatment periods. Neither 10 nor 30 mg oxazepam caused sedation in healthy volunteers. Subjective and objective sleepiness measures correlated significantly. Discussion  The lack of sedative effects after vespertine intake of oxazepam (10/30 mg) seems to be relevant with respect to product safety. With regard to the subjective perception at 30 mg, fatigue rather than sleepiness may be the underlying reason.

Accurate Potentiometric Determination of Lipid Membrane–Water Partition Coefficients and Apparent Dissociation Constants of Ionizable Drugs: Electrostatic Corrections

Purpose  Potentiometric lipid membrane–water partition coefficient studies neglect electrostatic interactions to date; this leads to incorrect results. We herein show how to account properly for such interactions in potentiometric data analysis. Materials and Methods  We conducted potentiometric titration experiments to determine lipid membrane–water partition coefficients of four illustrative drugs, bupivacaine, diclofenac, ketoprofen and terbinafine. We then analyzed the results conventionally and with an improved analytical approach that considers Coulombic electrostatic interactions. Results  The new analytical approach delivers robust partition coefficient values. In contrast, the conventional data analysis yields apparent partition coefficients of the ionized drug forms that depend on experimental conditions (mainly the lipid-drug ratio and the bulk ionic strength). This is due to changing electrostatic effects originating either from bound drug and/or lipid charges. A membrane comprising 10 mol-% mono-charged molecules in a 150 mM (monovalent) electrolyte solution yields results that differ by a factor of 4 from uncharged membranes results. Conclusion  Allowance for the Coulombic electrostatic interactions is a prerequisite for accurate and reliable determination of lipid membrane–water partition coefficients of ionizable drugs from potentiometric titration data. The same conclusion applies to all analytical methods involving drug binding to a surface.

Geostatistical analysis of DNA damage in oysters, Crassostrea virginica, in Lavaca Bay, Texas

This study evaluated the health of the marine ecosystem in Lavaca Bay, Texas using the Eastern oyster (Crassostrea virginica) as the sentinel species. Lavaca Bay has a history of having gradients of concentrations of pollutants present with some areas containing concentrations high enough to pose a threat to marine ecosystem health. The Comet assay was used to evaluate for the presence of genotoxic response in oyster hematocytes. Bayesian geostatistical analysis was then used to determine if the DNA damage in oyster hematocytes was spatially oriented and to develop continuous surface maps of the risk of DNA damage in this sentinel species. Results indicated that proximity to industrial facilities increased the locational risk of genotoxicity in this species.

Geostatistical analysis of biomarkers of genotoxicity in cattle, Bos taurus and Bos taurus × Bos indicus, sentinels near industrial facilities

This study, performed at the behest of ranchers living and working down-prevailing wind from industrial facilities located in Calhoun County, Texas investigated locational risks to ecosystem health associated with proximity to specific industrial complexes. Concerns expressed were for potential genotoxicity in cattle resulting from the release of complex chemical mixtures. The Comet Assay and flow cytometric evaluation of variations in DNA content were utilized to evaluate DNA damage. Bayesian geo-statistical analysis revealed the presence of important spatial processes. The Comet assay’s optical density provided a strong indication of increased damage down-prevailing wind from the industrial complexes. Results indicated that proximity to and location down-prevailing winds from industrial facilities increased the locational risk of genotoxicity in this sentinel species.

Effects of MDMA on sociability and neural response to social threat and social reward

Rationale  There has been controversy over the abuse potential of methylphenidate (MPH) in the context of treatment for attention deficit hyperactivity disorder (ADHD). Objective  The objective of this study was to compare the reinforcing and subjective effects of oral MPH in adults with and without ADHD. Materials and methods  Following screening, 33 adults (n = 16 with ADHD; n = 17 free from psychiatric diagnoses) completed four pairs of experimental sessions, each of which included a sampling session and a self-administration session. During sampling sessions, subjects received in randomized order 0 (placebo), 20, 40, and 60 mg MPH. During self-administration sessions, subjects completed a progressive ratio (PR) task to earn portions of the dose received on the corresponding sampling session. Subjective effects were recorded throughout all sessions. The main outcome measure for the study was the number of ratios completed on the PR task. Secondary measures included peak subjective effects and area-under-the-curve values for subjective effects. Results  Compared to the control group, the ADHD group completed more ratios on the PR task. Both groups showed robust effects of methylphenidate on subjective endpoints. Main effects of group were noted on subjective effects involving concentration and arousal. Conclusions  Compared to placebo, MPH produced reinforcing effects only for the ADHD group and not for the control group. Increases in stimulant-related subjective effects in non-ADHD subjects were not associated with drug reinforcement.

PQLI Key Topics - Criticality, Design Space, and Control Strategy

This paper gives an overview of progress made by the ISPE PQLI initiative - a global industry-led initiative aimed at facilitating the implementation of ICH Q8, Q9, and ultimately Q10 guidance. Through this initiative ISPE is spearheading the effort to help industry begin to define areas where they will be able to provide the technical framework for the implementation of key elements of Quality by Design (QbD) - a systematic approach to development that begins with predefined objectives and emphasizes product and process understanding based on sound science and quality risk management. Three topic areas, Design Space, Criticality, and Control Strategy were selected for specific focus and discussion, and this paper gives an overview of progress in these three areas.

Systemic Delivery of DNA or siRNA Mediated by Linear Polyethylenimine (L-PEI) Does Not Induce an Inflammatory Response

Purpose  The success of nucleic acid therapies depends upon delivery vehicle’s ability to selectively and efficiently deliver therapeutic nucleic acids to target organ with minimal toxicity. The cationic polymer polyethylenimine (PEI) has been widely used for nucleic acid delivery due to its versatility and efficiency. In particular, the last generation of linear PEI (L-PEI) is being more efficient in vivo than the first generation of branched PEI. This led to several clinical trials including phase II bladder cancer therapy and human immunodeficiency virus immunotherapy. When moving towards to the clinic, it is crucial to identify potential side-effects induced by the delivery vehicle. Materials and Methods  For this purpose we have analyzed the production of pro-inflammatory cytokines [tumor necrosis factor-α, interferon (IFN)-γ, interleukin (IL)-6, IL-12/IL-23, IFN-β and IL-1β] and hepatic enzyme levels (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase) in the blood serum of mice after systemic injection of DNA or siRNAs delivered with L-PEI. Results  Our data show no major production of pro-inflammatory cytokines or hepatic enzymes after injection of DNA or oligonucleotides active for RNA interference (siRNAs or sticky siRNAs) complexed with L-PEI. Only a slight induction of IFN-γ was measured after DNA delivery, which is probably induced by the CpG mediated response. Conclusion  Taken together our data highlight that linear polyethylenimine is a delivery reagent of choice for nucleic acid therapeutics.

Botanical origin of Indian celery seed (fruit)

In the course of our study on the traditional medicines and foodstuffs used in Pakistan, we investigated the origin of Indian celery by using the analysis of the internal transcribed spacer (ITS) sequence of nuclear rDNA and a phytochemical approach. We found that the source plant of the Indian celery containing coumarin derivatives such as seselin (1), bergapten (2) and isopimpinellin (3) was not common celery, Apium graveolens. Our results suggest the source plant is Seseli diffusum even though Indian workers reported that A. graveolens seeds contain the aforementioned compounds. In addition, a market survey of the Indian celery in Pakistan and related countries revealed that the Indian celery seeds in Pakistani markets are mainly composed of three species which have been confused in rural markets. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

Acute tryptophan depletion and self-injurious behavior in aggressive patients and healthy volunteers

Rationale  An association between serotonin (5-HT) activity and self-injurious (i.e., self-aggressive) behavior across the spectrum of lethality (from self-mutilation through completed suicide) is a well-replicated finding. Studies to date, however, have relied on nonexperimental designs to examine this relationship, limiting the causal inferences that can be drawn about the role of 5-HT in self-aggressive behavior. Objective  Examine the effect of experimentally altered 5-HT activity (via dietary tryptophan depletion) on self-aggressive behavior among adults with and without intermittent explosive disorder (IED). Individuals with a marked history of aggression, such as those with IED, are characterized by compromised 5-HT and heightened risk for self-aggression, making this a population of interest for examining the proposed relations. Materials and methods  IED patients (n = 16) and healthy controls (n = 16) received a tryptophan depletion and a placebo drink on separate days at least 1 week apart. Self-aggressive behavior was assessed on both study days using a well-validated laboratory-based behavioral assessment with self-aggression defined as the intensity of shock self-administered. Results  Tryptophan depletion facilitated selection of more intense shocks, on average, in both groups. Patients with IED were also more self-aggressive overall than healthy volunteers. No IED by drink condition interactions were found. Conclusion  Experimentally lowered 5-HT bioavailability enhances overall self-injurious behavior irrespective of aggression history.

Hypocretin mechanisms in nicotine addiction: evidence and speculation

Background  The hypocretin/orexin system has been implicated in arousal mechanisms, sleep, and sleep disorders, including narcolepsy, and more recently in drug addiction. Theoretically, hypocretin (hcrt) mechanisms appear to be potential substrates for nicotine addiction: arousal and attentional mechanisms influence use and withdrawal symptoms, and hcrt systems overlap anatomically with a number of brain regions associated with nicotine addiction. Objective  This review summarizes the studies that have examined hcrt mechanisms in the effects of nicotine and describes hcrt innervation of, and effects in, several brain regions implicated in nicotine addiction. The review speculates on the possible mechanisms by which hcrt may contribute to nicotine addiction in these regions, with the objective of encouraging research in this area. Results  In a small literature, both experimenter-administered and self-administered nicotine have been shown to elicit or depend on hcrt signaling. However, although untested in experimental designs, there is compelling evidence that hcrt mechanisms in the ventral tegmental area, the pontine region, thalamocortical circuits, the prefrontal cortex, and the amygdala could have a broad influence on nicotine addiction. Conclusions  Evidence reviewed leads to the conclusion that hcrt mechanisms could mediate several dimensions of nicotine addiction, including a multi-faceted regulation of mesocorticolimbic dopaminergic function, but beyond dopaminergic mechanisms, hcrt could influence nicotine use and relapse during abstinence through broadly based arousal/attentional effects. These speculative ideas need to be examined experimentally; the potential gains are a more thorough understanding of the pathophysiology of nicotine addiction, and the discovery of novel targets for the development of pharmacotherapeutics.

Discrete neurochemical coding of distinguishable motivational processes: insights from nucleus accumbens control of feeding

Background and objectives  The idea that nucleus accumbens (Acb) dopamine transmission contributes to the neural mediation of reward, at least in a general sense, has achieved wide acceptance. Nevertheless, debate remains over the precise nature of dopamine’s role in reward and even over the nature of reward itself. In the present article, evidence is reviewed from studies of food intake, feeding microstructure, instrumental responding for food reinforcement, and dopamine efflux associated with feeding, which suggests that reward processing in the Acb is best understood as an interaction among distinct processes coded by discrete neurotransmitter systems. Results  In agreement with several theories of Acb dopamine function, it is proposed here that allocation of motor effort in seeking food or food-associated conditioned stimuli can be dissociated from computations relevant to the hedonic evaluation of food during the consummatory act. The former appears to depend upon Acb dopamine transmission and the latter upon striatal opioid peptide release. Moreover, dopamine transmission may play a role in ‘stamping in’ associations between motor acts and goal attainment and perhaps also neural representations corresponding to rewarding outcomes. Finally, evidence is reviewed that amino acid transmission specifically in the Acb shell acts as a central ‘circuit breaker’ to flexibly enable or terminate the consummatory act, via descending connections to hypothalamic feeding control systems. Conclusions  The heuristic framework outlined above may help explain why dopamine-compromising manipulations that strongly diminish instrumental goal-seeking behaviors leave consummatory activity relatively unaffected.

Efficacy and safety of bifeprunox in patients with an acute exacerbation of schizophrenia: results from a randomized, double-blind, placebo-controlled, multicenter, dose-finding study

Rationale  Bifeprunox is a partial dopamine agonist with a unique receptor-binding profile and potential antipsychotic properties. Objectives  The current study evaluated the efficacy and safety of bifeprunox in patients with an acute exacerbation of schizophrenia. Materials and methods  In this 6-week, double-blind, placebo-controlled study, 589 patients were randomly assigned to once-daily treatment with bifeprunox 5, 10, or 20 mg, placebo, or risperidone 6 mg. Efficacy was assessed by changes in symptom rating scales [Positive and Negative Syndrome Scale (PANSS) total and subscale scores; PANSS-derived BPRS scores; Clinical Global Impression—Severity (CGI—S) and Clinical Global Impression—Improvement (CGI—I) scores]. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms (EPS), laboratory values, electrocardiograms, prolactin levels, and weight. Results  Compared with placebo, bifeprunox 20 mg produced a statistically significantly greater reduction from baseline to last assessment in the primary efficacy variable (PANSS total score; effect size = −0.339), as well as most secondary efficacy measures. No statistically significant differences in efficacy were seen with lower doses of bifeprunox. The most common treatment-emergent adverse events (TEAEs) noted with bifeprunox were gastrointestinal; no clear dose-related trend in the incidence of any TEAE was observed in the bifeprunox groups. Compared to placebo, treatment with bifeprunox led to small but statistically significant decreases in weight and prolactin levels. EPS were comparable between bifeprunox and placebo. The active reference in this study, risperidone 6 mg, showed statistically significant differences from placebo for the primary efficacy parameter (effect size = −0.628) and all secondary efficacy parameters. Conclusions  These data suggest that 20 mg of bifeprunox may be efficacious in improving symptoms in patients with an acute exacerbation of schizophrenia. Bifeprunox appeared to be safe and well tolerated by patients in this 6-week study.

A neurocomputational account of catalepsy sensitization induced by D2 receptor blockade in rats: context dependency,extinction, and renewal

Rationale  Repeated haloperidol treatment in rodents results in a day-to-day intensification of catalepsy (i.e., sensitization). Prior experiments suggest that this sensitization is context-dependent and resistant to extinction training. Objectives  The aim of this study was to provide a neurobiological mechanistic explanation for these findings. Materials and methods  We use a neurocomputational model of the basal ganglia and simulate two alternative models based on the reward prediction error and novelty hypotheses of dopamine function. We also conducted a behavioral rat experiment to adjudicate between these models. Twenty male Sprague–Dawley rats were challenged with 0.25 mg/kg haloperidol across multiple days and were subsequently tested in either a familiar or novel context. Results  Simulation results show that catalepsy sensitization, and its context dependency, can be explained by “NoGo” learning via simulated D2 receptor antagonism in striatopallidal neurons, leading to increasingly slowed response latencies. The model further exhibits a non-extinguishable component of catalepsy sensitization due to latent NoGo representations that are prevented from being expressed, and therefore from being unlearned, during extinction. In the rat experiment, context dependency effects were not dependent on the novelty of the context, ruling out the novelty model’s account of context dependency. Conclusions  Simulations lend insight into potential complex mechanisms leading to context-dependent catalepsy sensitization, extinction, and renewal. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

The botanical origin of kratom (<Emphasis Type="Italic">Mitragyna speciosa</Emphasis>; Rubiaceae) available as abused drugs in the Japanese markets

Kratom is the leaves of Mitragyna speciosa (Rubiaceae). Recently, kratom has been sold in street shops or on the Internet in Japan for the purpose of abuse due to its opium-like effects. In this study, we investigated the botanical origin of the commercial kratom products using the internal transcribed spacer (ITS) sequence analysis of rDNA in preparation for future regulation of this product. In addition, a previously reported method to authenticate the plant, utilizing polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied to the same products in order to estimate the method’s accuracy and utility. The ITS sequence analysis of the commercial kratoms revealed that most of them were derived from M. speciosa or closely related plants, while the others were made from the same tribe plant as M. speciosa. The reported PCR-RFLP method could clearly distinguish kratoms from the other psychoactive plants available in the Japanese markets and also from related plants. The authentication method is considered to be useful for the practical regulation of the plant due to its wide range of application, high accuracy and simplicity. Electronic supplementary material  The online version of this article () contains supplementary material, which is available to authorized users.

Identification of Novel Specific and General Inhibitors of the Three Major Human ATP-Binding Cassette Transporters P-gp,BCRP and MRP2 Among Registered Drugs

Purpose  To study the inhibition patterns of the three major human ABC transporters P-gp (ABCB1), BCRP (ABCG2) and MRP2 (ABCC2), using a dataset of 122 structurally diverse drugs. Methods  Inhibition was investigated in cellular and vesicular systems over-expressing single transporters. Computational models discriminating either single or general inhibitors from non-inhibitors were developed using multivariate statistics. Results  Specific (n = 23) and overlapping (n = 19) inhibitors of the three ABC transporters were identified. GF120918 and Ko143 were verified to specifically inhibit P-gp/BCRP and BCRP in defined concentration intervals, whereas the MRP inhibitor MK571 was revealed to inhibit all three transporters within one log unit of concentration. Virtual docking experiments showed that MK571 binds to the ATP catalytic site, which could contribute to its multi-specific inhibition profile. A computational model predicting general ABC inhibition correctly classified 80% of both ABC transporter inhibitors and non-inhibitors in an external test set. Conclusions  The inhibitor specificities of P-gp, BCRP and MRP2 were shown to be highly overlapping. General ABC inhibitors were more lipophilic and aromatic than specific inhibitors and non-inhibitors. The identified specific inhibitors can be used to delineate transport processes in complex experimental systems, whereas the multi-specific inhibitors are useful in primary ABC transporter screening in drug discovery settings. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.

Smoking stimuli from the terminal phase of cigarette consumption may not be cues for smoking in healthy smokers

Background  Stimuli from the terminal phase of smoke or drug intake are paired with drug effect but have surprisingly low cue reactivity. Smoking terminal stimuli were compared to cues under conditions of different perceived smoke intake to probe whether (1) terminal stimuli are only weak cues, (2) any effect is an artifact of rigid test conditions, and (3) terminal stimuli have a unique function during the intake ritual. Materials and methods  Nonabstinent, healthy smokers were tested in three experiments with one-session, within-subject cue reactivity tests. Smoking terminal stimuli and cues were compared using pictures depicting events after completion (END) and before start of smoke inhalation (BEGIN). Test pictures were presented alone and in combination with no-go symbols (from no-smoking signs) or with extra cues to decrease and to increase perceived smoke availability, respectively. Measured were subjective effects and affect modulation of the startle reflex. Results  END stimuli relative to BEGIN stimuli evoked less subjective craving and pleasure but more arousal. A no-go stimulus, which reduced reports of intention to smoke, reduced the reactivity to BEGIN but only marginally affected responses to END stimuli. This was confirmed with different sets of test pictures and using tests with the startle response. An extra cue did not affect reactivity to a BEGIN stimulus but increased craving and pleasure to the END stimulus, although not to the level of BEGIN stimuli alone. Conclusions  This first systematic study of terminal stimuli found their effects to be robust and have test generality. They are probably not weak cues but evoke reactivity, which may oppose reactivity of cues. They may signal poor availability of drug. Methodological, clinical, and theoretical implications were noted.