Central Nervous System Active Drugs Research Articles

Serendipity in anticancer drug discovery

It was found that the discovery of 5.8% (84/1437) of all drugs on the market involved serendipity. Of these drugs, 31 (2.2%) were discovered following an incident in the laboratory and 53 (3.7%) were discovered in a clinical setting. In addition, 263 (18.3%) of the pharmaceuticals in clinical use today are chemical derivatives of the drugs discovered with the aid of serendipity. Therefore, in total, 24.1% (347/1437) of marketed drugs can be directly traced to serendipitous events confirming the importance of this elusive phenomenon. In the case of anticancer drugs, 35.2% (31/88) can be attributed to a serendipitous event, which is somewhat larger than for all drugs. The therapeutic field that has benefited the most from serendipity are central nervous system active drugs reflecting the difficulty in designing compounds to pass the blood-brain-barrier and the lack of laboratory-based assays for many of the diseases of the mind.

Neonatal Complications After Maternal Concomitant Use of SSRI and Other Central Nervous System Active Drugs During the Second or Third Trimester of Pregnancy

Drugs acting on the central nervous system (CNS) and given to a pregnant woman during the latter part of pregnancy may affect neonatal morbidity of the infant. Little is known on the combined effects of different categories of such drugs. The redeeming of prescriptions for CNS-active drugs during the second or third trimester of pregnancy was studied by linkage between a register of prescribed drugs and the Swedish Medical Birth Register for the deliveries during 2006-2008 (n = 15,045 live-born infants). Neonatal morbidity was defined as the presence of neonatal diagnoses of respiratory problems, hypoglycemia, convulsions, or other CNS pathologic abnormalities including intraventricular hemorrhage, or low 5-minute Apgar score. The risk of such neonatal morbidity after maternal use of selective serotonin reuptake inhibitors (SSRIs) with or without other CNS-active drugs were evaluated as odds ratios or risk ratios, comparing with unexposed infants or infants only exposed to SSRI drugs. An increased risk for neonatal morbidity was seen for most studied groups of CNS-active drugs when used alone. Benzodiazepines seemed to have a stronger effect than other sedatives/hypnotics. The combination of SSRIs with 1 or more other CNS-active drug groups increased the risk for neonatal morbidity. This was seen for all types of sedatives/hypnotics, which may suggest a confounding by indication. Polypharmacy with CNS-active drugs during the later part of the pregnancy seems to increase the occurrence of neonatal morbidity but difference in nature or strength of underlying psychiatric pathology may confound the findings.

Design, synthesis and biological evaluation of brain-specific glucosyl thiamine disulfide prodrugs of naproxen

Glucosyl derivates exhibited favorable distribution to the brain. However, bidirectional transport of glucose transporter 1 might decrease concentrations of the prodrugs in brain before the release of parent drugs. To overcome this defect, glucosyl thiamine disulfide prodrugs 1a– 1c incorporating naproxen were designed and synthesized. Furthermore, prodrug 2 and 3 were also prepared as control. The favorable physicochemical properties of these prodrugs were verified by stability and metabolism studies. Results from the in vivo distribution study indicated that 1a– 1c, and 1b in particular, significantly increased the level of naproxen in brain when compared to 2 and 3. The study suggested glucosyl thiamine disulfide was a promising carrier to enhance the brain bioavailability of central nervous system active drugs.

In silico prediction of unbound brain-to-plasma concentration ratio using machine learning algorithms

Distribution over the blood–brain barrier (BBB) is an important parameter to consider for compounds that will be synthesized in a drug discovery project. Drugs that aim at targets in the central nervous system (CNS) must pass the BBB. In contrast, drugs that act peripherally are often optimised to minimize the risk of CNS side effects by restricting their potential to reach the brain. Historically, most prediction methods have focused on the total compound distribution between the blood plasma and the brain. However, recently it has been proposed that the unbound brain-to-plasma concentration ratio ( K p,uu,brain ) is more relevant. In the current study, quantitative K p,uu,brain prediction models have been built on a set of 173 in-house compounds by using various machine learning algorithms. The best model was shown to be reasonably predictive for the test set of 73 compounds ( R 2 = 0.58). When used for qualitative prediction the model shows an accuracy of 0.85 (Kappa = 0.68). An additional external test set containing 111 marketed CNS active drugs was also classified with the model and 89% of these drugs were correctly predicted as having high brain exposure.

Medical Practice Perspective: Identification and Mitigation of Risk Factors for Mortality Associated with Intrathecal Opioids for Non-Cancer Pain

The authors recently determined that early and longer term mortality after initiation or reinitiation of intrathecal opioid therapy is higher than previously appreciated: 0.088% within 3 days, 0.39% at 1 month, and 3.89% at 1 year. These rates were 7.5 (confidence interval, 5.7-9.8), 3.4 (confidence interval, 2.9-3.8), and 2.7 (confidence interval, 2.6-2.8) times higher, respectively, at each interval than expected based on the age- and gender-matched general U.S. population. A substantial portion of this excess mortality is probably therapy related and cannot be entirely accounted for by underlying demographic or patient-related factors, or by device malfunctions. We also analyzed multiple complementary internal, governmental, and insurance databases to quantify mortality and to identify medical practice patterns that appear to be associated with patient mortality risks, and to suggest measures for physicians and health care facilities to consider in order to reduce those risks. Both of those objectives involve judgments, which may be controversial and are subject to practical limitations. Multiple clinical and patient- or therapy-related factors appear to increase the risk for early post-implant mortality. Specific risk mitigation measures associated with each factor include: close attention to the starting intrathecal opioid dose (or restarting dose after therapy interruption); avoidance of outpatient implant or other device procedures that involve less than 24-hour monitoring for respiratory depression; supervision of concomitant opioid, respiratory depressant, or other central nervous system active drug intake early post-implant and chronically in the outpatient setting; and careful programming or dosage calculations and decisions in order to avoid the unintentional administration of high intrathecal opioid drug doses. Mortality after initiation of or device interventions in intrathecal drug delivery patients appears to occur as a result of multiple factors that present possible mitigation opportunities for physicians and health care facilities.

Drug-facilitated sexual assault in Ontario, Canada: Toxicological and DNA findings

The purpose of this study was to determine which persons reporting sexual assault to a hospital-based treatment centre may have been covertly drugged and to provide information about whether a sexual assault may have occurred. Each consecutive adolescent and adult presenting at a sexual assault treatment centre was screened for drug-facilitated sexual assault (DFSA). Urine was collected and tested for central nervous system active drugs. Oral, vaginal, and/or rectal swabs were tested for male DNA. Unexpected drugs were defined as those not reported as having been voluntarily consumed within the previous 72 h. Positive swabs for unexpected DNA were determined by whether the person reported having had consensual intercourse in the previous week. A total of 184 of 882 eligible participants met suspected DFSA criteria. Mean age was 25.8 years (SD = 8.5), 96.2% were female and 64.7% White. Urine samples were positive for drugs in 44.9% of cases, alcohol in 12.9%, and both drugs and alcohol in 18.0%. The drugs found on toxicological screening were unexpected in 87 of the 135 (64.4%) cases with a positive drug finding and included cannabinoids (40.2%), cocaine (32.2%), amphetamines (13.8%), MDMA (9.2%), ketamine (2.3%), and GHB (1.1%). Male DNA was unexpected in 30 (46.9%) of 64 cases where it was found. Among those persons presenting to a sexual assault treatment centre with a suspicion of DFSA, the presence of unexpected drugs and male DNA was common, lending support for their contention that they had been intentionally drugged and sexually assaulted. Most unexpected drugs found were not those typically described as ‘date rape drugs’.

Myocardium and striated muscle damage caused by licit or illicit drugs

Illicit and central nervous system active licit drug consumption related deaths are mainly the consequences of either unintentional or intentional overdose. According to the data in the relevant literature occurrences of different organ damages are also observable and this can play a role in death, as well. Organ damages may appear simultaneously with overdosing or can be extended in time, which may lead to proving the cause of death and establishing the relationships with previous medication difficult. The most frequent damage observed is rhabdomyolysis syndrome, which has been mainly described after cocaine or opium consumption. Authors present four cases from the autopsy documentation of the period between 2003 and 2008 at the Institute of Forensic Medicine, University of Szeged, Hungary in which illicit drug consumption or neuroleptic licit drug medication resulted in development of myocardium and striated muscle damage. The dominant clinical symptoms were hyperthermia, renal and circulatory failure. The laboratory tests showed renal and liver insufficiency; in addition the CK and CK-MB level increase suggested damage in striated muscles. The focal myocardium and striated muscle damage could be assessed as the cause of death in one case, but microscopic investigation proved the presence of damage in each.

Acute adult poisoning cases admitted to a university hospital in Tabriz, Iran

The aim of our study was to investigate the etiological and demographical characteristics of acute adult poisoning cases admitted to a university hospital in Tabriz, Iran. This retrospective study was performed on 1342 poisoning admissions to a university hospital from 2003 to 2005, by data collection from the medical records of patients. Poisonings were 5.40% of the total admissions. There was a predominance of female patients (55.7%) compared to male patients (44.3%) with a female-to-male ratio of 1.2:1. Most poisonings occurred in the age range of 11-20 years (38.9%). Drugs were the most common cause of poisonings (60.8%). Among the drug poisonings, benzodiazepines (40.31%) were the most frequent agents, followed by antidepressants (31.98%). The seasonal distribution in poisoning patients suggested a peak in spring (28%) and summer (27.5%). In 9.8% of cases accidental and in 90.2% intentional poisonings were evident. Most suicide attempts were made by women (58.51%) and unmarried people (51.4%).The mean duration of hospitalization was 3.02 +/- 2.8 days. There were 28 (2.3%) deaths; the majority (13 cases) was due to pesticides. This was a university hospital-based study, so these results may not be representative of the general population. Despite this drawback, these data still provide important information on the characteristics of the poisoning in this part of Iran. To prevent such poisonings, the community education about the danger of central nervous system-acting drugs and reducing the exposure period of people to pesticides are recommended.

Skeletal Effects of Central Nervous System Active Drugs: Anxiolytics, Sedatives, Antidepressants, Lithium and Neuroleptics

Many central nervous system active drugs can alter postural balance, increasing the risk of fractures. Anxiolytics and sedatives include the benzodiazepines, and these have been associated with a limited increase in the risk of fractures, even at low doses, probably from an increased risk of falls. No systematic differences have been shown between benzodiazepines with long and short half-lives. Although the increase in risk of fractures was limited, care must still be taken when prescribing for older fall-prone subjects at risk of osteoporosis. Neuroleptics may be associated with a decrease in bone mineral density and a very limited increase in fracture risk. Antidepressants are associated with a dose-dependent increase in the risk of fractures. The increase in relative risk of fractures seems to be larger with selective serotonin reuptake inhibitors (SSRIs) than with tricyclic antidepressants. The reason for this is not known but may be linked to serotonin effects on bone cells and the risk of falls. With the wide use of SSRIs, more research is needed. Lithium is associated with a decrease in the risk of fractures. This may be linked to its effects on the Wnt glycoprotein family, which is a specialised signalling system for certain cell types.

Methodology of an ongoing, randomized controlled trial to prevent falls through enhanced pharmaceutical care

Background: Falls are the leading cause of both fatal and nonfatal injuries among adults aged ≥65 years in the United States. Past research suggests that individuals taking multiple medications are at increased risk of falls. Central nervous system-active drugs in particular have been associated with increased risk. Objective: The goal of this research was to describe the design of a study evaluating the effectiveness of a community pharmacy-based falls prevention program. Also presented are the algorithms used to identify high-risk patients based on their prescription profile records and to deliver the experimental intervention. Methods: The study is a randomized controlled trial. The target population was community-dwelling older adults (aged ≥65 years) at high risk for future falls because: (1) they had experienced ≥1 fall within the 12-month period preceding study enrollment; (2) they were currently using ≥4 chronic prescription medications; and (3) they were taking ≥1 of the high-risk medications targeted by the intervention. Participants were recruited using pharmacy prescription profile records. Individuals in the intervention group received a face-to-face medication consultation provided by a community pharmacy resident. Identification of drug therapy problems and therapeutic recommendations was guided by a series of algorithms developed for this study. All participants were followed up for 24 months. The primary study end points were: (1) time to first fall; and (2) proportion of participants who experienced ≥1 fall during the first year of follow-up. Results: Participant enrollment began in September 2005 and was completed in August 2007. A total of 186 individuals were enrolled in the study (mean [SD] age, 74.8 [6.9] years; 132 women, 54 men), and 67 have completed the first year of follow-up. Conclusions: The study is using a rigorous randomized controlled research design, which will enhance the internal validity of its findings. Results of the study, which will be reported after the completion of follow-up data collection activities, will enable us to assess the effects of the intervention on both medication use and the incidence of falls. If the intervention is found to be effective, it will provide a resource for community pharmacists working with older adults at high risk of medication-related falls.

Effect of Psychotropic Drugs on the 21-Hydroxylation of Neurosteroids, Progesterone and Allopregnanolone, Catalyzed by Rat CYP2D4 and Human CYP2D6 in the Brain

We determined the effects of psychotropic drugs on the cytochrome P450 2D (CYP2D)-mediated 21-hydroxylation of progesterone (PROG) and allopregnanolone (ALLO) with the goal of clarifying whether neurosteroid levels are affected by psychotropic drugs in the brain. PROG or ALLO was incubated with rat CYP2D4 or human CYP2D6 in the presence of typical psychotropic drugs, fluoxetine, imipramine, desipramine, mazindol, and GBR12909, and the 21-hydroxylated metabolites of PROG and ALLO were determined by high performance liquid chromatography and liquid chromatography-tandem mass spectrometry, respectively. Fluoxetine competitively inhibited CYP2D4-mediated PROG 21-hydroxylation and increased both Km and Vmax values of CYP2D6-mediated PROG 21-hydroxylation. In addition, fluoxetine competitively inhibited ALLO 21-hydroxylation mediated by CYP2D4 and CYP2D6. Imipramine, desipramine, mazindol, and GBR12909 competitively inhibited PROG 21-hydroxylation mediated by CYP2D4 and/or CYP2D6, and all psychotropic drugs inhibited ALLO 21-hydroxylation mediated by CYP2D4 and/or CYP2D6. The inhibition constants (Ki values) of imipramine, desipramine, and mazindol against the 21-hydroxylation of PROG and ALLO by CYP2D6 were lower than those by CYP2D4. These results indicate that psychotropic drugs including fluoxetine affected the metabolism of neurosteroids, such as PROG and ALLO in the brain, suggesting that the regulation of the neurosteroid levels is modified by central nervous system-active drugs that inhibit brain CYP2D isoforms.

In Vitro Pharmacology of Clinically Used Central Nervous System-Active Drugs as Inverse H1 Receptor Agonists

The human histamine H(1) receptor (H(1)R) is a prototypical G protein-coupled receptor and an important, well characterized target for the development of antagonists to treat allergic conditions. Many neuropsychiatric drugs are also known to potently antagonize this receptor, underlying aspects of their side effect profiles. We have used the cell-based receptor selection and amplification technology assay to further define the clinical pharmacology of the human H(1)R by evaluating >130 therapeutic and reference drugs for functional receptor activity. Based on this screen, we have reported on the identification of 8R-lisuride as a potent stereospecific partial H(1)R agonist (Mol Pharmacol 65:538-549, 2004). In contrast, herein we report on a large number of varied clinical and chemical classes of drugs that are active in the central nervous system that display potent H(1)R inverse agonist activity. Absolute and rank order of functional potency of these clinically relevant brain-penetrating drugs may possibly be used to predict aspects of their clinical profiles, including propensity for sedation.

Changing Patterns of Drug and Alcohol Use in Fatally Injured Drivers in Washington State

We have previously reported on patterns of drug and alcohol use in fatally injured drivers in Washington State. Here we revisit that population to examine how drug use patterns have changed in the intervening 9 years. Blood and serum specimens from drivers who died within 4 h of a traffic accident between February 1, 2001, and January 31, 2002, were analyzed for illicit and therapeutic drugs and alcohol. Drugs when present were quantitated. Samples suitable for testing were obtained from 370 fatally injured drivers. Alcohol was detected above 0.01 g/100 mL in 41% of cases. The mean alcohol concentration for those cases was 0.17 g/100 mL (range 0.02-0.39 g/100 mL). Central nervous system (CNS) active drugs were detected in 144 (39%) cases. CNS depressants including carisoprodol, diazepam, hydrocodone, diphenhydramine, amitriptyline, and others were detected in 52 cases (14.1%), cannabinoids were detected in 47 cases (12.7%), CNS stimulants (cocaine and amphetamines) were detected in 36 cases (9.7%), and narcotic analgesics (excluding morphine which is often administered iatrogenically in trauma cases) were detected in 12 cases (3.2%). For those cases which tested positive for alcohol c. 40% had other drugs present which have the potential to cause or contribute to the driver's impairment. Our report also considers the blood drug concentrations in the context of their interpretability with respect to driving impairment. The data reveal that over the past decade, while alcohol use has declined, some drug use, notably methamphetamine, has increased significantly (from 1.89% to 4.86% of fatally injured drivers) between 1992 and 2002. Combined drug and alcohol use is a very significant pattern in this population and is probably overlooked in DUI enforcement programs.

A statistical approach for classifying change in cognitive function in individuals following pharmacologic challenge: an example with alprazolam

The effects of any drug treatment on cognitive function are typically studied in groups of subjects. Observations made about the behavior of the drug, in the study sample, are then generalized to the population from which the sample was drawn. However, the magnitude and pharmacodynamic qualities of the response to many central nervous system-active drugs are known to vary in the population. Therefore, it is useful to consider statistical models for the detection of cognitive change in response to a drug treatment in individual subjects. In this report, we first outline the statistical assumptions and requirements for the reliable estimation of clinically relevant individual change in cognition. We then used the sedative benzodiazepine, alprazolam, as a pharmacologic challenge in healthy volunteer subjects to test our statistical model, using a parallel groups placebo-controlled study design. After treatment, the nature and severity of alprazolam-induced cognitive change was determined for each individual. Our proposed method and analysis showed an excellent sensitivity and specificity for alprazolam-related cognitive deterioration in individuals. These findings, although preliminary, suggest that statistically reliable decisions about the effects of sedative drugs on cognition can be made for individuals.

Assessment of dynamic susceptibility contrast cerebral blood flow response to amphetamine challenge: A human pharmacological magnetic resonance imaging study at 1.5 and 4 T

Pharmacological MRI (phMRI) techniques can be used to monitor the neurophysiological effects of central nervous system (CNS) active drugs. In this study, we investigated whether dynamic susceptibility contrast (DSC) perfusion imaging employing the use of superparamagnetic iron oxide nanoparticles (Resovist) could be used to measure hemodynamic response to d-amphetamine challenge in human subjects at both 1.5 and 4 T. Significant changes in cerebral blood flow (CBF) were found in focal regions associated with the nigrostriatal circuit and mesolimbic and mesocortical dopaminergic pathways. More significant CBF responses were found at higher field strength, mainly within striatal structures. The results from this study indicate that DSC perfusion imaging using Resovist can be used to assess the efficacy of CNS-active drugs and may play a role in the development of novel psychiatric therapies at the preclinical level.

Drivers of brain plasticity

Neural plasticity represents a crucial mechanism of the human brain to adapt to environmental changes in the developing and adult human central nervous system. This property of the central nervous system contributes to learning and functional recovery from neurological diseases such as stroke. Novel interventional approaches have been proposed and are under investigation to modulate neural plasticity, enhance it when it plays an adaptive role and downregulate it when it is considered maladaptive. One of the purposes of research in neurorehabilitation has been to develop interventional approaches to enhance the beneficial effects of training. Procedures like cortical stimulation, administration of central nervous system active drugs and modulation of afferent input have been evaluated as drivers of neural plasticity in healthy subjects and in small groups of patients with stroke. So far, these studies have shown promising results and translation into the clinic is under investigation. Cortical stimulation and purposeful changes in afferent input that modulate neural plasticity impact on behavioral markers of performance, learning and functional recovery and represent promising tools in neurorehabilitation.

Bone mineral density in subjects using central nervous system-active medications

Purpose Decreased bone mineral density defines osteoporosis according to the World Health Organization and is an important predictor of future fractures. The use of several types of central nervous system-active drugs, including benzodiazepines, anticonvulsants, antidepressants, and opioids, have all been associated with increased risk of fracture. However, it is unclear whether such an increase in risk is related to an effect of bone mineral density or to other factors, such as increased risk of falls. We sought to examine the relationship between bone mineral density and the use of benzodiazepines, anticonvulsants, antidepressants, and opioids in a representative US population-based sample. Subjects and methods We analyzed data on adults aged 17 years and older from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). Total femoral bone mineral density of 7114 male and 7532 female participants was measured by dual-energy x-ray absorptiometry. Multivariable linear regression models were used to quantify the relation between central nervous system medication exposure and total femoral bone mineral density. Models controlled for relevant covariates, including age, sex, and body mass index. Results In linear regression models, significantly reduced bone mineral density was found in subjects taking anticonvulsants (0.92 g/cm 2; 95% confidence interval [CI]: 0.89 to 0.94) and opioids (0.92 g/cm 2; 95% CI: 0.88 to 0.95) compared with nonusers (0.95 g/cm 2; 95% CI: 0.95 to 0.95) after adjusting for several potential confounders. The other central nervous system-active drugs—benzodiazepines or antidepressants—were not associated with significantly reduced bone mineral density. Conclusion In cross-sectional analysis of NHANES III, anticonvulsants and opioids (but not benzodiazepines or antidepressants) were associated with significantly reduced bone mineral density. These findings have implications for fracture-prevention strategies.

Fancy Bioisosteres: Metallocene-Derived G-Protein-Coupled Receptor Ligands with Subnanomolar Binding Affinity and Novel Selectivity Profiles

Metallocene-derived bioisosteres lead to exceptionally strong binding G-protein-coupled receptor ligands, indicating substantial plasticity of the receptor excluded volume. Novel binding profiles of ferrocenylcarboxamides combining subnanomolar Ki values for the dopamine D4 receptor (1a, 0.52 nM; 1b, 0.63 nM) with superpotent serotonin 5-hydroxytryptamine1A (1a, 0.50 nM) and dopamine D3 receptor binding (1b, 0.64 nM) and selective D4 agonist properties of the ruthenocene 1c may be a starting point for highly beneficial central nervous system active drugs.

A study paradigm allowing comparison of multiple high‐resolution rCBV‐maps for the examination of drug effects

Owing to the neuro-vascular coupling, measurement of changes in regional cerebral blood flow and blood volume (rCBV) can be used as surrogates reflecting the effects of central nervous system active drugs on neural transmission. As most such drugs are administered orally or intramuscularly and, in many cases, beneficial effects due to drug treatment can be observed only after chronic administration for days or weeks, the evaluation of drug efficacy requires the development of acquisition and analysis tools that allow for comparison of imaging data sets obtained in multiple sessions and for multiple subjects. In the present study, high-resolution susceptibility contrast MR perfusion imaging using a super-paramagnetic contrast agent (CA) was applied to study the effect of a single oral administration of the acetylcholine-esterase inhibitor rivastigmine (Exelon) on rCBV in rats. rCBV maps were calculated from two T2-weighted three-dimensional fast-spin-echo scans recorded before and after the injection of the CA, respectively. All MRI data sets were mapped to a reference data set obtained from a normal male Sprague-Dawley rat using an automated co-registration procedure prior to the analysis for drug effects. Rivastigmine was orally administered at doses of 2, 4 or 8 mg/kg 1 h prior to the rCBV measurement. Rivastigmine increased rCBV in several brain areas including cortex, caudate putamen and hippocampus. The observed effects were dose-dependent and the changes reached the order of 5-12% as compared with baseline levels. Vehicle-treated animals showed no significant alterations of blood volume, demonstrating the reproducibility and stability of rCBV measurements.

Immunolocalization of TASK-3 (KCNK9) to a subset of cortical neurons in the rat CNS

Tandem pore domain (2P) K channels constitute the most diverse family of K channels and are responsible for background (leak or baseline) K currents. Of the 15 human 2P K channels, TASK-1, TASK-2, and TASK-3 are uniquely sensitive to physiologic pH changes as well as being inhibited by local anesthetics and activated by volatile anesthetics. In this study polyclonal antibodies selective for TASK-3 have been used to localize its expression in the rat central nervous system (CNS). TASK-3 immunostaining was found in rat cortex, hypothalamus, and hippocampus. Double immunofluorescent studies identified a discrete population of TASK-3 expressing neurons scattered throughout cortex. Using immunogold electron microscopy TASK-3 was identified at the cell surface associated with synapses and within the intracellular synthetic compartments. These results provide a more finely detailed picture of TASK-3 expression and indicate a role for TASK-3 in modulating cerebral synaptic transmission and responses to CNS active drugs.