Dose-related Effects Research Articles

Risk factors for natural cause mortality in a cohort of 1494 persons with serious mental illness

Persons with serious mental illness die on average more than 10 years younger than those in the overall population, mostly due to natural causes. Previous studies have identified predictors of natural cause mortality in this population but few have been prospective studies using clinical variables from in-person evaluations.A cohort of 1494 individuals with schizophrenia, bipolar disorder, or major depressive disorder were assessed at baseline and mortality status was determined from the US National Death Index after up to 20 years of follow-up. Analyses included multivariate Cox proportional hazard models to determine independent predictors of natural cause mortality. A total of 125 (8.4%) individuals died of natural causes. In multivariate models, the strongest predictor of mortality after age was tobacco smoking at baseline with a dose-related effect. Having diabetes, a cardiovascular condition, particularly hypertension, and lower cognitive functioning were also significant risks, along with divorced/separated status. The receipt of gabapentin or fluoxetine also significantly increased mortality risk. Premature death can be reduced by smoking cessation and the improved management of conditions such as hypertension and diabetes.

Assessments of Onset and Duration of Drug Effects and Pharmacokinetics by Dose Level of HSK3486, a New Sedative-Hypnotic Agent, in Healthy Female/Male Subjects: A Phase I Multiarm Randomized Controlled Clinical Trial [Retracted

Background Onset and duration of effects and pharmacokinetics of the novel anesthesia medication HSK3486 were examined after a single intravenous injection to evaluate its usefulness as a potential alternative to propofol. Methods Phase Ia (male-only, blinded) and Ib (female-only, open-label) trials were both prospective randomized, dose escalation trials of a single intravenous injection of HSK3486 or either placebo or propofol. The primary aim of this first-in-human trial was safety through measurements of dose-related effects on cardiorespiratory functions, the central nervous system, laboratory parameters, and reported adverse events. The secondary aims were to determine initial pharmacokinetic parameters and to establish a dose regimen for sedation and general anesthesia for subsequent later-phase clinical trials. Results A total of 50 healthy male subjects were enrolled in the phase Ia trial and 30 healthy female subjects in the phase Ib trial. No significant difference was found in the overall pattern of anesthetic effects between HSK3486 and propofol (all P > .05), but the sample size was not sufficiently large to make a confident assessment. Rapid onset and offset of dose-dependent sedation or general anesthesia after HSK3486 administration was found in male and female subjects with median central nervous system equilibrium half-life times of 1.3 and 1.8 minutes across cohorts in phases Ia and Ib and accompanied by mild hypotension and respiratory depression. Pharmacokinetics profiles revealed that there was no evidence that the groups were different (all P > .05), with a high clearance and distribution volume. In the phase Ia trial, the median terminal half-life (t1/2) for HSK3486 doses of 128, 192, 288, 432, 540, 648, and 810 μg/kg were 68.8, 64.7, 207.0, 210.7, 313.5, 293.5, and 245.7 minutes, respectively. In the phase Ib trial, the median t1/2 for HSK3486 doses of 288, 432, 540, 648, and 810 μg/kg were 68.5, 159.7, 122.7, 281.5, and 245.3 minutes, respectively. Treatment emergent adverse events (TEAEs) were reported in 50% and 53% of subjects in the phase Ia and Ib trials but were mostly related to minor events (eg, arterial catheter irritation). HSK3486 was well tolerated at dose levels up to 810 μg/kg in all subjects compared with propofol (odds ratio in phases Ia and Ib: 0.71 and 6.00; 95% confidence interval [CI], 0.09-4.85 and 0.47-314.71, respectively; all P > .05) and placebo (odds ratio in phase Ia: 0.95; 95% CI, 0.01-78.45; P > .05). Conclusions HSK3486 has potential clinical application for intravenous administration for the induction and maintenance of sedation and general anesthesia.

Antitumor proteinkinase inhibitor imatinib may be regarded as a potential correcting agent for COVID-19 associated pulmonary fibrosis

Imatinib mesilate (Glivec) is a well-known antitumor target inhibitor of protein tyrosine kinase, which is effective in different cancer types expressing Bcr / Abl and, in particular, in hemoblastosis. A higher interest to imatinib during the COVID-19 epidemic is explained by the fact that cancer patients are one of the COVID-19 risk groups. Moreover, imatinib target mechanism of action, which is effective in cancer, can have a high potential against the most severe COVID-19 complication such as the disease associated pulmonary fibrosis. COVID-19 associated interstitial pulmonary fibrosis develops as an autoimmune process caused by systemic inflammation with atypical (idiopathic) pneumonia resulting from acute respiratory distress syndrome with the tyrosine kinase mechanism of signaling pathway activation and cellular response. Experimental and clinical results showing antifibrotic and dose-related antithrombotic imatinib effect demonstrate perspective use of this antitumor agent to correct COVID-19 associated pneumonia causing a high death rate of patients with COVID-19.The review presents literature data of 2001–2020 discussing pathologic genetic and clinical characteristics of the fibrosis which exacerbates COVID-19 pneumonia in adults. The sequence of the disease processes demonstrates that disease progression with the decreasing oxygen saturation in the peripheral blood intensifies local thrombosis in the lungs. As a result, hypoxia is developing, which is difficult to control and can cause lethal outcome in severe cases. Yet, the conventional antifibrotic and thrombolytic agents can only partially control the process of pneumofibrosis including that of cancer patients. The approximate antifibrotic dose of imatinib 400 mg / day is therapeutic for oncopathology. The antitumor drug registered in many countries and well described side effects and contraindications needs no long-term registration studies for a new indication, therefore, it may be easily prepared for clinical testing.

Attenuation of Doxorubicin-induced Hepato- and Nephrotoxicity by Proanthocyanidins from Myrica nagi Bark in Wistar Rats

Due to dose-related toxic effects, doxorubicin, a very potent and often used anti-cancer medication, is largely limited. The current research investigated the protective impact of Myrica nagi bark (PMN)-isolated proanthocyanidins on hepato-induced doxorubicin and nephrotoxicity in Wistar rats. The animals were subdivided into six classes of five rats each. Group I got PMN (200 mg/kg, p.o.) for 21 days, Group II received Doxorubicin (DXR) (60 mg/kg, i.p.) once, 48 h before sacrifice, Group III received PMN (200 mg/kg, p.o.) for 21 days, Group IV, V, and VI received PMN (200 and 400 mg/kg, p.o.) and Limarin (25 mg/kg, p.o.) for 21 days and DXR (60 mg/kg, i.p.) once, 48 h before sacrifice, respectively. Animals were slaughtered after 21 days and blood samples were obtained for liver and kidney biomarker detection. For in-vivo antioxidant experiments, the upper liver lobe and the right kidney were dissected. There is a substantial decrease in levels of liver and kidney biomarkers in the pre-treatment of PMN in the doxorubicin-treated population. PMN substantially reversed DXR's effects on superoxide dismutase (SOD), catalase (CAT), GSH, and lipid peroxidation levels (LPO). In conclusion, data indicate that chronic administration of Myrica nagi improved DXR may have induced hepatotoxicity and nephrotoxicity via its antioxidant action. Keywords: Doxorubicin, hepatotoxicity, Myrica nagi, nephrotoxicity, proanthocyanidins Cite this Article Patil Rupali A., Kasar Mayur S., Pingale Prashant L. Attenuation of Doxorubicin-induced Hepato- and Nephrotoxicity by Proanthocyanidins from Myrica nagi Bark in Wistar Rats. Research & Reviews: A Journal of Toxicology. 2020; 10(3): 19–28p.

Low-Dose Ziprasidone in Combination with Sertraline for First-Episode Drug-Naïve Patients with Schizophrenia: A Randomized Controlled Trial

Background: Many patients with SCZ discontinue antipsychotics, frequently due to dose related multiple and severe adverse effects. This clinical trial was designed to investigate the efficacy, safety, and tolerability of adding sertraline to ziprasidone in order to substantially reduce its dose and potential side effects in first-episode and drug-naive (FEDN) patients with SCZ. Methods: This 24-week randomized, double-blinded controlled clinical trial randomly allocated 452 FEDN SCZ patients to receive a usual dose of ziprasidone (control group) or half the dose of ziprasidone in combination with sertraline (ZS group). Treatment outcome included the Positive and Negative Syndrome Scale (PANSS), the Hamilton Depression Rating Scale (HAMD), CGI-Severity (CGI-S) and the Personal and Social Performance Scale (PSP) at baseline and weeks 2, 4, 8, 12 and 24. Findings: Repeated measures ANCOVA showed significant treatment by time interactions on the PANSS negative symptom, general psychopathology and total scores, as well as CGI-S, HAMD and PSP scores (all p<0.05). Furthermore, the ZS group had greater reductions in PANSS negative symptoms, general psychopathology and total scores (all p<0.05) and greater increases in the PSP total score (p<0.01) than the control group. Importantly, adverse effects were lower in the ZS than control group. The reduction in PANSS, CGI-S or HAMD scores was not correlated with the increase in PSP. Sex and duration of disease predicted PSP improvement from baseline to week 24 in the ZS group. Interpretation: Our FEND patients with SCZ were effectively treated for their psychotic and depressive symptoms while experiencing significantly fewer adverse effects using half the usual ziprasidone dose when combined with sertraline. The implications for long term improved retention and compliance with treatment using this combination therapy are substantial for introducing them to life saving chronic care that will be optimally effective and minimally aversive due to antipsychotic side effects including cardiac problems. Trial Registration: The clinical trial was registered with ClinicalTrials.gov (ClinicalTrials.gov Identifier NCT04076371). Funding: Funding for this study was provided by the CAS Pioneer Hundred Talents Program. Declaration of Interest: None to declare. Ethical Approval: The study protocol was approved by the Institutional Review Board of First Hospital of Shanxi Medical University

Dose-Related Structural Effects of Photodynamic Therapy on Rabbit Choroidal Structure

Introduction: Photodynamic therapy with verteporfin (vPDT) has been shown to be effective against central serous chorioretinopathy (CSC) and was the preferred therapeutic for CSC treatment. However, alterations in choroidal structure after PDT were reported, and these effects were dose-dependent. This study aimed to compare the changes in choroidal structure after PDT with different doses of verteporfin in rabbits and may provide individualized therapeutic guidance for patients who failed to respond to initial half-dose vPDT. Methods: The full dose of verteporfin used in CSC was 6 mg/m², which was used in patients with neovascular age-related macular degeneration. Laser fluence was 50 J/cm² (irradiance, 600 mW/cm², 83 s). There were 4 different dose groups in this study (100%, 70%, 50%, and 30%). The alterations were examined at 1 day, 1 week, and 1 month after vPDT using color fundus imaging, indocyanine green angiography, and histopathology analysis. Results: Various degrees of choroidal alterations were demonstrated at different dose groups. Examinations on day 1 showed that gradually reduced verteporfin dose tended to decrease photochemical reactions to the choroid in terms of the number of occlusion vessels and area of the lesion. After 1 month, choroid vessel alteration persisted in high-dose groups (100% and 70%); nevertheless, alterations of low-dose groups (50% and 30%) returned to normal. Conclusions: vPDT can induce photochemical reactions of the choroid, high dose causes permanent change, and low dose causes recoverable change. The dose-dependent alterations need to be considered for the individual therapeutic plan according to the situation of a patient with CSC.

Lamotrigine loaded PLGA nanoparticles intended for direct nose to brain delivery in epilepsy: pharmacokinetic, pharmacodynamic and scintigraphy study

The present study aimed to investigate the brain targeting efficacy of Lamotrigine (LTG) loaded PLGA nanoparticles (LTG-PNPs) upon intranasal administration. LTG-PNPs were fabricated through the emulsification-solvent evaporation technique and evaluated for % Entrapment efficiency, particle size, in-vitro release, surface morphology, crystallinity, ex-vivo permeation & thermal behaviour. Biodistribution, gamma scintigraphy, and pharmacodynamic studies were performed in BALB/c mice, New Zealand rabbits, and Wistar rats respectively. LTG-PNPs exhibited % EE 71%; particle size 170.0 nm; Polydispersity index 0.191; zeta potential −16.60 mV. LTG-PNPs exhibited a biphasic release pattern. Biodistribution and gamma scintigraphy studies proved a greater amount of LTG in the brain following intranasal delivery of LTG-PNPs in comparison to LTG-SOL. Pharmacodynamic studies demonstrated delayed seizure onset time with LTG-PNPs in comparison to LTG-SOL. Intranasal administration of LTG-PNPs provided prolonged release, higher bioavailability, and better brain targeting bypassing the BBB. The developed formulation could be administered as a once-a-day formulation that would reduce the dosing frequency; dose; dose-related side effects; cost of the therapy and would be beneficial in the management of epilepsy as compared to the LTG-SOL. However, the proof of concept generated through these studies needs to be further validated in higher animals and human volunteers.

Continued use of Warfarin in lower dose has safe maternal and neonatal outcomes in pregnant women with Prosthetic Heart Valves.

Background and Objective:There has been concerns regarding the safety of Warfarin in pregnant females due to its teratogenic potential. At the same time warfarin provides best anticoagulation in patients with prosthetic valves. Various dosage regimes have been tried to strike a balance between safety of mother and the avoidance of congenital anomalies in the newborn. This study was conducted to observe the effect of Warfarin in pregnant mothers taking different doses of warfarin, and their neonatal outcome, in our outdoor patients.Methods:This is a cross sectional observational study conducted at the Faisalabad Institute of Cardiology. The pregnant mothers taking warfarin for prosthetic valve replacement who presented to our specialized clinic between November 2016 to April 2017 were included in the study. These included a total of 75 females between the age of 20-35 years. To compare the dose related effect of warfarin, two groups of the patients were formed. One group comprised of patients taking warfarin ≤5mg while the other group consisted of those who were taking >5mg of warfarin daily. These patients were followed till their delivery. The information was collected about the maternal and fetal outcomes. The maternal outcomes including mode of delivery/miscarriage, peripartum bleeding and any valve related thromboembolic complications. The fetal outcomes included birth weight, maturity, embryopathy and congenital anomaly in the baby.Results:Patient’s mean age was 29.25±3.75 years. The mitral valve replacement was present in 60% patients (n=45) while 25.3% patients (n=19) had aortic valve replacement and 14.7% patients (n=11) had double valve replacement. In this group 30 patients (40%) had taken <5 mg warfarin and 45 patients (60%) had received >5 mg warfarin medicine. Miscarriages, cesarean sections, low birth weight and prematurity were more common in patients receiving warfarin >5 mg with p-values 0.005, 0.046, 0.01 and 0.033 respectively. No case of fetal embryopathy was found in both groups.Conclusion:No case of embryopathy was found in each group which signifies that warfarin in lower doses is safe anticoagulant in patients with prosthetic valve replacements.

Long-term transcriptomic and proteomic effects in Sprague Dawley rat thyroid and plasma after internal low dose 131I exposure.

BackgroundRadioiodide (131I) is commonly used to treat thyroid cancer and hyperthyroidis.131I released during nuclear accidents, have resulted in increased incidence of thyroid cancer in children. Therefore, a better understanding of underlying cellular mechanisms behind 131I exposure is of great clinical and radiation protection interest. The aim of this work was to study the long-term dose-related effects of 131I exposure in thyroid tissue and plasma in young rats and identify potential biomarkers.Materials and methodsMale Sprague Dawley rats (5-week-old) were i.v. injected with 0.5, 5.0, 50 or 500 kBq 131I (Dthyroid ca 1–1000 mGy), and killed after nine months at which time the thyroid and blood samples were collected. Gene expression microarray analysis (thyroid samples) and LC-MS/MS analysis (thyroid and plasma samples) were performed to assess differential gene and protein expression profiles in treated and corresponding untreated control samples. Bioinformatics analyses were performed using the DAVID functional annotation tool and Ingenuity Pathway Analysis (IPA). The gene expression microarray data and LC-MS/MS data were validated using qRT-PCR and ELISA, respectively.ResultsNine 131I exposure-related candidate biomarkers (transcripts: Afp and RT1-Bb, and proteins: ARF3, DLD, IKBKB, NONO, RAB6A, RPN2, and SLC25A5) were identified in thyroid tissue. Two dose-related protein candidate biomarkers were identified in thyroid (APRT and LDHA) and two in plasma (DSG4 and TGM3). Candidate biomarkers for thyroid function included the ACADL and SORBS2 (all activities), TPO and TG proteins (low activities). 131I exposure was shown to have a profound effect on metabolism, immune system, apoptosis and cell death. Furthermore, several signalling pathways essential for normal cellular function (actin cytoskeleton signalling, HGF signalling, NRF2-mediated oxidative stress, integrin signalling, calcium signalling) were also significantly regulated.ConclusionExposure-related and dose-related effects on gene and protein expression generated few expression patterns useful as biomarkers for thyroid function and cancer.

Blepharitis: A Review on Human Clinical Trials with Synthetic and Natural Remedies

Blepharitis is an eyelid disorder characterized by inflammation and pain. It affects all the ages and ethnic groups. Primary cause of blepharitis is poor hygienic condition. Topical antibiotics are the preferred first line therapeutic agents along with eyelid cleansing and warm compresses are recommended. Topical steroids, oral antibiotics and calcineurin inhibitors are also recommended in severe conditions. However, recurrence of disease, dose related side effects and safety regimen are still uncertain with these agents. Blepharitis needs a long term treatment, thus novel formulations and products with natural components may be considered more reliable to overcome such issues. In this review article we have discussed human clinical trials (HCTs) conducted with conventional synthetic drugs, novel drug delivery systems developed with synthetic drugs and drugs of natural origin and other supportive measures. As compared to synthetic drugs, formulations with natural origin were found to be safe with minimum side effects.

Devices used for Treatment of Epilepsy

Epilepsy is a group of chronic neurological disorder of the brain that affects around 1-2% of the population across the world. According to the World Health Organization (WHO), epilepsy is characterized by periodically spontaneous seizures, which are usually due to excessive electrical discharges in a group of brain cells. The earlier day electroencephalogram (EEG) signals are useful tool for detection of epileptic seizures.Epileptogenesis is a slow process. After several months of initial insult, spontaneous recurrent seizures begin to appear. Epilepsy is considered to be resolved for individuals who are seizure-free for the last 10 years, with no seizure medicines for the last 5 years. Currently, used drugs available for treating epilepsy have draw backs like Epileptogenesis and other dose-related side effects. In spite of daily treatment, nearly 30% of patients continue to have convulsions and fail to provide a complete cure. Hence, there is a need for another alternative option to control the epileptic seizure and minimize the duration of seizure without taking a medicine and improving the quality of patient’s life. In current scenario the Vagus nerve stimulation (VNS) has become an important tool for controlling the epileptic seizure. Vagus nerve stimulation is used for patient with refractory and drug resistant epilepsy. Various non-drug therapies form preclinical to clinical for controlling seizures in epileptic patients with drug resistance current available have been highlighted in this review.

Development and Characterization of Controlled Porosity Osmotic Pump Tablets of Captopril

Background: The objective of the present study was to design a porous osmotic pump-based drug delivery system for the controlled release of captopril (Cap) which can maintain a constant therapeutic concentration, thus reducing dose-related side effects and dosing frequency. Methods: The study evaluated in vitro drug release for the controlled porosity osmotic pump tablet (CPOPT) of Cap. This in vitro drug release study investigated the influence of the tablet formulation variables such as the amount of mannitol, hydroxypropylmethylcellulose K4M (HPMCK4M), and polyvinyl pyrrolidone (PVP K-30) in the core and the concentration of cellulose acetate and polyethylene glycol 400 (PEG-400) in the coating solution. Results: It was found that the drug release was mostly affected by the amount of mannitol, HPMCK4M, and PVP K-30 in the core and the amount of cellulose acetate and PEG-400 in the coating solution. Conclusion: In general, the objective of the study was established by coating the core tablet containing osmotic and pore-forming agents. Therefore, the CPOPT of Cap could be a safe, effective, stable, and promising preparation in the future.

A randomized cross-over trial to define neurophysiological correlates of AV-101 N-methyl-d-aspartate receptor blockade in healthy veterans

The kynurenine pathway (KP) is a strategic metabolic system that combines regulation of neuronal excitability via glutamate receptor function and neuroinflammation via other KP metabolites. This pathway has great promise in treatment of depression and suicidality. The KP modulator AV-101 (4-chlorokynurenine, 4-Cl-KYN), an oral prodrug of 7-chlorokynurenic acid (7-Cl-KYNA), an N-methyl-d-aspartate receptor (NMDAR) glycine site antagonist, and of 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HAA), a suppressor of NMDAR agonist quinolinic acid (QUIN), is a promising potential antidepressant that targets glutamate functioning via the KP. However, a recent placebo-controlled clinical trial of AV-101 in depression found negative results. This raises the question of whether AV-101 can penetrate the brain and engage the NMDAR and KP effectively. To address this problem, ten healthy US military veterans (mean age = 32.6 years ± 6.11; 1 female) completed a phase-1 randomized, double-blind, placebo-controlled, crossover study to examine dose-related effects of AV-101 (720 and 1440 mg) on NMDAR engagement measured by γ-frequency band auditory steady-state response (40 Hz ASSR) and resting EEG. Linear mixed models revealed that 1440 mg AV-101, but not 720 mg, increased 40 Hz ASSR and 40 Hz ASSR γ-inter-trial phase coherence relative to placebo. AV-101 also increased 4-Cl-KYN, 7-Cl-KYNA, 4-Cl-3-HAA, 3-HAA, and KYNA in a dose-dependent manner, without affecting KYN and QUIN. AV-101 was safe and well tolerated. These results corroborate brain target engagement of 1440 mg AV-101 in humans, consistent with blockade of interneuronal NMDAR blockade. Future studies should test higher doses of AV-101 in depression. Suicidal behavior, which has been associated with high QUIN and low KYNA, is also a potential target for AV-101.

Surrogate post-coital testing for contraceptive efficacy against human sperm activity in the ovine vaginal model†.

High unintended pregnancy rates are partially due to lack of effective nonhormonal contraceptives; development of safe, effective topical vaginal methods will address this need. Preclinical product safety and efficacy assessment requires in vivo testing in appropriate models. The sheep is a good model for the evaluation of vaginally delivered products due to its close similarities to humans. The study objective was to develop an ovine model for efficacy testing of female nonhormonal contraceptives that target human sperm. Fresh human semen was pooled from male volunteers. Nonpregnant female Merino sheep were treated with control or vaginal contraceptive product (IgG antibody with action against sperm or nonoxynol-9 [N9]). Pooled semen was added to the sheep vagina and mixed with product and vaginal secretions. Microscopic assessment of samples was performed immediately and progressive motility (PM) of sperm was compared between treatments. Cytokines CXCL8 and IL1B were assessed in vaginal fluid after instillation of human semen. No adverse reactions or elevations in proinflammatory cytokines occurred in response to human semen. N9 produced signs of acute cellular toxicity while there were no cellular changes after IgG treatment. N9 and IgG had dose-related effects with the highest dose achieving complete sperm immobilization (no sperm with PM). Surrogate post-coital testing of vaginally administered contraceptives that target human semen was developed in an ovine model established for vaginal product preclinical testing. This expanded model can aid the development of much needed nonhormonal topical vaginal contraceptives, providing opportunities for rapid iterative drug development prior to costly, time-intensive human testing.

Oviposition-Site Selection of Phlebotomus papatasi (Diptera: Psychodidae) Sand Flies: Attraction to Bacterial Isolates From an Attractive Rearing Medium

Phlebotomine sand flies are worldwide vectors of Leishmania parasites as well as other bacterial and viral pathogens. Due to the variable impact of traditional vector control practices, a more ecologically based approach is needed. The goal of this study was to isolate bacteria from the most attractive substrate to gravid Phlebotomus papatasi Scopoli sand flies and determine the role of bacterial volatiles in the oviposition attractancy of P. papatasi using behavioral assays. We hypothesized that gravid sand flies are attracted to bacterially derived semiochemical cues associated with breeding sites. Bacteria were isolated from a larvae-conditioned rearing medium, previously shown to be highly attractive to sand flies. The isolated bacteria were identified by amplifying and sequencing 16S rDNA gene fragments, and 12 distinct bacterial species were selected for two-choice olfactometer bioassays. The mix of 12 bacterial isolates elicited strong attraction at the lower concentration of 107 cells per ml and significant repellence at a high concentration of 109 cells per ml. Three individual isolates (SSI-2, SSI-9, and SSI-11) were particularly attractive at low doses. In general, we observed dose-related effects, with some bacterial isolates stimulating negative and some positive dose-response curves in sand fly attraction. Our study confirms the important role of saprophytic bacteria, gut bacteria, or both, in guiding the oviposition-site selection behavior of sand flies. Identifying the specific attractive semiochemical cues that they produce could lead to development of an attractive lure for surveillance and control of sand flies.

Homo-PROTAC mediated suicide of MDM2 to treat non-small cell lung cancer

The dose-related adverse effects of MDM2‒P53 inhibitors have caused significant concern in the development of clinical safe anticancer agents. Herein we report an unprecedented homo-PROTAC strategy for more effective disruption of MDM2‒P53 interaction. The design concept is inspired by the capacity of sub-stoichiometric catalytic PROTACs enabling to degrade an unwanted protein and the dual functions of MDM2 as an E3 ubiquitin ligase and a binding protein with tumor suppressor P53. The new homo-PROTACs are designed to induce self-degradation of MDM2. The results of the investigation have shown that PROTAC 11a efficiently dimerizes MDM2 with highly competitive binding activity and induces proteasome-dependent self-degradation of MDM2 in A549 non-small cell lung cancer cells. Furthermore, markedly, enantiomer 11a-1 exhibits potent in vivo antitumor activity in A549 xenograft nude mouse model, which is the first example of homo-PROTAC with in vivo therapeutic potency. This study demonstrates the potential of the homo-PROTAC as an alternative chemical tool for tumorigenic MDM2 knockdown, which could be developed into a safe therapy for cancer treatment.

Prenatal developmental toxicity studies on fumes from bitumen in the rat

The prenatal developmental toxicity of bitumen fume was tested by nose-only inhalation in the rat. The fumes for exposure were collected from the headspace of a storage tank filled with a bitumen corresponding in composition to an anticipated worst-case occupational exposure. The composition of these fumes was compared to actual paving site fumes to ensure its representativeness for workplace exposures. In a dose-range-finding study male and female rats were exposed to 0, 103, 480 or 1043 mg/m3 of fume (as total organic mass), for 6 h/day during 20 days post conception (p.c.). Dose-related effects on body weight and lungs were observed in the mid- and high-dose groups. In the main study, dams were exposed to 0, 52, 151 and 482 mg/m3 of fume, for 6 h/day during 19 days p.c. The maternal NOAEL was 52 mg/m³. In the high-dose group treatment-related effects on body weight (gain), food consumption, lung weights, and histopathological changes in lungs and larynx were observed. In the mid-dose group only histopathological changes in the larynx and lungs were found. The NOAEL for prenatal developmental toxicity was 151 mg/m³ based on reduced fetal weight in the high-dose group (482 mg/m³). However, these changes are most likely a consequence of the maternal toxicity, in particular the reduction of maternal body weight gain by 26 % as compared to control. Nose-only exposure to bitumen fumes in concentrations up to 482 mg/m³ from days 1–19 p.c. did not induce any significant fetal anomalies.

Sex hormones partially explain the sex-dependent effect of lifetime alcohol use on adolescent white matter microstructure

Previous studies demonstrate profound sex-specific patterns of white matter microstructural neurodevelopment (i.e. fractional anisotropy; FA, and mean diffusivity; MD) during adolescence. While alcohol use has been associated with alterations in FA and MD, no studies have addressed the potential for sex-specific, alcohol-dose-dependent effects, during development. This prospective longitudinal study (2–4 visits, 310 total scans) used voxel-wise multilevel modeling, in 132 (68 female) adolescents (ages 12–21), to assess the sex-specific effects of lifetime alcohol use on FA and MD, during development. Follow-up analyses tested the role of sex hormones, testosterone and estradiol, in explaining the effects of alcohol use on FA and MD. In the splenium of the corpus callosum and posterior thalamic radiation, male adolescents demonstrated lower FA and greater MD as a function of more lifetime alcohol use, while female adolescents demonstrated the opposite. Further, significant associations between sex hormones and FA/MD partially explained the effect of alcohol use on FA and MD in male adolescents. These results provide evidence for sex-specific and dose-related effects of alcohol use on white matter microstructure, which are partially explained by sex hormones, and highlight the importance of studying sex and hormones when investigating the effects of alcohol use on the adolescent brain.

Enhanced Oral Absorption of All-trans Retinoic Acid upon Encapsulation in Solid Lipid Nanoparticles.

All-trans retinoic acid (ATRA) is widely employed in the treatment of various proliferative and inflammatory diseases. However, its therapeutic efficacy is imperiled due to its poor solubility and stability. Latter was surmounted by its incorporation into a solid matrix of lipidic nanoparticles (SLNs). ATRA loaded SLNs (ATRA-SLNs) were prepared using a novel microemulsification technique (USPTO 9907758) and an optimal composition and were characterized in terms of morphology, differential scanning calorimetry (DSC), and powder X-ray diffraction studies (PXRD). In vitro release, oral plasma pharmacokinetics (in rats) and stability studies were also done. Rod-shaped ATRA-SLNs could successfully incorporate 3.7 mg/mL of ATRA, increasing its solubility (from 4.7 μg/mL) by 787 times, having an average particle size of 131.30 ± 5.0 nm and polydispersibility of 0.283. PXRD, DSC, and FTIR studies confirmed the formation of SLNs. Assay/total drug content and entrapment efficiency of ATRA-SLNs was 92.50 ± 2.10% and 84.60 ± 3.20% (n=6), respectively, which was maintained even on storage for one year under refrigerated conditions as an aqueous dispersion. In vitro release in 0.01 M phosphate buffer (pH 7.4) with 3% tween 80 was extended 12 times from 2h for free ATRA to 24 h for ATRA-SLNs depicting Korsmeyer Peppas release. Oral administration in rats showed 35.03 times enhanced bioavailability for ATRA-SLNs. Present work reports preparation and evaluation of bioenhanced ATRA-SLNs containing a high concentration of ATRA (>15 times than that reported by others). Latter is attributed to the novel preparation process and intelligent selection of components. Lay Summary: All-trans retinoic acid (ATRA) shows an array of pharmacological activities but its efficacy is limited due to poor solubility, stability and side effects. In present study its solubility and efficacy is improved by 787 and 35.5 times, respectively upon incorporation into solid lipid nanoparticles (ATRA-SLNs). Latter extended its release by 12 times and provided stability for at least a year under refrigeration. A controlled and sustained release will reduce dose related side effects. ATRA-SLNs reported presently can thus be used in treatment /prophylaxis of disorders like cancers, tuberculosis, age related macular degeneration and acne and as an immune-booster.

Pupillary effects in habitual cannabis consumers quantified with pupillography

Driving under the influence of alcohol (DUIA) and drugs (DUID) is considered an elevated risk for traffic safety. When assessing a driver's fitness to drive, standardized and objective measurement methods are still required, in order to clarify the question whether an individual is under the influence of substances acting on the central nervous system (CNS). We exposed healthy test subjects (n=41) as well as persons who were under the influence of cannabis after repeated inhalation to multiple light stimuli using infrared technology and measured the pupillary light reflex (PLR).Toxicological tests of blood samples taken from every subject followed. The aims of this study were to assess the differences in pupillography response between cannabis consumers after a washout period and no cannabis consumers as well as the dose related effects on pupillography parameters of cannabis in cannabis consumers. All four pupillary parameters changed according to a weakened pupil function after acute administration of cannabis in all test subjects. Furthermore, it could be observed that habitual cannabis consumers showed an altered pupillary function just before the first dose was taken, suggesting that the long-term effects and addiction also have to be taken into account, when effects of the CNS are discussed. The results of the present study show that almost all pupil parameters could be reliable indicators for the detection of subjects under the acute effect of cannabis.