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British Journal of Cancer Aug 2017Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential...
BACKGROUND
Demand for cholesterol is high in certain cancers making them potentially sensitive to therapeutic strategies targeting cellular cholesterol homoeostasis. A potential approach involves disruption of intracellular cholesterol transport, which occurs in Niemann-Pick disease as a result of acid sphingomyelinase (ASM) deficiency. Hence, a class of lysosomotropic compounds that were identified as functional ASM inhibitors (FIASMAs) might exhibit chemotherapeutic activity by disrupting cancer cell cholesterol homoeostasis.
METHODS
Here, the chemotherapeutic utility of ASM inhibition was investigated. The effect of FIASMAs on intracellular cholesterol levels, cholesterol homoeostasis, cellular endocytosis and signalling cascades were investigated. The in vivo efficacy of ASM inhibition was demonstrated using melanoma xenografts and a nanoparticle formulation was developed to overcome dose-limiting CNS-associated side effects of certain FIASMAs.
RESULTS
Functional ASM inhibitors inhibited intracellular cholesterol transport leading to disruption of autophagic flux, cellular endocytosis and receptor tyrosine kinase signalling. Consequently, major oncogenic signalling cascades on which cancer cells were reliant for survival were inhibited. Two tested ASM inhibitors, perphenazine and fluphenazine that are also clinically used as antipsychotics, were effective in inhibiting xenografted tumour growth. Nanoliposomal encapsulation of the perphenazine enhanced its chemotherapeutic efficacy while decreasing CNS-associated side effects.
CONCLUSIONS
This study suggests that disruption of intracellular cholesterol transport by targeting ASM could be utilised as a potential chemotherapeutic approach for treating cancer.
Topics: Administration, Intravenous; Administration, Oral; Animals; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Autophagy; Biological Transport; Cell Survival; Cholesterol; Desipramine; Endocytosis; Endosomes; Female; Flupenthixol; Fluphenazine; Gene Expression Regulation; Gene Knockdown Techniques; HCT116 Cells; Homeostasis; Humans; Inhibitory Concentration 50; Liposomes; Lysosomes; MCF-7 Cells; Melanoma; Mice; Nortriptyline; Perphenazine; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; STAT3 Transcription Factor; Signal Transduction; Sphingomyelin Phosphodiesterase; bcl-2-Associated X Protein
PubMed: 28697173
DOI: 10.1038/bjc.2017.200 -
Clinical Pharmacology and Therapeutics Mar 2018Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we...
Although pregnancy is known to cause changes in drug pharmacokinetics, little is known about its impact on serum levels of antipsychotics. In this study we retrospectively assessed 201 routine serum antipsychotic therapeutic drug monitoring concentration measurements obtained from a total of 110 pregnancies in 103 women, and 512 measurements from the same women before and after pregnancy. Serum concentrations in the third trimester were significantly lower than baseline for quetiapine (-76%; confidence interval (CI), -83%, -66%; P < 0.001) and aripiprazole (-52%; CI, -62%, -39%; P < 0.001), but not for olanzapine (-9%; CI, -28%, +14%; P = 0.40). For the remaining antipsychotics (perphenazine, haloperidol, ziprasidone, risperidone, and clozapine), our dataset was limited, but it indicates that concentrations may decline at least for perphenazine and possibly also for haloperidol. Even though the clinical consequence of the serum concentrations decline remains to be elucidated, our results warrant close clinical monitoring throughout pregnancy, preferentially supported by therapeutic drug monitoring.
Topics: Adult; Antipsychotic Agents; Drug Administration Schedule; Drug Monitoring; Female; Humans; Norway; Pregnancy; Pregnancy Trimester, Third; Registries; Retrospective Studies; Young Adult
PubMed: 28643331
DOI: 10.1002/cpt.770 -
JAMA Psychiatry Jul 2017It has remained unclear whether there are clinically meaningful differences between antipsychotic treatments with regard to preventing relapse of schizophrenia, owing to...
IMPORTANCE
It has remained unclear whether there are clinically meaningful differences between antipsychotic treatments with regard to preventing relapse of schizophrenia, owing to the impossibility of including large unselected patient populations in randomized clinical trials, as well as residual confounding from selection biases in observational studies.
OBJECTIVE
To study the comparative real-world effectiveness of antipsychotic treatments for patients with schizophrenia.
DESIGN, SETTING, AND PARTICIPANTS
Prospectively gathered nationwide databases were linked to study the risk of rehospitalization and treatment failure from July 1, 2006, to December 31, 2013, among all patients in Sweden with a schizophrenia diagnosis who were 16 to 64 years of age in 2006 (29 823 patients in the total prevalent cohort; 4603 in the incident cohort of newly diagnosed patients). Within-individual analyses were used for primary analyses, in which each individual was used as his or her own control to eliminate selection bias. Traditional Cox proportional hazards multivariate regression was used for secondary analyses.
MAIN OUTCOMES AND MEASURES
Risk of rehospitalization and treatment failure (defined as psychiatric rehospitalization, suicide attempt, discontinuation or switch to other medication, or death).
RESULTS
There were 29 823 patients (12 822 women and 17 001 men; mean [SD] age, 44.9 [12.0] years). During follow-up, 13 042 of 29 823 patients (43.7%) were rehospitalized, and 20 225 of 28 189 patients (71.7%) experienced treatment failure. The risk of psychiatric rehospitalization was the lowest during monotherapy with once-monthly long-acting injectable paliperidone (hazard ratio [HR], 0.51; 95% CI, 0.41-0.64), long-acting injectable zuclopenthixol (HR, 0.53; 95% CI, 0.48-0.57), clozapine (HR, 0.53; 95% CI, 0.48-0.58), long-acting injectable perphenazine (HR, 0.58; 95% CI, 0.52-0.65), and long-acting injectable olanzapine (HR, 0.58; 95% CI, 0.44-0.77) compared with no use of antipsychotic medication. Oral flupentixol (HR, 0.92; 95% CI, 0.74-1.14), quetiapine (HR, 0.91; 95% CI, 0.83-1.00), and oral perphenazine (HR, 0.86; 95% CI, 0.77-0.97) were associated with the highest risk of rehospitalization. Long-acting injectable antipsychotic medications were associated with substantially lower risk of rehospitalization compared with equivalent oral formulations (HR, 0.78; 95% CI, 0.72-0.84 in the total cohort; HR, 0.68; 95% CI, 0.53-0.86 in the incident cohort). Clozapine (HR, 0.58; 95% CI, 0.53-0.63) and all long-acting injectable antipsychotic medications (HRs 0.65-0.80) were associated with the lowest rates of treatment failure compared with the most widely used medication, oral olanzapine. The results of several sensitivity analyses were consistent with those of the primary analyses.
CONCLUSIONS AND RELEVANCE
Clozapine and long-acting injectable antipsychotic medications were the pharmacologic treatments with the highest rates of prevention of relapse in schizophrenia. The risk of rehospitalization is about 20% to 30% lower during long-acting injectable treatments compared with equivalent oral formulations.
Topics: Adolescent; Adult; Antipsychotic Agents; Clozapine; Cohort Studies; Delayed-Action Preparations; Humans; Middle Aged; Outcome Assessment, Health Care; Patient Readmission; Schizophrenia; Secondary Prevention; Sweden; Treatment Failure; Young Adult
PubMed: 28593216
DOI: 10.1001/jamapsychiatry.2017.1322 -
Electronic Physician Dec 2016Multiple sclerosis (MS) is the most common debilitating neurological disease that affects adults, whether young adults or middle-aged. Although, most attention is toward...
Multiple sclerosis (MS) is the most common debilitating neurological disease that affects adults, whether young adults or middle-aged. Although, most attention is toward the neurological signs of the disease, the neuropsychiatric signs are not uncommon. This case report presents a 29 year old male with a record of obsessive-compulsive disorder (OCD) without psychotic disorder, which coincides with the diagnosis MS, has been stricken to auditory hallucinations and reference delusion. The patient received some antipsychotic drugs such as Haloperidol and Perphenazine irregularly, but any psychotic signs of the patient were never in control. During this period he had several active episodes of MS disease, wherein the symptoms had subsided due to hospitalization and received corticosteroids pulse. The first time the patient was submitted to the emergency unit of Rasoul Akram Hospital, there was the possibility of schizophrenia which was confirmed in subsequent visits. The signs of the patient were not controllable for a long time and finally fully controlled by a combination of Aripiprazole (abilizol), Risperidone and Sertraline, and currently, for almost 3 years, both psychotic symptoms and MS disease have been under control. Our patient seems to catch the MS disease and schizophrenia simultaneously. There was no relation between MS and psychosis episodes and the MS attacks. Since the onset the patient had several acute MS attacks of MS, and hospitalization several times. These findings and characteristics regarding our patient made him completely different from other reported cases of MS along with neuropsychiatric signs which may help doctors in diagnosis and managment of similar cases.
PubMed: 28163856
DOI: 10.19082/3409 -
Clinical Cancer Research : An Official... May 2017To identify potential molecular hubs that regulate oncogenic kinases and target them to improve treatment outcomes for glioblastoma patients. Data mining of The Cancer...
To identify potential molecular hubs that regulate oncogenic kinases and target them to improve treatment outcomes for glioblastoma patients. Data mining of The Cancer Genome Atlas datasets identified nicotinamide-N-methyl transferase (NNMT) as a prognostic marker for glioblastoma, an enzyme linked to the reorganization of the methylome. We tested our hypothesis that NNMT plays a crucial role by modulating protein methylation, leading to inactivation of tumor suppressors and activation of oncogenes. Further experiments were performed to understand the underlying biochemical mechanisms using glioblastoma patient samples, established, primary, and isogenic cells. We demonstrate that NNMT outcompetes leucine carboxyl methyl transferase 1 (LCMT1) for methyl transfer from principal methyl donor SAM in biological systems. Inhibiting NNMT increased the availability of methyl groups for LCMT1 to methylate PP2A, resulting in the inhibition of oncogenic serine/threonine kinases (STK). Further, NNMT inhibition retained the radiosensitizer nicotinamide and enhanced radiation sensitivity. We have provided the biochemical rationale of how NNMT plays a vital role in inhibiting tumor suppressor PP2A while concomitantly activating STKs. We report the intricate novel mechanism in which NNMT inhibits tumor suppressor PP2A by reorganizing the methylome both at epigenome and proteome levels and concomitantly activating prosurvival STKs. In glioblastoma tumors with NNMT expression, activation of PP2A can be accomplished by FDA approved perphenazine (PPZ), which is currently used to treat mood disorders such as schizophrenia, bipolar disorder, etc. This study forms a foundation for further glioblastoma clinical trials using PPZ with standard of care treatment. .
Topics: Animals; Carboxylic Ester Hydrolases; Cell Line, Tumor; Cell Proliferation; Gene Silencing; Genes, Tumor Suppressor; Glioblastoma; Humans; Methylation; Mice; Nicotinamide N-Methyltransferase; Perphenazine; Protein O-Methyltransferase; Protein Serine-Threonine Kinases
PubMed: 27810903
DOI: 10.1158/1078-0432.CCR-16-1323 -
Neuropsychopharmacology : Official... Mar 2017Typical antipsychotic drugs are widely thought to alleviate the positive symptoms of schizophrenia by antagonizing dopamine D receptors expressed by striatal spiny...
Typical antipsychotic drugs are widely thought to alleviate the positive symptoms of schizophrenia by antagonizing dopamine D receptors expressed by striatal spiny projection neurons (SPNs). What is less clear is why antipsychotics have a therapeutic latency of weeks. Using a combination of physiological and anatomical approaches in ex vivo brain slices from transgenic mice, it was found that 2 weeks of haloperidol treatment induced both intrinsic and synaptic adaptations specifically within indirect pathway SPNs (iSPNs). Perphenazine treatment had similar effects. Some of these adaptations were homeostatic, including a drop in intrinsic excitability and pruning of excitatory corticostriatal glutamatergic synapses. However, haloperidol treatment also led to strengthening of a subset of excitatory corticostriatal synapses. This slow remodeling of corticostriatal iSPN circuitry is likely to play a role in mediating the delayed therapeutic action of neuroleptics.
Topics: Animals; Antipsychotic Agents; Cerebral Cortex; Corpus Striatum; Female; Haloperidol; Male; Mice; Mice, Transgenic; Perphenazine; Signal Transduction
PubMed: 27577602
DOI: 10.1038/npp.2016.173 -
Journal of Clinical and Diagnostic... Jun 2016Parkinsonism is a neurodegenerative disease that is defined by certain symptoms such as muscle rigidity, impaired movement, catatonia, tremor and disorientation of body.
INTRODUCTION
Parkinsonism is a neurodegenerative disease that is defined by certain symptoms such as muscle rigidity, impaired movement, catatonia, tremor and disorientation of body.
AIM
The aim was to investigate the effect of red lentil extract on perphenazine-induced Catatonia in model of rat.
MATERIALS AND METHODS
This experimental study was done on 48 male albino rats (weight 180-200g) of the Sprague-Dawley strain. Animals were randomly divided into six groups and were pre-treated with a single dose of red lentil extract (200, 400, 800 and 1000 mg/kg), most effective dose of bromocriptine (30mg/kg) and normal saline (5ml/kg) via intraperitoneal (IP) route. perphenazine (5 mg/kg) was after 30 minutes, administered (IP) to induce catatonia. The scoring method of Morpurgo was used to determine the muscular rigidity of animals.
RESULTS
The results showed that the 200mg/kg red lentil extract treated group had no significant reduction in catatonic responses after perphenazine administration in comparison with control group while the groups that received 800 and 1000mg/kg of red lentil extract showed significant difference (p<0.05) at all the time points.
CONCLUSION
The results revealed that hydroalcoholic extract of red lentil has protective effect on Catatonia induced by perphenazine in rats. So this extract may be probably beneficial for catatonia in Parkinsonism.
PubMed: 27504309
DOI: 10.7860/JCDR/2016/17813.7977 -
European Journal of Pharmaceutical... Oct 2016The ionization constants (pKa) and the pH-dependent solubility (log S-pH) of six phenothiazine derivatives (promazine hydrochloride, chlorpromazine hydrochloride,...
The ionization constants (pKa) and the pH-dependent solubility (log S-pH) of six phenothiazine derivatives (promazine hydrochloride, chlorpromazine hydrochloride, triflupromazine hydrochloride, fluphenazine dihydrochloride, perphenazine free base, and trifluoperazine dihydrochloride) were determined at 25 and 37°C. The pKa values of these low-soluble surface active molecules were determined by the cosolvent method (n-propanol/water at 37°C and methanol/water at 25°C). The log S-pH profiles were measured at 24h incubation time in 0.15M phosphate buffers. The log S-pH "shape-template" method, which critically depends on accurate pKa values (determined independently of solubility data), was used to propose speciation models, which were subsequently refined by rigorous mass-action weighted regression procedure described recently. Differential scanning calorimetry (DSC), UV-visible spectrophotometry, potentiometric, and high performance liquid chromatography (HPLC) measurements were used to characterize the compounds. The intrinsic solubility (S0) values of the three least-soluble drugs (chlorpromazine·HCl, triflupromazine·HCl, and trifluoperazine·2HCl) at 25°C were 0.5, 1.1, and 2.7μg/mL (resp.). These values increased to 5.5, 9.2, and 8.7μg/mL (resp.) at the physiological temperature. The enthalpies of solution for the latter compounds were exceptionally high positive (endothermic) values (99-152kJ·mol(-1)). Cationic sub-micellar aggregates were evident (from the distortions in the log S-pH profiles) for chlorpromazine, fluphenazine, perphenazine, and trifluoperazine at 25°C. The effects persisted at 37°C for chlorpromazine and trifluoperazine. The solids in suspension were apparently amorphous in cases where the drugs were introduced as the chloride salts.
Topics: Calorimetry, Differential Scanning; Chromatography, High Pressure Liquid; Hydrogen-Ion Concentration; Micelles; Phenothiazines; Solubility; Spectrophotometry, Ultraviolet; Temperature
PubMed: 27449396
DOI: 10.1016/j.ejps.2016.07.013 -
Free Radical Biology & Medicine Aug 2016Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by progressive loss of motor neurons, gliosis, neuroinflammation and...
Amyotrophic lateral sclerosis (ALS) is an incurable neurodegenerative disease characterized by progressive loss of motor neurons, gliosis, neuroinflammation and oxidative stress. The aim of this study was to evaluate the involvement of NADPH oxidases (NOX) in the oxidative damage and progression of ALS neuropathology. We examined the pattern of NOX expression in spinal cords of patients and mouse models of ALS and analyzed the impact of genetic deletion of the NOX1 and 2 isoforms as well as pharmacological NOX inhibition in the SOD1(G93A) ALS mouse model. A substantial (10-60 times) increase of NOX2 expression was detected in three etiologically different ALS mouse models while up-regulation of some other NOX isoforms was model-specific. In human spinal cord samples, high NOX2 expression was detected in microglia. In contrast to previous publications, survival of SOD1(G93A) mice was not modified upon breeding with constitutive NOX1 and NOX2 deficient mice. As genetic deficiency of a single NOX isoform is not necessarily predictive of a pharmacological intervention, we treated SOD1(G93A) mice with broad-spectrum NOX inhibitors perphenazine and thioridazine. Both compounds reached in vivo CNS concentrations compatible with NOX inhibition and thioridazine significantly decreased superoxide levels in the spinal cord of SOD1(G93A) mice in vivo. Yet, neither perphenazine nor thioridazine prolonged survival. Thioridazine, but not perphenazine, dampened the increase of microglia markers in SOD1(G93A) mice. Thioridazine induced an immediate and temporary enhancement of motor performance (rotarod) but its precise mode of action needs further investigation. Additional studies using specific NOX inhibitors will provide further evidence on the relevance of NOX as drug targets for ALS and other neurodegenerative disorders.
Topics: Adult; Aged; Amyotrophic Lateral Sclerosis; Animals; Disease Models, Animal; Female; Gene Expression Regulation; Humans; Male; Mice; Middle Aged; Motor Neurons; NADPH Oxidase 1; NADPH Oxidase 2; Perphenazine; Spinal Cord; Superoxide Dismutase-1; Thioridazine
PubMed: 27212019
DOI: 10.1016/j.freeradbiomed.2016.05.016 -
The Journal of Veterinary Medical... Sep 2016Lymphoma is one of the most common malignant tumors in canine. Protein phosphatase 2A (PP2A), a well-conserved serine/threonine phosphatase, plays a critical role as a...
Lymphoma is one of the most common malignant tumors in canine. Protein phosphatase 2A (PP2A), a well-conserved serine/threonine phosphatase, plays a critical role as a tumor suppressor. Perphenazine (PPZ) is one of the phenothiazines and widely used as an antipsychotic drug. Recently, it is reported that PPZ directly binds with scaffolding subunit of PP2A complex and exerts anti-tumor effects on human T cell acute lymphoblastic leukemia. However, the effect of PPZ on canine lymphoma has not been studied. Here, we investigated the potential therapeutic role of PPZ and its molecular mechanism in canine T-cell lymphoma. In canine T-cell lymphoma cell lines, UL-1 and Ema, PPZ decreased cell survival in a dose-dependent manner. Increased caspase 3 activity and Annexin V positive cells suggested that PPZ induced apoptosis. PPZ dephosphorylated Akt, MEK1/2 and ERK1/2. Akt inhibitor, but not MEK1/2 inhibitor and ERK1/2 inhibitor, induced cell death, indicating the importance of Akt dephosphorylation for the anti-tumor effect of PPZ. Finally, we observed enhanced PP2A activity by PPZ treatment. The present results for the first time revealed that PPZ induced canine lymphoma cells apoptosis through Akt dephosphorylation via PP2A activation. Our study suggests the possible therapeutic application of phenothiazines for canine T-cell lymphoma.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Dog Diseases; Dogs; Dose-Response Relationship, Drug; Flow Cytometry; Immunoblotting; Lymphoma; Lymphoma, T-Cell; MAP Kinase Signaling System; Oncogene Protein v-akt; Perphenazine; Phosphorylation; Protein Phosphatase 2
PubMed: 27150024
DOI: 10.1292/jvms.15-0707