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Pharmaceutics Apr 2022The aim of the present study was to systematically examine the effects of variations in the process parameters of the antisolvent precipitation method employed in the...
The aim of the present study was to systematically examine the effects of variations in the process parameters of the antisolvent precipitation method employed in the preparation of excipient-free pure nanoparticles of five existing/potential psychotropic drugs, namely amitriptyline hydrochloride (AMI), coumarin 6 (COU), curcumin (CUR), nortriptyline hydrochloride (NOR), and prochlorperazine dimaleate (PRO). In the preparation protocols employed, AMI and NOR were expected to be charged enough to be identified as surface-active molecules. Through the employment of five different preparation protocols, the effects of varying the flow rate, the compound concentration in the solvent solution C0solvent, the solvent:antisolvent ratio (SAS-ratio), and pH of the antisolvent on the final size of the particles DHf were investigated in detail and the results were explained using available theories for the antisolvent precipitation method. We found that DHf increased with the average of the octanol-water partition coefficients (log) of the compound. Moreover, the average of the final particle sizes (DHf)av increased linearly with (log). These findings are useful for predicting the size of nanodrugs prepared through the antisolvent precipitation method.
PubMed: 35456653
DOI: 10.3390/pharmaceutics14040819 -
Life (Basel, Switzerland) Oct 2021A gradual increase in rat soleus muscle electromyographic (EMG) activity is known to occur after 3-4 days of hindlimb suspension/unloading (HS). The physiological...
A gradual increase in rat soleus muscle electromyographic (EMG) activity is known to occur after 3-4 days of hindlimb suspension/unloading (HS). The physiological significance and mechanisms of such activity of motoneurons under unloading conditions are currently unclear. Since hyperactivity of motoneurons and muscle spasticity after spinal cord injury are associated with KCC2 downregulation, we hypothesized that a decrease in potassium (K)/chloride (Cl) co-transporter 2 (KCC2) in motoneurons would be responsible for an increase in soleus muscle EMG activity during HS. We aimed to investigate the effect of prochlorperazine (KCC2 activator) on the electrical activity of rat soleus muscle under HS. Wistar rats were divided into the following groups: (1) vivarium control (C), (2) 7-day HS group (7HS) and (3) 7-day HS group plus intraperitoneal injections of prochlorperazine (10 mg/kg, daily) (7HS + P). Expression of proteins in the motoneurons of the lumbar spinal cord was determined by Western blotting. An electromyogram of the rat soleus muscle was recorded using intramuscular electrodes. KCC2 content after 7-day HS significantly decreased by 34% relative to the control group. HS-induced decrease in KCC2 protein content was prevented by prochlorperazine administration. HS also induced a significant 80% decrease in KCC2 Ser940 phosphorylation; however prochlorperazine did not affect KCC2 phosphorylation. The treatment of the rats with prochlorperazine prevented a HS-induced increase in Na(+)/K(+)/(Cl-) co-transporter 1 (KCC2 antagonist) protein content. In parallel with the restoration of KCC2 content, prochlorperazine administration during HS partially prevented an increase in the soleus muscle tonic EMG activity. Thus, prochlorperazine administration during 7-day HS prevents a decrease in KCC2 protein expression in motoneurons and significantly reduces the level of HS-induced soleus muscle electrical activity.
PubMed: 34833037
DOI: 10.3390/life11111161 -
Neuroepidemiology 2022Migraine headache is commonly diagnosed in emergency departments (ED). There is relatively little real-world information about the epidemiology, investigation,...
BACKGROUND AND AIM
Migraine headache is commonly diagnosed in emergency departments (ED). There is relatively little real-world information about the epidemiology, investigation, management, adherence to therapeutic guidelines and disposition of patients treated in ED with a final diagnosis of migraine. The primary aim of the current study is to get a snapshot of assessment and management patterns of acute migraine presentations to the different settings of EDs with a view to raise awareness.
METHODS
This is a planned sub-study of a prospective study conducted in 67 health services in 10 countries including Australia, New Zealand, Southeast Asia, Europe, and the UK investigating the epidemiology and outcome of adult patients presenting to ED with nontraumatic headache. Outcomes of interest for this study are demographics, clinical features (including severity), patterns of investigation, treatment, disposition, and outcome of patients diagnosed as having migraine as their final ED diagnosis.
RESULTS
The cohort comprises 1,101 patients with a mean age of 39 years (SD ± 13.5; 73.7% [811]) were female. Most patients had had migraine diagnosed previously (77.7%). Neuroimaging was performed in 25.9% with a very low diagnostic yield or significant findings (0.07%). Treatment of mild migraine was in accordance with current guidelines, but few patients with moderate or severe symptoms received recommended treatment. Paracetamol (46.3%) and nonsteroidal anti-inflammatory drugs (42.7%) were the most commonly prescribed agents. Metoclopramide (22.8%), ondansetron (19.2%), chlorpromazine (12.8%), and prochlorperazine (12.8%) were also used.
CONCLUSIONS
This study suggests that therapeutic practices are not congruent with current guidelines, especially for patients with severe symptoms. Efforts to improve and sustain compliance with existing management best practices are required.
Topics: Adult; Emergency Service, Hospital; Female; Humans; Metoclopramide; Migraine Disorders; Prochlorperazine; Prospective Studies
PubMed: 35021181
DOI: 10.1159/000520548 -
Journal of Minimal Access Surgery 2023To highlight a rare case of inner ear barotrauma as a post-operative complication following robot-assisted radical prostatectomy (RARP). A 65-year-old man diagnosed with...
To highlight a rare case of inner ear barotrauma as a post-operative complication following robot-assisted radical prostatectomy (RARP). A 65-year-old man diagnosed with localised prostate carcinoma underwent elective RARP in a steep Trendelenburg position. Postoperatively, the patient complained of bothersome dizziness and spinning of surroundings associated with nausea. The patient was diagnosed to have vestibular symptoms secondary to inner ear barotrauma. He was started on prochlorperazine 12.5 mg and antibiotics, following which the patient improved. Vestibular rehabilitation exercises were taught to the patient. After 3 days of treatment, the patient did well with no episodes of dizziness. The patient was discharged on tablet cinnarizine 25 mg thrice daily for a week. On follow-up, the patient is asymptomatic. Inner ear barotrauma can be a rare complication of a combination of prolonged steep Trendelenburg during robotic surgery and pneumoperitoneum. Only further reporting of such incidents can help determine predisposing factors and precautions for preventing such incidents.
PubMed: 35915540
DOI: 10.4103/jmas.jmas_95_22 -
Academic Emergency Medicine : Official... Mar 2020
Topics: Adult; Humans; Migraine Disorders; Prochlorperazine; Treatment Outcome
PubMed: 31592565
DOI: 10.1111/acem.13864 -
Biological & Pharmaceutical Bulletin 2021The clinical applications of antipsychotics for symptoms unrelated to schizophrenia, such as behavioral and psychological symptoms, in patients with Alzheimer's disease,...
The clinical applications of antipsychotics for symptoms unrelated to schizophrenia, such as behavioral and psychological symptoms, in patients with Alzheimer's disease, and the likelihood of doctors prescribing antipsychotics for elderly people are increasing. In elderly people, drug-induced and aging-associated urinary disorders are likely to occur. The most significant factor causing drug-induced urinary disorders is a decrease in urinary bladder smooth muscle (UBSM) contraction induced by the anticholinergic action of therapeutics. However, the anticholinergic action-associated inhibitory effects of antipsychotics on UBSM contraction have not been sufficiently assessed. In this study, we examined 26 clinically available antipsychotics to determine the extent to which they inhibit acetylcholine (ACh)-induced contraction in rat UBSM to predict the drugs that should not be used by elderly people to avoid urinary disorders. Of the 26 antipsychotics, six (chlorpromazine, levomepromazine (phenothiazines), zotepine (a thiepine), olanzapine, quetiapine, clozapine (multi-acting receptor targeted antipsychotics (MARTAs))) competitively inhibited ACh-induced contractions at concentrations corresponding to clinically significant doses. Further, 11 antipsychotics (perphenazine, fluphenazine, prochlorperazine (phenothiazines), haloperidol, bromperidol, timiperone, spiperone (butyrophenones), pimozide (a diphenylbutylpiperidine), perospirone, blonanserin (serotonin-dopamine antagonists; SDAs), and asenapine (a MARTA)) significantly suppressed ACh-induced contraction; however, suppression occurred at concentrations substantially exceeding clinically achievable blood levels. The remaining nine antipsychotics (pipamperone (a butyrophenone), sulpiride, sultopride, tiapride, nemonapride (benzamides), risperidone, paliperidone (SDAs), aripiprazole, and brexpiprazole (dopamine partial agonists)) did not inhibit ACh-induced contractions at concentrations up to 10 M. These findings suggest that chlorpromazine, levomepromazine, zotepine, olanzapine, quetiapine, and clozapine should be avoided by elderly people with urinary disorders.
Topics: Acetylcholine; Aging; Animals; Antipsychotic Agents; Chlorpromazine; Cholinergic Antagonists; Clozapine; Dibenzothiepins; Male; Mental Disorders; Methotrimeprazine; Muscle Contraction; Muscle, Smooth; Olanzapine; Quetiapine Fumarate; Rats, Wistar; Urinary Bladder; Urologic Diseases; Rats
PubMed: 34334499
DOI: 10.1248/bpb.b21-00363 -
Journal of Medical Case Reports Aug 2021Dystonia is a known neurological complication of certain medications; however, the mechanism behind such effects is often undetermined. Similarly, the clinical...
BACKGROUND
Dystonia is a known neurological complication of certain medications; however, the mechanism behind such effects is often undetermined. Similarly, the clinical pharmacogenomic effects associated with various alleles of the cytochrome P450 family of proteins, and their role in acute dystonic reactions, are also presently unknown.
CASE PRESENTATION
We describe a woman presenting with acute dystonic reactions to ondansetron, prochlorperazine, and metoclopramide followed by persistent focal dystonia. A similar family history was reported in her siblings and her father to prochlorperazine, drugs all metabolized by the cytochrome P450 2D6 (CYP2D6) enzyme. Pharmacogenomic testing indicated the patient was heterozygous for the intermediate metabolizer *41 allele (CYP2D6 2988G>A, NM_000106.6:c.985+39G>A, rs28371725). Her father was homozygous for this CYP2D6 *41 allele, and consequently, her siblings were obligate carriers.
CONCLUSIONS
The metabolism of ondansetron, metoclopramide, or prochlorperazine in patients with the *41 CYP2D6 allele has not been studied. In this family, clinical evidence implicates the *41 CYP2D6 allele as causing extrapyramidal adverse pharmacologic reactions. Patients with a family history of medication-induced dystonia involving these medications should be considered for pharmacogenomic testing, and patients carrying the *41 CYP2D6 allele should consider reduction or avoidance of CYP2D6-mediated medications to minimize the potential risk of adverse extrapyramidal effects.
Topics: Alleles; Cytochrome P-450 CYP2D6; Dystonia; Female; Genotype; Humans; Pharmacogenetics; Pharmacogenomic Testing
PubMed: 34407866
DOI: 10.1186/s13256-021-03022-x -
Computational and Structural... 2020The status quo for combating uprising antibacterial resistance is to employ synergistic combinations of antibiotics. Nevertheless, the currently available combination...
The status quo for combating uprising antibacterial resistance is to employ synergistic combinations of antibiotics. Nevertheless, the currently available combination therapies are fast becoming untenable. Combining antibiotics with various FDA-approved non-antibiotic drugs has emerged as a novel strategy against otherwise untreatable multi-drug resistant (MDR) pathogens. The apex of this study was to investigate the mechanisms of antibacterial synergy of the combination of polymyxin B with the phenothiazines against the MDR Gram-negative pathogens Acinetobacter baumannii, Klebsiella pneumoniae and Pseudomonas aeruginosa. The synergistic antibacterial effects were tested using checkerboard and static time-kill assays. Electron microscopy (EM) and untargeted metabolomics were used to ascertain the mechanism(s) of the antibacterial synergy. The combination of polymyxin B and the phenothiazines showed synergistic antibacterial activity in checkerboard and static time-kill assays at clinically relevant concentrations against both polymyxin-susceptible and polymyxin-resistant isolates. EM revealed that the polymyxin B-prochlorperazine combination resulted in greater damage to the bacterial cell compared to each drug monotherapy. In metabolomics, at 0.5 h, polymyxin B monotherapy and the combination (to a greatest extent) disorganised the bacterial cell envelope as manifested by a major perturbation in bacterial membrane lipids (glycerophospholipids and fatty acids), peptidoglycan and lipopolysaccharide (LPS) biosynthesis. At the late time exposure (4 h), the aforementioned effects (except LPS biosynthesis) perpetuated mainly with the combination therapy, indicating the disorganising bacterial membrane biogenesis is potentially behind the mechanisms of antibacterial synergy. In conclusion, the study highlights the potential usefulness of the combination of polymyxin B with phenothiazines for the treatment of polymyxin-resistant Gram-negative infections (e.g. CNS infections).
PubMed: 32952938
DOI: 10.1016/j.csbj.2020.08.008 -
Frontiers in Pharmacology 2022Major bleeding risks associated with non-vitamin K oral anticoagulants (NOACs) used with and without concurrent antipsychotics in patients with non-valvular atrial...
Major bleeding risks associated with non-vitamin K oral anticoagulants (NOACs) used with and without concurrent antipsychotics in patients with non-valvular atrial fibrillation (AF) were assessed. A total of 98,863 patients with non-valvular AF receiving at least one NOAC prescription from Taiwan's National Health Insurance database were enrolled. Major bleeding was defined as a primary diagnosis of intracranial or gastrointestinal hemorrhage or bleeding at other sites. The adjusted incidence rate difference (AIRD) per 1,000 person-years and adjusted rate ratio of major bleeding were estimated using Poisson regression and inverse probability of treatment weighting using the propensity score. A total of 8,037 major bleeding events occurred during 705,521 person-quarters with NOAC prescriptions. Antipsychotics were used in 26.35% of NOAC-exposed patients. Compared to using NOAC alone, co-medication of either typical (AIRD: 79.18, 95% confidence interval [CI]: 70.63-87.72) or atypical (AIRD: 40.5, 95% CI: 33.64-47.35) antipsychotic with NOAC had a significant increase in the adjusted incidence rate per 1,000 person-years of major bleeding. The concomitant use of a NOAC with chlorpromazine (AIRD: 103.87, 95% CI: 51.22-156.52), haloperidol (AIRD: 149.52, 95% CI: 125.03-174.00), prochlorperazine (AIRD: 90.43, 95% CI: 78.55-102.32), quetiapine (AIRD: 44.6, 95% CI: 37.11-52.09), or risperidone (AIRD: 41.55, 95% CI: 22.86-60.24) (All 0.01) showed a higher adjusted incidence rate of major bleeding than using NOACs alone. The concomitant use of typical (chlorpromazine, haloperidol, or prochlorperazine) or atypical (quetiapine or risperidone) antipsychotic with NOACs was associated with a significantly increased risk of major bleeding.
PubMed: 35496319
DOI: 10.3389/fphar.2022.819878 -
Current Issues in Molecular Biology Jun 2023Skeletal muscle disuse leads to pathological muscle activity as well as to slow-to-fast fiber-type transformation. Fast-type fibers are more fatigable than slow-type, so...
Skeletal muscle disuse leads to pathological muscle activity as well as to slow-to-fast fiber-type transformation. Fast-type fibers are more fatigable than slow-type, so this transformation leads to a decline in muscle function. Prochlorperazine injections previously were shown to attenuate autonomous rat soleus muscle electrical activity under unloading conditions. In this study, we found that prochlorperazine blocks slow-to-fast fiber-type transformation in disused skeletal muscles of rats, possibly through affecting calcium and ROS-related signaling.
PubMed: 37504270
DOI: 10.3390/cimb45070354