Endocytosis Inhibition in Humans to Improve Responses to ADCC-Mediating Antibodies.

A safe and controlled manipulation of endocytosis in vivo may have disruptive therapeutic potential. Here, we demonstrate that the anti-emetic/anti-psychotic prochlorperazine can be repurposed to reversibly inhibit the in vivo endocytosis of membrane proteins targeted by therapeutic monoclonal antibodies, as directly demonstrated by our human tumor ex vivo assay. Temporary endocytosis inhibition results in enhanced target availability and improved efficiency of natural killer cell-mediated antibody-dependent cellular cytotoxicity (ADCC), a mediator of clinical responses induced by IgG1 antibodies, demonstrated here for cetuximab, trastuzumab, and avelumab. Extensive analysis of downstream signaling pathways ruled out on-target toxicities. By overcoming the heterogeneity of drug target availability that frequently characterizes poorly responsive or resistant tumors, clinical application of reversible endocytosis inhibition may considerably improve the clinical benefit of ADCC-mediating therapeutic antibodies.

Prochlorperazine-induced neuroleptic malignant syndrome.

Neuroleptic malignant syndrome (NMS) is a rare yet severe condition typically associated with antipsychotic medications. Here, we present a case of NMS induced by prochlorperazine in a 76-year-old male with multiple comorbidities, aiming to delineate its clinical manifestation, diagnostic complexities, and treatment approaches. Our methodology involved a thorough documentation of the patient's medical history, initial symptoms, physical examination findings, laboratory results, diagnostic processes, and subsequent therapeutic interventions. The patient exhibited classic NMS symptoms, including fever, altered mental status, autonomic dysregulation, and generalized rigidity, consistent with diagnostic criteria. Notably, laboratory investigations failed to reveal the typical abnormalities often seen in NMS cases, highlighting the diverse presentation of this syndrome. Management strategies primarily focused on benzodiazepines and amantadine, leading to a gradual improvement in symptoms and eventual resolution of NMS. This underscores the critical role of early recognition and appropriate pharmacotherapy in managing prochlorperazine-induced NMS, even at standard dosage levels. The absence of characteristic laboratory findings in NMS poses challenges in diagnosis, necessitating a comprehensive clinical assessment for accurate identification. Moreover, this case emphasizes the need for further research to better understand the pathophysiology of prochlorperazine-induced NMS and optimize treatment protocols. In conclusion, our case report sheds light on the complexities surrounding NMS induced by prochlorperazine, emphasizing the importance of vigilant monitoring and tailored therapeutic strategies in mitigating its potentially life-threatening consequences.

Antiemetic treatment of hyperemesis gravidarum in 1,064 Norwegian women and the impact of European warning on metoclopramide: a retrospective cohort study 2002-2019.

BACKGROUND: Women suffering from severe nausea and vomiting during pregnancy, hyperemesis gravidarum, have poor quality of life and increased risk of potentially fatal maternal and fetal complications. There is increasing and reassuring knowledge about safety of antiemetics in pregnancy. In 2013, the European Medical Agency (EMA) issued a warning on metoclopramide limiting treatment to maximum five days. Metoclopramide was the most used antiemetic in pregnancy at the time the warning was implemented in the Norwegian hyperemesis guidelines (2014). We aimed at describing changes in the treatment of hyperemesis over time, including changes associated with the EMA warning. METHODS: Retrospective chart review of all women hospitalized for hyperemesis gravidarum with metabolic disturbances between 01/Jan/2002 and 31/Dec/2019 at a university hospital serving nearly 10% of the pregnant population in Norway. Time-series analysis described changes over time and interrupted time series analysis quantified changes in treatment and clinical outcomes related to the EMA warning. RESULTS: In total, 1,064 women (1.2% of the birthing population) were included. The use of meclizine, prochlorperazine, and ondansetron increased during 2002-2019. This led to a yearly increase in the percentage of women using any antiemetic of 1.5% (95%CI 0.6; 2.4) pre-hospital, 0.6% (95%CI 0.2; 1.1) during hospitalization, and 2.6% (95%CI 1.3; 3.8) at discharge. Overall, only 50% of the women received antiemetics pre-hospital. Following the EMA warning, prehospital use of metoclopramide dropped by 30% (95%CI 25; 36), while use of any antiemetic pre-hospital dropped by 20% (95%CI 5.7; 34). In timely association, we observed a decrease in gestational age (-3.8 days, 98.75%CI 0.6; 7.1) at first admission, as well as indication of increased rate of termination of pregnancy with an absolute increase of 4.8% (98.75%CI 0.9; 8.7) in 2014. CONCLUSION: During 2002-2019, the overall use of antiemetics in treatment of hyperemesis increased. The EMA-warning on metoclopramide in 2013 temporarily limited pre-hospital antiemetic provision associated with hospitalization at lower gestational length and indication of an increase in termination of pregnancy.

Development of Optimized Sumatriptan-Prochlorperazine Combined Orodispersible Films Without Disintegrant: in vitro, ex vivo and in vivo Characterization.

Sumatriptan succinate and prochlorperazine maleate are a clinically proven combination for treating migraine and associated nausea and vomiting. Classical oral dosage forms are not frequently workable in migraine because of the associated nausea/vomiting, and no effective fixed dose combination is available. Thus, the aim of the study was to optimize a combined sumatriptan-prochlorperazine orodispersible film for rapid release of drugs. Orodispersible films were prepared by solvent casting method using varied amounts of polyvinyl alcohol and glycerol as film former and plasticizer, respectively, along with fixed levels of other ingredients employing central composite design. The optimum film (VF) demonstrated disintegration and total dispersion times as 21 s and 2.3 min, respectively. Tensile strength and Young's modulus were 8.86 ± 0.37 MPa and 24.15 ± 0.07 MPa, respectively. The in vitro T80% of both drugs from the ODF was achieved within 4 min. The film was palatable and disintegrated in 2 min in buccal cavity of human volunteers. Permeation study through goat mucosa demonstrated 100% permeation of both drugs within 15 min. X-Ray diffraction and differential scanning calorimetry supported drugs being amorphous and Fourier transform infrared demonstrated drug-excipient compatibility in optimized film. A judicious combination of sumatriptan succinate and prochlorperazine maleate could be prepared in orodispersible films for the possible relief of migraine.

A prospective, randomized, double-blind trial of intravenous chlorpromazine versus intravenous prochlorperazine for the treatment of acute migraine in adults presenting to the emergency department.

OBJECTIVE: To compare the efficacy of intravenous chlorpromazine versus intravenous prochlorperazine for the treatment of acute migraine in adults presenting to the emergency department (ED). BACKGROUND: Migraine is a common, incapacitating neurological condition. Although chlorpromazine and prochlorperazine are known to be safe, efficacious treatments for migraine, they have never been directly compared. DESIGN: We performed a prospective, randomized, double-blind clinical trial at a tertiary hospital in Melbourne, Australia. Adults aged 18-65 years, who presented with migraine, were eligible for recruitment. Sixty-six patients were randomized to either chlorpromazine 12.5 mg or prochlorperazine 12.5 mg, both infused in 500 ml of sodium chloride 0.9% over 30 min. Headache severity score, nausea severity score, and the presence of photophobia and phonophobia were assessed at 0, 30, 60, and 120 min. Adverse effects and the need for rescue therapy were recorded. The primary outcome was a reduction in headache severity score from baseline at 60 min post-commencement of the study medicine infusion. RESULTS: Sixty-five patients were included in the analysis. There was a median reduction in headache severity score at 60 min of 3.0 (interquartile range 1.0-4.0) in the chlorpromazine arm versus 2.0 (1.0-4.0) in the prochlorperazine arm (median difference -0.5 (95% confidence interval, -1.9 to 0.9)). We saw no evidence of a difference in secondary outcomes at 30, 60, or 120 min. Side effects were reported in 16/32 (50%) patients in the chlorpromazine group versus 7/33 (21%) in the prochlorperazine group (p = 0.020). Rescue therapy was required in 7/32 (22%) patients in the chlorpromazine group versus 12/33 (36%) in the prochlorperazine group (p = 0.277). CONCLUSIONS: Both chlorpromazine and prochlorperazine are efficacious treatments for acute migraine in adult patients presenting to the ED. This trial found no evidence of superiority of either agent over the other. Caution should be used when prescribing these medicines in the borderline hypotensive patient; in that circumstance, prochlorperazine should be preferentially used.

A randomized study of IV prochlorperazine plus diphenhydramine versus IV hydromorphone for migraine-associated symptoms: A post hoc analysis.

OBJECTIVE: We conducted a randomized trial among emergency department patients with migraine to determine the relative impact on migraine-associated symptoms of hydromorphone, an opioid, versus prochlorperazine, an antidopaminergic antiemetic. METHODS: This was a post hoc analysis of data from a double-blind study registered at http://clinicaltrials.gov (NCT02389829). Patients who met International Classification of Headache Disorders, 3rd edition criteria for migraine without aura or for probable migraine without aura were eligible for participation. Participants received either hydromorphone 1 mg IV or prochlorperazine 10 mg IV plus diphenhydramine 25 mg IV and could receive a second dose of the same medication 1 h later if needed. The outcomes were sustained relief of nausea, photophobia, and phonophobia. RESULTS: A total of 127 patients were enrolled, of whom 63 received prochlorperazine and 64 received hydromorphone. Of 49 patients in the prochlorperazine arm who reported nausea at baseline, 34 (69.4%) reported complete resolution without relapse versus 15/49 (30.6%) in the hydromorphone arm (absolute risk reduction [ARR] = 38.8%, 95% CI: 20.5%-57.0%, p < 0.001). Of 55 patients in the prochlorperazine arm who reported photophobia at baseline, 23 (41.8%) reported complete resolution without relapse versus 13/62 (20.9%) patients treated with hydromorphone (ARR = 20.8%, 95% CI: 4.3%-37.3%, p = 0.014). Of 56 patients in the prochlorperazine arm who reported phonophobia at baseline, 25 (44.6%) reported complete resolution without relapse versus 16/59 (27.1%) in the hydromorphone arm (ARR = 17.5%, 95% CI: 0.3%-34.8%, p = 0.049). For adverse events, three patients in the prochlorperazine arm reported anxiety or restlessness, and nine patients in the hydromorphone arm reported dizziness or weakness. CONCLUSIONS: Prochlorperazine plus diphenhydramine is more efficacious than hydromorphone for the treatment of migraine-associated symptoms.

MAGraine: Magnesium compared to conventional therapy for treatment of migraines.

Due to the healthcare burden associated with migraines, prompt and effective treatment is vital to improve patient outcomes and ED workflow. This was a prospective, randomized, double-blind trial. Adults who presented to the ED with a diagnosis of migraine from August of 2019 to March of 2020 were included. Pregnant patients, or with renal impairment were excluded. Patients were randomized to receive intravenous magnesium, prochlorperazine, or metoclopramide. The primary outcome was change in pain from baseline on a numeric rating scale (NRS) evaluated at 30 min after initiation of infusion of study drug. Secondary outcomes included NRS at 60 and 120 min, ED length of stay, necessity for rescue analgesia, and adverse effects. A total of 157 patients were analyzed in this study. Sixty-one patients received magnesium, 52 received prochlorperazine, and 44 received metoclopramide. Most patients were white females, and the median age was 36 years. Hypertension and migraines were the most common comorbidities, with a third of the patients reporting an aura. There was a median decrease in NRS at 30 min of three points across all three treatment arms. The median decrease in NRS (IQR) at 60 min was -4 (2-6) in the magnesium group, -3 (2-5) in the metoclopramide group, and -4.5 (2-7) in the prochlorperazine group (p = 0.27). There were no statistically significant differences in ED length of stay, rescue analgesia, or adverse effects. Reported adverse effects were dizziness, anxiety, and akathisia. No significant difference was observed in NRS at 30 min between magnesium, metoclopramide and prochlorperazine.

In vitro anticancer activity of fluphenazine, perphenazine and prochlorperazine. A review.

Drug repositioning is an approach that could accelerate the clinical use of compounds in different diseases. The goal is to take advantage of the fact that approved drugs have been tested on humans and detailed information is available on their pharmacology, toxicity and formulation. It can significantly reduce the costs and time needed to implement necessary therapies on the market. In recent years, phenothiazines are being tested for cancer, viral, bacterial, fungal and other diseases. Most research focuses on chlorpromazine as a model drug in this class, but other drugs such as fluphenazine, perphenazine and prochlorperazine have been proven to inhibit the viability of different cancer cell lines. In this study, we performed an extensive literature search to find and summarize all papers on the chosen phenothiazines and their potential in treating different types of cancerin vitro for further animal/clinical trials. Fluphenazine, perphenazine and prochlorperazine possess anticancer activity towards different types of human cancer. The antitumor activity is mainly mediated by an effect of the drugs on the cell cycle, proliferation or apoptosis. Possible molecular targets of phenothiazine derivatives are the drug's efflux pumps (ABCB1 and P-glycoprotein) and two parallel pathways (AKT and Wnt) regulated by the D2 receptor antagonists. The drugs have the potential to reduce the viability of human cancer cell lines, fragment the DNA, stimulate apoptosis, inhibit cell migration and invasiveness as well as impair the production of reactive oxygen species. In addition, due to the sedative and antiemetic properties antipsychotics can be used as an adjuvant for the treatment of chemotherapy side effects.

The Efficacy and Safety of Prochlorperazine in Patients With Acute Migraine: A Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this review was to evaluate the efficacy and safety of prochlorperazine (PCP) in patients with acute migraine headache in the emergency department (ED). METHODS: Electronic databases (Medline, Scopus, Web of Science, and Cochrane) were searched for randomized clinical trials that investigated the effect of PCP on headache relief. The outcomes were the number of patients without headache or with reduced headache severity, the number of adverse events, and the need for rescue analgesia. RESULTS: From 450 citations, 11 studies (n = 771) with 15 comparison arms met the inclusion criteria. Overall, PCP was more effective than placebo (OR = 7.23; 95% CI = 3.82-3.68), metoclopramide (OR = 2.89; 95% CI = 1.42-5.86), and other active comparators (OR = 3.70; 95% CI = 2.41-5.67) for headache relief. The odds ratio of experiencing adverse events with PCP compared with placebo was 5.79 (95% CI = 2.43-13.79). When PCP compared with other active comparators, no statistical difference was found regarding the overall number of adverse events (OR = 1.88; 95% CI = 0.99-3.59). However, PCP significantly increased the odds of akathisia/dystonia (OR = 2.55; 95% CI = 1.03-6.31). The request for rescue analgesia was significantly lower in the PCP group compared with other groups (16% vs 84%; OR = 0.16; 95% CI = 0.09-27). CONCLUSIONS: For adult patients with acute migraine, PCP could effectively abort the acute attack and reduce the request for rescue analgesia in the ED. However, compared with placebo, PCP could increase the risk of adverse events.

Buccally absorbed vs intravenous prochlorperazine for treatment of migraines headaches.

OBJECTIVE: To compare the efficacy of buccally absorbed prochlorperazine (BAP) to intravenous prochlorperazine (IVP) for the abortive treatment of migraine headaches. METHODS: Randomized double-blind trial. Eighty subjects aged 18-65 presenting with migraines to the ED of a safety-net, urban hospital. Subjects were randomized to receive either 6 mg BAP plus 2.25 mL saline IV placebo or 10 mg IVP and buccally absorbed saccharine pill placebo. A 100 mm visual analog scale (VAS) was used to assess pain, nausea, and sedation. Comparisons between groups were analyzed by the Mann-Whitney U test or Fisher's exact test. RESULTS: Eighty subjects were recruited from November 2016 to December 2017; 79 completed the study. Demographics: 60 women and 19 men with a mean age of 38 ± 12.2 years. Initial mean VAS pain scores were similar between groups (BAP: 78.5 ± 19.9 mm vs IVP: 76.9 ± 19.5 mm). The improvement in mean VAS pain scores over 60 minutes for the BAP group was not significantly different from the IVP group (-54.9 ± 29.7 mm vs -66.7 ± 23.2 mm, respectively; P = 0.08). No significant differences were found in rates of nausea or sedation. Nine subjects in the BAP group required rescue treatment compared to 1 in the IVP group. Five subjects reported symptoms consistent with akathisia in the IVP group while no adverse effects were reported in the BAP group. CONCLUSION: Buccally absorbed prochlorperazine (BAP) is an effective, non-invasive treatment for migraine headaches when compared to intravenous prochlorperazine (IVP).

Multiple perianal ulcers due to suppositories.

We report a case of long-standing inexplicable perianal ulcers. After exclusion of an inflammatory, infectious or neoplastic origin, a thorough personal history revealed that for many years the patient had been using analgesic suppositories containing indomethacin, caffeine, and prochlorperazine dimaleate, four to five times a week, for migraine. On stopping the suppositories, there was complete healing within 12 weeks. We hypothesize that vasoconstriction and vascular damage were the pathogenetic mechanisms behind the perianal ulcers.

Efficacy of Prophylactic Treatment for Oxycodone-Induced Nausea and Vomiting Among Patients with Cancer Pain (POINT): A Randomized, Placebo-Controlled, Double-Blind Trial.

BACKGROUND: Although opioid-induced nausea and vomiting (OINV) often result in analgesic undertreatment in patients with cancer, no randomized controlled trials have evaluated the efficacy of prophylactic antiemetics for preventing OINV. We conducted this randomized, placebo-controlled, double-blind trial to evaluate the efficacy and safety of prophylactic treatment with prochlorperazine for preventing OINV. MATERIALS AND METHODS: Cancer patients who started to receive oral oxycodone were randomly assigned in a 1:1 ratio to receive either prochlorperazine 5 mg or placebo prophylactically, given three times daily for 5 days. The primary endpoint was the proportion of patients who had a complete response (CR) during the 120 hours of oxycodone treatment. CR was defined as no emetic episode and no use of rescue medication for nausea and vomiting during 5 days. Key secondary endpoints were the proportion of patients with emetic episodes, proportion of patients with moderate or severe nausea, quality of life, and proportion of treatment withdrawal. RESULTS: From November 2013 through February 2016, a total of 120 patients were assigned to receive prochlorperazine (n = 60) or placebo (n = 60). There was no significant difference in CR rates (69.5% vs. 63.3%; p = .47) or any secondary endpoint between the groups. Patients who received prochlorperazine were more likely to experience severe somnolence (p = .048). CONCLUSION: Routine use of prochlorperazine as a prophylactic antiemetic at the initiation of treatment with opioids is not recommended. Further research is needed to evaluate whether other antiemetics would be effective in preventing OINV in specific patient populations. IMPLICATIONS FOR PRACTICE: Prophylactic prochlorperazine seems to be ineffective in preventing opioid-induced nausea and vomiting (OINV) and may cause adverse events such as somnolence. Routine use of prophylactic prochlorperazine at the initiation of treatment with opioids is not recommended. Further research is needed to evaluate whether other antiemetics would be effective in preventing OINV in specific patient populations.

Movement Disorders From the Use of Metoclopramide and Other Antiemetics in the Treatment of Migraine.

Nausea and vomiting are a frequent accompaniment of migraine and anti-nausea medications are frequently used in its management. The majority of anti-nausea medications that are used in migraine are dopamine receptor blocking agents and therefore have the potential to cause drug-induced movement disorders. This article explores the risk of such drug-induced movement disorders in migraineurs who were treated with these medications.

Repurposing of prochlorperazine for use against dengue virus infection.

The increasing prevalence of dengue virus (DENV) infection presents serious disease and economic burdens in countries where dengue epidemics are occurring. Despite the clinical importance, no DENV vaccine or anti-DENV drug is available. In this study, we found that prochlorperazine (PCZ), a dopamine D2 receptor (D2R) antagonist approved to treat nausea, vomiting, and headache in humans has potent in vitro and in vivo antiviral activity against DENV infection. PCZ can block DENV infection by targeting viral binding and viral entry through D2R- and clathrin-associated mechanisms, respectively. Administration of PCZ immediately or 6 hours after DENV infection in a Stat1-deficient mouse model completely protected against or delayed lethality. Overall, PCZ showed a previously unknown antiviral effect against DENV infection, and D2R may play a role in the DENV life cycle. Prophylactic and/or therapeutic treatment with PCZ might reduce viral replication and relieve the clinical symptoms of patients with dengue.

Chlorpromazine for the treatment of migraine in a pediatric emergency department.

BACKGROUND: Migraine headache is a common presenting condition to the pediatric emergency department (PED). Dopamine receptor antagonists, such as prochlorperazine and metoclopramide, serve as the primary treatment for migraine headache in many emergency departments; however, in 2012, our institution experienced a shortage of these drugs, resulting in the use of alternative medications. Chlorpromazine was included as an option for treatment at our institution during this shortage, although limited data exist on the effectiveness in children. OBJECTIVE: The objectives of this study were: (1) to compare the treatment failure rate of chlorpromazine in the treatment of migraine headache in youth presenting to the PED with those who received prochlorperazine; and (2) to identify the frequency and type of adverse events, and change in pain score. METHODS: We performed a retrospective cohort study of patients 12-21 years of age treated for migraine headache in our emergency department. Our treatment group received intravenous chlorpromazine between February and April 2012, while the comparison group consisted of children treated with intravenous prochlorperazine between February and April 2011. The outcomes of interest were: (1) treatment failure, defined as need for additional therapy, hospitalization or 48-hour return; (2) adverse reactions to drug therapy; and (3) change in pain score. RESULTS: This study yielded 75 patients in the treatment group and 274 in the comparison group. Forty percent (30/75) of the treatment group had treatment failure compared with 15% (41/274) of the comparison group. There was no difference in mean change in pain score between the groups. The most common adverse effects included hypotension in the treatment group (12%) and akathisia in the comparison group (12%). CONCLUSIONS: This is the first study that has examined the use of chlorpromazine as a therapy in pediatric migraines. Abortive therapy for migraine headache in the PED with chlorpromazine is associated with greater need for rescue medication and hospitalization, and higher rates of hypotension.

Review of Dopamine Antagonists for Nausea and Vomiting in Palliative Care Patients.

Symptoms of nausea and vomiting are common in palliative care and hospice patients. One of the many classes of medications used for the treatment of nausea and vomiting is dopamine receptor antagonists which are particularly helpful for treating nausea mediated by the chemoreceptor trigger zone (CTZ) and impaired gastrointestinal function. While dopamine antagonists can be very effective treatments for nausea they should be used with caution as they carry the risk of QTc prolongation, have a FDA black box warning for tardive dyskinesia (TD), and increased risk of precipitating psychosis and death in patients with dementia. This review will cover haloperidol, olanzapine, prochlorperazine, and metoclopramide for treatment of nausea and vomiting including evidence of efficacy, pharmacokinetics, and pharmacodynamics to improve safe and effective utilization in clinical practice. This includes medication receptor site affinities at histaminic, muscarinic, serotonergic, and alpha-adrenergic receptors which can help providers anticipate potential adverse effects and risk of extrapyramidal symptoms (EPS), TD, and QTc prolongation. This review also includes considerations for dose adjustments based on renal function, hepatic function, and age. Understanding the pharmacology of dopamine antagonists can help providers choose the best treatment for control of nausea and vomiting and subsequently improve patients' quality of life.

Optimizing the fabrication of electrospun nanofibers of prochlorperazine for enhanced dissolution and permeation properties.

Despite being an approved antiemetic for more than five decades, the clinical usefulness of prochlorperazine is limited by its low solubility and inconsistent absorption in the gastrointestinal tract, which presents challenges for nanotherapeutic interventions. Here, we report the preparation of a highly soluble and permeable nanofiber formulation of prochlorperazine using the Quality-by-Design approach. The final nanofiber formulation with drug entrapment of 88.02 ± 1.14 % was obtained at 20.0 kV, with a flow rate of 0.5 ml/h and tip-to-collector distance of 19.9 cm. Physio-mechanical properties, such as thickness (0.42 ± 0.02 mm), pH resistance (7.04 ± 0.08), folding endurance (54 ± 5), and tensile strength (0.244 ± 0.02 N.mm-2), were appropriate for packaging and application to oromucosal surfaces. The content uniformity (93.48-106.63 %) and weight variation (<1.8 mg) of the optimal nanofiber formulation were within the permissible limits prescribed for orodispersible films. Microscopical investigations confirm a randomly deposited and dense network of woven nanofibers with an average diameter of 363 ± 5.66 nm. The drug particles were embedded homogeneously on the fiber in the nanoform (4.27 ± 1.34 nm). The spectral analysis using TEM-EDS shows diffraction peaks of sulfur and chlorine, the elemental constituents of prochlorperazine. The drug was amorphized in the nanofiber formulation, as led by the decline of the crystallinity index from 87.25 % to 7.93 % due to electrostatic destabilization and flash evaporation of the solvent. The enthalpy of fusion values of the drug in the nanofiber mat decreased significantly to 23.6 J/g compared to its pristine form, which exhibits a value of 260.7 J/g. The nanofibers were biocompatible with oral mucosal cells, and there were no signs of mucosal irritation compared to 1 % sodium lauryl sulfate. The fiber mats rapidly disintegrated within <1 s and released ≈91.49 ± 2.1 % of the drug within 2 min, almost 2-fold compared to the commercial Stemetil MD® tablets. Similarly, the cumulative amount of the drug permeated across the unit area of the oromucosal membrane was remarkably high (31.28 ± 1.30 µg) compared to 10.17 ± 1.11 µg and 13.10 ± 1.79 µg from the cast film and drug suspension. Our results revealed these nanofiber formulations have the potential to be fast-dissolving oromucosal delivery systems, which can result in enhanced bioavailability with an early onset of action due to rapid disintegration, dissolution, and permeation.

Pharmacokinetics, pharmacodynamics, safety, and tolerability of dopamine-receptor antagonists for the prevention of chemotherapy-induced nausea and vomiting.

INTRODUCTION: Dopamine (D)2,3-receptor antagonists (RAs) were the first antiemetics used in the prophylaxis of chemotherapy-induced nausea and vomiting (CINV). AREAS COVERED: Eight D2,3-RAs, amisulpride, domperidone, droperidol, haloperidol, metoclopramide, metopimazine, olanzapine and prochlorperazine are reviewed focusing on pharmacokinetics, pharmacodynamics, antiemetic effect and side effects. EXPERT OPINION: Since the introduction of D2,3-RAs, antiemetics such as corticosteroids, 5-hydroxytryptamine (5-HT)3-RAs and neurokinin (NK)1-RAs have been developed. The classical D2,3-RAs are recommended in the prophylaxis of CINV from low emetic risk chemotherapy, but not as a fixed component of an antiemetic regimen for moderately or highly (HEC) emetic risk chemotherapy. D2,3-RAs are also used in patients with breakthrough nausea and vomiting. It should be emphasized, that most of these drugs are not selective for dopamine receptors.The multi-receptor targeting agent, olanzapine, is recommended in the prophylaxis of HEC-induced CINV as part of a four-drug antiemetic regimen, including a 5-HT3-RA, dexamethasone and a NK1-RA. Olanzapine is the most effective agent to prevent chemotherapy-induced nausea.Side effects differ among various D2,3-RAs. Metopimazine and domperidone possess a low risk of extrapyramidal side effects. Domperidone and metoclopramide are prokinetics, whereas metopimazine delays gastric emptying and haloperidol does not influence gastric motility. Many D2,3-RAs increase the risk of prolonged QTc interval; other side effects include sedation and orthostatic hypotension.

Effectiveness and Safety of Prochlorperazine in Indian Patients with Acute Vertigo: Results from a Large, Prospective, Post-marketing Observational Study.

Aim: To assess the efficacy and safety of prochlorperazine in Indian patients with acute vertigo. Methods: In this prospective, multicenter, open-label, post-marketing observational study, patients with acute peripheral vertigo of different etiologies received 5 mg prochlorperazine thrice a day for 5 days. The primary endpoints were percentage of patients with improvement in (1) vertigo symptoms and (2) clinical response as per scale for vestibular vertigo severity level and clinical response evaluation (SVVSLCRE) from baseline to end of treatment (Day 6). The key secondary endpoints were (1) improvement in nystagmus grading, and (2) safety and tolerability Efficacy of prochlorperazine by route of administration of first prochlorperazine dose (oral or intramuscular) was also assessed. Results: Of 1716 enrolled patients (mean [standard deviation, SD]) age (42.0 [12.95] years; 53.6% men), 57.4% were diagnosed with Meniere's disease, followed by vestibular neuritis (17.4%), labyrinthitis (16.7%), or ear surgery (8.5%). In the overall population, 91.1% of patients showed improvement in clinical response per SVVSLCRE grading at Day 6 (p < 0.0001 vs. non-responders). Nystagmus grading was improved in 99.7% (of patients. No adverse drug reactions events were reported. Tolerability of prochlorperazine was rated as good, very good, and excellent by 43.6%, 32.9% and 20.7% of patients, respectively. Among patients with postoperative vertigo, 80.1% showed improvement in clinical response. In the intramuscular and oral subsets, 85.5% and 92.1% of patients showed improved clinical response, respectively. Conclusion: Prochlorperazine showed improvement in severity of symptoms and clinical response in all subsets of vertigo patients, with a good safety and tolerability profile. Trial Registration Number: CTRI/2022/01/039287. Date of Registration: 10 January 2022.