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Introduction: Integrating 3-dimensional (3D) printing with lipid-based formulation (LBF) is impacting pediatric pharmaceutical manufacturing by enabling personalized oral dosage forms tailored to children's specific needs. Serious challenges are created by manipulating conventional adult dosages to produce suitable dosages for the pediatric population. The study explores an emulsion gel with two model lipophilic drugs, Aprepitant and Irbesartan, using semi-solid extrusion (SSE) as a 3D printing method to produce patient-centered dosages. Method: The solubility of the two model drugs in the studied LBF type IIIA – MC was determined using the shake-flask method combined with High-Performance Liquid Chromatography with Ultraviolet Detection (HPLC-UV) analysis. Once determined, LBF was loaded with 90% of the soluble drug amount to later produce the emulsion by mixing the drug-loaded LBF with Milli-Q water. The emulsion gel was produced as the next step by adding three different polymers to the emulsion. The three polymers were Methylcellulose Methocel (A4C), Methylcellulose Methocel (A4M), and Sodium Crosscarmellose (AcDiSol). Lastly, tablets were 3D-printed using a BIO X 3D printer with a pneumatic printhead. The tablets were vacuum-dried and analyzed for mass and content uniformity, and disintegration time. Results: The thermodynamic solubility of Aprepitant in LBF IIIA – MC was determined to be 11.30 mg/g while the solubility of Irbesartan was 4.08 mg/g. The produced tablets contained lower concentrations of the drugs compared to the traditional dosages available on the market. The 3D-printed tablets passed the European Pharmacopeia requirements for mass and content uniformity, and disintegration time. Conclusion: The study showed justified results indicating the emulsion gel can be used to produce tablets loaded with different poorly water-soluble drugs. All characterization studies done on the 3D-printed tablets carried out according to the European Pharmacopeia

This is the first case of a patient taking aprepitant for a post-acute COVID-19 syndrome. This case may encourage researchers to look for the evidence for the efficacy and safety of a neurokinin 1 receptor antagonist in this frequent syndrome

Background: Recently, aprepitant has been recommended in carboplatin-based regimens, but there are limited reports on the efficacy of administering aprepitant, palonosetron, and dexamethasone (DEX) in carboplatincontaining regimens. Moreover, because aprepitant is an expensive drug, confirming its effectiveness is very important from the medical cost perspective. In this study, we examined the efficacy of prophylactically administered aprepitant, palonosetron and DEX, in paclitaxel and carboplatin (TC) combination chemotherapy. Methods: Patients with gynecologic cancer who were treated with paclitaxel (175 mg/m2) and carboplatin (area under the curve, AUC = 5–6) combination chemotherapy were retrospectively evaluated. The complete response (CR) rate, severity of nausea, and incidence of anorexia in the first course were compared between patients who did not receive aprepitant (control group) and those who received (aprepitant group). Results: The 106 patients were divided into two groups, consisting of 52 and 54 the control and aprepitant groups, respectively, and the patient background showed no significant difference between both groups. The CR rate of the overall phase between the control and aprepitant groups was 73.1 vs. 74.1%, that in the acute phase was 98.1 vs. 100%, and in the delayed phase was 75.0 vs. 74.1%, respectively, without any significant difference. The severity of nausea and incidence of anorexia were also not significantly different between both groups. Conclusions: The results of the study suggest that adding aprepitant to palonosetron and DEX does not prevent carboplatin-induced nausea and vomiting in gynecologic cancer patients. Therefore, adding aprepitant to palonosetron does not decrease carboplatin-induced nausea and vomiting in patients with gynecologic cancer.

This is the first case of a patient taking aprepitant for a post-acute COVID-19 syndrome. This case may encourage researchers to look for the evidence for the efficacy and safety of a neurokinin 1 receptor antagonist in this frequent syndrome.

With the rapid increase in the frequency of azole-resistant species, combination therapy appears to be a promising tool to augment the antifungal activity of azole drugs against resistant Candida species. Here, we report the effect of aprepitant, an antiemetic agent, on the antifungal activities of azole drugs against the multidrug-resistant Candida auris. Aprepitant reduced the minimum inhibitory concentration (MIC) of itraconazole in vitro, by up to eight-folds. Additionally, the aprepitant/itraconazole combination interfered significantly with the biofilm-forming ability of C. auris by 95 ± 0.13%, and significantly disrupted mature biofilms by 52 ± 0.83%, relative to the untreated control. In a Caenorhabditis elegans infection model, the aprepitant/itraconazole combination significantly prolonged the survival of infected nematodes by ~90% (five days post-infection) and reduced the fungal burden by ~92% relative to the untreated control. Further, this novel drug combination displayed broad-spectrum synergistic interactions against other medically important Candida species such as C. albicans, C. krusei, C. tropicalis, and C. parapsilosis (ƩFICI ranged from 0.08 to 0.31). Comparative transcriptomic profiling and mechanistic studies indicated aprepitant/itraconazole interferes significantly with metal ion homeostasis and compromises the ROS detoxification ability of C. auris. This study presents aprepitant as a novel, potent, and broad-spectrum azole chemosensitizing agent that warrants further investigation.

Breast cancer (BC) is the most frequently diagnosed cancer and the leading cause of cancer death among females. BC cells not showing HER-2/Neu amplification and not expressing estrogen/ progesterone receptors are named triple-negative BC (TNBC) cells. TNBC represents 10-15% of all BC and is associated with an aggressive clinical course. TNBC patient prognosis, survival and response to current therapies are poor and for this reason, it is crucial to search for new therapeutic targets in TNBC to develop new therapeutic strategies. One of these targets is the neurokinin-1 receptor (NK-1R). It is well known that the substance P (SP)/NK-1R system is involved in cancer progression. TNBC cells overexpress the NK-1R and, after binding to this receptor, SP promotes the proliferation/ migration of TNBC cells. Non-peptide NK-1R antagonists (e.g., aprepitant) are known to exert, via the NK-1R, an antitumor action; TNBC cells die by apoptosis. In this review, we update the data on a promising therapeutic innovation: the use of NK-1R antagonists for the treatment of TNBC patients.

AimTo assess the efficacy of oral NEPA (netupitant-palonosetron 300/0.50 mg) over multiple chemotherapy cycles.MethodsTwo randomized phase III studies evaluated a single dose of oral NEPA given on day 1 in chemotherapy-naive patients receiving anthracycline-cyclophosphamide (AC)-based (Study 1) or highly (HEC)/moderately (MEC) emetogenic chemotherapy (safety Study 2). Oral NEPA was compared with oral palonosetron 0.50 mg (Study 1) or oral aprepitant 125 mg day 1, 80 mg days 2-3/palonosetron 0.50 mg (Study 2; no formal statistical comparisons). Oral dexamethasone was administered in all treatment groups. Complete response (CR; no emesis/no rescue medication), no emesis, and no significant nausea (NSN) rates during acute (0-24 h) and delayed (>24-120 h) phases of chemotherapy cycles 1-4 in each study were evaluated.ResultsIn Study 1, 1450 patients received 5969 chemotherapy cycles; in Study 2, 412 patients received 1961 chemotherapy cycles. In each study, ≥75% of patients completed 4 or more cycles. In Study 1, oral NEPA was superior to palonosetron in preventing chemotherapy-induced nausea and vomiting (CINV) in the acute and delayed phases of cycle 1, with higher rates of CR (all P < 0.05), no emesis (all P < 0.05), and NSN (delayed phase P < 0.05 cycles 1, 2, and 4) reported across 4 cycles. In Study 2, oral NEPA had numerically higher CR and NSN rates in the acute and delayed phases than aprepitant-palonosetron in MEC/HEC patients.ConclusionOral NEPA was highly effective in preventing both acute and delayed CINV over multiple chemotherapy cycles of HEC, AC, and MEC regimens.Clinical trial registration numbersStudy 1, NCT01339260; Study 2, NCT01376297.

Nausea and emesis are two major concerns for patients undergoing chemotherapy for cancer. The 5HT3 receptors antagonist ondansetron is the major factor for preventing and treatment for CINV either alone or often is combination with dexamethasone. Even these treatment options exist, CINV remind as major adverse event for all chemotherapeutic agents. The adverse events have major impact on patients quality of life and compliance with treatment. Aprepitant, a novel neurokinin-1 (NK-1) antagonist has been introduced as a new class of drug to prevent CINV. Many trials and studies reveals that comparison of aprepitant to the standard ondansetron and dexamethasone is superior in protecting against CINV. Here this study evaluate and reveals the use and benefits of aprepitant in the management of CINV.

Hepatoblastoma (HB) is the most common malignant liver tumor that occurs during childhood. The prognosis of children with HB is favorable when a complete surgical resection of the tumor is possible, but for high-risk patients, the prognosis is much worse. New anti-HB strategies must be urgently developed. The undecapeptide substance P (SP) after binding to the neurokinin-1 receptor (NK-1R), regulates cancer cell proliferation, exerts an antiapoptotic effect, induces cell migration for invasion/metastasis, and triggers endothelial cell proliferation for neoangiogenesis. HB samples and cell lines overexpress NK-1R (the truncated form) and SP elicits HB cell proliferation. One of these strategies could be the use of non-peptide NK-1R antagonists. These antagonists exert, in a concentration-dependent manner, an antiproliferative action against HB cells (inhibit cell proliferation and induce the death of HB cells by apoptosis). NK-1R antagonists exerted a dual effect in HB: Decreased both tumor volume and angiogenic activity. Thus, the SP/NK-1R system is an important target in the HB treatment and NK-1R antagonists could act as specific drugs against HB cells. In this review, we update and discuss the use of NK-1R antagonists in the treatment of HB.

El receptor NK-1 es actualmente una diana terapéutica de gran relevancia debido a la amplia implicación de su ligando específico, la sustancia P, en diferentes procesos fisiopatológicos, entre los que cabe destacar el cáncer, la enfermedad de Parkinson, la migraña y la depresión, entre otros. A principios de los años 90 del siglo pasado se descubrió el primer antagonista no peptídico de los receptores NK-1 (CP-96345), lo que ha llevado a impulsar la investigación en este área, con el objetivo de identificar nuevos antagonistas de este receptor que sean selectivos y potentes. Actualmente, uno de los antagonistas de los receptores NK-1 más potentes comercializados es el Aprepitant (Emend®), un derivado morfolínico con tres centros quirales desarrollado por Merck, indicado en la emesis en terapia oncológica. Recientemente se ha demostrado que, bajo ciertas condiciones de concentración, el Aprepitant actúa como anticanceroso de amplio espectro. En este sentido, el Grupo de Investigación donde se ha desarrollado este Trabajo de Fin de Grado (TFG), cuenta con la metodología apropiada para la síntesis diastereoselectiva de nuevos análogos del Aprepitant a partir de materia prima de muy bajo coste, como son los hidratos de carbono. Al mismo tiempo, posee una amplia experiencia en la funcionalización de nanosistemas con moléculas de interés terapéutico. Por tanto, en este trabajo se presenta la síntesis de un sintón clave para la síntesis de nuevos análogos del Aprepitant con actividad antagonista de los receptores NK-1, que posee un grupo azida en su estructura, permitiendo asísu unión posterior a nanosistemas y favoreciendo así, el efecto de multivalencia.

__Background and Objectives:__ The cutaneous fentanyl patch is widely used to treat continuous pain in patients with cancer. Its use is hampered by a high inter- and intrapatient pharmacokinetic variability. Factors that influence this pharmacokinetic variability are largely unclear. The aim of these studies was to test if common patient variables, i) the use of the moderate CYP3A4 inhibitor aprepitant and ii) the localization of the fentanyl patch (upper arm versus thorax) influence systemic exposure to fentanyl in patients with cancer using a transdermal fentanyl patch. __Results:__ The AUC0-6 h of fentanyl was 7.1% (95% CI: -28% to +19%) lower if patients concurrently used aprep

Context: Prediction of the in vivo absorption of poorly soluble drugs may require simultaneous dissolution/permeation experiments. In vivo predictive media have been modified for permeation experiments with Caco-2 cells, but not for excised rat intestinal segments. Objective: The present study aimed at improving the setup of dissolution/permeation experiments with excised rat intestinal segments by assessing suitable donor and receiver media. Methods: The regional compatibility of rat intestine in Ussing chambers with modified Fasted and Fed State Simulated Intestinal Fluids (Fa/FeSSIFmod) as donor media was evaluated via several parameters that reflect the viability of the excised intestinal segments. Receiver media that establish sink conditions were investigated for their foaming potential and toxicity. Dissolution/permeation experiments with the optimized conditions were then tested for two particle sizes of the BCS class II drug aprepitant. Results: Fa/FeSSIFmod were toxic for excised rat ileal sheets but not duodenal sheets, the compatibility with jejunal segments depended on the bile salt concentration. A non-foaming receiver medium containing bovine serum albumin (BSA) and Antifoam B was nontoxic. With these conditions, the permeation of nanosized aprepitant was higher than of the unmilled drug formulations. Discussion: The compatibility of Fa/FeSSIFmod depends on the excised intestinal region. The chosen conditions enable dissolution/permeation experiments with excised rat duodenal segments. The experiments correctly predicted the superior permeation of nanosized over unmilled aprepitant that is observed in vivo. Conclusion: The optimized setup uses FaSSIF(mod) as donor medium, excised rat duodenal sheets as permeation membrane and a receiver medium containing BSA and Antifoam B.

Background. Aprepitant is a P/neurokinin-1 receptor antagonist approved for the prevention of CINV in moderate emetic risk chemotherapy. We explored its effectiveness in patients with leukemia receiving cytarabine-based chemotherapy. Methods. Patients were randomized to ondansetron (OND) 8 mg IV 30 minutes before cytarabine followed by 24 mg IV continuous infusion daily until 6-12 hours after the last dose of chemotherapy alone or with aprepitant (APREP) oral 125 mg 6-12 hrs before chemotherapy and 80 mg daily until 1 day after the last dose of chemotherapy. Results. Forty-nine patients were enrolled in each arm; 42 in OND and 41 in OND + APREP arm were evaluable for efficacy. The ORR with OND + APREP was 80% compared to 67% with OND alone (P = 0.11). On days 6 and 7, higher proportion of patients treated with OND + APREP were free from nausea (74%, 74% versus 68%, 67%; P = 0.27 and 0.18, resp.). Requirement of rescue medications on days 2 and 3 was fewer in OND + APREP arm 7% and 5% compared to 21% and 16% in the OND arm, respectively (P = 0.06 and P = 0.07). Conclusions. There was a trend for overall improvement in emesis with ondansetron plus aprepitant. The potential benefit of this approach with specific chemotherapy combinations remains to be determined.

Introduction Prevention of chemotherapy-induced nausea and vomiting (CINV) remains an important goal for patients receiving cytotoxic treatment. The objective of this study was to assess, from the Italian National Health Service payer perspective, the costs of an antiemetic regimen using aprepitant, a selective neurokinin-1 receptor antagonist, for patients receiving highly emetogenic chemotherapy. Methods A decision-analytic model was developed to compare an aprepitant regimen (aprepitant, ondansetron, and dexamethasone) with a standard antiemetic regimen (ondansetron and dexamethasone) for expected costs after highly emetogenic chemotherapy. The model was populated with clinical results from patients treated with high-dose cisplatin in a randomized trial of CINV prevention therapy. Only direct medical costs (pharmacological treatment and emesis) – Euro 2014 – were considered. Sensitivity and threshold analyses on key clinical and economic parameters were performed. Results The aprepitant regimen showed the lower expected treatment cost (aprepitant regimen: €109.01; standard antiemetic regimen: €110.44). The acquisition cost of aprepitant regimen (aprepitant regimen: €85.29; standard antiemetic regimen: €74.24) was offset by reduced health care resource utilization costs for CINV (aprepitant regimen: €23.72; standard antiemetic regimen: €36.20). Sensitivity and threshold analyses confirmed the base case results. Conclusions Results of this cost-consequence analysis suggest that, from the Italian National Health Service payer perspective, the aprepitant regimen is a cost-saving strategy compared with an antiemetic regimen without aprepitant in the prevention of highly emetogenic chemotherapy-induced nausea and vomiting.

原著, Background: Chemotherapy-induced nausea and vomiting (CINV) usually resolves within 5 days of chemotherapy initiation. However, some patients have CINV at 6 days or later after chemotherapy initiation (late CINV). We evaluated the incidence of late CINV and the effectiveness of aprepitant plus palonosetron in preventing late CINV. Methods: We retrospectively reviewed the records of 102 patients with esophageal or gastric cancer to determine CINV incidence on days 1 through 21 after initiation of cisplatin treatment. Sixty-six patients received a first-generation 5-hydroxytryptamine (serotonin) type 3 receptor antagonist, and 36 received aprepitant plus palonosetron. In addition, we compared the effectiveness of antiemetic regimens before and after administering aprepitant and palonosetron. CINV was defined as presence of grade 1 or higher vomiting or grade 2 or higher nausea. Results: In the aprepitant plus palonosetron group, the highest incidence of CINV (42%) was seen at 7 days after initiation of cisplatin treatment. CINV incidence started to gradually decrease at 8 days after cisplatin initiation. There was no significant intergroup difference in the incidence of late CINV. Conclusions: Late CINV may develop in patients receiving cisplatin for treatment of esophageal or gastric cancer. Our findings suggest that the widely used prophylaxis for delayed CINV resulting from highly emetogenic chemotherapy is not satisfactorily effective against late CINV. 背景と目的:抗がん剤により引き起こされる嘔気・嘔吐(chemotherapy-induced nausea and vomiting:CINV)は,投与後5日以内に消失すると考えられている.しかし,6日目以降も嘔気を訴える「超遅発性CINV」の患者も散見される.超遅発性CINVの発現頻度と,アプレピタント+パロノセトロンの制吐効果を調査した.対象および方法:食道癌または胃癌の患者102名を対象に,シスプラチン投与後21日間のCINV発現頻度を後ろ向きに調査した.アプレピタント+パロノセトロンの採用前後での制吐療法の効果も比較した.結果:アプレピタント+パロノセトロン群では,シスプラチン投与後7日目にCINV発現頻度が最高値(42%)となった.超遅発性期では,2群間の制吐効果に有意差はなかった.結論:シスプラチン投与を受ける食道癌または胃癌患者において,超遅発性CINVが存在することが示された.広く使われている制吐療法が,超遅発性CINVに対しては効果が十分ではないことが示唆された.

To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma’s compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.

Background: In the late 1990s, several professional organizations convened antiemetic guideline groups and published the findings of these expert panels. Each of these documents was based on analyses of the available published trials and provided nearly similar recommendations. Nonetheless, small differences in emetic risk categories and treatment recommendations led to confusion in antiemetics selection. With the emergence of new findings and agents since the guidelines were initially published, many of the oncology professional societies have updated the antiemetic guidelines. Materials and methods: A literature review up to March 2004 was carried out using MEDLINE with evaluation of the evidence by an expert panel composed of 23 oncology professionals in clinical medicine, medical oncology, radiation oncology, oncology nursing, statistics, pharmacy, medical policy and decision making, and pharmacology. The experts represented nine oncology professional societies and came from 11 different countries on four continents. Results: Recommendations on antiemetic regimens to prevent emesis induced by high, moderate, low and minimal risk chemotherapy were suggested as well as management of anticipatory emesis. Furthermore, recommendations for refractory emesis, emesis induced by high-dose chemotherapy and radiotherapy and for antiemetics in children receiving chemotherapy were elaborated. Conclusions: Recommendations about antiemetic prophylaxis in patients receiving treatment with chemo- and radiotherapy have been updated by representatives of nine oncological organizations. © 2005 European Society for Medical Oncology.

This paper uses an evidence-based approach whenever possible to formulate recommendations, emphasizing the results of controlled trials concerning the best use of antiemetic agents. We address issues of dose, schedule, and route of administration of five selective 5-HT3 antagonists. We conclude that for each of these five drugs, there is a plateau in therapeutic efficacy above which further dose escalation does not improve outcome. Furthermore, for all classes of antiemetic agents, a single dose is as effective as multiple doses or a continuous infusion. The oral route is as efficacious as the intravenous route of administration, even with chemotherapy of high emetic risk. Selective antagonists of the type 3 serotonin receptor (5-HT3) in combination with dexamethasone and aprepitant are the standard of care for the prevention of emesis following chemotherapy of high emetic risk.