-
Medicine Nov 2023Most cancer patients suffer from the pain of chemotherapy-induced nausea and vomiting (CINV). This meta-analysis was performed to evaluate the efficacy and safety of a... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Most cancer patients suffer from the pain of chemotherapy-induced nausea and vomiting (CINV). This meta-analysis was performed to evaluate the efficacy and safety of a regimen consisting of aprepitant, dexamethasone, and 5-HT3 receptor antagonists in the prevention and treatment of CINV.
METHODS
A systematic literature search was conducted across multiple databases, including PubMed, EMbase, Cochrane Library, MEDLINE, CENTRAL, HEED, CNKI, Wanfang, and VIP, to identify randomized controlled trials (RCTs) investigating the use of triple therapy (aprepitant, 5-HT3 receptor antagonist, and dexamethasone) to prevent and treat CINV. Meta-analysis was performed using RevMan 5.4 and Stata17 software, employing either a fixed-effect or random-effect model based on statistical heterogeneity.
RESULTS
A meta-analysis of 23 randomized controlled trials (RCTs) involving 7956 patients was conducted. Efficacy: Results showed significantly improved complete responses (CRs) for CINV in the test group versus the control group in the overall, acute, and delayed phases. Furthermore, in the test group, substantial alleviation of nausea symptoms was observed in the delayed and overall phases but not in the acute phase. Safety: There was no statistically significant difference in the incidence of febrile neutropenia, diarrhea, anorexia, and headache between the 2 groups. The incidence of fatigue and hiccups in the test group was higher than that in the control group; however, the incidence of constipation was significantly lower.
CONCLUSIONS
Aprepitant-containing triple therapy is highly effective in the prevention and treatment of CINV, with reliable medication safety.
Topics: Humans; Aprepitant; Antiemetics; Receptors, Serotonin, 5-HT3; Morpholines; Antineoplastic Agents; Vomiting; Nausea; Dexamethasone
PubMed: 38013306
DOI: 10.1097/MD.0000000000035952 -
Expert Opinion on Pharmacotherapy 2023Chemotherapy-induced nausea and vomiting (CINV) is an ongoing problem. While effectiveness of triplet antiemetic regimens in the delayed CINV phase (24-120 hours after... (Observational Study)
Observational Study
BACKGROUND
Chemotherapy-induced nausea and vomiting (CINV) is an ongoing problem. While effectiveness of triplet antiemetic regimens in the delayed CINV phase (24-120 hours after administration of chemotherapy) has been studied, their effectiveness in the long-delayed phase (120-168 hours post-administration) is unknown. We compared the efficacy of 3- and 5-day courses of a triplet antiemetic prophylaxis containing aprepitant (APR) in controlling long-delayed CINV after cisplatin (CDDP)-based chemotherapy.
RESEARCH DESIGN AND METHODS
We obtained patient-level data from a nationwide, multicenter, prospective observational study in Japan. The incidence and timing of CINV after 3- and 5-day APR-containing regimens were compared using inverse probability treatment weighting.
RESULTS
The analysis included 380 patients. The incidence rates of long-delayed nausea and vomiting were significantly reduced for the 5-day compared with the 3-day regimen (29.1% vs. 22.2%, = 0.0042; 6.7% vs. 0%, < 0.0001, respectively). Among those without CINV, vomiting was not reported after day 2 in the 5-day APR group but increased after day 4 in the 3-day APR group.
CONCLUSION
A 5-day regimen triplet antiemetic prophylaxis with APR decreased long-delayed vomiting compared with a 3-day regimen in patients receiving CDDP-based chemotherapy. However, the 5-day regimen showed no advantage over the 3-day regimen against long-delayed nausea.
Topics: Humans; Antiemetics; Antineoplastic Agents; Aprepitant; Cisplatin; Nausea; Vomiting
PubMed: 38009903
DOI: 10.1080/14656566.2023.2288288 -
Journal of Cutaneous Medicine and... Nov 2023Prurigo nodularis (PN) is a debilitating inflammatory skin disease characterized by red to violaceous pruritic lesions. The goal of therapy is to break the scratch-itch... (Review)
Review
IMPORTANCE
Prurigo nodularis (PN) is a debilitating inflammatory skin disease characterized by red to violaceous pruritic lesions. The goal of therapy is to break the scratch-itch cycle. Treatment varies and often requires a multimodal approach to target both immune and neural mediated aspects of disease.
OBJECTIVES
To review the efficacy of systemic treatment used to treat PN.
EVIDENCE REVIEW
A systematic search of keywords and Medical Subject Headings was performed in Ovid MEDLINE, Embase, Scopus, and ClinicalTrials.gov. The first 200 results of an abbreviated search in Google Scholar were also included. PRISMA guidelines were followed and the review was registered on PROSPERO (CRD42023412012). GRADE criteria were used to assess articles for quality of evidence.
FINDINGS
The search resulted in 1153 articles; 382 were duplicates, 643 were irrelevant, 19 were not retrieved, 21 were abstract only, and 88 are included in this review. There were 24 studies on dupilumab, 16 on thalidomide, 8 on cyclosporin, 7 on methotrexate, 3 each on lenalidomide and aprepitant, 2 each on alitretinoin, apremilast, baricitinib, gabapentin, intravenous (IV) immunoglobulins, pregabalin, tofacitinib, and 1 each on amitriptyline, azathioprine, butorphanol, isoquercitin, IV dexamethasone-cyclophosphamide/ oral cyclophosphamide, ketotifen, metronidazole, montelukast, nalbuphine, nemolizumab, serolopitant, tacrolimus, and herose derma zima capsule.
CONCLUSIONS AND RELEVANCE
Dupilumab reduces pruritus and appearance of lesions and is associated with the fewest number of side effects. Thalidomide and pregabalin are also effective, but their long-term use is limited by muscle and nerve pain. Janus Kinase inhibitors may be beneficial, but large population studies are lacking.
Topics: Humans; Thalidomide; Prurigo; Pregabalin; Cyclosporine; Pruritus; Cyclophosphamide
PubMed: 37987710
DOI: 10.1177/12034754231211797 -
Journal of Pain & Palliative Care... Mar 2024Intractable nausea can occur in numerous settings. We report on a 49-year-old woman with a past medical history of cystic fibrosis (CF) with chronic hypoxia, chronic...
Intractable nausea can occur in numerous settings. We report on a 49-year-old woman with a past medical history of cystic fibrosis (CF) with chronic hypoxia, chronic nausea, complex infection history and frequent hospitalizations who was admitted to an academic medical center with a CF exacerbation. Her chronic nausea worsened with the use of antimicrobials, and she was unable to tolerate dopamine or serotonin antagonist antiemetics. Nausea persisted despite the use of benzodiazepines and antihistamines. She was given a one-time dose of fosaprepitant 150 mg intravenously (IV) with marked improvement of her nausea. During subsequent exacerbations, she again developed severe nausea which continued to respond well to a one-time dose of fosaprepitant 150 mg IV. Fosaprepitant is a substance P/neurokinin-1 (NK1) receptor antagonist that is FDA-approved for the prevention of chemotherapy-induced nausea and vomiting and has been used to prevent post-operative nausea and vomiting. Its use in other contexts has not been well established. This case suggests a role for fosaprepitant in the management of nausea outside the context of chemotherapy or general anesthesia.
Topics: Female; Humans; Middle Aged; Morpholines; Anti-Infective Agents; Postoperative Nausea and Vomiting; Academic Medical Centers
PubMed: 37983131
DOI: 10.1080/15360288.2023.2282465 -
Cell & Bioscience Nov 2023Tachykinins and their cognate receptors, neurokinin receptors (NKs) including NK1, NK2, and NK3 play vital roles in regulating various physiological processes including...
BACKGROUND
Tachykinins and their cognate receptors, neurokinin receptors (NKs) including NK1, NK2, and NK3 play vital roles in regulating various physiological processes including neurotransmission, nociception, inflammation, smooth muscle contractility, and stimulation of endocrine and exocrine gland secretion. Their abnormal expression has been reported to be associated with neurological disorders, inflammation, and cancer. Even though NKs are expressed in the same cells with their expression being inversely correlated in some conditions, there is no direct evidence to prove their interaction. Understanding the functional crosstalk between NKs in mediated downstream signaling and cellular responses may elucidate the roles of each receptor in pathophysiology.
RESULTS
In this study, we showed that NKs were co-expressed in some cells. However, different from NK3, which only forms homodimerization, we demonstrated a direct interaction between NK1 and NK2 at the protein level using co-immunoprecipitation and NanoBiT-based protein interaction analysis. Through heterodimerization, NK2 downregulated substance P-stimulated NK1 signals, such as intracellular Ca mobilization and ERK phosphorylation, by enhancing β-arrestin recruitment, even at the ligand concentration that could not activate NK2 itself or in the presence of NK1 specific antagonist, aprepitant. In A549 cells with receptors deleted and reconstituted, NK2 exerted a negative effect on substance P/NK1-mediated cell migration.
CONCLUSION
Our study has provided the first direct evidence of an interaction between NK1 and NK2, which highlights the functional relevance of their heterodimerization in cellular responses. Our findings demonstrated that through dimerization, NK2 exerts negative effects on downstream signaling and cellular response mediated by NK1. Moreover, this study has significant implications for understanding the complexity of GPCR dimerization and its effect on downstream signaling and cellular responses. Given the important roles of tachykinins and NKs in pathophysiology, these insights may provide clues for developing NKs-targeting drugs.
PubMed: 37968728
DOI: 10.1186/s13578-023-01165-6 -
International Journal of Molecular... Nov 2023The substance P (SP)/neurokinin-1 receptor (NK-1R) system is involved in cancer progression. NK-1R, activated by SP, promotes tumor cell proliferation and migration,... (Review)
Review
The substance P (SP)/neurokinin-1 receptor (NK-1R) system is involved in cancer progression. NK-1R, activated by SP, promotes tumor cell proliferation and migration, angiogenesis, the Warburg effect, and the prevention of apoptosis. Tumor cells overexpress NK-1R, which influences their viability. A typical specific anticancer strategy using NK-1R antagonists, irrespective of the tumor type, is possible because these antagonists block all the effects mentioned above mediated by SP on cancer cells. This review will update the information regarding using NK-1R antagonists, particularly Aprepitant, as an anticancer drug. Aprepitant shows a broad-spectrum anticancer effect against many tumor types. Aprepitant alone or in combination therapy with radiotherapy or chemotherapy could reduce the sequelae and increase the cure rate and quality of life of patients with cancer. Current data open the door to new cancer research aimed at antitumor therapeutic strategies using Aprepitant. To achieve this goal, reprofiling the antiemetic Aprepitant as an anticancer drug is urgently needed.
Topics: Humans; Aprepitant; Neurokinin-1 Receptor Antagonists; Drug Repositioning; Quality of Life; Antineoplastic Agents; Receptors, Neurokinin-1; Substance P; Neoplasms
PubMed: 37958914
DOI: 10.3390/ijms242115936 -
BMC Medical Genomics Nov 2023We aim to investigate the correlation between gene polymorphisms and cisplatin chemotherapy-induced nausea and vomiting (CINV), which was prevented by olanzapine or... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
We aim to investigate the correlation between gene polymorphisms and cisplatin chemotherapy-induced nausea and vomiting (CINV), which was prevented by olanzapine or aprepitant triple antiemetic regimen.
METHODS
Before chemotherapy, the blood samples of 89 malignant tumor patients who received multi-day chemotherapy with cisplatin were collected for sequencing and typing. As there were duplicate patients enrolled in different chemotherapy cycles, there were a total of 190 cases. The patients were divided into two groups randomly, who received the triple antiemetic regimen of olanzapine or aprepitant combined with 5-HT3RA and dexamethasone. The main evaluation indicators were the total protection (TP) rate in the acute phase (0-24 h), the delayed phase (25-120 h) and the overall phase (0-120 h).
RESULTS
Univariate analysis was performed on genetic loci that reached H-W balance with TP. In the olanzapine group, increased TP in the acute phase was associated with HTR3A rs1176719 non-GG (P < 0.05) genotype etc. Increased TP in the delayed phase was associated with HTR3A rs1176719 non-GG (P < 0.05) genotype etc. In the aprepitant group, increased TP in the acute phase was associated with the MTHFR rs1801131 TT (P < 0.05) genotype etc. Increased TP in the delayed phase was associated with HTR3A rs1062613 CC (P < 0.05) genetype ect. Multivariate Logistic regression analysis showed that HTR3B rs7943062GG (P < 0.05) genotype etc. were correlated with increased TP in the delayed phase. MTHFR rs1801131TT genotype was associated with increased TP in the acute phase (P < 0.05) and delayed phase (P < 0.05).
CONCLUSION
This study found that gene polymorphisms, including HTR3B (rs1062613, rs1176719, rs2276303), HTR3B (rs45460698, rs7943062), HTR3C (rs6766410), ERCC1 (rs3212986), ERCC4 (rs744154) and MTHFR(rs1801131), may be independent prognostic factors for CINV.
Topics: Humans; Antiemetics; Antineoplastic Agents; Aprepitant; Cisplatin; Nausea; Olanzapine; Polymorphism, Genetic; Vomiting
PubMed: 37924126
DOI: 10.1186/s12920-023-01719-0 -
Biotechnology and Applied Biochemistry Feb 2024Neurokinin/tachykinin receptors are classified as the G-protein coupled receptor superfamily. The neurokinin 2 receptor (NK2R) is widely expressed in different tissues....
Neurokinin/tachykinin receptors are classified as the G-protein coupled receptor superfamily. The neurokinin 2 receptor (NK2R) is widely expressed in different tissues. NK2R is associated with a range of biological events, such as inflammation, smooth muscle contraction, intestinal motor functions, and asthma. Despite these diverse activities, no approved drugs targeting NK2R have been developed yet. Our study focuses on finding potential inhibitors for NK2R using virtual screening, molecular docking, and ADME (absorption, distribution, metabolism, and excretion) approaches. We used a homology modeling approach and AlphaFold DB to obtain the three-dimensional structure of mouse and human NK2R proteins, respectively. The homology model of NK2R was predicted using MODELLER v10.3 and further refined and validated using the 3Drefine tool and RAMPAGE server, respectively. Molecular docking was performed using a library of 910 structurally similar molecules to four NK1R antagonists: aprepitant, casopitant, fosaprepitant, and rolapitant. Molecular docking revealed six small molecules that displayed high Chemscore fitness scores, and binding energies with desirable ligand-NK2R interactions. The evaluation of the in silico ADME profile, solubility, and permeability of the ligand molecules has revealed that the small molecules are potentially nontoxic and have the chance of exhibiting biological activity after oral administration. Further experimental studies (in vitro and in vivo assays) are required to evaluate the effectiveness of these inhibitors as therapeutic targets.
Topics: Humans; Receptors, Neurokinin-2; Molecular Docking Simulation; Ligands; Molecular Dynamics Simulation; Asthma
PubMed: 37904319
DOI: 10.1002/bab.2533 -
International Journal of Molecular... Oct 2023As things stand in 2023, metastatic osteosarcoma commonly results in death. There has been little treatment progress in recent decades. To redress the poor prognosis of... (Review)
Review
As things stand in 2023, metastatic osteosarcoma commonly results in death. There has been little treatment progress in recent decades. To redress the poor prognosis of metastatic osteosarcoma, the present regimen, OSR9, uses nine already marketed drugs as adjuncts to current treatments. The nine drugs in OSR9 are: (1) the antinausea drug aprepitant, (2) the analgesic drug celecoxib, (3) the anti-malaria drug chloroquine, (4) the antibiotic dapsone, (5) the alcoholism treatment drug disulfiram, (6) the antifungal drug itraconazole, (7) the diabetes treatment drug linagliptin, (8) the hypertension drug propranolol, and (9) the psychiatric drug quetiapine. Although none are traditionally used to treat cancer, all nine have attributes that have been shown to inhibit growth-promoting physiological systems active in osteosarcoma. In their general medicinal uses, all nine drugs in OSR9 have low side-effect risks. The current paper reviews the collected data supporting the role of OSR9.
Topics: Humans; Osteosarcoma; Celecoxib; Aprepitant; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms
PubMed: 37895152
DOI: 10.3390/ijms242015474 -
European Journal of Pharmaceutics and... Dec 2023Intestinal drug solubility is a key parameter controlling absorption after the administration of a solid oral dosage form. The ability to measure fed state solubility in...
Intestinal drug solubility is a key parameter controlling absorption after the administration of a solid oral dosage form. The ability to measure fed state solubility in vitro is limited and multiple simulated intestinal fluid recipes have been developed but with no consensus which is optimal. This study has utilised nine bioequivalent simulated fed intestinal media recipes that cover over 90% of the compositional variability of sampled fed human intestinal fluid. The solubility of 24 drugs (Acidic; furosemide, ibuprofen, indomethacin, mefenamic acid, naproxen, phenytoin, piroxicam, valsartan, zafirlukast: Basic; aprepitant, atazanavir, bromocriptine, carvedilol, dipyridamole, posaconazole, tadalafil: Neutral; acyclovir, carbamazepine, felodipine, fenofibrate, griseofulvin, itraconazole, paracetamol, probucol) has been assessed to determine if structured solubility behaviour is present. The measured solubility behaviour can be split into four categories and is consistent with drug physicochemical properties and previous solubility studies. For acidic drugs (category 1) solubility is controlled by media pH and the lowest and highest pH media identify the lowest and highest solubility in 90% of cases. For weakly acidic, basic and neutral drugs (category 2) solubility is controlled by media pH and total amphiphile concentration (TAC), a consistent solubility pattern is evident with variation related to individual drug media component interactions. The lowest and highest pH × TAC media identify the lowest and highest solubility in 70% and 90% of cases respectively. Four drugs, which are non-ionised in the media systems (category 3), have been identified with a very narrow solubility range, indicating minimal impact of the simulated media on solubility. Three drugs exhibit solubility behaviour that is not consistent with the remainder (category 4). The results indicate that the use of two bioequivalent fed intestinal media from the original nine will identify in vitro the maximum and minimum solubility values for the majority of drugs and due to the media derivation this is probably applicable in vivo. When combined with a previous fasted study, this introduces interesting possibilities to measure a solubility range in vitro that can provide Quality by Design based decisions to rationalise drug and formulation development. Overall this indicates that the multi-dimensional media system is worthy of further investigation as in vitro tool to assess fed intestinal solubility.
Topics: Humans; Solubility; Hydrogen-Ion Concentration; Intestines; Pharmaceutical Preparations; Indomethacin; Intestinal Absorption
PubMed: 37890541
DOI: 10.1016/j.ejpb.2023.10.017