BACKGROUND: Despite advances in the treatment of cancer, pancreatic ductal adenocarcinoma (PDAC) remains highly lethal due to the lack of effective therapies. Our previous study showed that Luteolin (Lut), a flavonoid, suppressed pancreatocarcinogenesis and reduced the expression of dihydropyrimidine dehydrogenase (DPYD), an enzyme that degrades pyrimidines such as 5-fluorouracil (5-FU), in PDACs. In this study, we investigated the role of DPYD and evaluated the therapeutic potential of combining 5-FU with Lut in PDACs.
RESULTS: PDAC cells overexpressing DPYD showed increased proliferation, and invasiveness, adding to the resistance to 5-FU. The xenograft tumors of DPYD-overexpressing PDAC cells also exhibit enhanced growth and invasion compared to the control xenograft tumors. RNA-seq analysis of the DPYD-overexpressing PDAC xenograft tumors revealed an upregulation of genes associated with metallopeptidase activity-MMP9 and MEP1A. Furthermore, the overexpression of MEP1A in PDAC was associated with invasion. Next, we investigated the combined effects of Lut, a DPYD suppressor, and 5-FU on DPYD-overexpressing xenograft tumors and PDAC of Pdx1-Cre; LSL-KrasG12D/+; Trp53flox/flox(KPPC) mice. Neither single administration of 5-FU nor Lut showed significant inhibitory effects; however, the combined administration of 5-FU and Lut exhibited a significant tumor-suppressive effect in both the xenograft tumors and KPPC models.
CONCLUSIONS: We have elucidated that DPYD expression contributes to proliferation, invasiveness, and 5-FU resistance, in PDACs. The combination therapy of Lut and 5-FU holds the potential for enhanced efficacy against PDACs.

The efficacy and safety of combining H1 antihistamines (AHs) for treating urticaria are currently unclear. This scoping review aims to provide a comprehensive overview of the evidence regarding the efficacy and safety of H1 AH combinations in the management of urticaria up to May 2023. The search encompassed databases such as PubMed, Web of Science, the Cochrane Central Register of Controlled Trials, and the China Biological Medicine Database. The inclusion criteria comprised randomised controlled trials (RCTs), non-randomised trials (NRTs), case reports, and case series focusing on urticaria treatment. Initially screening 12,887 studies, this review ultimately selected 109 studies involving 11,435 patients. These studies documented 43 different combination treatments across 11 types of urticaria. In comparison to monotherapy, combination therapy exhibited superior efficacy in 94 studies that reported treatment efficacy. Regarding adverse drug reactions (ADRs), 67 studies disclosed ADR incidences, with combination therapy showing lower ADR rates in 32 studies. Additionally, 7 studies reported similar ADR rates between combination therapy and monotherapy with AHs. Common ADRs included symptoms such as drowsiness, nausea, fatigue, dry mouth, dizziness, and headache, while less frequent side effects encompassed hypotension, otitis media, polyuria, rhinorrhoea, abnormal liver function, and rash. ADR rates ranged from 0% to 21% in the treatment group, and from 0.5% to 75% in the control group. Importantly, patients generally tolerated these ADRs well, with symptoms resolving upon discontinuation of treatment. The study\'s findings suggest that combining AHs leads to enhanced efficacy and reduced safety risks compared to monotherapy in the context of urticaria treatment. These results advocate for considering combination therapy as a viable option in clinical practice, especially for chronic urticaria cases. Nonetheless, caution is advised, and close monitoring for potential ADRs is crucial during treatment.

ELEVATE (Study 410; NCT03288129) is the first prospective, multicenter, open-label, Phase IV study of perampanel as monotherapy or first adjunctive therapy in patients aged ≥ 4 years with focal-onset seizures or generalized tonic-clonic seizures in the United States. The study included Screening, Titration (≤ 13 weeks), Maintenance (39 weeks), and Follow-up (4 weeks) Periods. During Titration, perampanel was initiated at 2 mg/day and up-titrated to 4 mg/day at Week 3. Depending on response and tolerability, optional up-titrations to a maximum of 12 mg/day occurred. The primary endpoint was retention rate; additional endpoints included seizure-freedom rate, 50% responder rate, and incidence of treatment-emergent adverse events (TEAEs). At baseline, 10 (18.5%) patients were assigned to the monotherapy group and 44 (81.5%) patients to the first adjunctive therapy group. However, due to the addition of an anti-seizure medication along with perampanel on the first day of treatment, one patient was excluded from the monotherapy subgroup analyses. The mean perampanel exposure duration was 39.8 weeks and 32 (59.3%) patients completed the study. Retention rate at 12 months (or study completion) was 63.0% (monotherapy, 77.8%; first adjunctive therapy, 59.1%). Seizure-freedom rate during the Maintenance Period was 32.7% (monotherapy, 44.4%; first adjunctive therapy, 29.5%) and the 50% responder rate was 78.7% (monotherapy, 85.7%; first adjunctive therapy, 76.9%). TEAEs and serious TEAEs were reported by 88.9% (n = 48/54) and 7.4% (n = 4/54) of patients, respectively. Overall, the efficacy and safety of perampanel as monotherapy or first adjunctive therapy support the use of perampanel as early-line treatment for epilepsy.

UNASSIGNED: About one-fifth of cannabis users, the most commonly used illicit substance, have cannabis use disorder (CUD). Psychiatric disorders and suicide are more common in these patients, and the disability-adjusted life years were reported to be 0.69 million. Pharmacotherapy for CUD is an unmet public health need, as current evidence-based therapies have limited efficacy.
UNASSIGNED: After explaining the pathophysiology of CUD, the effects of emerging pharmacological interventions in its treatment obtained from randomized controlled trials were reviewed in light of mechanisms of action. Superiority over control of cannabidiol, gabapentin, galantamine, nabilone plus zolpidem, nabiximols, naltrexone, PF-04457845, quetiapine, varenicline, and topiramate were observed through the cannabinoid, glutamatergic, γ-aminobutyric acidergic, serotonergic, noradrenergic, dopaminergic, opioidergic, and cholinergic systems. All medications were reported to be safe and tolerable.
UNASSIGNED: Adding pharmacotherapy to psychotherapy is the optimal treatment for CUD on a case-by-case basis. Drug development to add to psychotherapy is the main path, but time and cost suggest repurposing and repositioning existing drugs. Considering sample size, follow-up, and effect size, further studies using objective tools are necessary. The future of CUD treatment is promising.

UNASSIGNED: This study tested the hypothesis that a neuroprotective combined therapy based on epidermal growth factor (EGF) and growth hormone-releasing hexapeptide (GHRP6) could be safe for acute ischemic stroke patients, admitting up to 30% of serious adverse events (SAE) with proven causality.
UNASSIGNED: A multi-centric, randomized, open-label, controlled, phase I-II clinical trial with parallel groups was conducted (July 2017 to January 2018). Patients aged 18-80 years with a computed tomography-confirmed ischemic stroke and less than 12 h from the onset of symptoms were randomly assigned to the study groups I (75 μg rEGF + 3.5 mg GHRP6 i.v., n=10), II (75 μg rEGF + 5 mg GHRP6 i.v., n=10), or III (standard care control, n=16). Combined therapy was given BID for 7 days. The primary endpoint was safety over 6 months. Secondary endpoints included neurological (NIHSS) and functional [Barthel index and modified Rankin scale (mRS)] outcomes.
UNASSIGNED: The study population had a mean age of 66 ± 11 years, with 21 men (58.3%), a baseline median NIHSS score of 9 (95% CI: 8-11), and a mean time to treatment of 7.3 ± 2.8 h. Analyses were conducted on an intention-to-treat basis. SAEs were reported in 9 of 16 (56.2%) patients in the control group, 3 of 10 (30%) patients in Group I (odds ratio (OR): 0.33; 95% CI: 0.06-1.78), and 2 of 10 (20%) patients in Group II (OR: 0.19; 95% CI: 0.03-1.22); only two events in one patient in Group I were attributed to the intervention treatment. Compliance with the study hypothesis was greater than 0.90 in each group. Patients treated with EGF + GHRP6 had a favorable neurological and functional evolution at both 90 and 180 days, as evidenced by the inferential analysis of NIHSS, Barthel, and mRS and by their moderate to strong effect size. At 6 months, proportion analysis evidenced a higher survival rate for patients treated with the combined therapy. Ancillary analysis including merged treated groups and utility-weighted mRS also showed a benefit of this combined therapy.
UNASSIGNED: EGF + GHRP6 therapy was safe. The functional benefits of treatment in this study supported a Phase III study.
UNASSIGNED: RPCEC00000214 of the Cuban Public Registry of Clinical Trials, Unique identifier: IG/CIGB-845I/IC/1601.

Cocaine disrupts dopamine (DA) and kappa opioid receptor (KOR) system activity, with long-term exposure reducing inhibiton of DA uptake by cocaine and increasing KOR system function. Single treatment therapies have not been successful for cocaine use disorder; therefore, this study focuses on a combination therapy targeting the dopamine transporter (DAT) and KOR. Sprague Dawley rats self-administered 5 days of cocaine (1.5 mg/kg/inf, max 40 inf/day, FR1), followed by 14 days on a progressive ratio (PR) schedule (0.19 mg/kg/infusion). Behavioral effects of individual and combined administration of phenmetrazine and nBNI were then examined using PR. Additionally, ex vivo fast scan cyclic voltammetry was then used to assess alterations in DA and KOR system activity in the nucleus accumbens before and after treatments. Chronic administration of phenmetrazine as well as the combination of phenmetrazine and nBNI-but not nBNI alone-significantly reduced PR breakpoints. In addition, the combination of phenmetrazine and nBNI partially reversed cocaine-induced neurodysregulations of the KOR and DA systems, indicating therapeutic benefits of targeting the DA and KOR systems in tandem. These data highlight the potential benefits of the DAT and KOR as dual-cellular targets to reduce motivation to administer cocaine and reverse cocaine-induced alterations of the DA system.

Given the numerous adverse effects of lung cancer treatment, more research on non-toxic medications is urgently needed. Curcumin (CUR) and berberine (BBR) combat drug resistance by controlling the expression of multidrug resistant pump (MDR1). Fascinatingly, combining these medications increases the effectiveness of preventing lung cancer. Their low solubility and poor stability, however, restrict their therapeutic efficacy. Because of the improved bioavailability and increased encapsulation effectiveness of water-insoluble medicines, surfactant-based nanovesicles have recently received a great deal of attention. The current study sought to elucidate the Combination drug therapy by herbal nanomedicine prevent multidrug resistance protein 1: promote apoptosis in Lung Carcinoma. The impact of several tween (20, 60, and 80) types with varied hydrophobic tails on BBR/CUR-TNV was evaluated. Additionally, the MDR1 activity and apoptosis rate of the BBR/CUR-TNV combination therapy were assessed. The encapsulation effectiveness of TNV was affected by the type of tween. With the TNV made from tween 60, cholesterol, and PEG (47.5: 47.5:5), more encapsulation effectiveness was attained. By combining CUR with BBR, especially when given in TNV, apoptosis increased. Additionally, when CUR and BBR were administered in combination, they significantly reduced the risk of MDR1 development. The current work suggests that the delivery of berberine and curcumin as a combination medication therapy via tween-based nanovesicles may be a potential lung cancer treatment.

UNASSIGNED: Autism spectrum disorder (ASD) is an early-onset disorder with a prevalence of 1% among children and reported disability-adjusted life years of 4.31 million. Irritability is a challenging behavior associated with ASD, for which medication development has lagged. More specifically, pharmacotherapy effectiveness may be limited against high adverse effects (considering side effect profiles and patient medication sensitivity); thus, the possible benefits of pharmacological interventions must be balanced against potential adverse events in each patient.
UNASSIGNED: After reviewing the neuropathophysiology of ASD-associated irritability, the benefits and tolerability of emerging medications in its treatment based on randomized controlled trials were detailed in light of mechanisms and targets of action.
UNASSIGNED: Succeeding risperidone and aripiprazole, monotherapy with memantine may be beneficial. In addition, N-acetylcysteine, galantamine, sulforaphane, celecoxib, palmitoylethanolamide, pentoxifylline, simvastatin, minocycline, amantadine, pregnenolone, prednisolone, riluzole, propentofylline, pioglitazone, and topiramate, all adjunct to risperidone, and clonidine and methylphenidate outperformed placebo. These effects were through glutamatergic, γ-aminobutyric acidergic, inflammatory, oxidative, cholinergic, dopaminergic, and serotonergic systems. All medications were reported to be safe and tolerable. Considering sample size, follow-up, and effect size, further studies are necessary. Along with drug development, repositioning and combining existing drugs supported by the mechanism of action is recommended.

We present the case of a 75-year-old female with simultaneous EGFR-mutated stage IV lung cancer and advanced BRCA2-mutated ovarian cancer, treated with a unique regimen. In this case report, the patient was treated with alternating months of osimertinib and olaparib to control her lung and ovarian cancers, respectively. When both diseases showed progression, the patient underwent a trial of concurrent therapy with both drugs, yet this was discontinued due to patient-reported adverse side effects. Combination targeted drug therapy may be required to treat complex diagnoses such as dual malignancies. However, combination drug therapy consisting of osimertinib and olaparib has not previously been explored. This case report represents the first to demonstrate osimertinib and olaparib combination therapy as a unique treatment regimen for concurrent lung and ovarian cancers. These two drugs can either be given in an alternating way or given together, short-term, with a higher but tolerable toxicity profile.

UNASSIGNED: Fluoroquinolones are one of the commonly used antibiotics for the initial empiric combination treatment. However, there is insufficient evidence to support the use of fluoroquinolones combination therapy for the treatment of hospital-acquired pneumonia (HAP). This study aimed to evaluate the effectiveness of fluoroquinolones as part of the empiric combination therapy for HAP using national health insurance claims data in Korea.
UNASSIGNED: We compared the clinical outcomes of patients with HAP who received fluoroquinolones combination and those treated with cefepime or piperacillin/tazobactam monotherapy. The primary outcome was hospital mortality, and the secondary outcome was readmission caused by pneumonia as the primary cause of hospitalization within 7 days after discharge from index hospitalization. The association between the combination with fluoroquinolones and outcomes was evaluated with logistic regression analysis.
UNASSIGNED: Among the 9,955 patients with HAP administered with cefepime or piperacillin/tazobactam, 4,918 (49%) received fluoroquinolones combination. During hospitalization, 1,059 (11%) patients with HAP died. Compared with the monotherapy group, the fluoroquinolones combination therapy group was associated with a higher mortality risk [adjusted odds ratio (OR), 1.30; 95% confidence interval (CI): 1.02-1.65]. After adjusting for potential confounding factors, the association remained significant in the non-high-risk HAP group (adjusted OR, 1.30; 95% CI: 1.02-1.66). Meanwhile, the mortality risk was similar between the fluoroquinolones combination therapy group and the monotherapy group of patients with high-risk HAP (adjusted OR, 0.99; 95% CI: 0.35-1.16). Among the patients alive and discharged (n=8,896), 152 (1.7%) were readmitted within 7 days after discharge. The fluoroquinolones combination therapy group was more likely to be readmitted because of pneumonia than the monotherapy group in patients with high-risk HAP (adjusted OR, 1.60; 95% CI: 1.04-2.47).
UNASSIGNED: Fluoroquinolones combined with β-lactams was prescribed in nearly half of patients with low-risk HAP, and it was associated with a higher mortality risk in real-world practice. However, it was not associated with hospital mortality even in patients with high-risk HAP.