TABLE 5.

Clinical trials and clinical applications of experimental approaches to increase ABCB1 expression.

Experimental approach	Clinical trials and applications
β-catenin signalinga	Osteoporosis (Wu et al., 2023), mood disorders (Bonnet et al., 2021)
Colupulone analogs	Larvicidal agents (Makri et al., 2022)
Exosomesb	AD (NCT04388982), COVID19 (Mitrani et al., 2021); craniofacial neuralgia (NCT04202783), depression (NCT04202770), cutaneous wound healing (NCT02565264), multiple organ dysfunction after surgical repair of acute aortic dissection (NCT04356300), dry eye in chronic host vs. graft disease (NCT04213248), type 1 diabetes (NCT02138331), metastatic pancreatic cancer (NCT03608631), diagnostic and prognostic biomarker analysis (Liu et al., 2018; Qin et al., 2020; Chang et al., 2021)
Ketone bodiesc	AD (NCT04701957), heart failure (NCT05768100), type 2 diabetes (NCT03657537, NCT04854330, NCT05155410), multiple sclerosis (NCT03740295), cardiogenic shock (NCT04642768), alcohol use disorder (NCT04616781), McArdle disease (NCT03945370), Parkinson’s disease and Lewy body dementia (NCT05778695), amyotrophic lateral sclerosis (ALS) (NCT02716662, NCT04820478), acute heart failure (NCT04442555, NCT05348460), eating disorders (NCT05507008), obesity (NCT03729934), polycystic ovary syndrome (NCT04163120), upper respiratory tract infections (NCT04019730), COVID-19 (NCT04573764), concussion (NCT04079907), aging (NCT06068803)
NMDA receptor agonists	Multidrug-resistant tuberculosis (Deshpande et al., 2018), urinary tract infections (Kugathasan et al., 2014), schizophrenia (Lakhan et al., 2013; NCT01474395, NCT00491569), nicotine dependency (Santa Ana et al., 2009), alcohol dependency (Watson et al., 2011), cocaine dependency (Price et al., 2009), major depression (NCT03062150), panic disorder (NCT00131339), post-traumatic stress disorder (NCT00215878, NCT00371176), depression (NCT01684163, NCT04721249), agoraphobia (NCT01928823), Parkinson’s disease (NCT00215904), obsessive-compulsive disorder (NCT02656342)
Nocodazoled	No human applications found
Oleocanthal/extra virgin olive oile	MCI (NCT03362996, NCT03824197), type 2 diabetes (NCT04419948), chronic lymphocytic leukemia (NCT04215367), neurofibromatosis (NCT05363267), multiple sclerosis (NCT04787497), metabolic syndrome (NCT05282316); also see Table 3
Pirenzepine	Gastric and duodenal ulcers (Ishimori and Yamagata, 1982; Carmine and Brogden, 1985), reflux esophagitis (Niemelä et al., 1986), myopia (Tan et al., 2005; Siatkowski et al., 2008), hypersalivation (Bai et al., 2001), peripheral neuropathy (NCT04005287, NCT05488873, NCT04786340), HIV-associated polyneuropathy (NCT05005078)
Prevention of ABCB1 ubiquitination	No human applications found
PXR agonistsf: Rifampicin	AD (Molloy et al., 2013), primary biliary cirrhosis (Hoensch et al., 1985), drug-resistant Acinetobacter Baumannii (NCT03622918), tuberculosis (NCT01311505. NCT01986543), multiple system atrophy (NCT01287221), rhinoscleroma (NCT03326050), Staphylococcal infections (NCT02782078), non-small cell lung cancer (NCT05631678), endometriosis (NCT02975440), Parkinson’s disease (NCT04070495), osteoarticular infection (NCT02599493), HIV (NCT02832778), diabetes mellitus (NCT03063580), pulmonary arterial hypertension (NCT01251835), neoplasms (NCT01322438), antibiotic-associated diarrhea (NCT00182429), osteoarticular prosthetic infection (NCT00906048)
PXR agonists: St. John’s wort	Acne (NCT05073211), osteoarthritis (NCT05663996), nicotine dependence (NCT00405912), depression (NCT05477472, NCT00861978, NCT00066859, NCT04315597), phobic disorders (NCT00035412), obsessive-compulsive disorder (NCT00035438), Reynaud’s syndrome (NCT00351117), irritable bowel syndrome (NCT00587860), contraception (NCT00026013), anxiety disorders (NCT00118833, NCT00451516), perineal injury (NCT05164926), hot flashes (NCT00110136), attention deficit hyperactivity disorder (NCT00782080), peritoneal carcinomatosis (NCT02840331)
TGF-β1g	Residual burn-related wounds (NCT04235296)
Vitamin D receptor activation	Chronic kidney disease (Cozzolino and Malindretos, 2010; Yang et al., 2018), anemia associated with inflammation (NCT02876211), type 2 diabetes (NCT01393808, NCT00421733)

^aβ-catenin signaling for treatment of osteoporosis includes administration of Romozumab, a monoclonal antibody targeting sclerostin, an inhibitor of Wnt/β-catenin signaling (Wu et al., 2023). The effects of other anti-sclerostin monoclonal antibodies are being investigated in postmenopausal patients with decreased bone mass density (Bonnet et al., 2021). GSK-3β inhibitors are the most widely used Wnt/β-catenin activators. The GSK-3β inhibitor lithium chloride is used to treat mood disorders including bipolar disorder (Machado-Vieira et al., 2009) and major depression (Bauer et al., 2014).

^bClinical trials involving exosomes were reviewed by Aheget et al. (2020). A pilot study (NCT04388982) was performed to investigate safety and efficacy of treating AD patients (n = 9, divided into three treatment arms) with intranasally administered allogenic adipose mesenchymal stromal cell exosomes. Results were published by Xie et al. (2023). Cognitive functioning, measured by ADAS-Alzheimer’s Disease Assessment Scale-Cognitive section (ADAS-cog) and Montreal Cognitive Assessment (MoCA), was suggested to have improved in the medium-dose treatment group. A preparation derived from exosomes and extracellular vesicles of human amniotic fluid was used to treat three patients with severe COVID19. Improved clinical status, including respiratory function, was reported (Mitrani et al., 2021).

^cA search of “ketone bodies” on ClinicalTrials.gov yielded 616 hits so only a partial list is shown. Notably, NCT04701957, “The Ketogenic Diet for Alzheimer’s Disease (CETOMA),” is evaluating the effects of a ketogenic diet on patients with early-stage AD. Patients will be followed for one year and changes in brain metabolism, cognition, quality of life, and activities of daily living functioning will be determined. The study is scheduled to be completed in March 2025.

^dNocodazole is an experimental anti-mitotic and anti-neoplastic drug which has been used to achieve cell cycle synchronization in vitro (Zieve et al., 1980; Blajeski et al., 2002; Khattab and Al-Karmalawy, 2021).

^eOleocanthal is a nonsteroidal anti-inflammatory agent found in extra virgin olive oil (Smith et al., 2005). Two clinical trials with extra virgin olive oil have been performed in subjects with MCI (NCT03362996, NCT03824197). Tzekaki et al. (2019) treated MCI patients with extra virgin olive oil for one year and compared serum fibrinolytic factors PAI-1 and a2-antiplasmin, as well as Aβ40, Aβ42, tau, and the oxidative stress marker malondialdehyde between these patients and non-treated MCI patients, AD patients, and healthy subjects. Post-treatment levels of both fibrinolytic factors and of tau and malondialdehyde decreased in the treatment group relative to the other groups, and the Aβ42/Aβ40 ratio in the treatment group was similar to that in the healthy subjects. In a later trial Kaddoumi et al. (2022) examined the effects of treating MCI patients with extra virgin olive oil or refined olive oil for six months. Treatment with extra virgin olive oil improved Clinical Dementia Rating scores and behavioral scores, while lowering BBB permeability and serum Aβ42/Aβ40 and p-tau/total tau ratios. Some of these effects were also found with refined olive oil. Other disorders in which the effects of oleocanthal have been investigated in clinical trials include type 2 diabetes (NCT04419948), chronic lymphocytic leukemia (NCT04215367), and neurofibromatosis (NCT05363267). Trials to examine the effects of extra virgin olive oil in multiple sclerosis (NCT04787497) and metabolic syndrome (NCT05282316) are recruiting.

^fPXR agonists include Rifampicin and St. John’s wort. A partial list is shown for Rifampicin trials registered on ClinicalTrials.gov; the search result generated 369 hits. A search of St. John’s wort on ClinicalTrials.gov generated 37 hits. A one-year clinical trial in which patients with mild-to-moderate AD were treated with Rifampicin found no evidence for benefits in cognition or function (Molloy et al., 2013).

^gClinical trial NCT04235296, “Mesenchymal Stem Cell Conditioned Medium-derived Pleiotropic Factor in Treating Residual Burn Wound,” examined the effects of conditioned medium from mesenchymal stem cells on burn-related residual wounds. Mesenchymal stem cell conditioned medium contains TGF-β (Noh et al., 2016) and many other biological effectors (Ivanisova et al., 2023). Clinical trials are identified by ClinicalTrials.gov identifier (NCT number). ABCB1, ATP binding cassette subfamily B member 1; AD, Alzheimer’s disease; HIV, human immunodeficiency virus; MCI, mild cognitive impairment; NMDA, N-methyl-D-aspartate; PXR, pregnane X-receptor; TGF-β1, transforming growth factor beta 1.