Explore the vast range of titles available.

Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their pharmacology, interactions, safety profiles, and how pharmacology is being manipulated to misuse these common medications, with the aim to expand on the subject outlined by the authors focusing on abuse prevention and prevalence rates. The reviewed literature was identified in several online databases through searches conducted with phrases created by combining the international non-proprietary names of the drugs with terms related to drug misuse. The results show that OTC opioids are misused as an alternative for illicit narcotics, or prescription-only opioids. The potency of codeine and loperamide is strongly dependent on the individual enzymatic activity of CYP2D6 and CYP3A4, as well as P-glycoprotein function. Codeine can also be utilized as a substrate for clandestine syntheses of more potent drugs of abuse, namely desomorphine (“Krokodil”), and morphine. The dangerous methods used to prepare these substances can result in poisoning from toxic chemicals and impurities originating from the synthesis procedure. OTC opioids are generally safe when consumed in accordance with medical guidelines. However, the intake of supratherapeutic amounts of these substances may reveal surprising traits of common medications.

5-Fluorouracil (5-FU), a cornerstone chemotherapeutic agent used for colorectal cancer therapy, has long been established as a first-line treatment. However, clinical evidence has suggested that a substantial proportion of patients develop resistance to 5-FU, notably compromising its therapeutic efficacy. The present study aimed to investigate whether loperamide (LOP) can enhance the sensitivity of colorectal cancer cells to 5-FU and to elucidate the potential underlying molecular mechanism. First, the IC50 values of LOP were determined in the 5-FU-sensitive HCT8 and 5-FU-resistant HCT8R colorectal cancer cell lines, using the Cell Counting Kit-8 assay to evaluate LOP-induced alterations in 5-FU sensitivity. The effects of LOP on cell proliferation were subsequently analyzed using 5-ethynyl-2′-deoxyuridine and colony formation assays. Cell migration was assessed through wound healing and Transwell migration assays, and apoptosis was evaluated using flow cytometric analysis with PI/Annexin V staining. Western blot analysis was performed to measure the expression levels of the autophagy-associated proteins microtubule-associated protein 1 light chain 3 (LC3) and Beclin, and autophagosome formation following LOP treatment was visualized. The role of autophagy in LOP-mediated reversal of drug resistance was further examined using autophagy inhibitors. Finally, xenograft experiments in nude mice were performed to investigate the in vivo effects of LOP on the 5-FU sensitivity of HCT8R cells. Compared with in the parental cell line, HCT8R cells exhibited enhanced migratory capabilities and resistance to 5-FU. Notably, LOP was revealed to potentiate the sensitivity of HCT8R cells to 5-FU, as evidenced by reduced rates of cell proliferation, suppressed migratory ability, increased levels of apoptosis, and decreased tumor weight and volume in subcutaneous xenografts in mice. LOP was also shown to induce upregulation of autophagy marker proteins, leading to the accumulation of autophagosomes within the cells. Blocking autophagy with 3-methyladenine led to a reversal of the inhibitory effect of LOP on HCT8R cell migration. LOP was also shown to enhance the sensitivity of HCT8R cells to 5-FU by activating cellular autophagy, thereby suppressing resistant cell proliferation and migration, promoting apoptosis and reversing drug resistance. Taken together, these findings provide novel insights into the mechanisms underlying 5-FU resistance, thereby highlighting potential therapeutic strategies for colorectal cancer.

Background—Populations at low risk of colonic cancer consume large amounts of fibre and starch and pass acid, bulky stools. One short chain fatty acid (SCFA), butyrate, is the colon’s main energy source and inhibits malignant transformation in vitro. Aim—To test the hypothesis that altering colonic transit rate alters colonic pH and the SCFA content of the stools. Patients—Thirteen healthy adults recruited by advertisement. Methods—Volunteers consumed, in turn, wheat bran, senna and loperamide, each for nine days with a two week washout period between study periods, dietary intake being unchanged. Before, and in the last four days of each intervention, whole gut transit time (WGTT), defaecation frequency, stool form, stool β-glucuronidase activity, stool pH, stool SCFA concentrations and intracolonic pH (using a radiotelemetry capsule for continuous monitoring) were assessed. Results—WGTT decreased, stool output and frequency increased with wheat bran and senna, vice versa with loperamide. The pH was similar in the distal colon and stool. Distal colonic pH fell with wheat bran and senna and tended to increase with loperamide. Faecal SCFA concentrations, including butyrate, increased with senna and fell with loperamide. With wheat bran the changes were non-significant, possibly because of the short duration of the study. Baseline WGTT correlated with faecal SCFA concentration (r=−0.511, p=0.001), with faecal butyrate (r=−0.577, p<0.001) and with distal colonic pH (r=0.359, p=0.029). Conclusion—Bowel transit rate is a determinant of stool SCFA concentration including butyrate and distal colonic pH. This may explain the inter-relations between colonic cancer, dietary fibre intake, stool output, and stool pH.

Background Loss of P-glycoprotein (P-gp) at the blood–brain barrier contributes to amyloid-β (Aβ) brain accumulation in Alzheimer’s disease (AD). Using transgenic human amyloid precursor protein (hAPP)-overexpressing mice (Tg2576), we previously showed that Aβ triggers P-gp loss by activating the ubiquitin–proteasome pathway, which leads to P-gp degradation. Furthermore, we showed that inhibiting the ubiquitin-activating enzyme (E1) prevents P-gp loss and lowers Aβ accumulation in the brain of hAPP mice. Based on these data, we hypothesized that repurposing the FDA-approved proteasome inhibitor, bortezomib (Velcade ® ; BTZ), protects blood–brain barrier P-gp from degradation in hAPP mice in vivo. Methods We treated hAPP mice with the proteasome inhibitor BTZ or a combination of BTZ with the P-gp inhibitor cyclosporin A (CSA) for 2 weeks. Vehicle-treated wild-type (WT) mice were used as a reference for normal P-gp protein expression and transport activity. In addition, we used the opioid receptor agonist loperamide as a P-gp substrate in tail flick assays to indirectly assess P-gp transport activity at the blood–brain barrier in vivo. We also determined P-gp protein expression by Western blotting, measured P-gp transport activity levels in isolated brain capillaries with live cell confocal imaging and assessed Aβ plasma and brain levels with ELISA. Results We found that 2-week BTZ treatment of hAPP mice restored P-gp protein expression and transport activity in brain capillaries to levels found in WT mice. We also observed that hAPP mice displayed significant loperamide-induced central antinociception compared to WT mice indicating impaired P-gp transport activity at the blood–brain barrier of hAPP mice in vivo. Furthermore, BTZ treatment prevented loperamide-induced antinociception suggesting BTZ protected P-gp loss in hAPP mice. Further, BTZ-treated hAPP mice had lower Aβ40 and Aβ42 brain levels compared to vehicle-treated hAPP mice. Conclusions Our data indicate that BTZ protects P-gp from proteasomal degradation in hAPP mice, which helps to reduce Aβ brain levels. Our data suggest that the proteasome system could be exploited for a novel therapeutic strategy in AD, particularly since increasing Aβ transport across the blood–brain barrier may prove an effective treatment for patients.

Background: Despite the enormous efforts made towards combating tuberculosis (TB), the disease remains a major global threat. Hence, new drugs with novel mechanisms against TB are urgently needed. Fatty acid degradation protein D32 (FadD32) has been identified as a promising drug target against TB, the protein is required for the biosynthesis of mycolic acids, hence, essential for the growth and multiplication of the mycobacterium. However, the FadD32 mechanism upon the binding of FDA-approved drugs is not well established. Herein, we applied virtual screening (VS), molecular docking, and molecular dynamic (MD) simulation to identify potential FDA-approved drugs against FadD32. Methodology/Results: VS technique was found promising to identify four FDA-approved drugs (accolate, sorafenib, mefloquine, and loperamide) with higher molecular docking scores, ranging from −8.0 to −10.0 kcal/mol. Post-MD analysis showed that the accolate hit displayed the highest total binding energy of −45.13 kcal/mol. Results also showed that the accolate hit formed more interactions with FadD32 active site residues and all active site residues displayed an increase in total binding contribution. RMSD, RMSF, Rg, and DCCM analysis further supported that the presence of accolate exhibited more structural stability, lower bimolecular flexibility, and more compactness into the FadD32 protein. Conclusions: Our study revealed accolate as the best potential drug against FadD32, hence a prospective anti-TB drug in TB therapy. In addition, we believe that the approach presented in the current study will serve as a cornerstone to identifying new potential inhibitors against a wide range of biological targets.

Autophagy is a lysosome-dependent cellular catabolic mechanism mediating the turnover of intracellular organelles and long-lived proteins. Reduction of autophagy activity has been shown to lead to the accumulation of misfolded proteins in neurons and may be involved in chronic neurodegenerative diseases such as Huntington's disease and Alzheimer's disease. To explore the mechanism of autophagy and identify small molecules that can activate it, we developed a series of high-throughput image-based screens for small-molecule regulators of autophagy. This series of screens allowed us to distinguish compounds that can truly induce autophagic degradation from those that induce the accumulation of autophagosomes as a result of causing cellular damage or blocking downstream lysosomal functions. Our analyses led to the identification of eight compounds that can induce autophagy and promote long-lived protein degradation. Interestingly, seven of eight compounds are FDA-approved drugs for treatment of human diseases. Furthermore, we show that these compounds can reduce the levels of expanded polyglutamine repeats in cultured cells. Our studies suggest the possibility that some of these drugs may be useful for the treatment of Huntington's and other human diseases associated with the accumulation of misfolded proteins.

New approaches for improving tuberculosis (TB) control using adjunct host-directed cellular and repurposed drug therapies are needed. Autophagy plays a crucial role in the response to TB, and a variety of autophagy-inducing drugs that are currently available for various medical conditions may serve as an adjunct treatment in pulmonary TB. Here, we evaluated the potential of loperamide, carbamazepine, valproic acid, verapamil, and rapamycin to enhance the antimicrobial immune response to Mycobacterium tuberculosis (Mtb). Human monocyte-derived macrophages (MDMs) and murine alveolar cells (MACs) were infected with Mtb and treated with loperamide, carbamazepine, valproic acid, verapamil, and rapamycin in vitro. Balb/c mice were intraperitoneally administered loperamide, valproic acid, and verapamil, and MACs were infected in vitro with Mtb. The induction of autophagy, the containment of Mtb within autophagosomes and the intracellular Mtb burden were determined. Autophagy was induced by all of the drugs in human and mouse macrophages, and loperamide significantly increased the colocalization of microtubule-associated protein 1 light chain 3 with Mtb in MDMs. Carbamazepine, loperamide, and valproic acid induced microtubule-associated protein 1 light chain 3 and autophagy related 16- like protein 1 gene expression in MDMs and in MACs. Loperamide also induced a reduction in TNF-α production. Loperamide and verapamil induced autophagy, which was associated with a significant reduction in the intracellular growth of Mtb in MACs and alveolar macrophages. The intraperitoneal administration of loperamide and valproic acid induced autophagy in freshly isolated MACs. The antimycobacterial activity in MACs was higher after loperamide treatment and was associated with the degradation of p62. In conclusion, loperamide shows potential as an adjunctive therapy for the treatment of TB.

Although effects of stress-induced anxiety on the gastrointestinal tract and enteric nervous system (ENS) are well studied, how ENS dysfunction impacts behaviour is not well understood. We investigated whether ENS modulation alters anxiety-related behaviour in rats. We used loperamide, a potent μ-opioid receptor agonist that does not cross the blood–brain barrier, to manipulate ENS function and assess changes in behaviour, gut and brain gene expression, and microbiota profile. Sprague Dawley (male/female) rats were acutely dosed with loperamide (subcutaneous) or control solution, and their behavioural phenotype was examined using open field and elevated plus maze tests. Gene expression in the proximal colon, prefrontal cortex, hippocampus, and amygdala was assessed by RNA-seq and caecal microbiota composition determined by shotgun metagenome sequencing. In female rats, loperamide treatment decreased distance moved and frequency of supported rearing, indicating decreased exploratory behaviour and increased anxiety, which was associated with altered hippocampal gene expression. Loperamide altered proximal colon gene expression and microbiome composition in both male and female rats. Our results demonstrate the importance of the ENS for communication between gut and brain for normo-anxious states in female rats and implicate corticotropin-releasing hormone and gamma-aminobutyric acid gene signalling pathways in the hippocampus. This study also sheds light on sexually dimorphic communication between the gut and the brain. Microbiome and colonic gene expression changes likely reflect localised effects of loperamide related to gut dysmotility. These results suggest possible ENS pharmacological targets to alter gut to brain signalling for modulating mood.

Diarrhea remains a major global health concern, particularly in developing countries. Resistance to conventional antibiotics underscores the need for effective, plant-based alternatives. Croton kinondoensis, a traditional Kenyan remedy for gastrointestinal ailments, has yet to be scientifically validated. This study assessed its antidiarrheal and antimotility effects in vivo mouse models. Leaf extracts were prepared using dichloromethane/methanol (1:1). Phytochemical screening confirmed the presence of flavonoids, tannins, alkaloids and phenolics. Acute toxicity was assessed via OECD guideline 425. Antidiarrheal activity was tested using a castor oil-induced diarrhea model, and gastrointestinal motility was evaluated using the charcoal meal test. Mice were divided into five groups (n = 6): negative control (distilled water), positive control (loperamide 3 mg/kg), and three test groups receiving C. kinondoensis extract at doses of 100, 200, and 400 mg/kg). Statistical significance was determined using ANOVA and Tukey's post hoc test to determine significance (p < 0.05). The extract showed no toxicity at 2000 mg/kg. In the castor oil-induced diarrhea model, the C. kinondoensis extract at 400 mg/kg inhibited diarrhea by 25.57% (p < 0.05), compared to 71.43% inhibition by loperamide (p < 0.001) e. The charcoal meal transit test, 400 mg/kg of the extract reduced intestinal transit by 27.98% (p < 0.01), compared to 33.43% by loperamide (p < 0.001. C. kinondoensis exhibits dose-dependent antidiarrheal and antimotility effects, supporting its traditional use. Although its efficacy was lower than loperamide, the extract demonstrated significant potential as a natural remedy for diarrhea.

Continence problems during treatment with orlistat (a lipase inhibitor) are caused when susceptible patients are exposed to increased volumes of loose, fatty stool. To investigate the dose-response effects of loperamide on continence and anorectal function in subjects susceptible to continence problems on orlistat. Ten obese subjects enterred a randomized controlled, double-blind study of loperamide at placebo, 2, 4, and 6 mg/day in a factorial design. Continence problems during orlistat treatment were self-assessed by patient diary. Anorectal function and continence were assessed by barostat, manometry, and retention testing. Loperamide increased stool consistency with dose (p = 0.07) and this effect reduced continence problems during orlistat treatment (p < 0.05). A bell-shaped dose-response relationship was present with anal sphincter function (p < 0.01) and anorectal sensitivity (p < 0.01). Loperamide has beneficial effects on stool consistency and continence in obese subjects taking orlistat. The effect on stool consistency appeared more important than effects on anorectal function.