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Lancet (London, England) Sep 2023Levonorgestrel, a standard drug for emergency contraception (EC), is not effective if administered post-ovulation. A cyclo-oxygenase inhibitor could contribute... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Levonorgestrel, a standard drug for emergency contraception (EC), is not effective if administered post-ovulation. A cyclo-oxygenase inhibitor could contribute synergistic effects. We investigated whether a single 40 mg oral dose of piroxicam as co-treatment with levonorgestrel improved emergency contraceptive efficacy.
METHODS
This was a randomised double-blind placebo-controlled trial carried out in a major community sexual and reproductive health service in Hong Kong. Women who required levonorgestrel EC within 72 h of unprotected sexual intercourse were recruited and block-randomised in a 1:1 ratio to receive a single supervised dose of levonorgestrel 1·5 mg plus either piroxicam 40 mg or placebo orally. Group assignment was concealed in opaque envelopes and masked to the women, clinicians, and investigators. At follow-up 1-2 weeks after the next expected period, the pregnancy status was noted by history or pregnancy test. The primary efficacy outcome was the proportion of pregnancies prevented out of those expected based on an established model. All women randomised to receive the study drug and who completed the follow-up were analysed. The trial was registered with ClinicalTrials.gov, NCT03614494.
FINDINGS
860 women (430 in each group) were recruited between Aug 20, 2018, and Aug 30, 2022. One (0·2%) of 418 efficacy-eligible women in the piroxicam group were pregnant, compared with seven (1·7%) of 418 in the placebo group (odds ratio 0·20 [95% CI 0·02-0·91]; p=0·036). Levonorgestrel plus piroxicam prevented 94·7% of expected pregnancies compared with 63·4% for levonorgestrel plus placebo. We noted no significant difference between the two groups in the proportion of women with advancement or delay of their next period, or in the adverse event profile.
INTERPRETATION
Oral piroxicam 40 mg co-administered with levonorgestrel improved efficacy of EC in our study. Piroxicam co-administration could be considered clinically where levonorgestrel EC is the option of choice.
FUNDING
None.
Topics: Female; Pregnancy; Humans; Contraception, Postcoital; Piroxicam; Levonorgestrel; Cyclooxygenase Inhibitors; Contraceptives, Postcoital
PubMed: 37597523
DOI: 10.1016/S0140-6736(23)01240-0 -
European Journal of Pharmacology Sep 2023Capsaicin and allyl isothiocyanate (AITC) activate transient receptor potential (TRP) vanilloid-1 (TRPV1) and TRP ankyrin-1 (TRPA1), respectively. TRPV1 and TRPA1...
Capsaicin and allyl isothiocyanate (AITC) activate transient receptor potential (TRP) vanilloid-1 (TRPV1) and TRP ankyrin-1 (TRPA1), respectively. TRPV1 and TRPA1 expression have been identified in the gastrointestinal (GI) tract. GI mucosal functions remain largely undefined for TRPV1 and TRPA1 with side-dependence and regional differences in signalling unclear. Here we investigated TRPV1- and TRPA1-induced vectorial ion transport as changes in short-circuit current (ΔI), in defined segments of mouse colon mucosa (ascending, transverse and descending) under voltage-clamp conditions in Ussing chambers. Drugs were applied basolaterally (bl) or apically (ap). Capsaicin responses were biphasic, with primary secretory and secondary anti-secretory phases, observed with bl application only, which predominated in descending colon. AITC responses were monophasic and secretory, with ΔI dependent on colonic region (ascending vs. descending) and sidedness (bl vs. ap). Aprepitant (neurokinin-1 (NK1) antagonist, bl) and tetrodotoxin (Na channel blocker, bl) significantly inhibited capsaicin primary responses in descending colon, while GW627368 (EP4 receptor antagonist, bl) and piroxicam (cyclooxygenase inhibitor, bl) inhibited AITC responses in ascending and descending colonic mucosae. Antagonism of the calcitonin gene-related peptide (CGRP) receptor had no effect on mucosal TRPV1 signalling, while tetrodotoxin and antagonists of the 5-hydroxytryptamine-3 and 4 receptors, CGRP receptor, and EP1/2/3 receptors had no effect on mucosal TRPA1 signalling. Our data demonstrates the regional-specificity and side-dependence of colonic TRPV1 and TRPA1 signalling, with involvement of submucosal neurons and mediation by epithelial NK1 receptor activation for TRPV1, and endogenous prostaglandins and EP4 receptor activation for TRPA1 mucosal responses.
Topics: Mice; Animals; Transient Receptor Potential Channels; TRPA1 Cation Channel; Capsaicin; Tetrodotoxin; Colon; Mucous Membrane; TRPV Cation Channels
PubMed: 37394028
DOI: 10.1016/j.ejphar.2023.175897 -
CA: a Cancer Journal For Clinicians 2024Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the... (Review)
Review
Pain is one of the most burdensome symptoms in people with cancer, and opioid analgesics are considered the mainstay of cancer pain management. For this review, the authors evaluated the efficacy and toxicities of opioid analgesics compared with placebo, other opioids, nonopioid analgesics, and nonpharmacologic treatments for background cancer pain (continuous and relatively constant pain present at rest), and breakthrough cancer pain (transient exacerbation of pain despite stable and adequately controlled background pain). They found a paucity of placebo-controlled trials for background cancer pain, although tapentadol or codeine may be more efficacious than placebo (moderate-certainty to low-certainty evidence). Nonsteroidal anti-inflammatory drugs including aspirin, piroxicam, diclofenac, ketorolac, and the antidepressant medicine imipramine, may be at least as efficacious as opioids for moderate-to-severe background cancer pain. For breakthrough cancer pain, oral transmucosal, buccal, sublingual, or intranasal fentanyl preparations were identified as more efficacious than placebo but were more commonly associated with toxicities, including constipation and nausea. Despite being recommended worldwide for the treatment of cancer pain, morphine was generally not superior to other opioids, nor did it have a more favorable toxicity profile. The interpretation of study results, however, was complicated by the heterogeneity in the study populations evaluated. Given the limited quality and quantity of research, there is a need to reappraise the clinical utility of opioids in people with cancer pain, particularly those who are not at the end of life, and to further explore the effects of opioids on immune system function and quality of life in these individuals.
Topics: Humans; Analgesics, Opioid; Cancer Pain; Anti-Inflammatory Agents, Non-Steroidal; Nociceptive Pain; Neoplasms; Pain Management
PubMed: 38108561
DOI: 10.3322/caac.21823 -
JBRA Assisted Reproduction Sep 2023Endogenous prostaglandins are involved in hemostasis, renal excretion of electrolytes, and implicated in dysmenorrhea. Piroxicam and Nitroglycerin are common drugs used...
OBJECTIVE
Endogenous prostaglandins are involved in hemostasis, renal excretion of electrolytes, and implicated in dysmenorrhea. Piroxicam and Nitroglycerin are common drugs used in treating dysmenorrhea by inhibiting the cyclooxygenase pathway involved in prostaglandin production. However, studies comparing the effects of these drugs on prostaglandin-modulated hemostasis and renal function are lacking.
METHODS
Fifteen female rats (120-160g) were divided into 3 groups (20 per group), namely Control (distilled water, 0.3 mL), Piroxicam treated (3mg/kg) and Nitroglycerin treated (1 mg/kg). Di-estrous phase was confirmed in animals in each group using the Pipette smear method. Treatment was administered for 4 days covering the estrous cycle. Bleeding and clotting time were assessed and blood concentrations of sodium, potassium, urea and platelet counts were evaluated in all phases. Data were analyzed using one-way ANOVA and Newman-Keuls post-hoc test. Statistical significance was considered at p<0.0.
RESULTS
The nitroglycerin-treated group showed significant increases in blood potassium during di-estrous while the piroxicam-treated group showed significant increases in blood potassium, urea and clotting time with a significant decrease in sodium levels during di-estrous compared to controls. Results obtained in other phases were not significant compared to controls.
CONCLUSIONS
The study showed that Nitroglycerin produces minimum alteration of blood and electrolyte indices compared to piroxicam during di-estrous.
Topics: Humans; Female; Rats; Animals; Piroxicam; Rats, Wistar; Nitroglycerin; Cyclooxygenase Inhibitors; Prostaglandins; Dysmenorrhea; Urea; Sodium; Electrolytes; Potassium
PubMed: 37134015
DOI: 10.5935/1518-0557.20220069 -
Drug Delivery Dec 2023Cyclodextrin nanosponges are solid nanoparticles, designed by cross-linking of cyclodextrin polymer; it has been used widely as a good delivery system for water...
Cyclodextrin nanosponges are solid nanoparticles, designed by cross-linking of cyclodextrin polymer; it has been used widely as a good delivery system for water insoluble drugs. The aim of this study is to enhance the solubility of Piroxicam (PXM) using β-Cyclodextrin based nanosponges formulations. PXM nanosponge (PXM-NS) formulations were prepared using β-cyclodextrin and carbonyldiimidazole as a cross linker, three ratios of β-cyclodextrin to crosslinker in addition to three drug to nanosponges ratios were tested. Piroxicam nanosponge formulations were characterized for its particle size, zeta potential, physical compatibility and in vitro release. Stability studies at three temperatures (4 °C, 25 °C and 40 °C) were done for optimal formula. Finally, the in vivo analgesic activity and pharmacokinetic parameters of the optimal formula were conducted. The optimized PXM-NS formula (PXM-NS10) showed particle size (362 ± 14.06 nm), polydispersity index (0.0518), zeta potential (17 ± 1.05 mV), and %EE (79.13 ± 4.33). The dissolution study showed a significant increase in the amount of PXM dissolved compared with the unformulated drug. Stability studies confirmed that nanosponge showed accepted stability for 90 days at 4 °C and 25 °C. In vivo analgesic studies verified that there was a significant enhancement in the analgesic response to PXM in mice, and 1.42 fold enhancement in the relative bioavailability of PXM-NS10 as compared to commercial tablets. Nanosponge prepared under optimal conditions is an encouraging formula for increasing the solubility and therefore the bioavailability of Piroxicam.
Topics: Mice; Animals; Piroxicam; Drug Carriers; Solubility; beta-Cyclodextrins; Analgesics
PubMed: 36744372
DOI: 10.1080/10717544.2023.2174208 -
Endocrine, Metabolic & Immune Disorders... 2024Non-steroidal Anti-Inflammatory Drugs (NSAIDs) are among the drugs that are most regularly administered to manage inflammation and pain. Over-the-Counter (OTC) NSAIDs... (Review)
Review
BACKGROUND
Non-steroidal Anti-Inflammatory Drugs (NSAIDs) are among the drugs that are most regularly administered to manage inflammation and pain. Over-the-Counter (OTC) NSAIDs are widely accessible, particularly in developing countries like India. This casual approach to using NSAIDs may operate as a magnet for NSAID-related adverse drug reactions (ADRs) among patients.
OBJECTIVES
As patients in India are less informed about the appropriate use of NSAIDs and consumption patttern, adverse drug reactions, and the importance of reporting ADRs, the current study's objective is to promote patient safety by using pharmacovigilance as a tool to educate patients.
METHODS
A targeted literature methodology was utilized to gather the data pertaining to NSAIDs, their ADRs and their pharmacovigilance. Different scientific databases, such as Science Direct, PubMed, Wiley Online Library, Springer, and Google Scholar, along with authentic textbooks, were explored as reference literature.
RESULTS
In general, NSAIDs consumption pattern depends upon the different age groups. Around 1.6 billion tablets of NSAIDs are consumed in India for ailments, such as headaches, arthritis, menstrual cramps, osteoarthritis, back pain, rheumatoid arthritis, gout, osteoporosis, tendinitis, cancer pain and chronic pain. Common ADRs of NSAIDs include nausea, vomiting, headache, gastritis, abdominal pain, and diarrhoea. Also, they can cause renal damage and cardiovascular problems if not consumed in a dose-dependent manner. However, Diclofenac and Ibuprofen have both been linked to depression and dementia. There have been reports of aplastic anaemia, agranulocytosis linked to phenylbutazone, Stevens-Johnson, and Lyell's syndrome linked to isoxicam and piroxicam, as well as the vulnerability of new-borns to Reye's syndrome after aspirin use. Lack of awareness, time constraints and unpredictability, poor training in ADRs identification, etc., are some of the reasons for the under-reporting of ADR of NSAIDs in India.
CONCLUSION
In order to rationally prescribe NSAIDs, it is essential to be aware of probable ADR's and establish prescription guidelines. Prescribers' behaviour can be changed toward excellent prescribing practices by conducting routine prescription assessments dealing with NSAIDs and providing feedback. In the near future, it will be critical to strengthen ADR data management and expand the reach of pharmacovigilance programs, ADR monitoring centers, and healthcare professionals' especially pharmacists' training in rural locations.
Topics: Humans; Pharmacovigilance; India; Anti-Inflammatory Agents, Non-Steroidal; Adverse Drug Reaction Reporting Systems; Drug-Related Side Effects and Adverse Reactions; Nonprescription Drugs
PubMed: 37855282
DOI: 10.2174/0118715303247469230926092404 -
The Journal of Headache and Pain Nov 2023Medication overuse headache (MOH) is a secondary headache that accompanies chronic migraine. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently used...
OBJECTIVE
Medication overuse headache (MOH) is a secondary headache that accompanies chronic migraine. Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently used analgesics worldwide and they are known to induce leaky gut. In this study, we aimed to investigate whether NSAID induced MOH is associated with altered circulating lipopolysaccharide binding protein (LBP) levels and inflammatory molecules.
MATERIALS AND METHODS
Piroxicam (10 mg/kg/day, po) for 5 weeks was used to induce MOH in female Sprague Dawley rats. Pain behavior was evaluated by periorbital withdrawal thresholds, head-face grooming, freezing, and head shake behavior. Serum samples and brain tissues were collected to measure circulating LBP, tight junction protein occludin, adherens junction protein vascular endothelial (VE)-cadherin, calcitonin gene-related peptide (CGRP), IL-6 levels and brain high mobility group box-1 (HMGB1) and IL-17 levels.
RESULTS
Chronic piroxicam exposure resulted in decreased periorbital mechanical withdrawal thresholds, increased head-face grooming, freezing, and head shake behavior compared to vehicle administration. Serum LBP, CGRP, IL-6, IL-17, occludin, VE-cadherin levels and brain IL-17 and HMGB1 levels were significantly higher in piroxicam group compared to controls. Serum LBP was positively correlated with occludin (r = 0.611), VE-cadherin (r = 0.588), CGRP (r = 0.706), HMGB1 (r = 0.618) and head shakes (r = 0.921), and negatively correlated with periorbital mechanical withdrawal thresholds (r = -0.740).
CONCLUSION
Elevated serum LBP, VE-cadherin and occludin levels indicating disrupted intestinal barrier function and leakage of LPS into the systemic circulation were shown in female rats with MOH. LPS induced low-grade inflammation and elevated nociceptive and/or pro-inflammatory molecules such as HMGB1, IL-6, IL-17 and CGRP may play a role in the development and maintenance of MOH. Interference with leaky gut and pro-inflammatory nociceptive molecules could also be a target for sustained management of MOH.
Topics: Rats; Female; Animals; Lipopolysaccharides; Calcitonin Gene-Related Peptide; HMGB1 Protein; Interleukin-17; Rats, Sprague-Dawley; Piroxicam; Occludin; Interleukin-6; Headache Disorders, Secondary; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 37940864
DOI: 10.1186/s10194-023-01672-4 -
BioRxiv : the Preprint Server For... Mar 2024Mitochondrial (Mito) dysfunction in IBD reduces mucosal O2 consumption and increases O2 delivery to the microbiome. Increased enteric O2 promotes blooms of facultative...
BACKGROUND
Mitochondrial (Mito) dysfunction in IBD reduces mucosal O2 consumption and increases O2 delivery to the microbiome. Increased enteric O2 promotes blooms of facultative anaerobes (eg. ) and restricts obligate anaerobes (eg. ). Dysbiotic metabolites negatively affect host metabolism and immunity. Our novel compound (AuPhos) upregulates intestinal epithelial cell (IEC) mito function, attenuates colitis and corrects dysbiosis in humanized mice. We posit that AuPhos corrects IBD-associated dysbiotic metabolism.
METHODS
Primary effect of AuPhos on mucosal Mito respiration and healing process was studied in ex vivo treated human colonic biopsies and piroxicam-accelerated (Px) mice. Secondary effect on microbiome was tested in DSS-colitis WT B6 and germ-free 129.SvEv WT or mice reconstituted with human IBD stool (Hu- ). Mice were treated orally with AuPhos (10- or 25- mg/kg; q3d) or vehicle, stool samples collected for fecal lipocalin-2 (f-LCN2) assay and microbiome analyses using 16S rRNA sequencing. AuPhos effect on microbial metabolites was determined using untargeted global metabolomics. AuPhos-induced hypoxia in IECs was assessed by Hypoxyprobe-1 staining in sections from pimonidazole HCl-infused DSS-mice. Effect of AuPhos on enteric oxygenation was assessed by (aerobic respiration-proficient) and mutant (aerobic respiration-deficient).
RESULTS
Metagenomic (16S) analysis revealed AuPhos reduced relative abundances of and increased blooms of in uninflamed B6 WT, DSS-colitis, Hu-WT and Hu- mice. AuPhos also increased hypoxyprobe-1 staining in surface IECs suggesting enhanced O2 utilization. AuPhos-induced anaerobiosis was confirmed by a significant increase in cydA mutant compared to WT (O2-utlizing) . Ex vivo treatment of human biopsies with AuPhos showed significant increase in Mito mass, and complexes I and IV. Further, gene expression analysis of AuPhos-treated biopsies showed increase in stem cell markers (Lgr4, Lgr5, Lrig1), with concomitant decreases in pro-inflammatory markers (IL1β,MCP1, RankL). Histological investigation of AuPhos-fed Px- mice showed significantly decreased colitis score in AuPhos-treated Px- mice, with decrease in mRNA of pro-inflammatory cytokines and increase in Mito complexes ( , ). AuPhos significantly altered microbial metabolites associated with SCFA synthesis, FAO, TCA cycle, tryptophan and polyamine biosynthesis pathways. AuPhos increased pyruvate, 4-hydroxybutyrate, 2-hydroxyglutarate and succinate, suggesting an upregulation of pyruvate and glutarate pathways of butyrate production. AuPhos reduced IBD-associated primary bile acids (BA) with concomitant increase in secondary BA (SBA). AuPhos treatment significantly decreased acylcarnitines and increased L-carnitine reflective of enhanced FAO. AuPhos increases TCA cycle intermediates and creatine, energy reservoir substrates indicating enhanced OxPHOS. Besides, AuPhos also upregulates tryptophan metabolism, decreases Kynurenine and its derivatives, and increases polyamine biosynthesis pathway (Putresceine and Spermine).
CONCLUSION
These findings indicate that AuPhos-enhanced IEC mitochondrial function reduces enteric O2 delivery, which corrects disease-associated metabolomics by restoring short-chain fatty acids, SBA, AA and IEC energy metabolism.
PubMed: 38559035
DOI: 10.1101/2024.03.14.584471 -
American Journal of Clinical Dermatology May 2024Field cancerization theory highlights that the skin surrounding actinic keratoses (AK) is also at increased risk for possible malignant transformation; thus,... (Review)
Review
Field cancerization theory highlights that the skin surrounding actinic keratoses (AK) is also at increased risk for possible malignant transformation; thus, field-directed treatments may both reduce the risk of AK recurrence and potentially reduce the risk of development of cutaneous squamous cell carcinoma (cSCC). Photodynamic therapy (PDT) with either aminolevulinic acid (ALA) or methylaminolevulinate (MAL), as well as topical treatments such as 5-fluorouracil (5-FU), diclofenac gel, piroxicam, imiquimod, and ingenol mebutate, have all shown higher efficacy than vehicle treatments. PDT is widely recognized for its high efficacy; however, concerns for associated pain have driven new studies to begin using alternative illumination and pretreatment techniques, including lasers. Among topical treatments, a combination of 5-FU and salicylic acid (5-FU-SA) has shown to be the most effective but also causes the most adverse reactions. Tirbanibulin, a new topical agent approved for use in 2020, boasts a favorable safety profile in comparison with imiquimod, 5-FU, and diclofenac. Meanwhile, ingenol mebutate is no longer recommended for the treatment of AKs due to concerns for increased risk of cSCC development. Moving forward, an increasing number of studies push for standardization of outcome measures to better predict risk of future cSCC and use of more effective measures of cost to better guide patients. Here, we present an updated and comprehensive narrative review both confirming the efficacy of previously mentioned therapies as well as highlighting new approaches to PDT and discussing the use of lasers and novel topical treatments for treatment of AK.
Topics: Humans; Keratosis, Actinic; Photochemotherapy; Skin Neoplasms; Carcinoma, Squamous Cell; Cell Transformation, Neoplastic; Administration, Cutaneous; Treatment Outcome; Antineoplastic Agents; Photosensitizing Agents; Laser Therapy
PubMed: 38351246
DOI: 10.1007/s40257-023-00839-8 -
Drug and Therapeutics Bulletin Feb 2024Li RHW, Lo SST, Gemzell-Danielsson K, et al. Oral emergency contraception with levonorgestrel plus piroxicam: a randomised double-blind placebo-controlled trial... (Randomized Controlled Trial)
Randomized Controlled Trial
Li RHW, Lo SST, Gemzell-Danielsson K, et al. Oral emergency contraception with levonorgestrel plus piroxicam: a randomised double-blind placebo-controlled trial [correction appears in 2023;402:850]. 2023;402:851-8.
Topics: Humans; Contraception, Postcoital; Levonorgestrel; Piroxicam; Double-Blind Method
PubMed: 38326010
DOI: 10.1136/dtb.2024.000011