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CNS Drug Reviews 2007DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at position sn-2 via a 5-carbon length linker. It is cleaved by phospholipase... (Review)
Review
DP-155 is a lipid prodrug of indomethacin that comprises the latter conjugated to lecithin at position sn-2 via a 5-carbon length linker. It is cleaved by phospholipase A2 (PLA)(2) to a greater extent than similar compounds with linkers of 2, 3, and 4 carbons. Indomethacin is the principal metabolite of DP-155 in rat serum and, after DP-155 oral administration, the half-life of the metabolite was 22 and 93 h in serum and brain, respectively, compared to 10 and 24 h following indomethacin administration. The brain to serum ratio was 3.5 times higher for DP-155 than for indomethacin. In vitro studies demonstrated that DP-155 is a selective cyclooxygenase (COX)-2 inhibitor. After it is cleaved, its indomethacin derivative nonselectively inhibits both COX-1 and -2. DP-155 showed a better toxicity profile probably due to the sustained, low serum levels and reduced maximal concentration of its indomethacin metabolite. DP-155 did not produce gastric toxicity at the highest acute dose tested (0.28 mmol/kg), while indomethacin caused gastric ulcers at a dose 33-fold lower. Furthermore, after repeated oral dosing, gastrointestinal and renal toxicity was lower (10- and 5-fold, respectively) and delayed with DP-155 compared to indomethacin. In addition to reduced toxicity, DP-155 had similar ameliorative effects to indomethacin in antipyretic and analgesia models. Moreover, DP-155 and indomethacin were equally efficacious in reducing levels of amyloid ss (Ass)42 in transgenic Alzheimer's disease mouse (Tg2576) brains as well as reducing Ass42 intracellular uptake, neurodegeneration, and inflammation in an in vitro AD model. The relatively high brain levels of indomethacin after DP-155 administration explain the equal efficacy of DP-155 despite its low systemic blood concentrations. Compared to indomethacin, the favored safety profile and equal efficacy of DP-155 establish the compound as a potential candidate for chronic use to treat AD-related pathology and for analgesia.
Topics: Alzheimer Disease; Analgesics; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cyclooxygenase 2; Drug Combinations; Group II Phospholipases A2; Humans; Indomethacin; Phosphatidylcholines; Phospholipases A; Phospholipases A2; Rats
PubMed: 17627676
DOI: 10.1111/j.1527-3458.2007.00014.x -
Revista Brasileira de Anestesiologia 2012Hemicrania Continua (HC) is a primary, disabling headache characterized by a continuous unilateral pain and responsive to indomethacin. There are symptoms common to the... (Review)
Review
BACKGROUND AND OBJECTIVES
Hemicrania Continua (HC) is a primary, disabling headache characterized by a continuous unilateral pain and responsive to indomethacin. There are symptoms common to the trigeminal-autonomic cephalalgias and migraine that complicate the diagnosis. This review aims to describe HC in a case series and review the best available evidence on alternative therapies.
METHOD
A systematic review of medical records and diaries of pain of 1,600 patients treated between January 1992 and January 2011 in a headache outpatient clinic.
RESULTS
Ten patients with a possible diagnosis of hemicrania continua were selected; seven were diagnosed with HC according to the II International Classification of Headache Disorders. None of the patients had received the correct diagnosis before being treated at the outpatient clinic and the average time for treatment was 12 years. Prophylactic treatment was effective in 66.6% of cases with amitriptyline, 20% with gabapentin and 10% with topiramate.
CONCLUSIONS
HC should be considered among the diagnostic hypotheses of patients with continuous headache, with no change in neurological examination and additional tests, regardless the age of onset. The standard treatment with indomethacin (100-150mg.day(-1)) has significant risks associated with both short and long term use and may not be a good choice for continuous use. Recent studies point out possible alternatives: gabapentin, topiramate, cyclooxygenase-2 inhibitors, piroxicam, beta-cyclodextrin, amitriptyline, melatonin. Other drugs were described in different reports as efficient, but most of them were considered inefficient in other HC cases.
Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Female; Headache; Humans; Indomethacin; Male; Middle Aged
PubMed: 22440373
DOI: 10.1016/S0034-7094(12)70116-2 -
Current Problems in Cardiology Sep 2023This was a first-time evaluation that sought to analyze the cost-effectiveness of oral paracetamol and intravenous (IV) indomethacin as alternatives to ibuprofen for PDA...
This was a first-time evaluation that sought to analyze the cost-effectiveness of oral paracetamol and intravenous (IV) indomethacin as alternatives to ibuprofen for PDA in neonates. Decision-analytic, literature-based, economic simulation models were constructed, to follow up the use and consequences of oral/IV ibuprofen versus IV indomethacin, and oral/IV ibuprofen versus oral paracetamol, as first-line therapies for PDA closure. Model outcomes of interest were "success", defined as PDA closure with/without adverse events, or "failure" due to no response to the first course of treatment, death or premature discontinuation of therapy due to adverse events. Oral ibuprofen is dominant/cost-effective over IV indomethacin in 97.9% of simulated cases, but oral paracetamol was 75.2% dominant/cost-effective over oral ibuprofen. Against IV ibuprofen, IV indomethacin was 55.3% dominant/cost-effective, whereas oral paracetamol was dominant/cost-effective in 98.5% of the cases. Sensitivity analyses confirmed the robustness of the study results. For PDA closure, while IV indomethacin was cost-effective against IV ibuprofen, oral paracetamol was cost-effective against both oral and IV ibuprofen.
Topics: Infant, Newborn; Humans; Indomethacin; Ibuprofen; Ductus Arteriosus, Patent; Acetaminophen; Infant, Premature; Cyclooxygenase Inhibitors; Infant, Low Birth Weight; Cost-Effectiveness Analysis
PubMed: 37088173
DOI: 10.1016/j.cpcardiol.2023.101751 -
Molecules (Basel, Switzerland) Feb 2023Differential scanning calorimetry and Raman spectroscopy were used to study the nonisothermal and isothermal crystallization behavior of amorphous indomethacin powders...
Differential scanning calorimetry and Raman spectroscopy were used to study the nonisothermal and isothermal crystallization behavior of amorphous indomethacin powders (with particle sizes ranging from 50 to 1000 µm) and their dependence on long-term storage conditions, either 0-100 days stored freely at laboratory ambient temperatures and humidity or placed in a desiccator at 10 °C. Whereas the γ-form polymorph always dominated, the accelerated formation of the α-form was observed in situations of heightened mobility (higher temperature and heating rate), increased amounts of mechanically induced defects, and prolonged free-surface nucleation. A complex crystallization behavior with two separated crystal growth modes (originating from either the mechanical defects or the free surface) was identified both isothermally and nonisothermally. The diffusionless glass-crystal (GC) crystal growth was found to proceed during the long-term storage at 10 °C and zero humidity, at the rate of ~100 µm of the γ-form surface crystalline layer being formed in 100 days. Storage at the laboratory temperature (still below the glass transition temperature) and humidity led only to a negligible/nondetectable GC growth for the fine indomethacin powders (particle size below ~150 µm), indicating a marked suppression of GC growth by the high density of mechanical defects under these conditions. The freely stored bulk material with no mechanical damage and a smooth surface exhibited zero traces of GC growth (as confirmed by microscopy) after >150 days of storage. The accuracy of the kinetic predictions of the indomethacin crystallization behavior was rather poor due to the combined influences of the mechanical defects, competing nucleation, and crystal growth processes of the two polymorphic phases as well as the GC growth complex dependence on the storage conditions within the vicinity of the glass transition temperature. Performing paired isothermal and nonisothermal kinetic measurements is thus highly recommended in macroscopic crystallization studies of drugs with similarly complicated crystal growth behaviors.
Topics: Crystallization; Indomethacin; Temperature; Transition Temperature; Particle Size; Calorimetry, Differential Scanning
PubMed: 36838556
DOI: 10.3390/molecules28041568 -
Annals of the Rheumatic Diseases Apr 1979Twenty patients with definite or classical rheumatoid arthritis entered and completed a sequential study of placebo for 1 week, oral indomethacin 25 mg 3 times a day for... (Clinical Trial)
Clinical Trial
Twenty patients with definite or classical rheumatoid arthritis entered and completed a sequential study of placebo for 1 week, oral indomethacin 25 mg 3 times a day for 3 weeks, and oral indomethacin 25 mg 3 times a day plus 100 mg indomethacin suppository at night for 3 weeks. Twelve of the patients had previously been classified as responders and eight as nonresponders to indomethacin by an independent assessor. At the end of each period patients were assessed by a blind observer for duration of morning stiffness, pain score, digital joint size, grip strength, articular index, analgesic tablet usage, and the patient's own overall global assessment and comparative global assessment. In 8 of the 9 tests used responders improved on indomethacin in comparison with placebo, while nonresponders did not improve. There were no significant differences between responders and nonresponders in the plasma half-life, plasma clearance of indomethacin, protein binding of indomethacin, or urinary excretion of free or conjugated indomethacin. There were no significant differences between responders and nonresponders in the urinary excretion of 7HDPA or in the platelet aggregation or platelet malonyldialdehyde production tests. In responders there was a significant positive correlation between the plasma indomethacin concentration (r=0.44, P<0.05) and the percentage inhibition of malonyldialdehyde production by the platelets. However, in nonresponders this correlation, while significant (P<0.05), was negative (r=-0.498). Both for responders and nonresponders there was a significant correlation between plasma indomethacin concentration and the percentage reduction in 7HDPA. There was no correlation between the clinical response and the plasma concentration of indomethacin. There appears to be a biochemical difference between responders and nonresponders, which, while not necessarily causally linked with the clinical response to indomethacin, is worthy of further study.
Topics: Adult; Aged; Arthritis, Rheumatoid; Blood Platelets; Clinical Trials as Topic; Female; Humans; Indomethacin; Male; Middle Aged; Platelet Aggregation
PubMed: 375848
DOI: 10.1136/ard.38.2.128 -
The Cochrane Database of Systematic... Apr 2008Gout is one of the most frequently occurring rheumatic diseases, worldwide. Given the well-known drawbacks of the regular treatments for acute gout (non-steroidal... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Gout is one of the most frequently occurring rheumatic diseases, worldwide. Given the well-known drawbacks of the regular treatments for acute gout (non-steroidal anti-inflammatory drugs (NSAIDs), colchicine), systemic corticosteroids might be safe alternatives.
OBJECTIVES
To assess the efficacy and safety of systemic corticosteroids in the treatment of acute gout in comparison with placebo, NSAIDs, colchicine, other active drugs, other therapies, or no therapy.
SEARCH STRATEGY
Searches were done in the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007); MEDLINE (1966 to 2007) through PubMed; EMBASE (1974 to 2007); Web of Science (1975 to 2007); LILACS (1986 to 2007); and databases of ongoing trials (up to April 2007).
SELECTION CRITERIA
Randomized controlled trials and controlled clinical trials investigating the use of systemic corticosteroids in the treatment of acute gout were included.
DATA COLLECTION AND ANALYSIS
Two review authors decided independently which trials to include. The same review authors also collected the data in a standardised form and assessed the methodological quality of the trial using validated criteria. When possible, continuous and dichotomous data were summarised statistically.
MAIN RESULTS
Three head to head trials involving 148 patients (74 systemic corticosteroids; 74 comparator drugs) were included. Placebo-controlled trials were not found. In the studies, different kinds of systemic corticosteroids and different kinds of control drugs were used, both administered in different routes. Intramuscular triamcinolone acetonide was compared respectively to oral indomethacine, and intramuscular adrenocorticotropic hormone (ACTH); oral prednisolone (together with a single intramuscular diclophenac injection) was compared to oral indomethacine (together with a single placebo injection). Outcome measurements varied: average number of days until total relief of signs, mean decrease of pain per unit of time in mm on a visual analogue scale (VAS) - during rest and activity. In the triamcinolone-indomethacine trial the clinical joint status was used as an additional outcome. Clinically relevant differences between the studied systemic corticosteroids and the comparator drugs were not found; important safety problems attributable to the used corticosteroids were not reported. The quality of the three studies was graded as very low to moderate. Statistical pooling of results was not possible.
AUTHORS' CONCLUSIONS
There is inconclusive evidence for the efficacy and effectiveness of systemic corticosteroids in the treatment of acute gout. Patients with gout did not report serious adverse effects from systemic corticosteroids, when used short term.
Topics: Acute Disease; Adrenal Cortex Hormones; Adrenocorticotropic Hormone; Gout; Humans; Indomethacin; Triamcinolone
PubMed: 18425920
DOI: 10.1002/14651858.CD005521.pub2 -
Drug Delivery Dec 2022Challenges associated with topical analgesics and anti-inflammatory drugs include poor drug penetration and retention at the desired lesion site. Therefore, improving...
Challenges associated with topical analgesics and anti-inflammatory drugs include poor drug penetration and retention at the desired lesion site. Therefore, improving these challenges would help to reduce the toxic and side effects caused by drug absorption into the systemic circulation and improve the therapeutic efficacy of topical therapeutic drugs. Pentapeptide (KTTKS) is a signal peptide in skin tissue, it can be recognized and bound by signal recognition particles. In the current study, we successfully prepared novel indomethacin (IMC) loaded KTTKS-modified ethosomes (IMC-KTTKS-Es), and the physicochemical properties and topical efficacy were investigated. Results showed that the prepared IMC-KTTKS-Es displayed a particle size of about 244 nm, a negative charge, good deformability, and encapsulation efficiency (EE) exceeding 80% for IMC, with a sustained release pattern. In vitro percutaneous permeation studies revealed that the skin retention was increased after the drug was loaded in the IMC-KTTKS-Es. Confocal laser scanning microscopy also showed improved skin retention of IMC-KTTKS-Es. In addition, IMC-KTTKS-Es showed improved topical analgesic and anti-inflammatory activity with no potentially hazardous skin irritation. This study suggested that the IMC-KTTKS-Es might be an effective drug carrier for topical skin therapy with a good safety profile.
Topics: Drug Carriers; Indomethacin; Microscopy, Confocal; Skin; Skin Absorption
PubMed: 35656937
DOI: 10.1080/10717544.2022.2081739 -
Molecules (Basel, Switzerland) Sep 2022Non-isothermal differential scanning calorimetry (DSC) was used to study the influences of particle size (d) and heating rate (q) on the structural relaxation, crystal...
Non-isothermal differential scanning calorimetry (DSC) was used to study the influences of particle size (d) and heating rate (q) on the structural relaxation, crystal growth and decomposition kinetics of amorphous indomethacin. The structural relaxation and decomposition processes exhibited d-independent kinetics, with the q dependences based on the apparent activation energies of 342 and 106 kJ·mol, respectively. The DSC-measured crystal growth kinetics played a dominant role in the nucleation throughout the total macroscopic amorphous-to-crystalline transformation: the change from the zero-order to the autocatalytic mechanism with increasing q, the significant alteration of kinetics, with the storage below the glass transition temperature, and the accelerated crystallization due to mechanically induced defects. Whereas slow q led to the formation of the thermodynamically stable γ polymorph, fast q produced a significant amount of the metastable α polymorph. Mutual correlations between the macroscopic and microscopic crystal growth processes, and between the viscous flow and structural relaxation motions, were discussed based on the values of the corresponding activation energies. Notably, this approach helped us to distinguish between particular crystal growth modes in the case of the powdered indomethacin materials. Ediger's decoupling parameter was used to quantify the relationship between the viscosity and crystal growth. The link between the cooperativity of structural domains, parameters of the Tool-Narayanaswamy-Moynihan relaxation model and microscopic crystal growth was proposed.
Topics: Calorimetry, Differential Scanning; Crystallization; Indomethacin; Temperature; Transition Temperature; Viscosity
PubMed: 36080433
DOI: 10.3390/molecules27175668 -
Molecules (Basel, Switzerland) Dec 2021Cyclodextrins have found wide application in contemporary chemistry, pharmacy and medicine. Because of their unique properties, cyclodextrins are constantly used in...
Cyclodextrins have found wide application in contemporary chemistry, pharmacy and medicine. Because of their unique properties, cyclodextrins are constantly used in research on solubility or stability improvement, as well as other physicochemical properties of medicinal substances. Indomethacin (IND) is a photolabile molecule that also attracts the interest of researchers due to its therapeutic potential and the need to overcome its problematic photosensitivity. Supramolecular complexes of indomethacin with β-cyclodextrin (CD) are already known, and they show greater stability compared to complexes with other types of cyclodextrins. So far, however, the sensitivity to light of physical mixtures and inclusion complexes in the solid phase has not been studied, and their various stoichiometries have not yet been investigated. Due to this fact, the aim of the present study is to obtain supramolecular systems (inclusion complexes and physical mixtures) of indomethacin with three different amounts of β-cyclodextrin. Assessment of the photochemical stability of indomethacin-β-cyclodextrin systems in the solid state is performed in order to find the best correlation between IND stability and the amount of CD. Comparative analysis of physicochemical degradation for stoichiometry systems [CD:IND] = [1:1], [0.5:1] and [0.1:1] is performed by using ultraviolet spectroscopy, transmission-FTIR, reflection-ATR-FTIR infrared spectroscopy and DSC calorimetry.
Topics: Drug Combinations; Drug Stability; Indomethacin; Photochemical Processes; Solubility; beta-Cyclodextrins
PubMed: 34946517
DOI: 10.3390/molecules26247436 -
The British Journal of Ophthalmology Jun 1988The case of a 33-year-old man with probable indomethacin retinopathy is presented. The relevant literature is reviewed and the differences between our case and those... (Review)
Review
The case of a 33-year-old man with probable indomethacin retinopathy is presented. The relevant literature is reviewed and the differences between our case and those previously reported are noted. Our patient appears to have suffered severe and irreversible ocular damage due to the very high dose of indomethacin ingested over a prolonged period.
Topics: Adult; Humans; Indomethacin; Male; Retinal Diseases
PubMed: 3291939
DOI: 10.1136/bjo.72.6.434