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Transplant International : Official... 2022To analyze the efficacy and tolerability of diflunisal for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. We performed a...
To analyze the efficacy and tolerability of diflunisal for the treatment of acquired amyloid neuropathy in domino liver transplant recipients. We performed a retrospective longitudinal study of prospectively collected data for all domino liver transplant recipients with acquired amyloid neuropathy who received diflunisal at our hospital. Neurological deterioration was defined as an score increase of ≥2 points from baseline on the Neurological Impairment Scale/Neurological Impairment Scale-Lower Limbs. Twelve patients who had received compassionate use treatment with diflunisal were identified, of whom seven had follow-up data for ≥12 months. Five patients (71.4%) presented with neurological deterioration on the Neurological Impairment Scale after 12 months ( = 0.0382). The main adverse effects were cardiovascular and renal, leading to diflunisal being stopped in five patients and the dose being reduced in two patients. Our study suggests that most domino liver transplant recipients with acquired amyloid neuropathy will develop neurological deterioration by 12 months of treatment with diflunisal. This therapy was also associated with a high incidence of adverse effects and low treatment retention. The low efficacy and low tolerability of diflunisal treatment encourage the search for new therapeutic options.
Topics: Amyloid Neuropathies; Diflunisal; Humans; Longitudinal Studies; Retrospective Studies; Transplant Recipients
PubMed: 35497887
DOI: 10.3389/ti.2022.10454 -
Molecules (Basel, Switzerland) Aug 2018Cyclooxygenase enzymes play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation, the additional involvement of COX-2...
Cyclooxygenase enzymes play a vital role in inflammatory pathways in the human body. Apart from their relation with inflammation, the additional involvement of COX-2 enzyme with cancer activity was recently discovered. In some cancer types the level of COX-2 enzyme is increased indicating that this enzyme could be a suitable target for cancer therapy. Based on these findings, we have synthesized some new diflunisal thiosemicarbazides and 1,2,4-triazoles and tested them against androgen-independent prostate adenocarcinoma (PC-3), colon carcinoma (HCT-116), human breast cancer (T47D), breast carcinoma (MCF7) and human embryonic kidney (HEK-293) cell lines. Specifically, the diflunisal and thiosemicarbazide functionality are combined during the synthesis of original compounds anticipating a potency enhancement. Compounds , , and did not show cytotoxic effects for the HEK293 cell line. Among them, compounds and demonstrated anticancer activity for the breast cancer cell line T47D, whereas compounds and which are thiosemicarbazide derivatives displayed anti-tumourigenic activity against the PC-3 cell line, consistent with the literature. However, no activity was observed for the HCT-116 cancer cell line with the tested thiosemicarbazide derivatives. Only compound displayed activity against the HCT-116 cell line. Therefore, it was speculated that the diflunisal and thiosemicarbazide functionalities potentiate anticancer activity on prostate cancer and the thiosemicarbazide functionality decreases the anticancer activity of diflunisal on colon cancer cell lines. In order to gain insight into the anticancer activity and COX-2 inhibition, molecular docking studies were carried out for COX-1 and COX-2 enzymes utilizing the newly synthesized compounds , and . Both and showed high selectivity and affinity toward COX-2 isozyme over COX-1, which is in agreement with the experimental results.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Survival; Cyclooxygenase 2 Inhibitors; Cyclooxygenase Inhibitors; Diflunisal; Drug Screening Assays, Antitumor; Female; HCT116 Cells; HEK293 Cells; Humans; MCF-7 Cells; Male; Molecular Docking Simulation; Semicarbazides; Structure-Activity Relationship
PubMed: 30082676
DOI: 10.3390/molecules23081969 -
Frontiers in Pharmacology 2018The accelerated metabolism of tumor cells, inevitable for maintaining high proliferation rates, is an emerging target for tumor therapy. Increased glucose and lipid...
The accelerated metabolism of tumor cells, inevitable for maintaining high proliferation rates, is an emerging target for tumor therapy. Increased glucose and lipid metabolism as well as mitochondrial activity have been shown in solid tumors but also in leukemic cells. As tumor cells are able to escape the blockade of one metabolic pathway by a compensatory increase in other pathways, treatment strategies simultaneously targeting metabolism at different sites are currently developed. However, the number of clinically applicable anti-metabolic drugs is still limited. Here, we analyzed the impact of the anti-diabetic drug metformin alone or in combination with two non-steroidal anti-inflammatory drugs (NSAIDs) diclofenac and diflunisal on acute myeloid leukemia (AML) cell lines and primary patient blasts. Diclofenac but not diflunisal reduced lactate secretion in different AML cell lines (THP-1, U937, and KG-1) and both drugs increased respiration at low concentrations. Despite these metabolic effects, both NSAIDs showed a limited effect on tumor cell proliferation and viability up to a concentration of 0.2 mM. In higher concentrations of 0.4-0.8 mM diflunisal alone exerted a clear effect on proliferation of AML cell lines and blocked respiration. Single treatment with the anti-diabetic drug metformin blocked mitochondrial respiration, but proliferation and viability were not affected. However, combining all three drugs exerted a strong cytostatic and cytotoxic effect on THP-1 cells. Comparable to the results obtained with THP-1 cells, the combination of all three drugs significantly reduced proliferation of primary leukemic blasts and induced apoptosis. Furthermore, NSAIDs supported the effect of low dose chemotherapy with cytarabine and reduced proliferation of primary AML blasts. Taken together we show that low concentrations of metformin and the two NSAIDs diclofenac and diflunisal exert a synergistic inhibitory effect on AML proliferation and induce apoptosis most likely by blocking tumor cell metabolism. Our results underline the feasibility of applying anti-metabolic drugs for AML therapy.
PubMed: 30450049
DOI: 10.3389/fphar.2018.01258 -
The Cochrane Database of Systematic... 2004Patellofemoral pain syndrome (PFPS) is common among adolescents and young adults. It is characterised by pain behind or around the patella and crepitations, provoked by... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Patellofemoral pain syndrome (PFPS) is common among adolescents and young adults. It is characterised by pain behind or around the patella and crepitations, provoked by ascending or descending stairs, squatting, prolonged sitting with flexed knees, running and cycling. The symptoms impede function in daily activities or sports. Pharmacological treatments focus on reducing pain symptoms (non-steroidal anti-inflammatory drugs (NSAIDs), glucocorticosteroids), or restoring the assumed underlying pathology (compounds containing glucosamine to stimulate cartilage metabolism, anabolic steroids to increase bone density of the patella and build up supporting muscles). In studies, drugs are usually applied in addition to exercises aimed at building up supporting musculature.
OBJECTIVES
This review aims to summarise the evidence of effectiveness of pharmacotherapy in reducing anterior knee pain and improving knee function in people with PFPS.
SEARCH STRATEGY
We searched the Cochrane Musculoskeletal Injuries Group and Cochrane Rehabilitation and Related Therapies Field trials registers, the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 4, 2003), PEDro (up to January 2004), MEDLINE (1966 to January 2004), EMBASE (1988 to January 2004), and CINAHL (1982 to January 2004).
SELECTION CRITERIA
Controlled trials (randomised or not) comparing pharmacotherapy with placebo, different types of pharmacotherapy, or pharmacotherapy to other therapies for people with PFPS.
DATA COLLECTION AND ANALYSIS
The literature search yielded 780 publications. Eight trials were included, of which three were of high quality. Data were analysed qualitatively using best evidence synthesis, because meta-analysis was impeded by differences in route of administration of drugs, care programs and outcome measures.
MAIN RESULTS
Four trials (163 participants) studied the effect of NSAIDs. Aspirin compared to placebo in a high quality trial produced no significant differences in clinical symptoms and signs. Naproxen produced significant short term pain reduction when compared to placebo, but not when compared to diflunisal. Laser therapy to stimulate blood flow in tender areas led to more satisfied participants than tenoxicam, though not significantly. Two high quality RCTs (84 participants) studied the effect of glycosaminoglycan polysulphate (GAGPS). Twelve intramuscular injections in six weeks led to significantly more participants with a good overall therapeutic effect after one year, and to significantly better pain reduction during one of two activities. Five weekly intra-articular injections of GAGPS and lidocaine were compared with intra-articular injections of saline and lidocaine or no injections, all with concurrent quadriceps training. Injected participants showed better function after six weeks, though only the difference between GAGPS injected participants and non-injected participants was significant. The differences had disappeared after one year. One trial (43 participants) found that intramuscular injections of the anabolic steroid nandrolone phenylpropionate significantly improved both pain and function compared to placebo injections.
REVIEWERS' CONCLUSIONS
There is only limited evidence for the effectiveness of NSAIDs for short term pain reduction in PFPS. The evidence for the effect of glycosaminoglycan polysulphate is conflicting and merits further investigation. The anabolic steroid nandrolone may be effective, but is too controversial for treatment of PFPS.
Topics: Anabolic Agents; Anti-Inflammatory Agents, Non-Steroidal; Controlled Clinical Trials as Topic; Glycosaminoglycans; Humans; Nandrolone; Patellofemoral Pain Syndrome
PubMed: 15266488
DOI: 10.1002/14651858.CD003470.pub2 -
Journal of Clinical Medicine Apr 2022Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressively debilitating, rare disease associated with high mortality. ATTR-CM occurs when TTR amyloid protein... (Review)
Review
Transthyretin amyloid cardiomyopathy (ATTR-CM) is a progressively debilitating, rare disease associated with high mortality. ATTR-CM occurs when TTR amyloid protein builds up in the myocardium along with different organs, most commonly the peripheral and the autonomic nervous systems. Managing the cardiac complications with standard heart failure medications is difficult due to the challenge to maintain a balance between the high filling pressure associated with restricted ventricular volume and the low cardiac output. To date, tafamidis is the only agent approved for ATTR-CM treatment. Besides, several agents, including green tea, tolcapone, and diflunisal, are used off-label in ATTR-CM patients. Novel therapies using RNA interference also offer clinical promise. Patisiran and inotersen are currently approved for ATTR-polyneuropathy of hereditary origin and are under investigation for ATTR-CM. Monoclonal antibodies in the early development phases carry hope for amyloid deposit clearance. Despite several drug candidates in the clinical development pipeline, the small ATTR-CM patient population raises several challenges. This review describes current and future therapies for ATTR-CM and sheds light on the clinical development hurdles facing them.
PubMed: 35456241
DOI: 10.3390/jcm11082148 -
British Journal of Clinical Pharmacology Feb 1977The analgesic efficacy and tolerance of diflunisal in patients with osteoarthritis has been compared with ibuprofen and acetylsalicylic acid (ASA) in two clinical... (Clinical Trial)
Clinical Trial Comparative Study Randomized Controlled Trial
The analgesic efficacy and tolerance of diflunisal in patients with osteoarthritis has been compared with ibuprofen and acetylsalicylic acid (ASA) in two clinical studies carried out double-blind for 12 weeks and then continued single-blind for a further 12 weeks. The studies involved 115 patients and 695 patients, respectively. Diflunisal was superior to ibuprofen in overall response, as assessed by both patients and investigators ( < 0.01), improvement in disease activity and by improvement in internal rotation of the hip ( < 0.05). Diflunisal was superior to ASA in overall response, as assessed by both patients and investigators, therapeutic index ( < 0.01), reduction in morning stiffness, and by improvement in performance of daily activities ( < 0.05). In the first study, the mean daily dose of diflunisal during the double-blind period was 702 mg and of ibuprofen 1 161 mg. In the second study, the mean daily dose of diflunisal was 612 mg and of ASA 2 461 mg. Diflunisal produced fewer gastrointestinal side-effects after 24 weeks of therapy than did ibuprofen ( < 0.01). Diflunisal produced fewer general side-effects and fewer gastrointestinal side-effects during the double-blind and the single-blind phases of the study ( < 0.01). Fewer patients discontinued therapy because of side-effects in the diflunisal group than in the ASA group ( < 0.05). Both ASA and diflunisal decreased serum uric acid, with diflunisal being more uricosuric than aspirin ( < 0.01).
Topics: Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Clinical Trials as Topic; Drug Evaluation; Fluorobenzenes; Humans; Ibuprofen; Osteoarthritis; Patient Dropouts; Salicylates; Time Factors
PubMed: 328034
DOI: 10.1111/j.1365-2125.1977.tb04514.x -
British Journal of Clinical Pharmacology Feb 1977In the fasting state, peak plasma levels of diflunisal were achieved within 2 hours. The drug was not metabolized and almost totally excreted in the urine as unchanged... (Review)
Review
In the fasting state, peak plasma levels of diflunisal were achieved within 2 hours. The drug was not metabolized and almost totally excreted in the urine as unchanged or conjugated drug. The terminal plasma half-life was approximately 8 hours. These results support a twice daily dose regimen. During multiple dose administration the time required to achieve steady-state plasma levels varied with the dose. A dose regimen of 125 mg twice daily required 2-3 d, whereas a regimen of 500 mg twice daily required 7-9 d to reach a steady-state plasma level. Clinically effective doses of diflunisal decreased the urinary excretion of the major prostaglandin E metabolite, 7α-hydroxy-5,11-diketotetranorprostane-1,16-dioic acid, and exhibited significant uricosuric activity. These same doses did not seem to cause tinnitus, nor did they significantly alter gastrointestinal blood loss, affect blood glucose, bleeding time, or platelet function. Clinically significant drug interactions may be anticipated during concomitant administration with at least one oral anticoagulant (acenocoumarol), but probably not anticipated during the coadministration of oral antidiabetic agents, thiazide diuretics, and non-steroidal anti-inflammatory/analgesic agents. Clinical and laboratory data accumulated during these studies indicated that diflunisal was well tolerated.
Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Benzothiadiazines; Blood Glucose; Blood Platelets; Diuretics; Drug Interactions; Fluorobenzenes; Gastrointestinal Hemorrhage; Hearing Disorders; Humans; Hypoglycemic Agents; Kinetics; Male; Prostaglandins; Salicylates; Sodium Chloride Symporter Inhibitors; Time Factors; Uric Acid
PubMed: 328032
DOI: 10.1111/j.1365-2125.1977.tb04511.x -
Biological & Pharmaceutical Bulletin 2018Hereditary transthyretin (TTR)-related amyloidosis is caused by mutations in the TTR gene. The mutations destabilize the tetramer and/or monomer of TTR, and thus the... (Review)
Review
Hereditary transthyretin (TTR)-related amyloidosis is caused by mutations in the TTR gene. The mutations destabilize the tetramer and/or monomer of TTR, and thus the stabilization of TTR is a key strategy for the treatment of TTR-related amyloidosis. In this review, we summarized the natural products and synthetic compounds that have been shown to inhibit the amyloidogenesis of TTR. The stabilizers and/or the amyloid fibril disrupters isolated from natural sources may become lead compounds for the treatment of TTR-related amyloidosis.
Topics: Amyloid; Amyloidosis; Anti-Inflammatory Agents, Non-Steroidal; Benzoxazoles; Biological Products; Diflunisal; Humans; Mutation; Prealbumin
PubMed: 29962408
DOI: 10.1248/bpb.b18-00166 -
Amyloid : the International Journal of... Jun 2023Transthyretin (TTR) dissociation is the rate limiting step for both aggregation and subunit exchange. Kinetic stabilisers, small molecules that bind to the native...
Transthyretin (TTR) dissociation is the rate limiting step for both aggregation and subunit exchange. Kinetic stabilisers, small molecules that bind to the native tetrameric structure of TTR, slow TTR dissociation and inhibit aggregation. One such stabiliser is the non-steroidal anti-inflammatory drug (NSAID), diflunisal, which has been repurposed to treat TTR polyneuropathy. Previously, we compared the efficacy of diflunisal, tafamidis, tolcapone, and AG10 as kinetic stabilisers for transthyretin. However, we could not meaningfully compare diflunisal because we were unsure of its plasma concentration after long-term oral dosing. Herein, we report the diflunisal plasma concentrations measured by extraction, reversed phase HPLC separation, and fluorescence detection after long-term 250 mg BID oral dosing in two groups: a placebo-controlled diflunisal clinical trial group and an open-label Japanese polyneuropathy treatment cohort. The measured mean diflunisal plasma concentration from both groups was 282.2 M 143.7 M (mean standard deviation). Thus, quantification of TTR kinetic stabilisation using subunit exchange was carried out at 100, 200, 300, and 400 concentrations, all observed in patients after 250 mg BID oral dosing. A 250 M diflunisal plasma concentration reduced the wild-type TTR dissociation rate in plasma by 95%, which is sufficient to stop transthyretin aggregation, consistent with the clinical efficacy of diflunisal for ameliorating transthyretin polyneuropathy.
Topics: Humans; Diflunisal; Prealbumin; Anti-Inflammatory Agents, Non-Steroidal; Excipients; Polyneuropathies; Amyloid Neuropathies, Familial
PubMed: 36444793
DOI: 10.1080/13506129.2022.2148094 -
Orphanet Journal of Rare Diseases Jan 2021Despite emerging treatments for hereditary transthyretin (ATTRv) amyloidosis, the disease is often misdiagnosed, with reported diagnostic delays of up to several years....
BACKGROUND
Despite emerging treatments for hereditary transthyretin (ATTRv) amyloidosis, the disease is often misdiagnosed, with reported diagnostic delays of up to several years. Knowledge of the patient journey leading up to diagnosis may help to promote earlier intervention. The study's objective was to examine patient clinical characteristics and healthcare utilization prior to ATTRv amyloidosis diagnosis.
METHODS
Patients ≥ 18 years and newly diagnosed with ATTRv amyloidosis identified in IBM® MarketScan® Commercial and Medicare Supplemental data using a claims-based algorithm as follows: diagnosis required ≥ 1 medical claim with relevant amyloidosis diagnosis code (ICD-10-CM: E85.0-.4, E85.89, E85.9; excludes light chain and wild type) during identification (ID) period (1/1/2016-12/31/2017), and ≥ 1 occurrence of qualifying criteria during 2011-2017: ≥ 15 days diflunisal use without > 30-day gap, liver transplant, or claim with specific codes E85.1 or E85.2. The index date was defined as the date of first claim with amyloidosis diagnosis code in ID period. Patients had continuous enrollment ≥ 5 years pre-index date (look-back period). Occurrence of selected comorbid conditions and symptoms and healthcare utilization (testing, emergency department visits and hospitalization) measured during the look-back period; demographics, physician specialty, and Charlson comorbidity index (CCI) measured 1 year pre-index. Patients with an ICD-9/10 amyloidosis code during the look-back period were excluded. An ATTRv-free reference cohort was created from a random sample of enrollees who lacked any diagnosis of amyloidosis and matched 3:1 to ATTRv patients on age, gender, and region to provide reference values; same index and enrollment requirement as match.
RESULTS
For the 141 qualifying patients with ATTRv and 423 matched controls, mean (standard deviation) age was 62.5 (14.2) years and 53.9% were female. Mean CCI for ATTRv cohort was 2.7 (3.0) versus 1.1 (1.9) among controls. Selected comorbidities, testing, visits, and hospitalization were common among patients with ATTRv during the look-back period with higher rates versus controls.
CONCLUSIONS
Patients with ATTRv amyloidosis experience multiple neurological, cardiovascular, and other clinical manifestations, testing, and hospitalization prior to diagnosis. Occurrence of potential markers of illness is most common in the year before diagnosis.
Topics: Aged; Amyloid Neuropathies, Familial; Biomarkers; Cohort Studies; Female; Humans; Male; Medicare; Middle Aged; Prealbumin; United States
PubMed: 33430941
DOI: 10.1186/s13023-020-01623-1