Indoprofen prevents muscle wasting in aged mice through activation of PDK1/AKT pathway.

BACKGROUND: Muscle wasting, resulting from aging or pathological conditions, leads to reduced quality of life, increased morbidity, and increased mortality. Much research effort has been focused on the development of exercise mimetics to prevent muscle atrophy and weakness. In this study, we identified indoprofen from a screen for peroxisome proliferator-activated receptor γ coactivator α (PGC-1α) inducers and report its potential as a drug for muscle wasting. METHODS: The effects of indoprofen treatment on dexamethasone-induced atrophy in mice and in 3-phosphoinositide-dependent protein kinase-1 (PDK1)-deleted C2C12 myotubes were evaluated by immunoblotting to determine the expression levels of myosin heavy chain and anabolic-related and oxidative metabolism-related proteins. Young, old, and disuse-induced muscle atrophic mice were administered indoprofen (2 mg/kg body weight) by gavage. Body weight, muscle weight, grip strength, isometric force, and muscle histology were assessed. The expression levels of muscle mass-related and function-related proteins were analysed by immunoblotting or immunostaining. RESULTS: In young (3-month-old) and aged (22-month-old) mice, indoprofen treatment activated oxidative metabolism-related enzymes and led to increased muscle mass. Mechanistic analysis using animal models and muscle cells revealed that indoprofen treatment induced the sequential activation of AKT/p70S6 kinase (S6K) and AMP-activated protein kinase (AMPK), which in turn can augment protein synthesis and PGC-1α induction, respectively. Structural prediction analysis identified PDK1 as a target of indoprofen and, indeed, short-term treatment with indoprofen activated the PDK1/AKT/S6K pathway in muscle cells. Consistent with this finding, PDK1 inhibition abrogated indoprofen-induced AKT/S6K activation and hypertrophic response. CONCLUSIONS: Our findings demonstrate the effects of indoprofen in boosting skeletal muscle mass through the sequential activation of PDK1/AKT/S6K and AMPK/PGC-1α. Taken together, our results suggest that indoprofen represents a potential drug to prevent muscle wasting and weakness related to aging or muscle diseases.

The effect of a dexibuprofen mouth rinse on experimental gingivitis in humans.

OBJECTIVES: The pharmacodynamic properties of ibuprofen are related nearly exclusively to the S(+)enantiomer (dexibuprofen). This study investigated the effect of a 1.5% dexibuprofen mouth rinse in an experimentally induced gingivitis. MATERIALS AND METHODS: The trial was a randomized, double-blinded, placebo-controlled, two-period and two-sequence parallel group cross-over study in 24 healthy volunteers aged 21-30 years (16 males, eight females). Customized guards were worn during tooth brushing to prevent any plaque removal from the experimental area (first and second pre-molars and molars in one upper quadrant). After 22 days of plaque accumulation, the mouth rinses (1.5% dexibuprofen and placebo) were administered under supervision three times daily (rinsing for 1 min. with 15 ml) for 8 days. The wash-out time between the two study periods was 14 days. Parameters evaluated at days 0, 7, 14, 22, and 30 were the Löe & Silness gingival index (GI) and the Quigley & Hein plaque index (QHI). Data were tested for treatment, period, and carry-over effects (parametric cross-over analysis). RESULTS: There was no statistically significant difference (p=0.240) in GI between placebo and dexibuprofen. However, the decrease in QHI was significantly greater (p=0.019) with dexibuprofen as compared with the placebo. CONCLUSION: In the present study, a 1.5% dexibuprofen mouth rinse had no effect on gingivitis whereas an anti-plaque effect was demonstrated.

[Indoprofen in chronic intermittent peritoneal dialysis: effects in the clearance of small molecules and protein loss]. / Indoprofeno en peritoneo diálisis crónica intermitente: efectos en ladepuración de moleculas pequeñas y perdida de proteinas.

We studied the effects of indoprofen on urea and creatinine clearance and on protein loss in 6 patients submitted to intermittent peritoneal dialysis. The patients had no evidence of peritonitis. Dialysis fluid contained indoprofen (50 mg/l) or no drug. Mean protein loss into dialysis solution was 51.2 g without and 44.7 g with indoprofen (NS). Urea clearance was 33.3 and 33.6 ml/min and creatinine clearance 24.7 and 36.0 ml/min, respectively (NS). Levels of PGF2 alpha in the dialysate, measured in 2 subjects, were not affected by indoprofen. These results suggest that prostaglandins are not the main factors involved in control of urea and creatinine clearance and protein loss during intermittent peritoneal dialysis.

Transsynovial kinetics of indoprofen in patients with rheumatoid arthritis and cyclooxygenase-inhibition in vitro.

Twenty-four patients suffering from rheumatoid arthritis and requiring articular punctures were treated with 200 mg of indoprofen thrice daily for four days. The subjects were divided into four groups each of six patients. Following the last dose, blood and synovial fluid samples were taken simultaneously according to different time schedules. Maximum plasma levels of 17.5 micrograms/ml were observed after 2.5 h. Peak synovial fluid concentrations amounted to 8.1 micrograms/ml 4 h following the last dose. Elimination from synovial fluid occurred at 10.6 h compared to 9.3 h from plasma. Free synovial fluid levels of approximately 50 ng/ml are in the range of concentrations necessary for cyclooxygenase inhibition in mouse peritoneal macrophages.

Pharmacokinetic profile of indoprofen in elderly subjects.

Multiple dosing four times daily for 7 days of indoprofen 200 mg, a non-steroidal anti-inflammatory drug with a short half-life (t1/2), revealed drug accumulation in eight elderly subjects. This indicates a substantially longer t1/2 (11 h) than that reported in young persons (3 h). A reduction in dose compared to younger subjects is recommended in elderly patients with osteoarthritis.

The non-steroidal anti-inflammatory agent, indoprofen, does not protect against hydrochloric acid induced lung injury in the rat.

The effects of pulmonary instillation of hydrochloric acid on solute flux from the lung (measured as the clearance of 99mTcDTPA) together with an index of oedema formation (the ratio of lung wet weight to lung dry weight) was measured in rats. There was a significant increase in 99mTcDTPA clearance (P less than 0.001) and also in lung wet:dry weight ratio (P less than 0.01) 4-5 h following acid challenge. There was no difference in the effects of challenge with acid of pH1 and pH2. In addition, intravenous injection of indoprofen (20mg/kg) a non-steroidal anti-inflammatory agent failed to produce any beneficial effect on the variables under study when given after acid (pH2) challenge. There was also histological evidence of an influx and sequestration of granulocytes into the lung. Despite this, the plasma concentration of thiobarbituric acid reactive material (used as an index of cell-derived, oxidant-free radical production) was significantly reduced in all acid-treated groups. These data show that hydrochloric acid will initiate a severe inflammatory response in the lung of the rat and that the non-steroidal anti-inflammatory agent indoprofen when given after the injury produced no evidence of a beneficial effect on this inflammatory response.

Clinically controlled comparative study of intravenous single doses of suprofen versus indoprofen.

The analgesic effects of single intravenous doses of alpha-methyl-4-(2-thienyl-carbonyl)phenylacetic acid (suprofen, Suprol) 200 mg/ml and alpha-4-(2-isoindolinyl-2-one)-phenylpropionic acid (indoprofen) 200 mg were compared within the scope of a randomized single-blind study. The test population consisted of 87 patients for whom analgesic treatment was indicated as soon as severe to major pain set in following meniscectomy or disease of a ligament. The treatment groups were homogeneous with respect to demographic data and intensity of pain prior to treatment. In the pain models chosen both drugs resulted in rapid pain relief within 15 min following their application. As to decreased intensity of pain (SPID) and pain relief (TOTPAR), the results obtained 2 h after the test were with indoprofen statistically significantly superior to those obtained with suprofen. The investigator's global appreciation of effectiveness revealed no intergroup differences. Therapeutic results were seen in 95.5% of the subjects on suprofen and in 97.6% of those on indoprofen. The tolerability of suprofen was very good in 95.3% of the cases on suprofen and in 97.3% of those on indoprofen. Four patients in the suprofen group experienced adverse reactions that were, however, not drug related.

Indoprofen-induced aplastic anemia in active connective tissue disease detected by drug-specific lymphocyte transformation.

In connective tissue diseases, the differentiation of disease-related hematological aberrations from drug-induced cytotoxic or allergic blood-cell dyscrasias is often difficult. In this paper we report on the positive identification of an indoprofen-induced severe pancytopenia in a multi-drug-treated patient with active systemic lupus erythematosus by use of a drug-specific lymphocyte transformation test.

The effects of indoprofen vs paracetamol on swelling, pain and other events after surgery.

The capability of indoprofen compared to paracetamol in reducing swelling, pain and other events of an acute inflammatory reaction was tested in a double-blind crossover study with bilateral oral surgery. Identical surgical procedures were performed on two separate occasions in 24 patients. After one operation they received tablets of indoprofen, after the other, paracetamol. A double-placebo method was used, as dosage regimens for the two treatments were different. Medication started 3 h after surgery and continued for 3 days. Almost identical swelling was measured after both treatments indicating that indoprofen has the same anti-inflammatory activity as previously found with paracetamol, which reduces swelling with about 30% compared to placebo. The pain and preference assessments were significantly in favor of indoprofen. Subjective bleeding scores were significantly increased with indoprofen. However, bleeding was minimal, and the occurrence of hematoma/ecchymosis was not increased with indoprofen. The results indicate that indoprofen is capable of reducing an acute, post-operative inflammatory reaction. For this purpose, it appears to be more efficient than other non-steroid anti-inflammatory drugs like ibuprofen, oxyphenbutazone, indomethacin and naproxen.

Analgesic treatment in acute myocardial infarction: a comparison between indoprofen and morphine by a double-blind randomized pilot study.

On the basis of the results of an earlier study, showing that i.v. indoprofen induced no clinically significant changes in hemodynamic parameters of patients with acute myocardial infarction (AMI), a double-blind randomized trial was carried out in 40 AMI patients to evaluate the analgesic activity of 400 mg i.v. indoprofen in comparison with 10 mg i.m. morphine hydrochloride. Pain severity was recorded before and at several intervals within 24 h after drug administration. The average analgesic response was prompt and progressive up to the 6th hour in both treatment groups, with no significant difference between drugs in various pain descriptors. However, the proportion of responding patients in indoprofen group was greater than in morphine group at all observation times, indicating a significant difference (p less than 0.05) in favor of indoprofen. In view of its good tolerability, i.v. indoprofen is worth considering in early AMI as an alternative to morphine in those patients in whom non-opiate analgesia might be preferable.

Indoprofen--a new non-opioid analgesic. A comparison with pethidine.

Indoprofen (400 mg), a non-opioid, non-steroidal anti-inflammatory drug, was compared on a random, double-blind basis with pethidine (1,5 mg/kg) after elective caesarean section (40 patients) and after orthopaedic surgery (40 patients). The drugs were given intravenously during anaesthesia and provided adequate analgesia for a period of up to 2 hours postoperatively. No significant differences between the two drugs were noted in terms of efficacy and side-effects.

A study of the analgesic potency of indoprofen and pentazocine in postoperative pain.

The relative potency of intravenous indoprofen and intramuscular pentazocine in postoperative pain was evaluated. Indoprofen was administered in 200- and 400-mg single doses and pentazocine was given in 15- and 30-mg doses. Pain was assessed at different time intervals, and additional medication consumption was recorded, as well as side effects and overall evaluations. An analysis of peak pain intensity difference (PID) has shown a significant dose-effect relationship for both drugs and a potency ratio of 1:7 between indoprofen and pentazocine (mg to mg). Based on the frequency of patients requiring remedication and those reporting total pain relief in at least one instance, the potency ratio of indoprofen:pentazocine was 1:13 and 1:10, respectively. The mean peak PID of the pooled data for both doses of each drug was significantly greater for indoprofen. Intravenous indoprofen 400 mg was ranked the most effective overall.

Double-blind preference and compliance multicentre study in osteoarthritis: once-a-day treatment.

Two-hundred-and-three female patients (mean age: 58 yrs; SD: 8.2 yrs) suffering from osteoarthritis entered this late phase IV multicentre, stratified according to previous therapy (e.g. ketoprofen, naproxen, aspirin, indomethacin or indoprofen), randomized, double-blind, between within-patient trial of 2-week duration. Each patient received either diclofenac SR 100 mg/day (D), piroxicam 20 mg/day (P), or placebo (P1 by oral route. Clinical evaluation (functional class; pain assessment; osteoarthritic condition; joint motility and stiffness) was performed at entry, as well as after the first and the second week. Patient compliance and reported signs and symptoms were recorded after the first week and at the end of the trial. Patient preference, as regards previous therapy, and global evaluation (both by the physicians and the patients) were checked at the end of the trial. The clinical evaluation showed a superiority of D and P over P1. No difference was seen between the two active drugs. Placebo effect was very strong. Global evaluation was significantly in favour of D and P. Patient compliance was extremely good (greater than or equal to 95%). Diclofenac was preferred to naproxen, aspirin and indomethacin, while piroxicam and placebo were preferred only to aspirin. The tolerability of the two active drugs was good and comparable. A significantly lower number of patients complaining of unwanted effects (u.e.) was detected in the placebo group. The number of patients withdrawn for u.e. was similar in the three trial groups.

A comparative oral analgesic study of indoprofen, aspirin, and placebo in postpartum pain.

The purpose of this study was to evaluate the analgesic efficacy and adverse effect liability of single oral doses of indoprofen, 50 mg, 100 mg, and 200 mg, compared with aspirin, 300 mg and 600 mg, and placebo in the relief of moderate to severe postpartum pain. Two hundred-ten patients entered a randomized, double-blind, parallel group study and were evaluated over a six-hour period by a single nurse-observer. There was a significant imbalance in the distribution of pain types across treatments that compromises the interpretation of the results. In addition to analyzing the data from all patients, the subsets with episiotomy/cesarean section pain and uterine cramp pain were examined separately. The latter group had too few patients to permit distinction between drugs. The 100 mg and 200 mg doses of indoprofen were significantly (P less than or equal to .05) more effective than placebo for many variables including the following summary values: sum of pain intensity difference (SPID), sum of hourly relief values (TOTPAR), and % SPID for all patients as well as in the subset of patients with episiotomy/cesarean section pain. Aspirin, 600 mg, was also significantly more effective than placebo for many of the same measures of analgesia in the episiotomy/cesarean section subset. Pairwise differences were also seen between placebo and aspirin, 300 mg, but on fewer variables. Indoprofen, 100 mg, was significantly more effective than aspirin, 600 mg, at hour 6 for pain intensity difference (PID) in the episiotomy/cesarean section subset. The effect of indoprofen appeared to plateau above 100 mg.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimigraine drugs in the management of daily chronic headaches: clinical profiles of responsive patients.

Flunarizine, a Ca-antagonist with demonstrated antimigraine properties, and indoprofen, an anti-inflammatory non-steroidal agent, were used in the treatment of daily chronic headache. Forty-two migraineurs with interval headache (MIH) were treated with flunarizine in a 6-month open trial, while indoprofen was administered to 23 patients with MIH and 7 with chronic tension headache (CTH) in a 2-month, double-blind, cross-over placebo-controlled study. Flunarizine was found effective in over 65% of the patients, while indoprofen was able to improve headache severity in only 30% of the subjects. In the responder patients, the effectiveness of both drugs is more pronounced in MIH, and seems to be ascribable to the ability of the treatments to reduce number and severity of attacks. A higher incidence of previous affective disturbances is found in non-responsive cases. The analysis of factors converting episodic into chronic headache shows slight but not significant differences between responders and non-responders. An impairment of plasma beta-endorphin levels, in the presence of normal ACTH, cortisol and nociceptive RIII threshold values, characterizes daily chronic headache (DCH) patients. Moreover, indoprofen does not significantly affect these biological and neurophysiological parameters independently of the therapeutic response.

Novo conceito no tratamento agudo da cólica renal: nota prévia / New concept in the acute treatment of renal colic preliminary report

Os autores analisam a resposta de 26 pacientes com cólica renal à administraçäo endovenosa de indoprofen, comparativamente à associaçäo hioscina e dipirona. Os casos foram vistos de forma consecutiva e alocados a grupos ingerindo quantidades livres ou controladas de líquidos. Ressalta-se o efeito no mínimo täo eficaz do antiinflamatório no alívio à dor quanto a terapêutica tradicionalmente utilizada, além de um maior período de açäo analgésica. Näo se observou maior incidência de paraefeitos no grupo recebendo indoprofen. Concluímos que a terapia con antiinflamatórios na fase aguda da cólica renal é eficaz e obedece aos princípios fisiopatogênicos do quadro

Comparison of a narcotic (oxicone) and a non-narcotic anti-inflammatory analgesic (indoprofen) in the treatment of renal colic.

Intravenous indoprofen (400 mg), a cyclooxygenase inhibitor, was compared with intramuscular oxicodone hydrochloride (= oxicone 10 mg), a narcotic analgesic agent, in regard to efficacy and side effects in the treatment of renal colic. Oxicone was combined with papaverine (20 mg). Patients were randomized to either treatment, and the drugs were given in double-dummy fashion, i.e. one injection of active drug plus one placebo injection. Pain intensity before and after treatment was registered by the patient (visual analog scale) and by a nurse, who also registered side effects. Oxicone was given to 46 patients and indoprofen to 48. The groups did not differ in body weight, age, sex distribution, or pretreatment intensity of pain. More patients required additional treatment in the oxicone than in the indoprofen group (19 v. 10). At 2-5 min after injection, pain reduction was greater with indoprofen, and more patients in this group had pain relief after 3-5 hours. Side effects were less frequent with indoprofen than with oxicone (1 v. 20 patients), in particular from the central nervous system. This difference probably was related to indoprofen's slow and poor penetration of the blood-brain barrier. The study affirmed that non-narcotic cyclooxygenase inhibitors can replace narcotic analgesics for acute pain alleviation in renal colic. Indoprofen seems to be a useful alternative, with low risk of central nervous side effects.