Neuroprotection of the Inner Retina Also Prevents Secondary Outer Retinal Pathology in a Mouse Model of Glaucoma.

Purpose: We examined structural and functional changes in the outer retina of a mouse model of glaucoma. We examined whether these changes are a secondary consequence of damage in the inner retina and whether neuroprotection of the inner retina also prevents outer retinal changes. Methods: We used an established microbead occlusion model of glaucoma whereby intraocular pressure (IOP) was elevated. Specific antibodies were used to label rod and cone bipolar cells (BCs), horizontal cells (HCs), and retinal ganglion cells (RGCs), as well as synaptic components in control and glaucomatous eyes, to assess structural damage and cell loss. ERG recordings were made to assess outer retina function. Results: We found structural and functional damage of BCs, including significant cell loss and dendritic/axonal remodeling of HCs, following IOP elevation. The first significant loss of both BCs occurred at 4 to 5 weeks after microbead injection. However, early changes in the dendritic structure of RGCs were observed at 3 weeks, but significant changes in the rod BC axon terminal structure were not seen until 4 weeks. We found that protection of inner retinal neurons in glaucomatous eyes by pharmacological blockade of gap junctions or genetic ablation of connexin 36 largely prevented outer retinal damage. Conclusions: Together, our results indicate that outer retinal impairments in glaucoma are a secondary sequalae of primary damage in the inner retina. The finding that neuroprotection of the inner retina can also prevent outer retinal damage has important implications with regard to the targets for effective neuroprotective therapy.

Effect of Pharmacological Inhibition of Fat-Mass and Obesity-Associated Protein on Nerve Trauma-Induced Pain Hypersensitivities.

Genetic knockout or knockdown of fat-mass and obesity-associated protein (FTO), a demethylase that participates in RNA N6-methyladenosine modification in injured dorsal root ganglion (DRG), has been demonstrated to alleviate nerve trauma-induced nociceptive hypersensitivities. However, these genetic strategies are still impractical in clinical neuropathic pain management. The present study sought to examine the effect of intrathecal administration of two specific FTO inhibitors, meclofenamic acid (MA) and N-CDPCB, on the development and maintenance of nociceptive hypersensitivities caused by unilateral L5 spinal nerve ligation (SNL) in rats. Intrathecal injection of either MA or N-CDPCB diminished dose-dependently the SNL-induced mechanical allodynia, heat hyperalgesia, cold hyperalgesia, and spontaneous ongoing nociceptive responses in both development and maintenance periods, without altering acute/basal pain and locomotor function. Intrathecal MA also reduced the SNL-induced neuronal and astrocyte hyperactivities in the ipsilateral L5 dorsal horn. Mechanistically, intrathecal injection of these two inhibitors blocked the SNL-induced increase in the histone methyltransferase G9a expression and rescued the G9a-controlled downregulation of mu opioid receptor and Kv1.2 proteins in the ipsilateral L5 DRG. These findings further indicate the role of DRG FTO in neuropathic pain and suggest potential clinical application of the FTO inhibitors for management of this disorder.

Renal Effects of Cyclooxygenase Inhibition When Nitric Oxide Synthesis Is Reduced and Angiotensin II Levels Are Enhanced.

The involvement of both cyclooxygenase (COX) isoforms in regulating renal function is well known but their interactions with other regulatory mechanisms, such as angiotensin II (Ang II) and nitric oxide (NO), are not well defined. This study has evaluated the relative contribution of both COX isoforms in regulating renal function when NO synthesis is reduced with and without a simultaneous increment in Ang II levels. The renal responses to a nonselective (meclofenamate) or a selective COX2 (nimesulide) inhibitor were examined in dogs pretreated with L-NAME with or without an intrarenal Ang II infusion. Meclofenamate induced a greater (P < 0.05) renal vasoconstriction than nimesulide in dogs pretreated with L-NAME. This vasoconstriction seems to be Ang II-dependent because it was reduced (P < 0.05) by captopril administration. Meclofenamate also induced a greater (P < 0.05) renal vasoconstriction than that elicited by nimesulide in dogs with reduced NO synthesis and elevated Ang II levels. The renal vasoconstriction induced by nimesulide but not that elicited by meclofenamate in dogs pretreated with L-NAME and Ang II, decreased (P < 0.05) during an extracellular volume expansion. These results demonstrate that the nonselective COX inhibition induces a greater renal vasoconstriction than that elicited by the selective COX2 inhibition when NO synthesis is reduced, and when NO synthesis is reduced and Ang II levels are elevated.

Meclofenamate elicits a nephropreventing effect in a rat model of ischemic acute kidney injury by suppressing indoxyl sulfate production and restoring renal organic anion transporters.

Indoxyl sulfate (IS), a putative low-molecular weight uremic toxin, is excreted in the urine under normal kidney function, but is retained in the circulation and tissues during renal dysfunction in acute kidney injury and chronic kidney disease. IS, which is one of the most potent inducers of oxidative stress in the kidney and cardiovascular system, is enzymatically produced in the liver from indole by cytochrome P450-mediated hydroxylation to indoxyl, followed by sulfotransferase-mediated sulfate conjugation. We used rat liver S9 fraction to identify inhibitors of IS production. After testing several compounds, including phytochemical polyphenols, we identified meclofenamate as a potent inhibitor of IS production with an apparent IC50 value of 1.34 µM. Ischemia/reperfusion (I/R) of rat kidney caused a marked elevation in the serum IS concentration 48 hours after surgery. However, intravenous administration of meclofenamate (10 mg/kg) significantly suppressed this increase in the serum level of IS. Moreover, IS concentrations in both kidney and liver were dramatically elevated by renal I/R treatment, but this increase was blocked by meclofenamate. Serum creatinine and blood urea nitrogen were markedly elevated in rats after renal I/R treatment, but these increases were significantly restored by administration of meclofenamate. Renal expression of both basolateral membrane-localized organic anion transporters rOAT1 and rOAT3 was downregulated by I/R treatment. However, expression of rOAT1 and rOAT3 recovered after administration of meclofenamate, which is associated with the inhibition of I/R-evoked elevation of prostaglandin E2. Our results suggest that meclofenamate inhibits hepatic sulfotransferase-mediated production of IS, thereby suppressing serum and renal accumulation of IS. Meclofenamate also prevents the prostaglandin E2-dependent downregulation of rOAT1 and rOAT3 expression. In conclusion, meclofenamate was found to elicit a nephropreventive effect in ischemic acute kidney injury.

Antitumor effect of meclofenamic acid on human androgen-independent prostate cancer: a preclinical evaluation.

PURPOSE: Prostate cancer is a worldwide public health problem and its treatment continues to be a therapeutic challenge especially in patients with metastatic androgen-independent cancer. Inflammation is a process that has been involved in the origin of this cancer and its inhibition has been postulated as a prophylactic and therapeutic strategy. The present study evaluated two non-steroidal anti-inflammatory drugs (meclofenamic acid and mefenamic acid) that have been studied very little in regard to cancer treatment. METHODS: In vitro, the cytotoxic effects of meclofenamic acid and mefenamic acid were determined in human prostate cancer cell lines (LNCaP: androgen-dependent; and PC3: androgen-independent). In vivo trials were divided into two phases; meclofenamic acid toxicity was initially determined at different doses (0, 5, 10 and 20 mg/kg/day/25 days) in BALB/c mice, after which a trial using non-toxic doses was carried out to evaluate the antitumor efficacy of the drug in a PC3/nude-mouse model of human androgen-independent prostate cancer. RESULTS: In vitro trials showed that only meclofenamic acid is highly cytotoxic in neoplastic prostate cells. The 5 and 10 mg/kg/day/25 day doses did not cause relevant toxicity in the BALB/c mouse trial, and so both doses were used in the nude-mouse model of cancer trial. This latter trial showed that meclofenamic acid significantly reduces tumor growth, prolongs survival, and is even capable of generating total tumor regression in up to 25% of mice treated at high dose. CONCLUSIONS: Meclofenamic acid was shown to be a potential antineoplastic agent for both androgen-dependent and androgen-independent prostate cancer.

Antiepileptic effect of gap-junction blockers in a rat model of refractory focal cortical epilepsy.

PURPOSE: Epilepsy is the most common serious neurologic disease, and current treatments are ineffective for or=1 h before drug infusion and for >or=3 h afterward. No ill effects were observed. RESULTS: An immediate and marked reduction in percentage of seizure time was seen in rats receiving carbenoxolone (baseline, 69.4%+/- 7.0% (SEM); maximum effect, 9.3%+/- 3.5%, p

Starch-based microspheres produced by emulsion crosslinking with a potential media dependent responsive behavior to be used as drug delivery carriers.

This paper describes the development and characterization of starch microspheres for being used as drug delivery carriers in tissue engineering applications. The developed starch microspheres can be further loaded with specific growth factors and immobilized in scaffolds, or administrated separately with scaffolds. Furthermore and due to the processing conditions used, it is expected that these microspheres can be also used to encapsulate living cells. The aim of this study was to evaluate the efficacy of this methodology for further studies with biologically active agents or living cells. The starch microspheres were prepared using an emulsion crosslinking technique at room temperature to allow for the loading of biologically active agents. A preliminary study was performed to evaluate the incorporation of a model drug (nonsteroidal anti-inflammatory drug-NSAID) and investigate its release profile as function of changes in the medium parameters, such as ionic strength and pH. The developed starch-based drug delivery system has shown to be dependent on the ionic strength of the release medium. From preliminary results, the release seems to be pH-dependent due to the drug solubility. It was found that the developed microspheres and the respective processing route are appropriate for further studies. In fact, and based in the processing conditions and characterization, the developed system present a potential for the loading of different growth factors or even living cells on future studies with these systems for improving bone regeneration in tissue engineering, especially because the crosslinking reaction of the microspheres takes place at room temperature.

Pharmacokinetics of sodium meclofenamate in pre-ruminant cattle

O perfil do meclofenamato sódico, uma droga antiinflamatória não-esteroidal, foi determinado em seis bezerros pré-ruminantes após administração intravenosa e intramuscular na dose de 2,2mg/kg de peso vivo. As concentrações de meclofenamato foram medidas empregando-se cromatografía líquida de alta performance. A farmacocinética do meclofenamato sódico, após as administrações intravenosa e intramuscular, caracterizou-se por rápida fase de distribuição (t½a ), 15,45±4,85min e 23,14± 7,24min para a administração intravenosa e intramuscular, respectivamente, seguida por longa fase de eliminação (t½b ), após a aplicação intramuscular (17,55±6,52h.). O volume aparente de distribuição (Vd) da administração intravenosa da droga foi moderado (0,72±0,12l/kg), e após um lapso da aplicação intramuscular, foi alta (3,51±1,05l/kg). Isso pode ser explicado pelo efeito flip-flop ou por evitar a via enteroépatica. A biodisponibilidade obtida após administração intramuscular foi de 61 por cento.

In vivo and in vitro action of endothelin-1 on goat cerebrovascular bed.

This study concerned the effects and mechanisms of action of endothelin-1 on the cerebral circulation. Cerebral blood flow was electromagnetically measured in awake goats. Endothelin-1 (0.01-0.3 nmol) produced dose-dependent decreases in this flow (maximal reduction = 34%) and increases in cerebrovascular resistance (maximal increase = 74%) (P < 0.01). IRL 1620 (Suc-[Glu9, Ala11,15]endothelin-1-(8-21), agonist for endothelin ET(B) receptors, 0.01-0.3 nmol) slightly decreased cerebral blood flow. The effects of endothelin-1, but not those of IRL 1620, on cerebral blood flow were diminished by 50% during infusion of the antagonist for endothelin ET(A) receptors, BQ-123 (cyclo-(D-Asp-Pro-D-Val-Leu-Trp), 2 nmol min(-1)), but not affected during infusion of the antagonist for endothelin ET(B) receptors, BQ-788 (N-[N-[N-[(2,6-dimethyl-1-piperidinyl)carbonyl]-4-methyl-L-Leucyl-1-(met hoxycarbonyl)-D-tryptophyl]-Dnorleucine monosodium), 2 nmol min(-1)). Intravenous administration of NW-nitro-L-arginine methyl ester (L-NAME, 47 mg kg(-1)) or NW-nitro-L-arginine (L-NNA, 47 mg kg(-1)) reduced basal cerebral blood flow by 39 and 33%, increased cerebrovascular resistance by 108 and 98% and mean arterial pressure by 23 and 17%, and decreased heart rate by 27 and 25%, respectively (all at least P < 0.05). The increases in cerebrovascular resistance (as absolute values) induced by endothelin-1 were not affected during either L-NAME or L-NNA (as absolute values and percentages). Intravenous administration of meclofenamate (5 mg kg(-1)) did not change the cerebrovascular effects of endothelin-1 and IRL 1620. In isolated goat cerebral arteries under control, resting conditions, endothelin-1 (10(-11)-10(-7) M) induced concentration-dependent contractions (EC50 = 4.78 X 10(-9) M; maximal contraction = 3177+/-129 mg), whereas IRL 1620 (10(-11)-10(-7) M) produced no effect. This contraction produced by endothelin-1 was competitively blocked by BQ-123 (10(-7)-3 X 10(-6) M), and was not affected by BQ-788 (10(-6) and 10(-5) M). L-NAME (10(-4) M), meclofenamate (10(-5) M), indomethacin (10(-5) M), L-NAME (10(-4) M) plus meclofenamate (10(-5) M) and phosphoramidon (10(-4) M) did not affect the contraction in response to endothelin-1. Endothelium removal increased the response to endothelin-1, as well as the BQ-123 antagonism against endothelin-1 (pA2 values, 7.62 vs. 6.88; P < 0.01). In both intact and de-endothelized arteries precontracted with prostaglandin F2alpha endothelin-1 induced a further contraction, and IRL 1620 caused no effect. These results suggest that: (1) endothelin-1 produces cerebral vasoconstriction by activating endothelin ET(A) receptors probably located in smooth muscle; (2) endothelin ET(B) receptors, nitric oxide and prostanoids might be not involved in the cerebrovascular action of endothelin-1, and (3) endothelium removal may increase cerebrovascular reactivity by increasing sensitivity of endothelin ET(A) receptors to endothelin-1.

Role of nitric oxide and prostaglandins in the long-term control of renal function.

Previous studies have reported evidence of an important interaction between nitric oxide (NO) and prostaglandins in the acute regulation of renal function. The objective of this study was to determine in conscious dogs whether the renal effects of the prolonged administration of a cyclooxygenase inhibitor are enhanced when NO synthesis is reduced. Meclofenamate infusion (5 microg x kg(-1) x min(-1)) during 4 consecutive days (n=8) elicited a continuous decrease (P<0.05) in renal blood flow and plasma renin activity and a transitory decrease in sodium excretion. NG-Nitro-L-arginine methyl ester (L-NAME) infusion (5 microg x kg(-1) x min(-1)) during 6 days (n=8) produced a significant increase in arterial pressure and a transitory decrease (P<0.05) in both renal blood flow and plasma renin activity. The simultaneous inhibition of NO and prostaglandin synthesis (n=7) led to an increase in arterial pressure and a decrease in renal blood flow similar to those observed during the administration of either L-NAME or meclofenamate. In contrast, this simultaneous inhibition produced a decrease in glomerular filtration rate, which was not observed in the previous groups, and also induced an increase in renal vascular resistance and a decrease in sodium excretion greater (P<0.05) than those found during the inhibition of either NO or prostaglandins. Only a transitory decrease in plasma renin activity was found during meclofenamate infusion in this group. The results of this study present new evidence that the renal vasoconstrictor and antinatriuretic effects induced by the prolonged infusion of a cyclooxygenase inhibitor are significantly enhanced when NO synthesis is reduced. These results suggest that renal function may be more sensitive to the prolonged administration of a cyclooxygenase inhibitor in situations where NO production is reduced.

Effects of verapamil on the renal actions induced by nitric oxide and prostaglandin synthesis inhibition.

This study was designed to determine the effects of a calcium antagonist (verapamil) on the renal actions induced by nitric oxide synthesis inhibition, with and without simultaneous prostaglandin synthesis inhibition. The renal effects of verapamil (2 micrograms/kg/min) were examined in anesthetized dogs before and after an increase of extracellular volume and during the reduction of nitric oxide synthesis (1 microgram/kg/min NG-nitro-L-arginine methyl ester [L-NAME]), with and without the administration of a cyclooxygenase inhibitor (5 micrograms/kg/min meclofenamate). Nitric oxide synthesis inhibition produced an increase in proximal sodium reabsorption (lithium clearance technique) and a decrease in the excretory response to volume expansion that was prevented by the administration of verapamil. The administration of a cyclooxygenase inhibitor, during nitric oxide synthesis inhibition, elicited an increase in arterial pressure, an important renal vasoconstriction, and reduced the renal excretory response to volume expansion. The antinatriuretic effect produced by the simultaneous reduction of nitric oxide and prostaglandin synthesis, before and after the volume expansion, was abolished with the verapamil infusion. However, the increase of arterial pressure and renal vasoconstriction were only partly affected by verapamil. We found that the antinatriuretic effect secondary to the reduction of nitric oxide synthesis, during an increase in extracellular volume, is prevented by the administration of verapamil. Additionally, the administration of verapamil completely prevents the antinatriuretic, but not the vasoconstrictor, effects induced by the administration of a cyclooxygenase inhibitor when nitric oxide is slightly reduced.

Influence of closure of the reticular groove on the bioavailability and disposition kinetics of meclofenamate in sheep.

Sodium meclofenamate is a non-steroidal anti-inflammatory drug with anaphylactic protective activity in cattle. The objectives of this study were to describe the pharmacokinetic behaviour of sodium meclofenamate after intravenous and oral administration to sheep and to determine the influence of closure of the reticular groove on the bioavailability of the drug. Sodium meclofenamate was administered by the intravenous (2.2 mg/kg) and oral (20 mg/kg) routes to sheep (n = 6). During the oral study the reticular groove was closed by intravenous administration of lysine vasopressin (0.3 IU/kg) or left open (saline solution). The closure of the reticular groove was assessed by determination of the blood glucose curves after oral administration of a glucose solution. After intravenous administration of meclofenamate, the distribution and elimination half-lives of the drug were 7.2 min and 542 min respectively, Vss was 1.68 L/kg and ClB was 2.47 mliter/min kg. Two different patterns of the plasma concentration curves were observed after oral administration of sodium meclofenamate. When the reticular groove was closed, two peaks were observed (tmax-1 12-15 min, Cmax-1 3.30-24.01 micrograms/mliter; and tmax-2' 52.50-75 min, Cmax-2, 6.45-11.08 micrograms/mliter).

Comparison of the kinetics of sodium meclofenamate versus meclofenamic acid after oral administration to sheep.

Meclofenamates are non-steroidal anti-inflammatory agents used in ruminants for the prevention and the treatment of anaphylactic processes. The objective of the present work was to study possible kinetic variations due to the chemical form of meclofenamates administered by the oral route to adult sheep. Six Rubia del Molar female sheep (2-3 years old, 47-57 kg) were used. Initially, an intravenous administration of sodium meclofenamate (2.2 mg/kg bwt) was given; the obtained kinetic results were in agreement with data from other authors. Oral administrations (20 mg/kg bwt) of sodium meclofenamate and meclofenamic acid were then given. When the reticular groove was opened, both drug forms showed a single meclofenamate plasma peak; t2max were 60.0 +/- 10.61 min and 127.50 +/- 22.5 min for the sodium and acid form, respectively. The elimination rate constants (beta) were not significantly different, but the absorption half-lives were (14.69 +/- 3.21 min for the sodium form and 61.07 +/- 21.7 min for the acid form). The bioavailability was 48.6 +/- 4.3% for sodium meclofenamate and 65.1 +/- 2.8% for meclofenamic acid. Thus, the chemical form (sodium versus acid) alters the oral bioavailability and tmax of meclofenamates in adult sheep. These findings agree with the behaviour of meclofenamates in man.

Single dose and multidose analgesic study of ibuprofen and meclofenamate sodium after third molar surgery.

The purpose of this study was to compare the analgesic efficacy and safety of meclofenamate sodium with ibuprofen after dental impaction surgery. This study was double-blind and used a unique methodology. Patients (N = 254) were first randomized into the single dose phase of the study that included placebo, meclofenamate 50 mg, meclofenamate 100 mg, ibuprofen 200 mg, and ibuprofen 400 mg, followed by a 7-day multidose phase in which patients in the placebo group were rerandomized into one of the active treatment cells. In the single dose phase, all active treatments were significantly more efficacious than placebo for every summary analgesic measure. A positive dose-response was seen for both active drugs with meclofenamate 100 mg and ibuprofen 400 mg exhibiting the greatest efficacy for pain relief, pain reduction, time to remedication, and overall evaluation. Side effects were reported by 26 patients. They were evenly distributed among treatment groups with headache and drowsiness being the most common. During the multidose phase, there were only small differences in efficacy measures among active treatment groups. However, meclofenamate produced a higher incidence of stomach cramps and diarrhea than did ibuprofen (8.8% and 7.2% versus 0.8% and 0.8%). This study indicates that higher doses of nonsteroidal anti-inflammatory drugs are most effective immediately after surgery and that lower doses of these drugs can be used after the first postoperative day. The side effect profile of nonsteroidal anti-inflammatory analgesics is best observed with the use of a multidose study design.

Efficacy of meclofenamate sodium (Meclomen) in the treatment of rapidly progressive periodontitis.

This 6-month, double-blind, controlled clinical trial determined the efficacy of the non-steroidal anti-inflammatory drug, meclofenamate sodium (Meclomen), as an adjunct to scaling and root planing in the treatment of rapidly progressive periodontitis (RPP). 22 subjects (7 male, 15 female) aged 36.5 +/- 7.88 years with RPP and disease-active sites as determined by pretreatment bone scan had standardized radiographs at baseline and 6 months, and clinical measurements at baseline, 3 and 6 months. Following full-mouth scaling and root planing, subjects were randomly assigned to either a placebo, 50 or 100 mg meclofenamate sodium bid group. Bone change over the 6-month period as assessed by subtraction radiography was the primary efficacy determinant. Specialized software was used to isolate the lesion from the subtraction image and to measure bone change along the root surface. ANOVA using the subject as the unit of analysis revealed a significant dose response (p < 0.001) with the placebo group having a mean bone loss of 0.42 +/- 0.06 mm and the low and high dose groups having mean bone gains of 0.07 +/- 0.05 and 0.20 +/- 0.07 mm, respectively. These findings indicate that meclofenamate sodium may be a useful adjunct in the treatment of rapidly progressive periodontitis.

Identification of two different rate-limiting mechanisms controlling the release of NSAIDs from silastic polymeric devices, and possible implications.

Two different rate-limiting mechanisms have been found by examining the release characteristics of meclofenamic acid, BW755C.hydrochloride, and diclofenac sodium from silastic polymeric rods into phosphate (0.1 M, pH 7.3) at 37 degrees C. Experiments were performed using rods with initial drug concentrations of 3, 6 and 9% w/w and plots of Q-t and Q-t1/2 were made (Q, cumulative amount of drug released into solution; t, time). For each of the three loadings of meclofenamic acid, the Q-t1/2 plot was linear which indicated a matrix controlled release of the drug. With diclofenac sodium, each of the three loadings gave a Q-t plot that was linear thereby indicating a partition controlled release of this drug. For BW755C.HCl, the release of the drug from rods at the two lowest loadings was matrix controlled, but release from rods at the highest loading was partition controlled. The possible implications of these findings are discussed in regard to medicated vaginal devices or intracervical devices.

An attempt at real prophylaxis of primary dysmenorrhea: comparison between meclofenamate sodium and naproxen sodium.

Dysmenorrhea is a widespread phenomenon, affecting mainly young nulliparous women, often inducing difficulties in study or in work. Its pathogenesis involves a release of local vasoconstrictors like Prostaglandins and Leukotrienes. Modern therapy is based firstly on the administration of prostaglandin-Synthetase Inhibitors or Contraceptive Pills, with the aim of reducing the menstrual excess of pain inducing substances. In order to achieve more efficacy, on the basis of the already proven effectiveness of the Non Steroid Anti-Inflammatory Drugs (NSAID)s in this field, we recently set out to prevent dysmenorrhea in a double-blind randomized study with Meclofenamate Sorium and Naproxen Sodium. Through the observation of the drop in Basal Body Temperature which usually precedes menstrual flow, we were able to instruct our patients in the earlier recognition of impending menstrual onset, leading to earlier prevention of Prostaglandin and Leukotriene release. Meclofenamate Sodium in particular led to considerable pain reduction, with very good patient compliance and without significant complications, probably of its additional receptor effect.

Studies of meclofenamic acid and two metabolites in horses--pharmacokinetics and effects on exercise tolerance.

The pharmacokinetics and the effects on treadmill exercise of the anti-inflammatory drug meclofenamic acid were studied in seven Standardbred horses after single intravenous and/or oral doses. The decline in plasma concentration after a single intravenous dose of meclofenamic acid (2.2 mg/kg b.wt) was described by a two-compartment open model. The average elimination half-life was 1.4 h, the apparent volume of distribution 0.14 l/kg and the plasma clearance 0.12 l/h kg. Absorption was the rate-limiting step after oral administration. Non-compartmental analysis showed a mean absorption time of 4.3 h. The pharmacokinetics of two metabolites of meclofenamic acid were also studied in two of the horses. The elimination half-lives of the two metabolites were virtually the same in each horse (3.0 h and 3.4 h). The blood lactate response to exercise was significantly decreased after treatment with meclofenamic acid, indicating a lower utilization of the glycolytic ('anaerobic') energy contribution during exercise. Circulatory capacity was apparently unaffected with an unchanged heart rate response to exercise.

Effects of meclofenamic acid in the treatment of lesions deriving from minor traumatology.

The clinical efficacy and tolerability of topical 5% meclofenamic acid gel versus placebo and oral sodium meclofenamate versus sodium naproxen were evaluated in patients affected with minor traumatologies. Ninety patients were studied: 60 were treated with either meclofenamic acid gel or placebo for 10 days, and 30 were administered with either sodium meclofenamate capsules or sodium naproxen capsules for 7 days. The 5% meclofenamic acid gel and its sodium salt in capsules proved significantly more rapid and efficient than did the reference compounds in reducing pain symptomatology. In the patients treated with 5% meclofenamic acid gel, a greater effect was seen as regards rapidity of spontaneous movement and nocturnal pain reduction. In other variables examined, that is, surface and deep hyperalgesia, and swelling and functional restriction, there was also a significantly higher efficacy than with placebo. Confirmation of the therapeutic efficacy of meclofenamic acid (sodium salt) was obtained with the capsule formulation, that was seen to exert a significant analgesic and antiphlogistic action; the onset of this action was particularly rapid. Both formulations of meclofenamic acid (gel and capsules) were found to be well tolerated. Thus, in the examined formulations, meclofenamic acid proved to be a useful tool in the treatment of lesions in the minor traumatology category.