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A patient with acute interstitial nephritis secondary to ingestion of a Chinese herbal medicine adulterated with mefenamic acid is presented. Following hemodialysis and cessation of the medication the patient's renal function returned to normal.
Indomethacin added to the perfusing buffer inhibited pressor responses to noradrenaline, angiotensin II, arginine vasopressin, histamine, serotonin, calcium ions and potassium ions in the male rat mesenteric vascular bed. For every pressor agent the indomethacin concentration which inhibited response amplitude by 50% was about 7 microg/ml (2.1 X 10(-5) M). With every pressor agent, prostaglandin (PG) E2 could restore normal responsiveness in indomethacin-blocked preparations even while the indomethacin was still present in the buffer. The concentration of PGE2 required was proportional to the concentration of indomethacin. Preparations completely inhibited by indomethacin needed about 5ng/ml PGE2 for complete restoration of normal responses. Aspirin and mefenamic acid could also inhibit responses to all pressor agents tested but with these drugs only a partial restoration could be achieved by PGE2.
Manual crushing of one blastocyst performed on 181 bicornuate twin pregnancies between Days 24 and 45 has shown that the uncrushed blastocyst can either survive and develop normally to full term or may be rejected and resorbed like its crushed twin, depending mainly on the stage of pregnancy. Crushing, which causes rupture of fetal membranes, results in a rapid fall in the survival rate of the uncrushed blastocyst when performed after Day 31. In some mares rupture is not possible after Day 35 even if extreme pressure is used. Crushed, but unruptured, blastocysts mainly between Days 35 and 45 may (a) resorb as does the uncrushed twin (60%) (b) resorb without loss of the uncrushed twin (20%) or (c) survive, as does the uncrushed twin, even when several attempts on alternate days are made to destroy the blastocyst (20%). At no stage of pregnancy is the uncrushed embryo resorbed unless the crushed twin is destroyed. The rejection and resorption of the uncrushed twin is not due to transference of pressure, but presumably to physiological processes involving prostaglandin. Mefenamic acid appears to increase survival rates especially when crushing is performed after 31 days, although the twin of apparently successful crushings at this stage may be lost between Days 50 and 70.
Challenge tests with some analgesics in common use were performed in five aspirin-sensitive asthmatics. Marked falls in FEV(1) were observed after ingestion of paracetamol, indomethacin, mefenamic acid, and dextropropoxyphene in some subjects. The mechanisms of analgesic-induced asthma are discussed: it is believed to be a non-immunological process of great practical importance when prescribing analgesics to asthmatics.
Endothelin-1 (ET-1) induces persistent vasoconstriction via a sustained increase in intracellular free Ca2+ concentrations ([Ca2+]i). The mechanisms of the elevation of [Ca2+]i operating at physiologically low concentrations of ET-1 are controversial. Here we report that both native ETA receptors in vascular smooth-muscle cells and recombinant ET(A) receptors expressed in mouse fibroblasts (Ltk cells) are functionally coupled with a non-selective cation channel, which is permeable to Ca2+ and is blocked by mefenamic acid. The channel is persistently activated by a low concentration of ET-1 (10(-10) M) without stimulation of inositol triphosphate (IP3) formation and mediates sustained vasoconstriction.
OBJECTIVE: Many patients with chronic disease use alternative therapies. Our objective was to investigate complications resulting from the use of Chinese herbal medications containing undeclared prescription drugs, and to analyze these pills. METHODS: Medical records of 5 patients with complications were reviewed. Pills from symptomatic and asymptomatic individuals were analyzed for possible content of undeclared prescription drugs. RESULTS: All pills analyzed contained mefenamic acid and diazepam. Complications related to the presence of these substances included, among others, massive gastrointestinal bleeding. CONCLUSION: Chinese herbal medications may contain undeclared prescription drugs including nonsteroidal antiinflammatory drugs and benzodiazepines.
Infectious virus could no longer be detected in the trigeminal ganglia removed from mice 25 days after infection with herpes simplex virus type 1 (HSV-1) by the lip route. When the ganglia were cultured in vitro for 1 or 2 days, infectious HSV-1 was again detected in the ganglia, indicating the reactivation of latent HSV-1. The effect of indomethacin on this reactivation was examined. When the ganglia were cultivated in the presence of 5 X 10(-4) M-indomethacin, the appearance of infectious virus in the ganglia was almost completely inhibited. After removal of indomethacin, infectious virus appeared and the virus titre reached levels found in the ganglia cultured in indomethacin-free medium, indicating that the inhibition of the reactivation may not be due to the cytotoxic effect of indomethacin on the ganglionic cells. The inhibitory effect of indomethacin was only seen when it was added shortly after explantation. These results suggest that indomethacin affects some early processes of viral reactivation in the explanted ganglia. The synthesis of prostaglandins (PGE and PGB) found in the explanted ganglia was strongly suppressed by indomethacin, as was the viral reactivation. Other inhibitors of prostaglandin synthesis, i.e. tetracaine, mepacrine and mefenamic acid, also inhibited viral reactivation in the explanted ganglia. These results suggest that the inhibitory effect of indomethacin on the reactivation of latent HSV-1 may be due to the inhibition of prostaglandin synthesis, although it is possible that other cellular changes which could be caused by indomethacin contributed to the suppression of reactivation.
Blood mononuclear cell suspensions from patients with a severe form of periodontal disease failed to respond by in vitro stimulation to a sonicate from the oral bacterium, Veillonella alcalescens. The proliferative response could be restored by the depletion of TG cells by rosetting with IgG-coated ox erythrocytes and by reconstitution of the cell suspension with 10% plastic-adherent monocytes. Small but statistically significant restoration of the Veillonella response was also achieved by the addition of indomethacin or mefenamic acid to unfractionated cell cultures, indicating only a minor role of prostaglandin (PG) synthesis in the expression of suppressor cells. Since the in vitro response to an unrelated antigen PPD had been found unimpaired, the described TG-cell-mediated suppression of the Veillonella response is apparently antigen-specific.
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of inflammatory diseases. NSAIDs inhibit cyclooxygenase (COX), the rate limiting enzyme responsible for the conversion of arachidonic acid into prostaglandins. Recent studies have shown the existence of two isoforms of cyclooxygenase: COX-1, now often referred to as the constitutive form, and COX-2, an inducible form which is the major isoenzyme involved in prostaglandin synthesis in inflammation and other pathological situations. Since inhibition of prostaglandin production in tissues where they play a physiological role leads to important side effects, a COX-2 preferential inhibitor would present therapeutical advantages. In the present study, we evaluated the inhibitory properties of cyclooxygenase inhibitors on human COX-1 and COX-2 using a heterologous expression system. We investigated instantaneous inhibition and pre-incubation inhibition as well as time recovery of cyclooxygenase activity assays with the aid of four NSAIDs: mefenamic acid, indomethacin, aspirin and NS-398. Our results demonstrate that instantaneous inhibition assays have little correlation with clinical results. Inhibition assays using pre-incubation with the drugs tested, however, more closely resemble the data from in vivo studies. Cyclooxygenase recovery assays enabled better characterization of simple competitive inhibitors, competitive reversible time-dependent inhibitors and irreversible time-dependent inhibitors. The data illustrate the usefulness of our system in allowing a better determination of the pharmacological characteristics of NSAIDs as well as permitting a comparison among different drugs.
We examined the effect of fixed-volume hemorrhage (10 ml/kg) on microvascular diameters and blood flow in the small intestine of the rat using in vivo videomicroscopic techniques. We found that hemorrhage in the absence of a potent cyclooxygenase inhibitor results in a transient decrease in intestinal blood flow and a preferential redistribution of intramural blood flow toward the mucosa because of a localized vasodilator response of the premucosal microvessels. In the presence of the selective cyclooxygenase inhibitor, mefenamic acid, the decrease in intestinal blood flow was more substantial and prolonged, and the localized vasodilator response of the premucosal microvasculature was abolished. Our results suggest that vasodilator prostaglandins contribute to the compensatory response of the intestine to hemorrhage and are responsible for the shunting of blood toward the mucosa during hemorrhagic hypotension.
Six patients with menorrhagia due to dysfunctional uterine bleeding and one patient with an intrauterine contraceptive device were treated with prostaglandin-synthetase inhibitors in an attempt to reduce their excessive menstrual blood-loss. Mefenamic acid (six patients) or flufenamic acid (one patient) taken during menstruation for 2-3 cycles reduced menstrual loss in each patient. These preliminary observations suggest a new treatment for a common gynaecological problem and could imply that prostaglandins are involved in the aetiology of excessive menstrual blood-loss in such patients.
Rabbit peripheral blood was tested for the ratio of T and B lymphocytes and for the number of plaque forming cells (PFC) on day 5 and 6 after immunization with sheep erythrocytes. Fever was induced by intravenous injection of lipopolysaccharide (LPS) of E. coli. At higher doses, suppressing the fever, only indomethacin (40 mg/kg per day) inhibited the number of lymphocytes, subpopulation of B cells and their capability for hemolytic antibodies synthesis. This effect was not observed with indomethacin at five fold lower dose. Mefenamic acid (60 mg/kg per day) and acetylsalicylic acid (200-900 mg/kg per day) per se irrespectively of the dose applied, do not affect lymphocyte subpopulations and the primary humoral response. All the three drugs investigated counteracted with the changes in the number of B lymphocytes and PFC induced by LPS.
Both pituitary adenylate cyclase-activating polypeptide-38 (PACAP-38) and growth hormone-releasing hormone (GRH) stimulated growth hormone (GH) release from perfused rat anterior pituitary cells. Tetrodotoxin (TTX) blunted the GH release induced by PACAP-38 but not by GRH. Mefenamic acid, a blocker of non-selective cation channels, unaffected GH release elicited by PACAP-38 and GRH. These results suggest an involvement of TTX-sensitive Na+ channels but not Ca2+-activated nonselective cation channels in PACAP-38-induced GH secretion, and that post-receptor mechanisms for PACAP-38 are different from those activated by GRH.
To demonstrate the role of endogenous renal prostaglandins as modulators of the renin-angiotensin-system in renal hypertension, rats with acute and chronic renal hypertension were pretreated with different inhibitors of the prostaglandin biosynthesis (indomethacin, mefenamic acid, acetylsalicylic acid. Development and course of acute and chronic renal hypertension after treatment were highly significantly different from untreated animals concerning elevation, duration and intensity of renal hypertension. Moreover, indomethacin enhanced renal vasoconstrictor effect of angiotensin II in the dog; accordingly, inhibition of prostaglandin biosynthesis increases acute and chronic renal hypertension. It seems that prostaglandins play an important part in blood pressure regulation.
We studied the effect of transforming growth factor-beta (TGF-beta) on prostaglandin E2 (PGE2) production and mitogenesis in human amnion cells and compared the response in amnion cells with that in A431 cells. Both amnion cells and A431 cells respond to epidermal growth factor (EGF) with increased production of PGE2 whereas EGF promotes mitogenesis in amnion cells but not in A431 cells. In amnion cells, TGF-beta was not mitogenic, and did not alter the mitogenic response of cells to EGF. Treatment of amnion cells with TGF-beta did, however, cause a decrease in PGE2 production relative to untreated cells, although EGF stimulated PGE2 production was not attenuated. In A431 cells, TGF-beta acted to decrease PGE2 production relative to untreated cells and to attenuate the stimulation of PGE2 production effected by EGF. The inhibitory action of TGF-beta on PG production in amnion and A431 cells is contrary to the stimulation of PG production in mouse calvaria reported by others and is suggestive that the effect of TGF-beta on prostaglandin production, like its effect on growth, varies between different cell types. Inhibition of PG production by treatment of amnion or A431 cells with mefenamic acid did not alter thymidine incorporation into DNA in response to EGF; similarly, the addition of PGE2 or PGF2 alpha to culture media of amnion or A431 cells had no effect on mitogenesis (in the absence or presence of EGF). Based on these findings, we conclude that PG production and EGF action on proliferation (stimulation in amnion cells; inhibition in A431 cells) are dissociated.
We have described the case of a 58-year-old woman in whom acute hemolytic anemia, renal failure, and granulocytopenia developed after intake of mefenamic acid and diclofenac. Results of direct and indirect Coombs' tests were negative, but the lymphocyte transformation test was positive for these two nonsteroidal antiinflammatory drugs (NSAIDs). We suggest that the immune complex mechanism could have induced these adverse reactions. Although these drugs are very popular, simultaneous administration should be avoided because serious adverse effects can potentially occur.
A quantitative method for measuring pain threshold by the use of ultrasonic stimulation in man was designed and the possibility of clinical application in assessing analgesics was investigated. Ultrasonic stimulus was given to Japanese subjects on the palmer distal part of the 2nd, 3rd and 4th fingers of both hands. The latent time between start of the stimulation and withdrawal of the hand when perceiving pain was considered the pain threshold. The ultrasonic evoked pain was a sharp pin-prick type, without sensations such as thermal and mechanical. The pain threshold lowered with increasing either stimulus intensity or water bath temperature when the hand of the subject was immersed during measurement. Normal threshold to ultrasonic stimulation measured in both 50 men and 50 women gave nearly normal distribution curves; women being more sensitive to ultrasonics than men. Analgesia with codeine phosphate (20 mg p.o.), aspirin (1.5, 1.0, 0.5 g p.o.), aminopyrine (100 mg p.o.) and mefenamic acid (500 mg p.o.) in volunteers of both sexes was demonstrated significantly using this method under double blind circumstances. Pentobarbital, diazepam, butylscopolamine, bromelain and placebo each in the usual dose used clinically failed to alter the pain threshold. Humans were at least 25 fold more sensitive than mice to the analgesics used herein.
Medications currently available for the prophylaxis and treatment of migraine provide only limited relief. The pathophysiology of migraine is still poorly understood but it is widely accepted that various 'triggers', including fluctuations in the concentrations of circulating ovarian steroid levels, may initiate alterations in the activity of the intracranial vasculature and its efferent and afferent innervation. Recent pharmacological studies utilizing human intracranial artery preparations have addressed two distinct therapeutic stratagems. First, aspirin-like analgesics, which inhibit prostanoid synthesis, are widely used to treat migraine headache. Recent findings suggest that the ability of mefenamic acid to antagonise certain prostanoid actions, in addition to inhibiting synthesis, enhances its effectiveness. Thus, development of selective antagonists of the intracranial vasoconstrictor and the hyperalgesic actions of prostanoids could provide effective and selective migraine remedies. Second, with regard to prophylaxis, particularly of menstrually-related migraine, drugs which mimic the vascular smooth muscle 'stabilizing' action of ovarian steroids, possibly by enhancing potassium channel activation, are likely to be effective if used at concentrations that have minimal hypotensive effects.