Zomepirac sodium salt (McN-2783-21-98)

Zomepirac (Zomax, McNeil Pharmaceutical)

Zomepirac Sodium (Zomax) is a pyrrole-acetic acid structurally related to tolmetin sodium (see Figure 1). Zomepirac is a prostaglandin synthetase inhibitor and is not an opioid, an opioid antagonist, or a salicylate. It is the sodium salt of 5-(4-chlorobenzoyl)-1,4 dimethyl-1H-pyrrole-2-acetate dihydrate. Zomepirac has recently been approved by the Food and Drug Administration for marketing in the United States as an analgesic. It is indicated for all forms of mild to moderately severe pain, and is being promoted as a "comprehensive, non-addicting analgesic."

Drug-related headache

A survey was made of 10,506 reports to the WHO Collaboration Centre for International Drug Monitoring from five countries concerning headache, migraine, aggravated migraine and intracranial hypertension associated with drugs. The ten drugs most frequently reported to be associated with headache were indomethacin, nifedipine, cimetidine, atenolol, trimethoprim-sulphamethoxazole, zimeldine, glyceryl trinitrate, isosorbide dinitrate, zomepirac and ranitidine. Regarding migraine, oral contraceptives were also among the most implicated drugs. Most reports of intracranial hypertension concerned tetracyclines, isotretinoin and trimethoprim-sulphamethoxazole. Vasodilatation and salt and water retention with subsequent redistribution of intracranial fluid seem to be common mechanisms underlying drug-related headache. For certain frequently reported drugs, however, the mechanisms of the headache are unknown.

The analgesic and antiinflammatory activity and pharmacologic properties of bromfenac

Bromfenac sodium (2-amino-3-(4-bromobenzoyl)benzeneacetic acid sodium salt sesquihydrate, AHR-10282B) is a potent long-acting, peripheral, analgesic compound possessing antiinflammatory, antipyretic, and prostaglandin synthetase-inhibiting properties. In the acetylcholine abdominal constriction assay in mice, bromfenac (bromfenac sodium) by the oral route at pretreatment times of 10, 20 and 300 min was respectively 3.7, 6.5 and 2.9 times more potent than zomepirac and 3.4, 6.6., and 44.2 times more potent than suprofen. In dogs bromfenac when given orally was 5.8 times more potent than zomepirac in blocking the nociceptive response to bradykinin. Naloxone did not alter the analgesic properties of bromfenac in mice; and after repeated administration, tolerance to analgesia did not develop. Bromfenac, given orally, was more potent than indometacin in suppressing acute (7.5-20 times) and chronic (3.8 times) inflammation. The gastric and intestinal toxicity potencies of bromfenac, given orally, were comparable with and 1.8 times more potent than indometacin, respectively. Bromfenac was 6.1 to 32.8 times more potent than indometacin in inhibiting the formation of prostaglandin E2 and F2 alpha from microsomes of bovine seminal vesicles, rabbit uteri, and rabbit renal medullae; but it did not block the direct action of prostaglandin E1 (abdominal constriction) and prostaglandin F2 alpha (contraction of the uterus). Bromfenac produced no unwanted central nervous system, cardiovascular, or autonomic effects.

Determination of analgesic drug efficacies by modification of the Randall and Selitto rat yeast paw test

This report describes a modified Randall and Selitto (1957) rat yeast paw test that can evaluate differences in efficacy of different analgesics. The modifications consist of a decrease in the rate of acceleration of the noxious stimulus (mechanical pressure) on the inflamed paw from 20 to 12.5 mmHg/sec and an extension of the cut-off time from 15 to 60 sec. All the narcoticlike drugs tested (morphine, codeine, and pentazocine) increased the response latencies of the inflamed paws to the cut-off time. The nonsteroidal antiinflammatory-like drugs tested (acetylsalicylic acid, acetaminophen, indomethacin, phenylbutazone, and proquazone) showed plateaus in their analgesic effects (i.e., increasing the dose failed to produce significantly greater increases in the response latencies compared to the next lower dose). Zomepirac (80-240 mg/kg p.o.) did not show this plateau effect, but was unable to increase response latencies to greater than 30 sec because of the toxicity of higher doses (320 mg/kg p.o.). Flunixin NMG (the meglumine salt of flunixin), a nonnarcotic analgesic, did not display a plateau effect and increased response latencies to maximum values. The methodology was therefore able to discriminate analgesics active against mild to severe clinical pain (narcoticlike) from those only useful against mild to moderate pain (nonnarcotic-like).

Continuous body fluid monitoring for zomepirac by fully automated high-performance liquid chromatography

A sensitive, specific and rapid determination of 5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrole-2-acetic acid sodium salt dihydrate (zomepirac sodium, Zomax) in human plasma and urine by a continuous body fluid monitoring system based on high-performance liquid chromatography is described. Samples are directly injected into the apparatus which consists of commonly available HPLC-modules. Manual sample clean-up procedures as well as the addition of an internal standard are not needed. Using 50-microliter aliquots, the detection limit is lower than 0.05 microgram/ml and the calibration ranges from 0.5 to 100 micrograms/ml are linear for both, spiked samples and references. The recovery is 97% for plasma and 95% for urine samples at a sampling rate of about 15 samples/h.