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ZALTOPROFEN: AN EFFECTIVE NSAID FOR PAIN MANAGEMENT


ABOUT AUTHORS:
Saxena Vaishali*, Bhale Shweta, Dantoriya Sanjay, Mathariya Arun k., Mahajan S.C., Bhandari Govind
Mahakal Institute of Pharmaceutical studies,
Ujjain (m.p)
*vaishali.saxena0390@gmail.com

ABSTRACT:
Pain management is important for ongoing pain control, especially if you suffer with long-term or chronic pain. NSAIDs or nonsteroidal anti-inflammatory drugs are among the most common pain relief medicines in the world. Every day more than 30 million peoples use them to soothe headaches, sprains, arthritis symptoms, and other daily discomforts, according to the American Gastroenterological Association. Propionic acid derivatives are widely regarded as the drugs of first choice in the management of patients with inflammatory joint disease because they are the class of NSAIDs with the lowest incidence of side effects. Zaltoprofen (ZLT) is a propionic acid derivative of non steroidal anti inflammatory class, which has excellent effect on post-surgery or post trauma chronic inflammation of the drug. So, Zaltoprofen may serve as a potent and superior analgesic for the treatment of pain. Zaltoprofen has the dose of 80 mg three times a day which reduce patient compliance and used in the treatment of rheumatoid arthritis, osteoarthritis, and other chronic inflammatory Pain conditions. ZLT has recently been reported to cause potent inhibition of cyclooxygenase-2 with fewer side effects on the gastro-intestinal tract than other non steroidal anti inflammatory drugs.


REFERENCE ID: PHARMATUTOR-ART-1858

INTODUCTION:
Pain is an unpleasant feeling often caused by intense or damaging stimuli, such as stubbing a toe, burning a finger, putting alcohol on a cut, and bumping the "funny bone."(1, 2)The International Association for the Study of Pain's widely used definition states: "Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage".(3) On a basic level, pain is the result of an electrical signal being sent from your nerves to your brain. But the process is not only electrical. When you get injured, say with a sprain, he damaged tissue releases chemicals called prostaglandins, which are like hormones. These prostaglandins cause the tissue to swell. They also amplify the electrical signal coming from the nerves. Basically, they increase the pain you feel. (4)

NSAIDs: Non steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medication in clinical practice because of their well established efficacy in reducing pain and inflammation. NSAIDs are a necessary choice in pain management, because of the integrated role of the COX pathway in the process of inflammation. NSAIDs are widely used in both the clinical setting like acute or chronic pain setting. (5, 6)


CLASSIFICATION OF NONSTEROIDAL ANALGESICS: Table 1 ( 5, 7)

ZALTOPROFEN:

Description- Zaltoprofen is an effective NSAIDs, which is came from Japan. ZLT, 2-(10, 11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) pro-pionic acid is a potent non-steroidal anti-inflammatory drug (NSAID).8 Propionic acid derivatives are widely regarded as the drugs of first choice in the management of patients with inflammatory joint disease because they are the class of NSAIDs with the lowest incidence of side effects. Ibuprofen was “the first of the propionic” launched in 1969. Since then, Ibuprofen proved to be effective as a prescription drug in a range of painful non rheumatic condition and on the basis of its good safety. It has been used clinically for treatment of post-operative pain and record was approved as an OTC analgesic in 1983 in the United Kingdom and in 1984in the USA. In India, the drug is widely used in clinical practice. ZLT belongs to this class of NSAIDs. (5,9,10) It has been used clinically for treatment of post-operative pain and low back pain for more than ten years. Zaltoprofen is a preferential COX-2 inhibitor3 and selectively inhibits prostaglandin E2 (PGE2) production at inflammatory sites.2 and to induce apoptosis in a variety of cell lines. Zaltoprofen is a unique compound that also has anti-bradykinin activity. Its analgesic effects may be a result of inhibition of bradykinin B2 receptor-mediated bradykinin responses not only of cyclooxygenases but also of bradykinin-induced 12-lipoxygenase inhibitors.8 (FIG.1)

WHY ZALTOPROFEN IS SUPERIOR AS COMPARE TO OTHER NSAIDs?
There are two type of COX enzyme- COX-1 constitutive (responcible for normal GI functions) and COX-2 inducible (responcible for pain). ZLT is the preferential COX-2 inhibitor. ZLT inhibit COX-2 inducible enzyme, while other NSAIDs inhibit both COX-1 and COX-2 enzyme( constitutive and inducible) and damage the normal body function.  So, ZLT does not interfere with normal GI functions.Zaltoprfen shows excellent GI safety as compare to other NSAIDs.12 (Fig.2)

DRUG PROFILE:13   Table2

GEOMETRY:14

  • Dreiding energy = 65.56 kcal/mol
  • Volume = 257.85 Å3
  • Minimal projection area = 44.27 Å2
  • Min z length = 13.85 Å
  • Maximal projection area = 82.63 Å2
  • Max z length = 8.75 Å   (fig.3)

MODE OF ACTION: Zaltoprofen is a nonsteroidal anti-inflammatory drug that exhibits anti-inflammatory, analgesic and antipyretic activities. It is a COX-2 preferential inhibitor. The main mechanism of zaltoprofen is prostaglandin biosynthesis inhibitory action due to the COX inhibition in the arachidonic acid metabolism system. Besides this, membrane stabilizing action such as leukocyte migration inhibitory action and lysosomal enzyme inhibitory action are also observed with zaltoprofen.(fig.4) Experimental studies have shown that Prostaglandin biosynthesis inhibitory action in the stomach tissue is weaker with ZLT than in case of indomethacin. ZLT was shown to have more powerful inhibitory effect to bradykinin-nociceptor than other NSAIDs. (5, 15)

ZALTOPROFEN NSAID WITH NOVEL ANTIBRADYKININ PROPERTY: Zaltoprofen specially blocks the nociceptive response induced by bradykinin. It has a strong inhibitory effect on bradykinin induced swelling and pain.(5,16) Bradykinin and prostaglandin are among the most potent autacoids involved in vascular, inflammatory and pain process. Mixture of these products released due to tissue damage is known as “Inflammatory Soup”. ZLT exerts its analgesic effect by blocking the B2 receptor mediated signalling pathway on primary sensory neuron. (17) ZLT has a strong inhibitory effect on bradykinin induced pain at 5-20mg/kg. (2,18) (fig.5)

PHARMACOKINETIC: Zaltoprofen is well absorbed on oral administration, with more than 82% absorption. ZLT is more than 98% bound to plasma proteins. No accumulation is observed after repeated dose of ZLT. It is predominantly metabolized by CYP2C9 and UGT2B7 in liver. ZLT is also biotransformed to S-oxide zaltoprofen (M-2), 10-hydroxy zaltoprofen (M-3) and S-oxide-10-hydroxy-zaltoprofen (M-5) in humans, and conjugate of M-2 and M-3 are excreted in urine, although urinary level of each of these metabolites account for less than 10% of the dose. After oral administration, 62% of the dose is excreted as conjugate in the urine and only 3% is excreted as unchanged compound by this route. (table3) There is a biphasic reduction in plasma concentration. (T1/2α around 0.9hours and T1/2β around 9hours). (5, 10)

PHARMACODYNAMIC: Zaltoprofen is a NSAID with powerful anti-inflammatory and analgesic effects on inflammatory pain. It is a preferential COX-2inhibitor; it selectively inhibits PGE2 production at site of inflammation. It exhibits a powerful anti-inflammatory effect with ED50, 1-5mg/kg, p.o.dose.(5,20) COX activity for various NSAIDs drugs. Higher IC50 ratio of COX-1/COX-2 indicates selectively for COX-2. (5,16) (Table4)

MICROMERITIC PROPERTIES:

Surface morphology:The results of surface morphology studies were shown in Scanning Electron Microscopy (SEM). The parent zaltoprofen crystals were in the form of fine needle. This long-needle form of zaltoprofen leads to very poor flow and compressional difficulties.(21, 22) (fig.6)

IR spectroscopy:IR spectroscopy studied the possible interaction between the drug and the carrier. (fig.7)The interaction often leads to identifiable changes in the IR profile and melting point of drug.(21)  The principal IR peaks of pure zaltoprofen were shown in Table5.

Differential Scanning Calorimetry Study: The DSC thermograms of pure zaltoprofen were shown in Fig.8. Pure zaltoprofen showed a sharp endotherm at 140.81oC corresponding to its melting point. (21, 22)

FT-IR Spectrum: Fourier-transform infrared (FT-IR) spectra were obtained using an FT-IR spectrometer. The zaltoprofen pure drug was mixed with KBr. The KBr discs were prepared by compressing the powders at a pressure of 5 tons for 5 min in a hydraulic press, which were analysed. (fig.9)All spectra acquired scans between 400 to 4000 cm-1.(23)

High-performance liquid chromatography study: A high-performance liquid chromatography (HPLC) methodology useful for the quantification of ZLT in human plasma samples was reported. An accurately weighed sample (50 mg) of ZLT reference standard was transferred to a 100 mL volumetric flask and dissolved in acetonitrile to make a stock solution of 0.5 mg mL−1. Aliquots from the stock solution were diluted with the diluent to give the solutions in the concentration range 10-140 μg mL−1. (fig.10)The solutions were injected in HPLC and area was measured for each solution. The calibration curve was obtained by plotting peak area on ordinate against drug concentration on abscissa.24

X-Ray Diffraction Study: The atomic planes of a crystal cause an incident beam of X-rays to interfere with one another as they leave the crystal. The phenomenon is called X-ray diffraction. X-ray diffraction study is used for measure the average spacings between layers or rows of atoms, determine the orientation of a single crystal or grain, find the crystal structure of an unknown material, measure the size, shape and internal stress of small crystalline region.25 (fig.11)

Animal studies:The Pharmacokinetics of Zaltoprofen was studied after a Single Intravenous and Oral Administration in Rats. Zaltoprofen was administered intravenously (0.3 mg/kg) and orally (1 mg/kg) to male Wistar rats as a solution. At predetermined time points, plasma was collected from rats and analysed for zaltoprofen by HPLC. Data were analysed using noncompartmental analysis model. After intravenous dosing, the plasma concentration of zaltoprofen declined monoexponentially with a terminal half-life of 2.82 h. Zaltoprofen was absorbed rapidly after oral dosing with 84% bioavailability. After oral dosing (1 mg/kg), the peak plasma concentration of zaltoprofen was 2516 ± 319 ng/mL.26 (Table 6)

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