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Cellular Ultra Structural Damage by Heavy Metal Cadmium Toxicity

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Cellular Ultra Structural Damage by Heavy Metal Cadmium Toxicity

    Comparison Between Two NSAIDs (Non selective & selective

    COX-2 Inhibitor) According to their Renal Toxicity on Elderly

     People

     *Haydar F. Hadi,

     :ح???ناا

     ل?? ??ن??? .خ?ع?نا? م????نا م???ي ?ا??ا فهر??ن ىن??نا ء???ا م? ?? ?اش??? ح????ش?ر??ا خ?ت??رن?ا خا??عي م??ر?ذ

     ?ي حه??? خاشر?ن ده??ر?ا ا?ا ح??? ?ه?نا ح????ن ??ر???? ??ش???ذ م?ي ح?ث??? خاش???ذ ??ن ??? ح?ئ?????نا خ?ث?ش?نا م?

     ض?شذ ح?اس?نا ?ز? .ح?ظشي ح??ه? ?ا ح?ثهق م???ي ى???ن ?ا ى???ن ?ه?نا ح???? ?????ا ?ي ???ا ?????? ??زنا? ??نا س?ث?

     ??????ي????ا ??? (COX) ى?ض?ا ???ذ?ت ?ئ??ر?ا ? ?????ا خ?ث?ش?نا ?ز? ?ي ????? ح?س???ت كن?? ?ح???نا ?ز? ?ه?

     ش??ذ سا??ي ز??ت كن?? ?ه?نا ?ه? ى?ر???? ى?ش???ذ ة??? ?و??????ه??نا ??? (COX-2) ى?ض?ا ???ذ?ت ح?ئ??ر?ا ?? ش??ا?

     ل???? ?ش?ا ???ذا ??? .?????ت ح?س???هن ??نا س?ث? ?ه? ح???نا ?ز? م?ي ?ه? مئ??? (S. K+) ? (S. Cr), (BUN) ى?ق

     .? ?ا ح???نا ?ز? ج???ص ?? ????ذ ?ظش?نا ء?ؤ? ??? ح??ه? ?ا ح?ثهق م???ي ???? ?ا م? ??ث? ?ا

     ا?ش?ر?ا? ?ح??ه? ?ا ح?ثهق م???ي ?ي ????? ش??ا ط?ثنا? ء???ا ى?ع?ت ???ن?ت ?اش?ث? ??ع?شي 08 ح?اس?نا ?ز? ده??

     ?ي ا?ء?? ?رنا حه???نا ???ن ????ا ءا??? ??ث?ش?نا ??ا ا???ا ??? وض?ذ?يشنا? م????هن ح??? ح??س?? ج???? ?ي

     .??ي?? 51 ج??ن? ??ه?ا

     ح?ث???نا خاش???رنا ??? ??ثث?? )COX ـهن ?ئ??ر??ا ش?غ? ?ئ??ر??ا( ??ث?ش?نا ?? ??ت ح?اس?نا ?ئ?ر? ?ي ???ظا? ش??

     ?اش??ا ?ز? ج???ص ?? ?ا????? ?ق ح??ه? ?ا ح?ثهق حه??ي ???? ?ا ??? ??ن?ت س?ث?نا ?ظش?نا ء?ؤ?ن ?ه?نا ح???? ?ه?

     ح?ن??? ????? ?ا ح??ه?نا ب?ث??ا ?? و?نا ??ظ ???ذسا م?ي ?اشي?ا ح???? ?ه?نا ح???? ?ه? خ?ث?ش?نا ?ز? ح??? ?ا

     .?ظش?نا ?ه?نا

     Abstract :

    The nonsteroidal anti-inflammatory drugs (NSAIDs) are widly used all over the world for different rheumatic musculoskeletal disorders. Like any other chemical compounds, they have different side effects like renal toxicity that becomes very serious when used for long time especially from elderly people whose already have a reduced renal function or those

     This with renal or cardiac problems that may increase the incidence of such toxicity.

     Clinical pharmacy department/College of Pharmacy/ Baghdd University.

    study focusing on this point, by comparing between 2 NSAIDs, a non selective-COX inhibitor (Indomethacin) and selective COX-2 inhibitor (Meloxicam) according to their renal toxicity on elderly patients, depending on changes in values of blood urea nitrogen

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    +(BUN), serum creatinine (S. Cr.) & serum potassium (S. K) concentrations as parameters

    of such toxicity. In another way we investigate whether the renal or cardiac problems will

     increase such toxicity of NSAIDs on elderly patients or not.

    The study involved 80 elderly patients, healthy and with renal or cardiac problems,

    selected from rheumatologic outpatient clinic and given one of the 2 NSAIDs as adrug of

     choice for their present complaints for a period of 15 days.

    It was clearly appeared from results, that both NSAIDs couse similar extent of renal

    side effects and the presence of renal and/or cardiac problems could increase the

     susceptibility of such toxicity especially renal impairment & renal hypertension.

     Introduction:

    All NSAIDs can inhibit the prostaglandin (PG) mediated renal function due to inhibition (1)of kidney PG synthesis. This effect increase in patients with PG depending renal

    problems to oppose the increased vasoconstrictive influence of norepinephrine and (2)angiotensin , in addition to the activity of PG in increasing glomerular filtration rate (3)(GFR) and blood flow, Those PG dependent disease states include volume depletion, (4)cirrhosis, congestive heart failure, nephrosis & chronic renal failure . The

    manifestations of NSAIDs associated renal toxicity include hyperkalemia, (5)tubulointerstitial nephritis and acute renal failaure . In the past, the COX-1 enzyme

    isoform was believed to be the important enzyme involved in renal prostaglandin

    synthesis. However, the COX-2 enzyme was recently noted to have an important role in (6)prostaglandin production during inflammatory process. As a result, this isoform was

    considered to be constitutive and integral to the maintenance of organs (such as kidney & (6), (7)GI tract) integrity . Although the effect of selective COX-2 inhibition on renal

    function was essentially not known, the recent studies suggest a role of this enzyme in the (8),(9)regulation of rennin release. A study of isolated human kidney (nephrotomy

    specimen) showed constitutive expression of COX-2 in location, it is localized in

    endothelial and smooth muscle cells of arteries, arteriols, veins & vasa recta of the (9) medulla .

    The ubnormal laboratory findings may include increasing in BUN, increasing S. Cr,

    protineurea, heamaturea & albuminurea. In case of Indomethacin, serum potassium

    concentration increase by 0.5 mEq/L within 12-36 hours after the administration in +normal renal function but in renal impairment, S.K increase by more than 1 mEq/L and

    reach more than 5 mEq/L and this mainly happen in an elderly, renal dysfunction &

     hypertensive patient (10).

     Method and patients:

    80 elderly male & female patients aged between 57 & 73 years, were involved in this study

    & selected from rheumatologic out patient clinic. They were suffering from deferent

    rheumatic & musculoskeletal disorders in which the NSAIDs are the 1st choice treatment

     prescribed by the physician.

    The patients were divided into 4groups, 20 healthy patients taking indomethacine

    capsules 25 mg 3 times daily in group-1, another 20 patients with renal and/or cardiac

    problems taking also indomethacine capsules 25 mg 3 times daily in group-2, group-3

    involved 20 healthy patients taking meloxicam 7.5mg once daily & finally group 4

    involved 20 patients with renal and/or cardiac problems taking meloxicam 7.5mg once

     daily. The treatment period is 15 days.

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    Age, sex, systolic & diastolic blood pressure, s.cr., BUN & s.k+ for all the patients were

    reported at baseline using Jaff's method , enzymatic method, and the Flame Emission

    Spectrophotemetry method( FES )for estimation of those parameters respectively , taking

    into account the normal value for each parameter according to the method used as follow

    ( male s.cr. 0.9-1.3 mg/dl , female s.cr. 0.6-1.1 mg/dl ),( over 60 year BUN 6-20 mg/dl ) and

     finally ( s.k 3.5-501 mmol/L) .

    Treatment discontinuation was required for all patients with a history of peptic ulcer,

    known sensitivity to NSAIDs and used NSAIDs within 2 weeks prior to start of this

    treatment. In addition, treatment discontinued if s.cr, BUN & s.k+ increased above

     prespecified safety values or even in any abnormal physical examination.

    All patients informed and educated to come to the clinic for checking and for taking blood

    sample to measure BUN,s.cr & sk+ after 4 days, 8 days , 12 days & after 15 days . 10 mls

    of venous blood was taken before starting the treatment (baseline) and at the design days

    for measuring the laboratory parameters (BUN,S.cr & s.k+) in which abnormal changes

    of those parameters used as a detector for renal toxicity for the compared 2 NSAIDs ,

     indomethacine & meloxicam.

    All results are expressed as mean ? SD, T-test for unpaired data was employed & P-value

     of less than 0.05 was considered significant.

     Results:

    All treatment were well tolerated & the patients completed the treatment period with the

    exception of 2 patients in group-2 in which the measurements of laboratory parameters

    after 12 days of treatment show a high increase that the physician preferred to

    discontinue the treatment, also 3 patients from gronp-4 were excluded due to the same

    reason in which high values of the laboratory parameters after the same period (12 days)

     necessate the discontinuation of treatment.

    Figure-1 shows that there is significant differences (p<0.05) in BUN concentration after

    treatment with indomethacin in both grup-1 & group-2 patients when compared with

     control (baseline) of the same group.

    In figure-2, Also there is a significant difference (p<0.05) in BUN concentration with

     meloxicam in both group-3 & group-4.

    There is a significant difference in S. Cr. Concentration after treatment with

    indonethacin in both group-1 & group-2 in comparison with the contral of each group as

     shown in figure-3.

    The same result can be shown in figure-4 in which there is a significant difference

    (p<0.05) in S. Cr. Concentration after treatment with meloxicam in both group-3 &

     group-4 patients in comparison with their control.

    Figure-5 & figure-6 show the same significant difference (p<0.05) in S. K+ concentration

    after treatment with indomethacine & meloxicam respectively in comparison with the

     control of each group.

    The figures from 7 to 12 show the comparison between the 2 compounds according to

    their extent of changes on the laboratory parameters. So, in figure-7, there is no

    significant difference (p>0.05) in BUN level between the healthy patients treated with

     Indomethacine & those treated with meloxicam (group 1&3).

    The comparison between the effect of treatment with Indomethacine & meloxicam on

    patients with cardiac and/or renal problems (grup-2 & 4) show only a significant

     difference in BUN concentration after 4 & 8 days of treatment as shown in figure-8.

    Figure-9 shows that there is only a significant difference in S. Cr. concentration after 12

     days of treatment, between group-1 patients & group-3.

    Figure-10 shows that there is a significant difference in S. Cr. concentration after 4 &8

     days of treatment between the patients of group-2 & group-4.

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    Figure-11 shows that there is a significant difference in S. K+ concentration between the patients of group-1 & group-3 while in figure-12 there is only a significant difference in S.

     K+ concentration after 4 & days of treatment between group-2 & 4 patients.

     Discussion:

An important factor that affects the renal function is the age in which this function

    in elderly people undergoes a remarkable decline with age. This effect could be worsen more in presence of NSAIDs therapy and may lead to serious conditions if accompanied by one or more of renal or cardiac problems which include electrolyte disturbances,

     edema, hypertension, acute & chronic nephritis & acute renal failure.

    Impaired synthesis of renal prostaglandins produced locally in the kidney by NSAIDs

     underlies the pathological process in most cases (11).

    In this study, it was clearly shown that both selective COX-2 inhibitor (meloxicam) & the nonselective COX-inhibitor (Indomethacin) cause a significant increase in the laboratory parameters of kidney function (BUN, S. Cr. & S. K+) in comparison with the control value as shown in the figures 1 to 6. This significant increase occurs in both healthy elderly patients & in orderly patients suffering from cardiac or renal problems. Although, the higher degree of changes in laboratory parameters occur in group-2 & group-4 patients, whose with such problems, which may indicate the probable risk factors that lead to increase renal toxicity of NSAIDs. The degree of increase of the laboratory parameters in those patients excluded from the study may support this result, those 5 patients (2 patients from grup-2 & 3 patients from group-4) already suffer from mild to moderate renal impairment with hypertension and/or with congestive heart failure. The BUN, S. Cr & S.K+ increase after the treatment to values that make the physician to discontinue the treatment after 12 days of treatment, the values of these parameters for

     after 12 the 5 patients were found as follow: (BUN control: 47, 45, 45, 47 & 48 mg /dldays: 64, 63, 63, 68, 69 mg/dl), (S. Cr control: 1.6, 1.8, 1.7, 1.6 & 1.6 mg/dl after 12

     days: 2.6, 2.5, 2.5, 2.7 & 2.8 mg/dl) & finally (S. K+ control: 5.2, 5.0, 4.9, 5.2 &

     after 12 days: 6.4, 6.3, 6.3, 6.2 & 6.4 mEq/l). The another point that 5.0 mEq/l

    support our finding is that such higher values of the laboratory parameters began to decrease after discontination of the treatment and reach to levels near control with the

     use of Bumetanide tab, a loop diuretic, preseribed by the physician.

    These results were in agreement with other study when rofecoxib was compared with Indomethacine in 60 healthy subjects whose ages ranged from 65 to 80 years and whose baseline creatinine clearance ranged from 30 to 80 ml/min, both rofecoxib and Indomethacine significantly reduced GFR equivalently 10% to 12% than control

     value(12).

    Another study that support our results was the report by Perzella and Eras(11), & Whelton(13) et al who studied the effect of NSAIDs on both elderly with renal problems

     and healthy elderely patients.

    In such cases, cardiac and/or renal problems (ex: congestive heart failure & myocardial failure) in which these is low renal volume perfusion, act as risk factors to increase NSAIDs renal toxicity because those drugs act as renal afferent arteriole vasoconstrictors, and in the presence of other medications used for such problems like vasodilators (ex: angiotensin converting enzyme inhibitors) which act as efferent arteriole vasodilators, this lead to alter renal homodynamic. In addition to such mechanism, NSAIDs have direct

     effect on glomeruli leading to nephropathic condition (14).

    On another way in our study, the figures from 7-12 show the comparison between the 2 types of NSAIDs, the selective COX-2 inhibitor (Meloxican) and the non selective- COX inhibitor (Indomethacin) according to their extent of changing effect on laboratory parameters on elderley patients. It was clearly shown that in spite of the significant

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    differences in the effect of 2 compounds on laboratory parameters in different period of treatment, there is no significant changes between the 2 compounds in affecting the renal function of elderly patients, this mean that the 2 compounds cause similar extent of renal toxicity on those patients. Those results are in agreement with other studies, in 29 healthy elderly subjects without renal insufficiency, treatment with celecoxib for 10 days was compared with nonselective COX-inhibitor naproxen, in a prospective cross over trial, the GFR declined at the 6th day of treatment and the urinary excretion of prostaglandins was significantly reduced with both drugs, but no significant differences in urinary levels

     was noted between the 2 medications (15).

Conclusions:

     Both healthy elderly patients & elderely with renal and/or cardiac problems might be at risk when using the NSAIDs due to their renal toxicity, with increasing the risk probability in those that suffer from impaired renal function, uncontrolled renal hypertension and congestive heart failure in which the prostaglandin play important role in kidney function. So, those drugs should be avoided or at least used cautionusly for short periods of time in those patients due to increasing the risk of developing acute renal failure because the over all toxic effect of those compounds increase parallel to the period of using them. In addition, both selective-COX and nonselective COX-inhibitor can cause the same renal side effects.

References:

    1- Gerson M. Rocha, Luis F.Michea, Eugenia M.: Direct toxicity of NSAIDs for renal medullary cells. Proc Nalt Acad sci USA, 98(9): 5317-5322, April 24,2001.

    2- Borda, I.T., and Koff., R. S. (eds.), NSAIDs. Aprofited adverse effects. Hanley and Belfus. Inc. philadelphia, 1992.

    3- Craig Brater, Cynthia Harvis and et al. Renal effects of COX-2 selective inhibitors, Am J of Nephrology. Vol. 21: 1-15, January- February 2001.

4- Dunn MJ: NSAIDs and renal function. Annu Rer Med. 35: 411-428, 1984.

    5- Brater DC. Effects of NSAIDs on renal function: focus on cyclooxygenase-2-selective inhibition. Am J med ; 107: 655-715,1999.

    6- Herschman HR: Prostaglandin synthase 2. Biochim, Biophys Acta 1299:125- 140, 1996.

    7- Dubois RN, Abramson SB, Crofford L, Gupta RA, Simon LS, vande Putte LB, Lipsky PE: Cyclooxygenase in biology and disease. FASEB J 12: 1063-1073, 1998.

    8- Khon KNM, Venturini CM, Bunch RT, Brassard JA, Kok: AT, Morris DL, Trump BF, Maziasz, TJ, Alden CL: Interspecies differences in renal localization of Cyclooxy genase isoforms: Implications in NSAIDs-related nephrotaiaty. Toxicol patho 26:612-620, 1998. 9- Yang T, Singh I, Pham H, Sun D, Smart A, Schner mann. JB, Briggs JP: Regulation of cyclooygenase expression in the kidiny by dietary salt intake. Am J Physiol 274 (Renal Physiol 43): 481-489, 1998.

    10- American Hospital formulary Sevice (ASHP), Drag Informutions p-1617-1623, 1998.

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    11- Marke A. perazella, MD, and Jennifer Eras, MD: Are selectine COX-2 Inhibitors Nephrotexic?, Ame. J. of kidney Dis. Vol 35, no. 5 (may), p 937-940,2000.

    12- Swan SK. Lasseter KC, Ryan CF, Buochel KL, Lunberet LJ, pinto MB, Renal effects of multiple-dose rofecoxib in olderly subject. J Am Soc Nepherol 10: 641A, 1999.

    13- Whelton A, Brater DC, Sicx DA: Effect of celecoxib & Naproxeue on renal function in chronic renal insufficiency patient: J Am Soc Nephrol 10:92A, 1999.

    14- Mary Anne Koda-Kimble & Royd Yee Young: Applied Therapeutics, the clinical use of Drugs. Vol. 2001, P:29-1. 22.

    15- Ohnaka k. numaguchi k: Induction of cyclooxygenase-2 by angiotensin II in cultured rat vasecular smooth musele cells. Hypertension 35: 68-75, 2000.

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     60** * *BUN level for a a50 normal individualstreated with 40 * **Indomethacin * (gp.1) 830 aBUN level forBUN level (mg/dl)20individuals with renal and cardiac 10problems treatedwith Indomethacin 0(gp.2) Baseline after 4daysafter 8daysafter 12daysafter 15days

    Figure-1: Comparison between control and the effect of treatment with Indomethacin on BUN for group-1 & group-2 patients. (*: significant difference in comparison with

     control of the same group).

     60 * * *50 *

     * *40 * *BUN level for normalindividuals treated with a30Meloxicam (gp.3) BUN level for individuals 20with renal and cardiacBUN level (mg/dl)problems treated with Meloxicam (gp.4) 10

     0 Baseline after 4daysafter 8daysafter 12daysafter 15days

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    Figure-2: Comparison between control and the effect of treatment with Meloxicam on

    BUN for group-3 & group-4 patients. (*: significant difference in comparison with control

     of the same group).

     7

    2.5

     2

     Serum creatinine level for normal individuals treated1.5with Indomethacin (gp.1)

     Serum creatinine level for1individuals with renal and cardiac problems treated with Indomethacin (gp.2)creatinine level (mg/dl)0.5

     0

    Baseline after 4daysafter 8daysafter 12daysafter 15days

    Figure-3: Comparison between control and the effect of treatment with Indomethacin on S.Cr for group-1 & group-2 patients. (*: significant difference incomparison with

     control of the same group).

     2.5

     * * *2 * Serum creatinine level for * *1.5 normal individuals treated **with Meloxicam (gp.3) a 1Serum creatinine level for individuals with renal andcreatinine level (mg/dl)cardiac problems treated 0.5with Meloxicam (gp.4)

     0 Baseline after 4daysafter 8daysafter 12daysafter 15days

    Figure-4: Comparison between control and the effect of treatment with Meloxicam on S.Cr for group-3 & group-4 patients. (*: significant difference in comparison with control

     of the same group).

     8

     7

     * *6 * *

    5 * *Serum potassium * *level for normal individuals treated4 with Indomethacin(gp.1) 3 Serum potassiumlevel for individuals 2Potassium level (mEq/L) with renal and cardiac problems treatedwith Indomethacin1 (gp.2) 0 Baseline after 4daysafter 8daysafter 12daysafter 15days

    Figure-5: Comparison between control and the effect of treatment with Indomethacin on S.K+ for group-1 & group-2 patients. (*: significant difference in comparison with

     control of the same group).

     6 * * * * * *5 * * Serum potassium4 level for normalindividuals treated with Meloxicam (gp.3) 3

     Serum potassium2level for individuals with renal and cardiacPotassium level (mEq/dl) problems treatedwith Meloxicam (gp.4) 1

     0

     Baseline after 4daysafter 8daysafter 12daysafter 15days

    Figure-6: Comparison between control and the effect of treatment with Meloxicam on S.K+ for group-3 & group-4 patients. (*: significant difference in comparison with control

     of the same group).

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     45

     40

    BUN level for 35normal individuals 30treated with Indomethacin (gp.1) 25 20BUN level for normal individuals15BUN level (mg/dl) treated with10Meloxicam (gp.3) 5 0 Baseline after 4daysafter 8daysafter 12daysafter 15days

    Figure-7: Comparison between the effect of treatment with Indomethacin & Meloxicam on BUN for group-1 & group-3 patients. (*: significant difference between the

     2 compounds at same time.)

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     60BUN level for individuals with renal *50and cardiac *problems treated with Indomethacin40(gp.2)

    30 BUN level forindividuals with renal BUN level (mg/dl)and cardiac20 problems treatedwith Meloxicam 10(gp.4)

    0 Baseline after 4daysafter 8daysafter 12daysafter 15days

    Figure-8: Comparison between the effect of treatment with Indomethacin & Meloxicam on BUN for group-2 & group-4 patients. (*: significant difference between the

     2 compounds at same time.)

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