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THE BEHAVIOURAL TERATOGENIC EFFECT OF CIMETIDINE ON THE OFFSPRING’S OF ALBINO RATS

CHAPTER ONE

1.1      INTRODUCTION

The guinea pig (cava parellus), also called cavy, and the genus cavia. Despite their common name, these animals are not in the pig family, nor are they from guinea, they originated in the Andes, and earlier studies based on biochemistry and hybridization suggested they are domestic descendants of a closely related species of cavy such as Cavia aperea, C. fulgida, or c. tschudii and therefore do not exist naturally in the wild (Ounnum  2010).

Guinea pigs were popular laboratory animals until the later 20th century; about 2.5 million guinea pigs were used annually in the U.S. for research in the 1960s. (Gad, 2007), but that total decreased to about 375,000 by the mid-1990s. as of 20007, they constitute approximately 2% of the current total of labory animals in the past they were widely used to standardize vaccines and antiviral agent they were also often employed in studies on the production of antibodies in response to extreme allergic reaction or anaphylaxis.

The most readily identified aspect of animal sexual behavior is the mounting response. It is an essential component of the male mating pattern but frequently occurs in females, especially during estrus. In a successful mating sequence the male mounts the female from the rear. The forelegs are placed on the back or around the sides of a female with the bind legs in the ground. The posture and motion permit the male to insert the exact penis into the females vagina not all mounting, however, in oriented to the rear of the female. The male may mount the female. The male may mount ths side or head of the partner and may or any not execute peptic thrusts; but in some species, such as the rat and dog mounting by females is not restricted to any particular part of the estrous cycle. The mount executed by a female is frequently indistinguishable from that of from that of the male. Thus, the typography of the behaviour does not identify the sex of the animal. Mounting occurs between members of the same or opposite sex and across species in some instances.

Male guinea pigs engage in several species. Eypical precopulatory behaviours, including nibbling the female’s fur on her head and neck, sniffing her amogenital regin,and making guttural sounds while either circling the female or shiffing his weight on his two rear feet while keeping his forepaws stationary. The male then approaches the female the rear, places his chest over the female’s back while claspring her sides, and begins petric thrusting, while usually results in a veginal intromission. Males can intromit at a rate of approximately 1 per minute, and so can ejaculate in a 15 mins test. Although a male that ejaculates with a single female usually does not reinitiate copulation within the next hour, he may copulate with a deferent tamale (Horm, 2007).

Cimetidine is an histamine H2-receptor antagonist that inhibits stomach acid production. It is largely used in the treatment of heartburn and peptic ulcers. It has been marketed by GlaxoSmithKline (which is selling the brand to prestige brands) under the trade name tagemet (sometimes tagemet HB or Tagamet HB 200). Cimetidine was approved UK in 1976 and was approved in the US by the food and Drug administration for prescriptions starting January 1, 1979.

Cimetidine, approved by the FDA for inhibition of gastric acid secretion, has been advacated for a member of dermatological disease. (Scheimfeld, 2003). Cimietidine was the prototypical histamine H2-receptor antagonist from which the later members of the class were developed. Cimmietidine was the culmination of a project at smith, klrin and French (SK & F; Moro claxosmithkhine) by James W. Black, C. Robin canetllin, and others to develop a histamine receptor antagonist to suppress stomach acid secretion (American chemical society, 2012). This was one of the first drugs discovered using a rational drug design approach. Sir. James w. black shared the 1988 Nobel prize in physiology or medicine for the discovery of proppranolol and also in credited for the discovery of cimetidine, actually the medicinal chemists would have made the discovery. (Silverman and Richard, 2004).

At the time (1964), his tamine was known to strinulate the secretion of stomach acid, but also that traditirt amithistamines had no effect on acid production. In the porcert, the SK & F scientist also proved the existence of histamine H2-receptors. The SK & F ream used a rational drug design structure starting from the structure of his tamine the only design lead, since nothing was known of the then hypthtical H2-receptor. Hundreds of modified compounds were synthesized in an effort to develop a model of the receptor. The first breakthrough was as-guanylhistamine, a partial H2-receptor anlagonist from this lead the receptor model was further refined and eventually let to the development of burianarmide, the first H2-receptor antagonist. Burimanide, a specific competitive antagonist at the H2-receptor, 100 times more potent than N-guanylhristamine, provide the existence of the H2-receptor. Burimamide was still insufficiently potent for oral administration and further modification of the structure, based on modifying the PKa of the compound, led to the development of metiamide. Metiamide was an effective agents. It was associated, however, with inacceptable nephrotoxicity and agranulocylosis (American chemical society 2012). Then toxicity was proposed to arise from the thourea group and similar guaidine analogues were investigated until the ultimate discovery of cimetidine was first marketed in the united kingdom in 1976, therefore, it took 12 years from initiation of the H2-receptor aotagonist program to commercialize. The commercial; name “tagamet” was decided upon by fusing the two words “anatagonist” and “cimietidine”. (American chemical society 2012) subsequent to the introduction onto the US dug market. Tow other H2-receptor antagonist were approved. Ranitidine (Anatac, Glaxo Labs) and cimetidine became the first drug ever to reach more than $ 1billion a year in sales, this making of the first blockbuster drug. (Volntney, Take, 2006) in a deating expected to take effect in 2012, Glaxosmithklme sold Tagement and 16 other grant to prectige brands. (Ranii, David. 2011).

In some studies cimetidine has beed fonnd to reduce the debilitating pain and symptoms of herpes zorter, presumably by blocking the H2-receptor of T-typrptocyte suppress or cells. (Faloon, et al 2001).

A number of “open label” studies showed cimietidine was effective in the treatment of common wards, but more rigorous double-blind clinical trials suggested it to be no more effective than a placeto. However, the researchers in this study admit their results may not be sound, due to small sample size, and did not explore brigher dosing options. (fit KE, William PC 2007) another study by yokogama, et al used cimietidine for the treatment of chronic calcific tendiritis of the shoulder, a (Yokogama  2003). The small scale study too 16 individual with calcific tendimitis in one shoulder, all of which had previously attempted other forms to therapy, including steroid injection and arthroxcoptic lavage. During the course of the study, 10 patients reported an elimination of pain and a disappearance of calcium deposits with results being on a small scale, cimitidine, for the treatment of chrionic calcific trendrintis of the shoulder, has been recommended to be opened to large scale clinical trials (Masailo Skeletal pain 2008).

In asia, cimietidine, which molecularly targets EGF, VEGF and E-selection associated with sialylated leins biomakers and metastasis, has been combined with longer term continous low does. SFU (Matsumoto  2002) or metronomic tagefur-uracil chemotherapy for advanced epithetial cancers, with usually long survive (Marsumoto  2004) including for stage 111 colorectal cancers, (Matsumoto  2002) as well as refractory and recurrent cancers.

Cimietidine has been reported for use as an anagelsic  in experimental treatments of interestital cystitis pretreatment with cimietidine improves the accuracy of measured creatinine clearance testing when using urine collection analysis.

Cimetidine as a known intribitor of many isozymes of the cytpcrome P450 enzymes system. (Specifically CYP1A2, CYPWC9, CYP2E19, CYP206, CYP2E1, and CYP3A4). This inhibition forms the basis of the numerious drug interaction that occur between cimetidine and other drugs for example, cimetidine is a competitive antagonist at the dihydrotesterone (DHT) receptor, leading to exaggerated effects of estorgens, in women, this can lead to galectorrhea, whereas in men gynecomastia has been reported during post marketing surveillance in the 1980s. Cases of male sexual dysfumetion were also reported. Cimietidne also affects the metabolism of methadone, sometimes resulting in higher blood levels and a bright incidence of side effects, and may interact in the antimalarial medication hydroxychloroquire. Crimetidine is also known to potentiate the effects of several opioids which are partially metabolized via the cytochronic P450 pathway via inhibiting their metabolism and temporary decrease of liver function due to reduced hepatic blood flow. This can lead to extreme plasma levels of these drugs and can easily lead to a fatal over dose.

Antacid preparations such as cimetidine work by suppressing acid mediated break down of proteins, leads to an elevated risk to developing food or drug allergies. This happens due to undigested proteins then passing into the gastrointestinal tract where sensitization occurs. It is unclear whether this risk occurs with only long-term use or with short term use as well. (Pati-Scholl and Jensen-Jarolin, 2011) it is also important to recognize that cimetidine can interact with a number of different psychoactive medications, including those in the classes of Trcyclic antidepressants and selective serotonin reuptake inhibitors, causing incread blood levels of these drugs and subsequent toxicity. The development of longer acting H2-receptor antagonists with reduced adverse effects, such as ranitidine, proved to be the downfall of cimetidine and, though it is still used it is no longer among the more widely used H2-receptor antagonists. Side effect can include, dizziness, and more rarely, headache.

Following administration of cimetidine, the half life and AUC of Zolmitriptan and its active metabolites were approximately doubled (see clinical pharmacology) see complete drug inferatctions for Zonrig (triptan succinate used for migrarie relief) in package insert.

Crinetidine is a potent inhibitor of tubular creatrnine secretion. Creatiniine is a metabolic by-porduct of creatine, breakdown.. accumulation of creatinine is associated with uremia, but he sumptoms of creatinine accumulation are unknown, as they are hard to separate from other introgenout waste buildups (Drug Metab. Parmacokinet 2005).

Crimetidine has also been found to possess chrically significant antiantrogen properties at high doses that are especially noticeable in men. It directly antagonizes the binding of testosterone and DHT to the androgen receptor in Animals in addition also in animals. It interferes with the metabolism of estrogen and increases it serum concentration. Accordingly, cimidtidine has been found to be effective in small clinincal trials for the treatment of acne and androgenic alopecia though not in hirsutism or in sex trormones associated cancer such as breast and prostate cancer (Rossing  2000) cimetidine’s antiandrogen properties likely explain certain side effects seen with it such as galactrorrhea and arnenorrhea in women and gynecomastia and impotence in men.

Cimetidine may inhibit the microsomal enzems. Sytem and thereby reduce the metabolism, prolong scrum half-lives, and increase the serum level of several drugs. It may also reduce the hepatic blood flow and reduce the amount of thepatic extraction bring drugs may be affected: beta-blockers (e.g. propranolol), lidocarine, chloraphenicol, quinidrne, calcium channel blockers (fro example, verapanil), diazepain (and other benzodiazepries), ethanol, metroindazole, phenyloin, quinidrine, theophyllrine, and warfarin. Dosage adjustment or increased thearapeutic monitoring may be necessary. Cimetidine may increase the renal clearance of procainanide. Cimetidine may exacerbate leukpenias when used with other agents that can cause this problem. Stagger doses (separate by 2 hours if possible) of cimetidine with antacids, metavhoprainde, sucralfate, diagoxin and ketoconazole. Does for guinea pigs 5-10my/kg po,Im or Sc 9 6-12h (mech-vet, 2008).

Having exustively explained the meaning and history of what cimetidine is all about, etets take a look at cimetidine as a teratogenic agent. (Doccy and Travers, 2002),s antrocfk (2006), observed that teratogens are any agent that can cause abnormalities and such agents include drugs, chemicals, infections, materials health state, alcohol, smoking an pollutants. Cimetidine (tagamet) has been reported to cause sexual impotence, expecially in men taking very high doses. Impotence usually defined as a total inability to achieve an erection, an insistent ability to do so, or a tendency to sustain only brief erections has been said to be caused by this teeratogenic agents.

Teratology is derived from the Greek word “teratos” which means “demon or Monster” substances which causese these defects are known as “Teratogenic agents or developmental toxicant” neutron hebbavioural teratology or psychoteralology deals with the effects of these substance on the development of development of behavior. Nenro behavioral teratology is the study of functional brain defect/defincilts. (Like learning disorders) that result from something going wrong during developments.

A teratogen is an agent, which be acting on the monitoring behaviour of male rodent can cause a structural abnormality. (Anad and Van Thiiel 1932) chained that cimetidine interferes with psychosexual differentiation in animals. Male rats exposed to cimetidine in utero, and whilot sucking showed.

- Increase mount latency

- reduced mounting behavior

When they were exposed to a sexually receptive female rat for a 15minutes test of their sexual behaviors. Anad & van thel interpreted this result as indicating that cimetidine significantly reduced.

-      sexual motivation (mount latency)

-      sexual performance (number of mounts)

Teratologist have discovered the following priciples in animals and human shidies by roilson’s. Susceptibility to teratogenesis varies with the developmental stage at the time of exposure of an adverse influence there are critical periods of susceptibility to agents and organs system affected by these agents.

Teratogneic agents act in specific way in developing cell and tissues to initiate sequences of abnormal developmental events.

-      The access of adverse influences to developing tissues depends on the nature of the influence. Several factors affect the ability of a teratogen to contact a developing conceptive as the nature of the agent itself, route and degree of material exposure, rate of placental transfer and systemic absorption and composition of the maternity tetal genotypes.

-      There are few manifestations of deviant development (Death malformation and functional defect).

-      Manifestation of deviant development increases in frequency and degree as dosage increase from the no observable adverse effect level (NOAEC) to a dose producing 100% lethability (LD100) studies designed to test the teratogenic potential of environmental agents use animal model system (e.g., rat, mouse, rabbit, dog, guinea pig and monkey). (James G. Wilson, 1973).

Finally exposure to teratogens can result in a wide range of structure abnormalities such as chefflip, cheff poltiate, dysmelia, auencephally, ventricular septal defect exposure to single agent can be produce various abnormalities depending on the stage of development occurs specific birth defect are not characteristic of nay single agent. (Gilbert. Barless E. 2008).

1.2  STATEMENT OF PROBLEM

It have been reported that, naturally, during pregnancy, rooment od thave a burning sensation in the heart. However some assume it is ulcer, as such they take ulcer drugs, since cimetidine is one of the most common and effective ulcer drugs, it is administered to them either by self administration and although the unborn child, seemed to be protected, completely immured to some external and internal influence surrounding the mother, that could cause defilitating effect at different developmental  stages.

Cimetidine has been shown to be a teratogenic drug as a teratogenicf drug iti could cause serious abnormality during prenatal and postnatal live to offsprings of mother who used it during pregnancy. However this study is aimed at revealing the effect of cimetidine on offspring of mother who where exposed to ti during pregnancy.

1.3      PURPOSE OF STUDY

This study aims to examine:

1)  If exposure to cimetidine will manifest any significant effect on the behaviour of their offsprings.

2)   If the intake of cimetidine during pregnancy have an effect on the birth weight of offspring.

3)   If the intake of cimetidine during pregnancy affect learning and memory in offsprings whose mother’s where exposed to cimetidine.

1.3  SIGNIFICANCE OF THE STUDY

This study stands to reveal the teratogneic effect of cimetide on offspirngs of mothers who where exposed to it during pregnancy and it is mainly directed to pregnant women who self medicate during pregnancy as well as men and women who may not know till date the side effect of cimetidne intake.

This research will serve as a guide to the medical practitioners (on how to administer doses of cimetidine, especially during pregnancy) as well as the general public on issues based on the teratogenic effect of cimetidine intake.