CIMETIDINE’S BEHAVIORAL TERATOGENIC IMPACT
FIRST CHAPTER INTRODUCTION
The genus cavia and the guinea pig (Cava parellus), also known as cavy. As they originated in the Andes and are not related to pigs or guinea pigs despite their common name, it is likely that they are domestic descendants of a closely related species of cavy, such as Cavia aperea, C. fulgida, or C. tschudii. As a result, they do not naturally occur in the wild (Ounnum 2010).
Up until the latter part of the 20th century, guinea pigs were common laboratory animals; in the 1960s, about 2.5 million of them were employed annually in the U.S. for study. (Gad, 2007), but by the mid-1990s, that number had dropped to roughly 375,000. In the past, they were frequently used to standardize vaccinations and antiviral agents. They were also frequently used in experiments on the generation of antibodies in response to severe allergic reaction or anaphylaxis. As of 2007, they make up around 2% of all working animals.
The mounting reaction is the component of animal sexual behavior that is easiest to identify. Although it frequently happens in females, especially during estrus, it is an integral part of the male mating behavior. An effective mating sequence involves the male mounting the female from behind. With the bound legs in the ground, the forelegs are wrapped around the flanks or back of a female. Not all mounting, nevertheless, is oriented to the female’s back, so the posture and movements allow the male to put the exact penis into the female’s vagina. Males are permitted to mount females. The male may mount the partner’s side or head and make strong thrusts, or not;
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, vcircling the female or shifting his weight to his two back feet while keeping his forepaws still, sniffing her amogenital region, and producing guttural noises. After that, the male approaches the female from behind, rests his chest on her back while holding her sides, and starts petric thrusting, which typically causes a veginal intromission. Men can ejaculate for 15 minutes at a pace of about 1 intromission per minute. In spite of the fact that a man who ejaculates with a single female typically does not initiate copulation again within an hour, he may do so with a different tamale (Horm, 2007).
The histamine H2-receptor antagonist cimetidine prevents the generation of stomach acid. It is mostly used to treat peptic ulcers and heartburn. Under the trade name tagemet, it has been promoted by GlaxoSmithKline, which is selling the brand to prestige brands (sometimes tagemet HB or Tagamet HB 200). In the UK, cimetidine was licensed in 1976, and on January 1, 1979, the Food and Drug Administration approved it in the US for prescription use.
Cimetidine, which the FDA has approved for preventing gastric acid secretion, has been recommended for a person with a dermatological condition. 2003 (Scheimfeld). The early members of the class were created from the prototype histamine H2-receptor antagonist known as cimimetidine. James W. Black, C. Robin Canetllin, and others worked on a study at Smith, Kirin, and French (SK & F; Moro claxosmithkhine) to create a histamine receptor antagonist to reduce stomach acid output. This project resulted in cimmietidine (American chemical society, 2012). One of the first medications to be found utilizing a rational drug design technique was this one. For discovering proppranolol and being credited with discovering cimetidine, Sir. James W. Black shared the 1988 Nobel Prize in physiology or medicine. However, it was actually medicinal chemists who made these discoveries.
Histamine was known to inhibit the secretion of stomach acid at the time (1964), but traditional antihistamines had no such effect. The SK & F scientist also established the existence of histamine H2-receptors in the porcert. As the then-hypthtical H2-receptor was unknown, the SK & F ream utilized a rational drug design structure, starting with the structure of his tamine as the only design lead. To create a model of the receptor, hundreds of altered substances were created. As-guanylhistamine, a partial H2-receptor antagonist, represented the first significant advance. This allowed for further development of the receptor model and ultimately the creation of burianarmide, the first H2-receptor antagonist.
The H2-receptor’s existence is demonstrated by burimanide, a highly effective competitive antagonist at the H2-receptor that is 100 times more potent than N-guanylhristamine. Burimamide was still too weak to be administered orally, thus subsequent structural alterations based on changing the compound’s PKa resulted in the creation of metiamide. The agent metiamide was efficient. However, it was linked to unfavorable nephrotoxicity and agranulocylosis (American chemical society 2012). Up until the eventual discovery of cimetidine, which was initially sold in the United Kingdom in 1976, comparable guaidine analogues were studied and toxicity was hypothesized to result from the thourea group. The H2-receptor antagonist program was started, and it took 12 years until it was commercialized. By combining the words “anatagonist” and “cimietidine,” the brand name “tagamet” was chosen. Upon its entry to the US dug market, (American Chemical Society 2012). The approval of two additional H2-receptor antagonists. Cimetidine and ranitidine (Anatac, Glaxo Laboratories) were the first medications to sell more over $1 billion annually, making them the first “blockbuster” medications.
(Volntney, Take, 2006) Glaxosmithklme sold Tagement and 16 other grants to prestige brands in a deal that was supposed to go into effect in 2012. David Raanii (2011).
Cimetidine has been found in certain studies to lessen the agonizing pain and herpes zoster symptoms, perhaps by blocking the H2-receptor of T-typrptocyte suppressor cells. Faloon et al. 2001.
Cimietidine was beneficial in treating common wards according to a number of “open label” research, but more thorough double-blind clinical trials found it was no more effective than a placeto. The authors of this study acknowledge that, because of the small sample size and lack of investigation of stronger dose choices, their findings might not be reliable. Another study by Yokogama, et al. employed cimietidine for the treatment of chronic calcific tendiritis of the shoulder (fit KE, William PC 2007). (Yokogama 2003). The tiny study included 16 patients with one shoulder’s calcific tendimitis, all of whom had previously tried alternative forms of therapy, such as steroid injection and arthroxcoptic lavage. Cimitidine has been suggested to be opened to large-scale clinical trials for the treatment of chrionic calcific tendinitis of the shoulder after 10 patients reported pain relief and the disappearance of calcium deposits during the course of the study (Masailo Skeletal pain 2008).
Cimietidine, which molecularly targets EGF, VEGF, and E-selection linked to sialylated leins biomakers and metastasis, has been used in combination with continuous low doses for a longer period of time in Asia. Stage 111 colorectal malignancies, as well as refractory and recurring tumors, can all be treated with SFU (Matsumoto 2002) or metronomic tagefur-uracil chemotherapy, both of which have a typically extended survival time (Marsumoto 2004).
In experimental therapies for interstitial cystitis, cimietidine has been reported to be used as an anagelsic. Pretreatment with cimietidine increases the precision of measured creatinine clearance tests when employing urine collection analysis.
As a known intribitor of numerous isozymes of the system of cytochrome P450 enzymes, cimetidine. (Exactly CYP1A2, CYPWC9, CYP2E19, CYP206, CYP2E1, and CYP3A4). The numerous pharmacological interactions that take place between cimetidine and other medications are caused by this inhibition. Cimetidine, for instance, is a competitive antagonist at the DHT receptor, causing the effects of estrogens to be amplified. In women, this might result in galectorrhea, while in men, gynecomastia has been documented during post-marketing surveillance in the 1980s. Male sexual dysfumetion cases were also noted. Moreover, cimietidne alters the metabolism of methadone, occasionally raising blood levels and increasing the likelihood of side effects. Cimetidine is a well-known intribitor of many isozymes of the cytochrome P450 enzyme system (Exactly CYP1A2, CYPWC9, CYP2E19, CYP206, CYP2E1, and CYP3A4). This inhibition is what leads to the various pharmacological interactions between cimetidine and other drugs. For instance, cimetidine acts as a competitive antagonist at the DHT receptor, amplifying the actions of estrogens. This could cause galectorrhea in females, whereas gynecomastia in males has been observed during post-marketing surveillance in the 1980s. Cases of male sexual dysfumetion were also reported. Moreover, cimietidne changes the way that methadone is metabolized, occasionally elevating blood levels and raising the possibility of side effects.
and the antimalarial drug hydroxychloroquire may interfere. Crimetidine is also known to temporarily limit liver function due to diminished hepatic blood flow and block the metabolism of many opioids that are partially metabolized via the cytochronic P450 pathway, potentiating their effects. This may result in extremely high plasma levels of these medications and may quickly result in a lethal overdose.
Inhibiting the acid-mediated breakdown of proteins is how antacid medications like cimetidine function, which increases the chance of developing food or medication allergies.Undigested proteins getting into the digestive tract, where sensitization happens, causes this to happen. It is unknown if this risk just pertains to frequent use or if it also pertains to infrequent use. Pati-Scholl and Jensen-Jarolin from 2011 Also, it’s crucial to be aware that cimetidine may interact negatively with a number of psychiatric drugs, such as those from the Trcyclic antidepressant and Selective Serotonin Reuptake Inhibitor classes, causing toxicity by increasing blood levels of these drugs.
Cimetidine’s demise was caused by the introduction of H2-receptor antagonists with longer half-lives and fewer side effects, such as ranitidine. Although it is still used, cimetidine is no longer one of the more popular H2-receptor antagonists. Headache and, less frequently, dizziness are possible side effects.
The half life and AUC of Zolmitriptan and its active metabolites were about doubled after cimetidine administration (see clinical pharmacology); for a detailed list of drug interactions, consult the package information for Zonrig, a brand name for the migraine medication triptan succinate.
A powerful inhibitor of tubular creatine secretion is cristotidine. A metabolic by-product of the breakdown of creatine is creatinine. Uremia is connected with the accumulation of creatinine, although the symptoms of creatinine accumulation are unknown since it is difficult to distinguish them from other introgenous waste buildups (Drug Metab. Parmacokinet 2005).
At large doses, crimetidine has also been discovered to have clinically substantial antiantrogen effects that are most obvious in men. Moreover in animals, it directly inhibits the binding of DHT and testosterone to the androgen receptor.
It alters estrogen metabolism and raises the serum levels of the hormone. Because of this, cimidtidine has been shown to be effective in modest clinical trials for the treatment of acne and androgenic alopecia, but not for the treatment of hirsutism or sex hormone-related cancers including breast and prostate cancer (Rossing 2000) Cimetidine’s antiandrogen qualities likely account for several of its side effects, including gynecomastia and impotence in males and galactrorrhea and anorexia in females.
Microsomal enzymes may be inhibited by cimetidine. Sytem and subsequently slow down the metabolism, extend the half-lives of a number of medications, and raise their serum levels.
Drugs like beta-blockers (such as propranolol), lidocaine, chloraphenicol, quinidrine, calcium channel blockers (such as verapanil), diazepam (and other benzodiazepines), ethanol, metroindazole, phenyloin, quinidrine, theophyllrine, and warfarin may also be impacted. It could be essential to modify the dosage or do more therapeutic monitoring. Procainanide’s renal clearance may be enhanced by cimetidine. When combined with other substances that can cause leukpenias, cimetidine might make the condition worse. Cimetidine dosages should be spaced apart by at least two hours from those of antacids, metavhoprainde, sucralfate, diagoxin, and ketoconazole. Does for guinea pigs 5–10 mg/kg i.m. or sc 9 for 6–12 hours (mech-vet, 2008).
After thoroughly delineating the purpose of cimetidine and its background, experts examine if it is a teratogenic substance. Teratogens are any agents that can result in abnormalities, according to (Doccy and Travers, 2002), according to antrocfk (2006). These agents include medications, chemicals, diseases, materials health states, alcohol, smoking, and pollutants. Sexual impotence has been linked to cimetidine (tagamet), particularly in men taking extremely high doses. These teeratogenic agents are thought to be the cause of impotence, which is typically defined as a complete inability to create an erection, an insistent capacity to do so, or a tendency to sustain only brief erections.
The term “teratogenic agents” or “developmental toxicant” refers to substances that induce these problems. Teratology is derived from the Greek word “teratos,” which means “devil or monster.” The effects of these drugs on the formation of behavior are the subject of behavioral teratology or psychoteratology. Functional brain defects are the subject of nenro behavioral teratology. (Like learning problems) brought on by mistakes made during the growth process.
A teratogen is a substance that, when it interacts with a male rodent’s monitoring behavior, can result in a structural defect. Cimetidine interferes with animal psychosexual differentiation, according to (Anad and Van Thiiel 1932). Cimetidine exposure in utero was observed in male rats while they were sucking.
amplify mount latency
fewer mounting actions
During a 15-minute evaluation of their sexual habits, they were exposed to a female rat that was sexually responsive. This study, according to Anad & van Thel, shows that cimetidine dramatically lowered.
day daydaydaydaydaydaydaydaydaydaydaydayday (mount latency)
sexual activity (number of mounts)
The following principles have been identified by teratologists in both animal and human shidies. There are key times of susceptibility to agents and organ systems impacted by these agents at the time of exposure to a detrimental influence. Susceptibility to teratogenesis varies with the developmental stage.
Teratogneic substances work on developing cells and tissues in a certain manner to start a chain of aberrant developmental events.
Depending on the type of effect, unfavorable affects may enter growing tissues. The nature of the agent, the route and intensity of material exposure, the velocity of placental transfer and systemic absorption, and the makeup of the maternal tetal genotypes are some of the elements that influence a teratogen’s potential to contact a developing conceptive.
- There aren’t many signs of abnormal development (Death malformation and functional defect).
Studies aimed to investigate the teratogenic potential of environmental agents use animal model systems. – Manifestation of aberrant development rises in frequency and degree as dosage increases from the no observable adverse effect level (NOAEC) to a dose yielding 100% lethality (LD100) (e.g., rat, mouse, rabbit, dog, guinea pig and monkey). (1973, James G. Wilson).
Lastly, exposure to teratogens can cause a variety of structural abnormalities, including chefflip, cheff poltiate, dysmelia, auencephally, and ventricular septal defect. But, depending on the stage of development, exposure to a single agent can also cause other abnormalities. 2008; Gilbert; E. Barless.
SUMMARY OF THE PROBLEM
Naturally, it has been claimed that women who are pregnant often get heartburn. Cimetidine is one of the most popular and successful ulcer medications, therefore some people assume it is an ulcer and treat it as such.
And last, teratogen exposure can result in a number of structural abnormalities, such as chefflip, cheff poltiate, dysmelia, auencephally, and ventricular septal defect. However, exposure to a single chemical might also result in various anomalies, depending on the stage of development. Gilbert; E. Barless; 2008.
A NARRATIVE OF THE PROBLEM
Understandably, it has been asserted that heartburn is a common symptom for pregnant women. Although cimetidine is one of the most well-liked and effective ulcer treatments, some people mistakenly believe they have an ulcer and treat it as such.
AIM OF THE STUDY
This investigation will look at:
if the behavior of their kids will be significantly impacted by exposure to cimetidine.
if the birth weight of the child is affected by the consumption of cimetidine during pregnancy.
Whether cimetidine use during pregnancy has an impact on learning and memory in children whose mothers were exposed to the drug.
NECESSITY OF THE STUDY
This study aims to shed light on the teratogenic effects of cimetide on the offspring of mothers who were exposed to it while pregnant. It is primarily aimed at expectant moms who self-medicate as well as men and women who might not be aware of the negative effects of cimetidine use to this point.
This study will work as a manual for medical professionals (on how to give cimetidine doses, particularly during pregnancy) and the general public on matters based on the teratogenic effect of cimetidine use.