Non-clinical Aspects. Outline. • Overview of Legal and Regulatory requirements. • Structure of the dossier (CTD). • Overview of Scientific Non-clinical Guidelines. These highlights do not include all the information needed to use CYCLOSET safely and effectively. See full prescribing information for CYCLOSET. CYCLOSET. Also, in clinical studies bromocriptine did not influence follicle stimulating .. For a recent overview of possible strategies to develop drug.

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To illustrate the process of addressing adverse preclinical findings APFs as outlined in the first part of this review, a number of cases with unexpected APF in toxicity studies with drug candidates is discussed in this second part. The emphasis is on risk characterization, especially regarding the mode of action MoAand risk evaluation regarding relevance for man. While severe APFs such as retinal toxicity may turn out to be of little human relevance, minor findings particularly in early toxicity studies, such as vasculitis, may later pose a real problem.

Rodents are imperfect models for endocrine APFs, non-rodents for human cardiac effects.

Liver and kidney toxicities are frequent, but they can often be monitored in man and do not necessarily result in early termination of drug candidates. Novel findings such as the unusual lesions in the gastrointestinal tract and the bones presented in this review can be difficult to explain. It will be shown that well known issues such as phospholipidosis and carcinogenicity by agonists of peroxisome proliferator-activated receptors PPAR need to be evaluated on bromoccriptine case-by-case basis.

General toxicologists and pathologists need some understanding of the principles of genotoxicity and reproductive toxicity testing. Both types of preclinical toxicities are major APF and clinical monitoring is difficult, generally leading to permanent use restrictions. In the first part of this review processes for dealing with unexpected adverse preclinical findings APFs were discussed and dummary overview over APFs associated with drug classes and safety issues often encountered in preclinical studies was given.

Bromocriptine – Wikipedia

The various steps in dealing with APFs involve:. To arrive at a full weight of evidence WoE evaluation other factors such as therapeutic indication, medical need, and alternative drugs already on the market must also be taken into account.

Toxicologic pathologists together with toxicologists play an important role for recognizing potential Wummary They contribute to resolve issues related to such findings and to support the risk management process. They must feel accountable for the health of humans to be exposed to the drug candidate, but must also avoid being overcautious, thus preventing potentially useful drugs to reach the market.

This second part of the review concentrates on a more detailed discussion of selected APFs of drugs as far as possible with reference to their MoA and regarding their relevance for man.

Examples will cover morphologic toxicity and tumorigenicity as well as some additional aspects of functional toxicity. Experience regarding APFs in reproductive and genotoxicity studies will be included as far as relevant to the general toxicologist and toxicologic pathologist.

Unsuccessful attempts to resolve preclinical toxicity issues may not be published. However, if an APF did not stop drug development, findings are often mentioned in the package insert.

It may be somewhat comforting that most package inserts actually show that APFs were detected during the development of the drug. Last but not least, personal experience of the authors has played an important role in writing this review. Nerve cells are special, as after birth they can not multiply and therefore do not regenerate with partial exception of severed nerve processes. CNS toxicity in preclinical safety studies is a severe APF and relatively rare with drug candidates, but a number of industrial chemicals are known to be neurotoxic 3 — 5.

The developing brain appears to be particularly vulnerable 4. CNS toxicity may also be secondary e. For functional CNS toxicity see first part of this review. Peripheral neuropathy, also not frequently seen with drug candidates, may occur e.

Retinal toxicity is a special type of neural toxicity and needs to be distinguished in particular from light-induced retinopathy of albino rodents Some drugs which induce retinotoxicity in laboratory animals are discussed in the following paragraph. The eye is one of those organs where toxicity is not acceptable, particularly if potentially leading to permanent visual impairment.


Early retinal toxicity can manifest itself already in a two week study, initially by a subtle decrease in the number of nuclei e. With longer treatment, nuclear layers may disappear, and the pigment epithelial layer may become disrupted. Do such findings mean that development of the drug candidate needs to be abandoned? Not necessarily, as illustrated by a number of drugs on the market, which produce toxicity in laboratory animal eyes—though often only in one animal species or strain, mainly in albino rats— but are deemed safe for humans The retina of rats and mice is damaged e.

A number of animal species is adversely affect by nalidixic acid 14a drug against urinary tract infection, and tranexamic acid 15 against angioneurotic edema.

However, some drugs such as hydroxychloroquine, are toxic also for the human eye and may lead to irreversible retinopathy 16 Besides being hepatotoxic, adversely affecting the endocrine and cardiovascular system, and inducing phospholipidosis, some CNS drugs are also known to be retinotoxic in animals, partly at relatively low doses.

Such animal retinotoxicity was seen e. However, no retinal changes were detected in humans treated with these drugs by careful eye monitoring.

If retinal toxicity is observed, it is not sufficient to refer to literature or other sources of information related to the APF. It is necessary to characterize the hazard, that is to. In addition to ophthalmoscopy, electroretinogram ERG investigations in animals may have to be considered.

However, recording and interpreting ERGs is a demanding expert task. Species-related differences regarding the function of the retina limit the predictive value of these tools 19 At least initially it is important to monitor humans by ophthalmoscopy, vision tests, ERG, etc.

Binding of drugs to eye melanin of laboratory animals is not predictive bromocriptnie ocular toxicity Increased incidences of endocrine tumors are seen with many drug candidates in chronic toxicity and lifetime bioassay studies.

These tumors generally result from disturbance of the hormonal balance. They are often due to the specific endocrine physiology of rodents for more details see the first part of this review and therefore without relevance to man A few examples are discussed below. Dopaminergic drugs have endocrinological and neurological clinical indications. Among them are ergot alkaloids which, based on their structure-activity relationship, can be divided into three classes: Lysergic acid amines e.

Nonclinicall ergot alkaloids have significant endocrine effects in rodents, particularly in rats, through their inhibitory effect on the secretion of prolactin PRL from the anterior pituitary The elucidation of the MoA of dopaminergic drug candidates in laboratory animals also illustrates the importance of carefully planning additional experiments, as an explanation for the uterine findings is only possible taking into account the age-specific nobclinical hormone climate in aging rats.

The typical appearance with squamous cell metaplasia, polypoid structures, and some ssummary inflammation is shown in Fig.

In the lifetime bioassay with lower doses 1. Uterine adenocarcinomas nonclincal an OFA rat treated in feed for weeks with The MoA of bromocriptine leading to these uterine changes is summarized in Table 1.

Because of high PRL and low luteinizing hormone LHuntreated older rats stop cycling and remain in diestrus pseudopregnancy with relatively high progesterone production.

By lowering PRL bromocriptine treatment initiates regular cyclical activity, but this is short-lived, as the insufficient preovulatory LH surge can not trigger ovulation thus leading to cystic follicles. As a consequence of the lack of estrous broocriptine, also corpora lutea tend to persist. However, because of the low PRL levels these corpora lutea do not produce significant amounts of progesterone.

This physiological reaction facilitates endometritis and pyometra, which through irritation results in increased cell proliferation and, if sustained, may give rise to neoplasia.

No comparable uterine findings were detected in a 52 week dog study or in a carcinogenicity study in mice. Xummary, in clinical studies bromocriptine did not influence follicle stimulating hormone FSHLH, estradiol or progesterone levels in female patients. Endometrial biopsies of bromocriptinne treated patients did not show any drug-related changes The uterine APF in rats is without relevance for women and considered to be an exaggerated pharmacodynamic effect of bromocriptine specific for aging female rats 23 For reasons not related to the APF discussed here, it did not reach the market, but a successor drug with similar properties has been registered as drug.


In the carcinogenicity study of weeks with mesulergine at doses of 0. The typical appearance of this tumor and the precursor lesion, namely focal and diffuse LC hyperplasia, is shown in Fig. The seminiferous tubules are partly atrophic, which may be due both to pressure produced by the large LC tumors and the disturbed endocrine regulation.

Leydig cell hyperplasia one focus in the center of the figure and adenomas one seen on the right side of the figure of the testis of a Kfm: WIST rat treated in feed for weeks with 1. The occurrence of variants of LC tumors did not change the final assessment that the syndrome appears to be rat-specific, which was confirmed by members of a workshop on rodent LC adenomas and human relevance Similar changes are not found in other laboratory animal species or man.

Increased LH levels in men are seen e. Other drugs—such as busereline, carbamazepine, cimetidine, finasteride, flutamide, gemfibrozil, histrelin, hydralazine, indomethacin, isradipine, lactitol, leuprolide, metronidazole, mesulergine, nafarelin, norprolac, and vidarabine—may also disturb the closed-loop feedback mechanism of the hypothalamo-hypophyseal-gonadal axis Although the precise cause noncljnical the perturbation may vary depending on the drug type, the end result appears to be similar 26 However for new drug candidates the hypothesis of a hormonal disturbance in laboratory animals needs to be proven on a case-by-case basis Tumors shmmary the pituitary are frequent in rodent bioassays, sometimes in a dose-dependent manner, suggesting a causal relationship with treatment.

The following case triggered a number of additional investigations, but could not be completely resolved regarding the MoA.


However, biomarkers identified during the various steps of addressing the APF allowed monitoring of man for the corresponding disturbance and allaying concern. In addition, clinical data—the drug was on the market for many years prior to the tumor finding—did not reveal any evidence that these rat pituitary tumors were brkmocriptine to man. Salmon and porcine calcitonin are calcium-lowering hormones used e.

The drugs are also used for many other indications, often off-label, and therefore an increased incidence of tumors in the pars distalis of the pituitary in rats treated for 52 weeks with subcutaneous doses of 1. Pituitary tumors were seen in male rats at all doses and pituitary hyperplasic foci in female rats at the high dose In a follow-up study these tumors were found to be non-functioning, that is the serum levels of traditional nonflinical hormones were not bromocriptlne altered with exception of a two-fold increase of TSH.

After many years of repeated investigations it can be concluded that the drugs are safe. It is important to carefully examine the early short-term studies for heart lesions 33though this does not replace functional testing, mostly measurement of the QT time see first part of this review. Drug candidates can exert their toxicity via a direct action on myocytes, e.

Depending on noncliniccal species, cardiotoxicity can manifest itself nonclinival different parts of the heart.

This can possibly be explained by differences of the atrial vascularization: Minipigs are right coronary artery predominant, while the left coronary artery is dominant in most other species. As heart and skeletal muscles are partly significantly different 35skeletal statin myopathies are generally not associated with significant cardiac toxicity 36 — However, there is evidence that besides having a cardioprotective effect, statins may also be cardiotoxic 39 summart In addition, it is suspected that agonists of peroxisome proliferator bromocriphine receptors PPAR may not only cause rhabdomyolysis, but also adversely affect the heart see section on PPAR agonists below.