Collaborative Work to Evaluate Toxicity on Male Reproductive Organs by Repeated Dose Studies in Rats : Overview of the Studies

Sakai, Toshiharu; Takahashi, Michihito; Mitsumori, Kunitoshi; Yasuhara, Kazuo; Kawashima, Kunio; Mayahara, Hiroshi; Ohno, Yasuo

doi:10.2131/jts.25.specialissue_1

Cited by 53 publications

(17 citation statements)

References 51 publications

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“…With this large number of in-vivo hormonal assays and semen analysis. Even though cooperative efforts have been made to establish strict guidelines for reproductive toxicity assessment during drug development, standard protocols have not yet been established and, as a consequence, discrepancies between research centres and countries still exist [48]. Drug safety relies on studies for genetic, carcinogenic, reproductive and development toxicity [49].…”

Section: Methodsmentioning

confidence: 99%

“…In order to identify the best approach for genotoxicity assessment, researchers have conducted numerous validation studies to calculate the effectiveness of current screening tools. For instance, it was reported that a 2-week drug treatment was sufficient to analyse drug toxicity-induced damages to male rat reproductive organs [48]. In humans, since each spermatogenic cycle takes about 76 days, testicular toxicity analysis should be performed at the beginning and at each two months [50,51].…”

Section: Methodsmentioning

confidence: 99%

“…Several techniques have been developed to study genotoxicity in-vitro, such as testicle organ slice evaluation and sperm suspensions [59][60][61].These methods not only can provide more real determinations regarding drug toxic effects but can also aid to develop biomarkers to be latter used for toxicity monitoring [62]. Furthermore, researchers must acknowledge that in-vitro findings do not represent the real physiological conditions as lack tissue interactions [48].…”

Section: Methodsmentioning

confidence: 99%

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Assessing Male Reproductive Toxicity during Drug Development

Sousa¹,

Ferreira²,

Rabaça³

et al. 2017

Andrology

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Medical drug development is a crucial research field that attends to population healthcare needs, comprising several preclinical and clinical steps before the approval of a new compound. One major cause of pharmaceutical drug development failure is toxicity, especially in respect to kidney and liver. Nonetheless, the male reproductive system may also be a target for drug toxicity. Although the reproductive health is an important component of the person life, reproductive toxicology testing is rarely performed, both in pre-clinical and clinical trial phases. As reproductive and testicular toxicity is found at a low incidence during the early stages of drug development, companies devote the majority of research investments to more frequent areas of toxic occurrence. It is here suggested the inclusion of comprehensive studies and more precise methods to uncover the toxic reproductive effects and causes when developing new pharmacological drugs.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Assessing Male Reproductive Toxicity during Drug Development

Sousa¹,

Ferreira²,

Rabaça³

et al. 2017

Andrology

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“…The first was a detailed review of known male reproductive toxicants, which revealed that testicular weights and histopathology detected the majority of male reproductive toxicants (Ulbrich and Palmer, 1995). The second was a Japanese collaboration (Takayama et al, 1995;Sakai et al, 2000) showing that most testicular toxicants could be detected by histopathology after only 2-4 weeks of administration.…”

Section: Evolution Of the Design Of Fertility Studiesmentioning

confidence: 99%

The nonclinical fertility study design for pharmaceuticals

Lerman¹,

Hew²,

Stewart³

et al. 2009

Birth Defects Research Pt B

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Assessment of potential developmental and reproductive toxicity of human pharmaceuticals is currently guided by the ICH S5(R2) document, "Detection of Toxicity to Reproduction for Medicinal Products and Toxicity to Male Fertility." Studies that assess a candidate drug's effect on fertility are generally conducted in rats. The evolution of, and ultimate harmonization of, fertility study designs are reviewed, and specific elements of an acceptable design, as well as the recommendations for presentation of data, are described in detail. Additionally, the timing of nonclinical fertility studies in relation to clinical studies that enroll men and women of reproductive potential is reviewed. Possible strategies for combining fertility assessment with other study designs are also presented. This article provides testing laboratories, sponsors, and regulatory agencies with a comparison of current methods and designs, with the aim of providing a common understanding of the critical design features.

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“…According to the ICH agreement (ICH guidelines, 29 November 1995), however, Segment is not necessarily required to enter clinical trials. The adverse effects of under-development drugs on male fertility have been examined by histopathological examination of male reproductive organs in repeated-dose toxicity studies before clinical trials (Sakai et al, 2000). Sperm function and libido, however, cannot be analyzed by histopathological examination.…”

Section: Introductionmentioning

confidence: 99%

Investigation of usefulness of sperm analyses in dogs for male fertility study.

et al. 2001

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The usefulness of sperm analyses in dogs, including sperm motion analysis, was investigated. Sperm motion analysis was performed with the CellSoft-4000 computer-assisted sperm analysis (CASA) system. First, we examined the conditions for preservation of optimal semen quality. We found that sperm retained more of their motility at 4 than at 37 . Secondly, we observed sperm motion, concentration and morphology in dog semen continuously for 11 weeks. We collected semen samples during the test period, and the samples retained sperm motion, concentration and morphology. Finally, we administrated -chlorohydrin, which decreases rodent sperm motion, at a single oral dose of 100 mg/kg or 150 mg/kg to dogs. Sperm motion was inhibited immediately after -chlorohydrin treatment, and recovered after 2 weeks. None of the experimental animals were sacrificed in the above-mentioned examinations.We thus confirmed that sperm analyses including motion analysis in dogs are useful in male fertility studies.

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Collaborative Work to Evaluate Toxicity on Male Reproductive Organs by Repeated Dose Studies in Rats : Overview of the Studies

Cited by 53 publications

References 51 publications

Assessing Male Reproductive Toxicity during Drug Development

Assessing Male Reproductive Toxicity during Drug Development

The nonclinical fertility study design for pharmaceuticals

Investigation of usefulness of sperm analyses in dogs for male fertility study.

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