Azosemide‐Induced Fetal Wavy Ribs and Their Disappearance after Birth in Rats

Hayasaka, Ichirô; Tamaki, Fumikazu; Uchiyama, K.; Kato, Z.; Murakami, Kazuo

doi:10.1111/j.1741-4520.1985.tb01003.x

Cited by 18 publications

(20 citation statements)

References 8 publications

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“…However, in the case of the pesticide S-53482 (Kawamura et al, 1995), rats showed wavy ribs and bent scapulae but rabbits showed no effect. For the loop diuretic, azosemide (Hayasaka et al 1984(Hayasaka et al , 1985(Hayasaka et al , 1990Kumazawa et al, 1997), rats and mice showed an increase in all three skeletal changes but rabbits showed no effect. Except for artesunate, rabbits appear to be much less sensitive to the induction of wavy ribs and bent long bones and scapulae; alternatively, these alterations may not be evident at birth in rabbits because they are remodeled during the longer fetal period.…”

Section: Resultsmentioning

confidence: 99%

“…Figure 3 is an illustration of the progressive decrease in incidence of wavy ribs during lactation based on data from Nishimura et al (1982). Hayasaka et al (1984Hayasaka et al ( , 1985 found normal conformation of long bones and scapulae in postnatal rat pups whose dams had been exposed to azosemide. More recently, Mitchard and Stewart (2014) reported on skeletal effects in Han Wistar rats which have a variable incidence of a "chondrodystrophy" syndrome that includes wavy ribs and bent long bones and scapulae at term.…”

Section: Resultsmentioning

confidence: 99%

“…Wavy ribs disappeared by PND 9.Rabbits: no effect. Hayasaka et al (1984Hayasaka et al ( , 1985Hayasaka et al ( , 1990 Kawamura et al (1995Kawamura et al ( , 1996 pup could be examined at multiple ages. Complete recovery of bent long bones and scapulae was reported in this study.…”

Section: Resultsmentioning

confidence: 99%

“…The exception is the study of De Schaepdrijver et al (2014) who were able to do micro-CT scanning on the same pups at multiple postnatal ages. In addition, the incidence rate of bent bones at birth in the Hayasaka et al (1985) study was very high, so that most of the pups examined postnatally could be assumed to have had bent bones at birth.…”

Section: Resultsmentioning

confidence: 99%

“…Bent long bones and scapulae, as well as wavy ribs were examined postnatally in several studies and also appeared to be transient (Hayasaka et al, 1984(Hayasaka et al, , 1985De Schaepdrijver et al, 2014;Mitchard and Stewart, 2014). De Schaepdrijver et al (2014) using micro-CT scanning were able to examine the same pups sequentially at several ages postnatally and observed remodeling of bone conformation.…”

Section: Discussion Pre-and Postnatal Bone Formationmentioning

confidence: 99%

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Relationship Between Bent Long Bones, Bent Scapulae, and Wavy Ribs: Malformations or Variations?

Kimmel

Garry

DeSesso

2014

Birth Defects Research Pt B

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BACKGROUND: Shortened and bent long bones and bent scapulae are sometimes reported in fetuses with wavy ribs (Carney and Kimmel, 2007). Wavy ribs are typically seen in the presence of maternal and developmental toxicity, are transient and reversible postnatally, and are considered to be variations rather than malformations. METHODS: We further assessed the literature cited in Kimmel and Carney (2007) as well as papers published since then to determine under what conditions bent long bones in the absence of gross limb defects and bent scapulae were reported and whether information was available on the transient or permanent nature of these effects. RESULTS: Long bone and/or scapular changes almost always occurred at a lower incidence than wavy ribs. In every case, maternal and fetal toxicity occurred at the same dose levels. In a few studies, pups were followed sequentially after birth and bent long bones and scapulae were transient in nature and appeared normal by the time of weaning. Rabbits were much less likely to show wavy ribs or long bone and scapular changes at birth, even in the presence of severe maternal and fetal toxicity. This species difference may be due in part to the great increase in bone mass and remodeling that occurs during the first few postnatal weeks in rodents, but which takes place during the longer fetal period in rabbits. CONCLUSION: Our conclusion from this review is that bent long bones and scapulae, like wavy ribs, appear to be secondary to maternal and developmental toxicity, are transient, and like wavy ribs should be considered variations rather than malformations.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussion Pre-and Postnatal Bone Formationmentioning

confidence: 99%

See 3 more Smart Citations

Relationship Between Bent Long Bones, Bent Scapulae, and Wavy Ribs: Malformations or Variations?

Kimmel

Garry

DeSesso

2014

Birth Defects Research Pt B

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Pharmacokinetics and pharmacodynamics of azosemide

Suh¹,

Kim²,

Lee³

2003

Biopharm & Drug Disp

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Azosemide is used in the treatment of oedematous states and hypertension. The exact mechanism of action is not fully understood, but it mainly acts on both the medullary and cortical segments of the thick ascending limb of the loop of Henle. Delayed tolerance was demonstrated in humans by homeostatic mechanisms (principally an increase in aldosterone secretion and perhaps also an increase in the reabsorption of solute in the proximal tubule). After oral administration to healthy humans in the fasting state, the plasma concentration of azosemide reached its peak at 3-4 h with an absorption lag time of approximately 1 h and a terminal half-life of 2-3 h. The estimated extent of absolute oral bioavailability in humans was approximately 20.4%. After oral administration of the same dose of azosemide and furosemide, the diuretic effect was similar between the two drugs, but after intravenous administration, the effect of azosemide was 5.5-8 times greater than that in furosemide. This could be due to the considerable first-pass effect of azosemide. The protein binding to 4% human serum albumin was greater than 95% at azosemide concentrations ranging from 10 to 100 microg/ml using an equilibrium dialysis technique. The poor affinity of human tissues to azosemide was supported by the relatively small value of the apparent post-pseudodistribution volume of distribution (Vdbeta), 0.262 l/kg. Eleven metabolites (including degraded products) of azosemide including M1, glucuronide conjugates of both M1 and azosemide, thiophenemethanol, thiophencarboxylic acid and its glycine conjugate were obtained in rats. Only azosemide and its glucuronide were detected in humans. In humans, total body clearance, renal clearance and terminal half-life of azosemide were 112 ml/min, 41.6 ml/min and 2.03 h, respectively. Azosemide is actively secreted in the renal proximal tubule possibly via nonspecific organic acid secretory pathway in humans. Thus, the amount of azosemide that reaches its site of action could be significantly modified by changes in the capacity of this transport system. This capacity, in turn, could be predictably changed in disease states, resulting in decreased delivery of the diuretic to the transport site, as well as in the presence of other organic acids such as nonsteroidal anti-inflammatory drugs which could compete for active transport of azosemide. The urinary excretion rate of azosemide could be correlated well to its diuretic effects since the receptors are located in the loop of Henle. The diuretic effects of azosemide were dependent on the rate and composition of fluid replacement in rabbits; therefore, this factor should be considered in the evaluation of bioequivalence assessment.

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Bone development in laboratory mammals used in developmental toxicity studies

DeSesso

2018

Birth Defects Research

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Evaluation of the skeleton in laboratory animals is a standard component of developmental toxicology testing. Standard methods of performing the evaluation have been established, and modification of the evaluation using imaging technologies is under development. The embryology of the rodent, rabbit, and primate skeleton has been characterized in detail and summarized herein. The rich literature on variations and malformations in skeletal development that can occur in the offspring of normal animals and animals exposed to test articles in toxicology studies is reviewed. These perturbations of skeletal development include ossification delays, alterations in number, shape, and size of ossification centers, and alterations in numbers of ribs and vertebrae. Because the skeleton is undergoing developmental changes at the time fetuses are evaluated in most study designs, transient delays in development can produce apparent findings of abnormal skeletal structure. The determination of whether a finding represents a permanent change in embryo development with adverse consequences for the organism is important in study interpretation. Knowledge of embryological processes and schedules can assist in interpretation of skeletal findings. K E Y W O R D Sembryology, developmental toxicity testing, embryofetal toxicology testing, ossification, skeletal development, supernumerary ribs, wavy ribs | DEFINITION OF THE PROBLEMDevelopmental toxicity testing includes assessment of the near-term fetal skeleton in laboratory animals, particularly rats, mice, and rabbits. Alterations associated with treatment usually are categorized as malformations or variations, defined in section 2, below. The distinction between variations and malformations is not always clear, and different laboratories may produce different assessments. The biological importance of variations may also be unclear. We will review the published data on these skeletal findings with emphasis on the biological significance of the skeletal changes that have been the most variably interpreted.We are not the first authors to undertake an assessment of developmental changes in the skeleton. Among the helpful reviews in the literature are those by Kimmel and Wilson (1973), Chernoff and Rogers (2004), Tyl, Chernoff, and Rogers (2007), Daston and Seed (2007), Carney and Kimmel (2007), Beyer et al. (2011), Kimmel, Garry, andDeSesso (2014), and Hofmann, Buesen, Schneider, and van Ravenzwaay (2016). | REGULATORY REQUIREMENTS | TechniquesMost pharmaceutical and many non-pharmaceutical chemicals are evaluated for developmental toxicity in experimental animals prior to marketing approval. The requirements for pharmaceutical chemicals have been harmonized for use in Europe, the US, and Japan (ICH, 2005(ICH, , 2017 wileyonlinelibrary.com/journal/bdr2 1157 examination of preferably all fetuses is part of the developmental toxicity evaluation; however, the method of skeletal examination is not specified. The newer techniques of microcomputerized tomography and magnetic resonance imaging ...

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Azosemide‐Induced Fetal Wavy Ribs and Their Disappearance after Birth in Rats

Cited by 18 publications

References 8 publications

Relationship Between Bent Long Bones, Bent Scapulae, and Wavy Ribs: Malformations or Variations?

Relationship Between Bent Long Bones, Bent Scapulae, and Wavy Ribs: Malformations or Variations?

Pharmacokinetics and pharmacodynamics of azosemide

Bone development in laboratory mammals used in developmental toxicity studies

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