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PubMed1990

Morphology of the pubis and preauricular area in relation to parity and age at death in Macaca mulatta.

Some adult human females show bone resorption (pitting) at the dorsal aspect of the pubis and preauricular area of the ilium. The etiology of pelvic bone resorption is attributed alternatively to reproduction and to pelvic anatomy. While most researchers infer that pelvic pitting is related to reproduction, only a few studies are based on women of known parity. Degree of pubic resorption is directly associated with both parity (Suchey et al.: Am. J. Phys. Anthropol. 51:517-539, 1979; Bergfelder and Hermann: J. Hum. Evol. 9:611-613, 1980) and age (Suchey et al.: Am. J. Phys. Anthropol. 51:517-539, 1979). The relationship between parity and degree of resorption of the preauricular area is equivocal, found to be significant by Dunlap (A Study of the Preauricular Sulcus in a Cadaver Population, Ph.D. dissertation, East Lansing, Michigan State University, 1981) but not by Spring et al. (Am. J. Phys. Anthropol. 79:247-252, 1989); both studies report that age is not associated with resorption of the preauricular area. Other mammals evidence public resorption, but the morphology of the preauricular area is less well known. This study addresses the issue on the etiology of pelvic bone resorption using a sample of Macaca mulatta (the free-ranging population from Cayo Santiago) for which parity and age at death are known for all specimens. The following results are reported. Resorption of the pubis is common among females but infrequent among males. Contrary to Rawlins (Am. J. Phys. Anthropol. 42:477-488, 1975), the degree of pubic resorption in female macaques is significantly related to both parity and age at death.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗
PubMed1991

Ontogeny and evolution of pelvic diameters in anthropoid primates and in Australopithecus afarensis (AL 288-1).

Pelvic diameters (both anteroposterior [AP] and transverse [TR]) were investigated in a series of anthropoid primates. The ratio of diameters (AP/TR) in each of three pelvic planes (inlet, midpelvis, and outlet) was calculated. In addition to the above, the length of the iliac, pubic, and ischial axes and the angles between these axes were determined. The AP/TR ratio at the pelvic inlet is (reported in millimeters, +/- SD, unless otherwise specified) 1.81 +/- 0.27 in New World monkeys (Cebidae) and Macaca mulatta; 1.53 +/- 0.17 in hylobatids and pongids; 0.87 +/- 0.08 in Homo sapiens; and 0.58 in Australopithecus afarensis (AL 288-1). The AP/TR ratio in the midpelvis is 1.61 +/- 0.23 in nonhominid primates (Cebidae, M. mulatta, hylobatids, and pongids), 1.12 +/- 0.11 in humans, and 0.59 in AL 288-1. In monkeys (Cebidae and M. mulatta), hylobatids, pongids, H. sapiens, and AL 288-1, the ratios of the length of the pubic axis over the ischial axis were 0.84 +/- 0.06, 0.95 +/- 0.07, 1.10 +/- 0.15, and 1.46, respectively; the pubis-ilium angles were 96 +/- 11, 120 +/- 10, 131 +/- 11, and 147 degrees, respectively; and the ischium-pubis angles were 106 +/- 11, 86 +/- 8, 96 +/- 7, and 68 degrees, respectively. In none of these pelvic features was AL 288-1 "intermediate" between pongids and H. sapiens. The anatomical peculiarities of the pelvis in AL 288-1 are explained primarily as the result of early adaptation to erect posture, which resulted in the reduction of the distance between the sacroiliac joint and the hip joint. As a consequence, the sacral promontory moved toward the pubic symphysis, and this resulted in shortening of the AP diameter and widening of the TR diameter at the pelvic inlet.

Animals↗
PubMedDate not supplied

Gastrointestinal metabolism of N-acetylcysteine in the rat, including an assay for sulfite in biological systems.

The intestinal metabolism of N-acetylcysteine was studied in the rat. Isolated intestinal epithelial cells were shown to rapidly deacetylate [14C]-N-acetylcysteine to [14C]-cysteine, with slight oxidation of the latter to disulfide species. The cells did not accumulate reduced or oxidized cysteine, and N-acetylcysteine itself was not detected either free or in oxidized species intracellularly. Further metabolism of this NAC-derived cysteine to inorganic sulfite or glutathione was not detected. Following the administration of [14C]-N-acetylcysteine (50 mg/kg; 25 microCi) in vivo into the ilium, small quantities of both reduced and oxidized [14C]-N-acetylcysteine were demonstrated in hepatic portal vein plasma. [14C]-cysteine and inorganic sulfite were demonstrated as the major metabolites of N-acetylcysteine. These were present in the portal vein plasma at levels five and three times greater than the parent drug, respectively, 30 min after dosing. Additionally, [14C]-glutathione was shown to be a minor metabolite of N-acetylcysteine accumulating in portal vein plasma. These results may provide an explanation for the apparent low bioavailability of N-acetylcysteine when administered orally in humans and are discussed in terms of the origins of the protective effect of the drug in cases of paracetamol intoxication in humans.

Acetylcysteine↗
PubMed2005

Osteosarcoma of the pelvis in children and young adults: the St. Jude Children's Research Hospital experience.

BACKGROUND: Pelvic osteosarcomas are difficult to resect. The authors reviewed their institution's experience with patients who had such tumors to characterize the patients' clinical findings and to assess the impact of surgical resection on outcome. METHODS: A review was conducted of the records from patients with pelvic osteosarcoma who were treated at the authors' institution between January, 1970 and March, 2004. RESULTS: Among 442 patients with osteosarcoma, 19 patients (4%) had high-grade tumors arising in the pelvic bones, including the ilium in 15 patients, the pubis in 2 patients, and the sacrum in 2 patients. The median patient age at diagnosis was 16.8 years. Four tumors were secondary to radiation therapy. Five patients had metastases in the lung (n = 4 patients) or bone (n = 1 patient) at diagnosis. Ten tumors were chondroblastic. The median greatest tumor dimension for the 13 tumors with known size was 10 cm. Ten patients had unresectable pelvic tumors, and 9 patients underwent hemipelvectomy (2 internal and 7 external); complete resection with negative margins was achieved in 5 patients. Four patients survived, including one patient who survived with disease. Of the three patients who survived disease-free, one patient underwent complete resection, one patient underwent incomplete resection (nonviable tumor at the soft tissue margin) with a good response to chemotherapy, and one patient with a sacral tumor underwent radiotherapy only for local control. Of the 9 patients who underwent resection, 7 experienced disease recurrence (n = 5 patients) or progression (n = 2 patients) at distant sites and died. All patients with metastatic disease at diagnosis died. CONCLUSIONS: Pelvic osteosarcomas often were large and unresectable. A high propensity for metastasis contributed to the poor outcome of patients with pelvic osteosarcoma. New therapeutic approaches are needed.

Adolescent↗
PubMed2005

Dedifferentiated parosteal osteosarcoma: the experience of the Rizzoli Institute.

BACKGROUND: Dedifferentiated parosteal osteosarcoma (DPOS) is a variant of osteosarcoma in which a high-grade sarcoma coexists with a conventional parosteal osteosarcoma (c-POS), either at presentation (synchronous type) or at the time of recurrence (metachronous type). Only approximately 60 patients have been reported in the literature. The objective of this study was to analyze the clinicopathologic and radiographic features of a relatively large number of patients with DPOS in an attempt to define further the histologic and biologic behavior of this rare entity. METHODS: In a series of 120 patients with parosteal osteosarcoma who were seen at the Rizzoli Institute from 1958 to 2000, the authors identified 29 patients who were diagnosed with DPOS. The authors reviewed the clinical and radiologic features, histologic sections, treatments, and outcomes in this group of patients with DPOS. RESULTS: Twelve patients were male, and 17 patients were female. The patients ranged in age from 15 years to 65 yrs (average, 36 years; median, 32 years). One tumor involved the scapula, one involved the ilium, and another involved the skull. All 26 of the other tumors were located in the long bones (14 in the femur, 5 in the humerus, 3 in the tibia, 3 in the fibula, and 1 in the ulna). In 18 patients, radiographic areas of lucency were seen within an otherwise sclerotic lesion. Histologically, the dedifferentiated component was high-grade osteoblastic osteosarcoma in 14 patients, fibroblastic osteosarcoma in 10 patients, giant cell-rich osteosarcoma in 3 patients, and chondroblastic osteosarcoma in 2 patients. All tumors were Stage IIB, and invasion of the medullary canal was detected in 19 patients (65%). Twenty-eight patients underwent surgery, and 18 of those patients received chemotherapy (5 patients received neoadjuvant chemotherapy, and 13 patients received adjuvant). Nine patients were dead and 20 patients were alive (average follow-up, 107 months; range, from 3 months to 36 years) at the last follow-up. Of the nine patients who died, one patient received no treatment, five patients underwent surgery (with three patients achieving adequate margins) in combination with chemotherapy, and three patients underwent surgery only (with adequate margins achieved). Of the 20 patients who remained alive, 13 patients underwent surgery (with 10 patients achieving adequate margins) in combination with chemotherapy, whereas 7 patients underwent surgery only (all with adequate margins). Seven of the nine patients who died had widespread metastases. One patient died of causes unrelated to the tumor, and another patient died shortly after undergoing resection of a lesion in the skull. CONCLUSIONS: Dedifferentiation occurred in approximately 24% of patients with c-POS. The prognosis for patients with DPOS was better than the prognosis for patients with dedifferentiated central and dedifferentiated peripheral chondrosarcoma.

Adolescent↗
PubMed2007

Biodegradable polyurethane cancellous bone graft substitutes in the treatment of iliac crest defects.

Porous scaffolds were produced from newly designed biodegradable, segmented aliphatic polyurethanes of various chemical compositions and hydrophilic-to-hydrophobic segment ratios. The scaffolds were implanted into monocortical defects in the iliac crest of healthy sheep for 6 months. The resected cortex was not repositioned. The ilium defects, which were not implanted with polyurethane scaffolds, were used as controls. In none of the control defects was there bone regeneration at the time of euthanasia. The defects implanted with porous scaffolds from polyurethanes were healed to varying extents with cancellous bone. The structure of the regenerated cancellous bone was radiographically denser than the structure of native bone. New bone that was formed in the scaffolds with a higher amount of hydrophilic component contained more calcium phosphate deposit than the bone formed in the scaffolds with a lower amount of the hydrophilic component. There was no new cortex formed over the defect, but a thin layer of soft tissue covered the newly formed cancellous bone.

Animals↗
PubMed1990

Quantitative bone histomorphometry and circulating T lymphocyte subsets in postmenopausal osteoporosis.

To explore the influence of the immune system on the development of osteoporosis, 19 untreated postmenopausal women with osteoporosis were studied by means of quantitative histomorphometry of the ilium and an analysis of T lymphocyte subsets in the peripheral blood. Osteoporotic women had lower OKT3+ and OKT8+ counts and a higher OKT4+/OKT8+ ratio than nonosteoporotic control subjects. Linear regression analyses disclosed that the age of subjects correlated with bone mineral density (BMD; r = -0.634, p less than 0.01) and some of the histomorphometric parameters for bone formation (r = -0.694 to -0.467, p less than 0.01-0.05). The number of OKT4+ cells showed weak but significant negative correlation with the parameters for bone resorption (r = -0.549 to -0.462, p less than 0.05). In a multiple regression analysis, the advanced age, the increase in OKT3+, and the decrease in OKT4+ and OKT8+ counts were shown to be significant predictors for the decrease in BMD (R = 0.882, p less than 0.01). According to the regression formula obtained from the analysis, the parameters for bone formation were related only to the age of subjects whereas those for bone resorption were tightly associated with the number of OKT4+ and OKT8+ cells but not with the age of subjects. These results indicated that, in addition to the age factor, abnormalities of the peripheral T lymphocyte subsets, especially those of OKT4+ and OKT8+ cells, are closely associated with the decrease in bone mass in postmenopausal osteoporosis, supporting the causal relationship between T lymphocyte functions and the development of postmenopausal osteoporosis.

Aged↗
PubMed2002

Functional morphology of the hindlimb of tupaiids (Mammalia, Scandentia) and its phylogenetic implications.

In this study, the hindlimb of 12 species of tupaiids was analyzed functionally and compared to that of primates, dermopterans, and chiropterans. Many aspects of the tupaiid hindlimb vary in relation to differential substrate use. These differences include width of the ilium, shape of the acetabulum, size of the anterior inferior iliac spine, size of the greater and third trochanters, depth of the femoral condyles, shape of the patellar groove, and size of the tibial tuberosity. The hindlimb of the arboreal Ptilocercus lowii, the only ptilocercine, is better adapted for arboreal locomotion, whereas that of tupaiines is better adapted for rapid terrestrial (or scansorial) locomotion. The hindlimb of Ptilocercus seems to be habitually flexed and has more joint mobility, a condition necessary for movement on uneven, discontinuous arboreal supports. The tarsus of Ptilocercus facilitates inversion of the foot and its grasping hallux is capable of a great range of abduction. Tupaiines, on the other hand, are characterized by more extended hindlimbs and less mobility in their joints. These restricted joints limit movements more to the parasagittal plane, which increases the efficiency of locomotion on a more even and continuous surface like the ground. The hindlimb of tupaiines is adapted for powerful flexion and extension. Even the most arboreal tupaiines remain similar to terrestrial tupaiines in their hindlimb morphology, which probably reflects the terrestrial ancestry of Tupaiinae (but not Tupaiidae). Many attributes of the tupaiid hindlimb, especially those of the foot, reflect the arboreal ancestry of Tupaiidae and it is proposed that the ancestral tupaiid was arboreal like Ptilocercus. Also, compared to the hindlimb character states of tupaiines, those of Ptilocercus are more similar to those of other archontans, and it is proposed that the hindlimb features of Ptilocercus are primitive for the Tupaiidae. Hence, Ptilocercus should be considered in any phylogenetic analysis that includes Scandentia.

Animals↗
PubMed2006

Skeletal development of the Mexican spadefoot, Spea multiplicata (Anura: Pelobatidae).

The larval chondrocranium of Spea multiplicata is described, as is the development and adult morphology of the skeleton. There are major modifications to the larval chondrocranium throughout development, including the presence of embryonic trabeculae in young tadpoles and significant reorganization of cartilaginous structures at metamorphosis. The first bone to ossify is the parasphenoid (Stage 35), followed by the presacral neural arches, ilium, and femur (Stage 36). By Stage 39, most of the postcranial elements have begun to ossify. Metamorphic climax is accomplished over three Gosner stages (39-41) and involves major modifications to the chondrocranium, as well as the appearance of three cranial elements (septomaxilla, nasal, and premaxilla). After metamorphosis, the exoccipital, vomer, dentary, angulosplenial, squamosal, pterygoid, sphenethmoid, ischium, and hyoid begin to ossify. The stapes, mentomeckelian, operculum, carpals, and tarsals do not appear until juvenile and adult stages. The development of the hyoid and cartilaginous condensations of the carpals and tarsals are described. In addition, phenotypic plasticity within the genus and the absence of a palatine (= neopalatine) bone are discussed.

Animals↗
PubMed2001

Relationship between bone marrow cellularity and apparent diffusion coefficient.

This study was performed to determine if there is a relationship between apparent diffusion coefficient (ADC) and cellularity of bone marrow of the posterior ilium. Four groups of various marrow cellularity underwent diffusion-weighted echo-planar imaging: 1) adults with normal hypocellularity (21 patients); 2) adults with normal normocellularity (13 patients); 3) young children with normal hypercellularity (5 patients); and 4) adults with lymphoma-related hypercellularity (3 patients). In all adults, marrow cellularity was confirmed by uni-or bilateral bone marrow biopsies. In children, the iliac marrow was presumed hypercellular because of their ages. A total of 66 ADC values of bone marrow calculated from diffusion-weighted images with b-values of 30 and 300 seconds/mm(2) was evaluated. Hypercellular marrow (normal and lymphoma-related) showed the highest mean ADC, and hypocellular the lowest ADC. Statistically significant differences were found between three groups of normal marrow: hypocellular, normocellular, and hypercellular. There is a positive correlation between ADC and cellularity of bone marrow. J. Magn. Reson. Imaging 2001;13:757-760.

Adult↗
PubMed1985

Contact finite element stress analysis of the hip joint.

Two-dimensional finite element analyses were conducted of the normal hip using contact elements at the joint surface. The models studied were constructed for a slice through the pubis, acetabulum, and ilium. In the analyses the proximal femur was pressed into the acetabulum and intraarticular pressures and principal stresses in the joint region were determined for different load magnitudes and directions and various boundary conditions. Three sets of boundary conditions were examined: (a) deformable pubic symphysis, (b) rigid pubic symphysis, and (c) simulations of experimental studies. In the deformable model the pubic symphysis was free to displace in the sagittal plane and rotate. In the rigid model the pubic symphysis was rigidly fixed. Superoposterior loading resulted in high-contact pressures at the acetabular dome for all sets of boundary conditions. For the deformable model subject to a more medially directed load the acetabulum closed in such a manner as to squeeze the head of the femur creating high-contact pressures superiorly and inferiorly. This resulted in significant compressive stresses in the superior dome cancellous bone and inferior cancellous bone. The cumulative effect of this squeezing action with normal biological remodeling may cause elongation of the femoral head resulting in asphericity and incongruity of the unloaded hip joint articular surfaces. Rigidly fixing the pubic symphysis stiffened the model and resulted in principal stress patterns that did not reflect trabecular density or orientations as well as those of the deformable pubic symphysis model. Finite element simulations of previous experimental studies modeled the close proximity of the fixation to the excised acetabulum. These boundary conditions prevented the squeezing caused by pelvis deformations. The resulting contact areas, pressure distributions, and bone stresses were very different from those of the more anatomic, deformable pubic symphysis model. These findings demonstrate the sensitivity of hip contact pressures and stresses to imposed boundary conditions and indicate that care should be taken to simulate anatomic conditions in experimental and theoretical studies.

Acetabulum↗
PubMed1987

Load-displacement behavior of sacroiliac joints.

We measured the load-displacement behavior of both single and paired sacroiliac (SI) joints in fresh cadaver specimens obtained from eight adults between the ages of 59 and 74 years. With both ilia fixed, static test loads were applied to the center of the sacrum along and about axes parallel and normal to the superior SI endplate. Test forces up to 294 N were applied in the superior, inferior, anterior, posterior, and lateral directions. Moments up to 42 N-m were applied in flexion, extension, lateral bending, and axial torsion. Displacements of the center of the sacrum were measured 60 s after each load increment was applied, using dial gauges and an optical lever system. The tests were then repeated with only one ilium fixed. Finally, the three-dimensional location and overall geometry of each SI joint were measured. For an isolated left joint at the maximum test loads, the mean (SD) sacral displacements in the direction of the force ranged from 0.76 mm (1.41) in the medial to 2.74 mm (1.07) in the anterior direction. The mean rotations in the directions of the moments ranged from 1.40 degrees (0.71) in right lateral bending to 6.21 degrees (3.29) in clockwise axial torsion viewed from above. We also examined load-displacement behavior under larger loads. Single sacroiliac joints resisted loads from 500 to 1440 N, and from 42 to 160 N-m without overt failure.

Aged↗
PubMed1991

Anterior and posterior internal fixation of vertical shear fractures of the pelvis.

A laboratory study was undertaken to evaluate the effectiveness of alternative methods of fixation of unilateral vertical shear fractures of the pelvis. Prior to experimental testing, a biomechanical analysis was performed to estimate the forces that displace the hemipelvis in the presence of two different patterns of injury: an interforaminal sacral fracture and a disruption of the sacroiliac joint. These lesions were then experimentally created in five unembalmed human pelvises and sequentially fixed with an external Hoffmann frame alone, a Hoffmann frame with sacral bars, or sacral bars with either one or two bone plates placed across the symphysis pubis. Each pelvis/fixator system was mechanically tested by loading along the direction of the resultant muscle force predicted by the biomechanical analysis. During loading the proximal migration of the ilium was continuously recorded with a transducer. At intervals during loading, the three-dimensional displacement of the detached hemipelvis at the pubic symphysis was also measured using a stereophotographic technique. With both the sacral fracture and the sacroiliac disruption, the addition of posterior sacral rods substantially increased the strength and rigidity of fixation provided by the Hoffmann fixation frame alone (p less than 0.01). In specimens with a sacral fracture, the use of anterior plates with posterior rods restored 65-71% of the strength of the intact pelvis, in comparison with 46% observed with the combination of sacral rods with an anterior Hoffmann frame (p less than 0.01). All of the methods of fixation evaluated in this study were less successful in stabilizing the sacroiliac disruption.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomechanical Phenomena↗
PubMed2004

VEGF-promoted surgical angiogenesis in necrotic bone.

The ability of vascular endothelial growth factor (VEGF) to accelerate neoangiogenesis from implanted arterovenous (AV) bundles in necrotic bone was evaluated. A saphenous AV bundle was placed in a necrotic segment of rabbit ilium. In group II, VEGF (100 ng/h x 3 days) was administered by continuous infusion. Bone blood flow was measured with radioactive-labeled microspheres, and capillary density was determined by microangiography combined with Spälteholtz bone clearing at 1, 2, and 4 weeks. Neovascularization was observed along the implanted vascular bundle in both groups. One week after surgery, bone blood flow and vessel area were significantly higher in VEGF-treated animals (P < 0.05). No significant difference was observed at later times. Direct VEGF administration increased surgical angiogenesis and improved blood flow and neovascularization in necrotic bone 1 week after AV bundle implantation. Thereafter, a robust angiogenic response from the AV bundle was seen in both groups.

Animals↗
PubMed1994

Experimental study and clinical observations on hypertrophy of vascularized bone grafts.

In order to understand the mechanisms involved in the hypertrophy of vascularized bone grafts, a series of animal experiments were carried out and 32 clinical cases were studied. A defect in the tibial shaft was created in puppies and the ipsilateral fibula was transferred into the medullary cavity of the tibia with the anterior tibial artery and vein. The same procedure was performed on a control group but without vessel supply. Radiologically, in the vascularized group mild hypertrophy in the fibula was seen at 2 weeks, became marked by 4 weeks, but in no case did the thickening (hypertrophy) of the graft ever exceed the diameter of the recipient tibia. The control group did not show hypertrophy but fracture callus formed in the recipient tibia at both ends of the graft. On histological evaluation no reactive bone formation was evident in the control group but some reactive bone formation was seen in the vascularized group just beneath the periosteum. There was no change in the periosteum itself. In the clinical cases 47% of patients showed hypertrophy. Hypertrophy was noted mainly in the fibulae but rarely in other bones such as ilium or rib. The important factors were age and good vascularity of the grafted bone. During the period of study, weight-bearing was eliminated, so that the effects of mechanical force did not explain hypertrophy. We conclude from these studies that true hypertrophy is an essentially different process from reactive callus which forms normally in response to fracture healing. Vascularized bone grafts show remarkable hypertrophy of the grafted bone, but the exact mechanism is ill defined.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Primary Hodgkin's disease of the bone.

A primary extranodal presentation occurs in less than 0.25% of patients with Hodgkin's disease (HD) and we describe the primary clinicopathologic findings in a rare case of a 21-year-old female with primary bony involvement of Hodgkin's disease. The patient presented with microcytic, hypochromic anemia and shoulder pain. The diagnosis of HD (lymphocyte depleted type) was made by biopsy taken from a lytic lesion in the lateral third of the clavicle. Staging work-up revealed an additional lesion in the ilium, but there was no evidence of lymph node involvement. MOPP/ABV (nitrogen mustard, Oncovin, procarbazine, prednisone/adriamycin, bleomycin, and vinblastine) chemotherapy resulted in complete response lasting, to date, 36 months. To the best of our knowledge, this is only the second reported case of disseminated primary Hodgkin's disease of the bone and all have had a favourable response to combination chemotherapy. A review of the literature is also presented.

Adult↗
PubMed1995

Developmental toxicity of mangafodipir trisodium and manganese chloride in Sprague-Dawley rats.

Mangafodipir trisodium (MnDPDP) is a manganese chelate being developed as a contrast agent for magnetic resonance imaging of the hepatobiliary system. The intended clinical dose is 5 mumol/kg. The potential for MnDPDP to induce embryotoxicity and/or teratogenicity in Sprague-Dawley rats was investigated. Twenty five inseminated rats/group were intravenously administered 0, 2, 5, or 20 mumol/kg MnDPDP from days 6-17 of gestation. Maternal toxicity was not observed at any dose of MnDPDP. There were no treatment-related effects on the numbers of fetuses, fetal viability, numbers of resorptions, implantations and corpora lutea, or the percent of pre- and post-implantation losses. However, at 20 mumol/kg, fetal body weights were significantly decreased (3.3 g vs. 3.9 g for control) and increased skeletal malformations were observed (141/270 vs. 0/285 in control). The malformations were of a specific type, which included angulated or irregularly shaped clavicle, femur, fibula, humerus, ilium, radius, scapula, tibia, and/or ulna. To better define the developmental stage that is most susceptible to the effects of MnDPDP, a segmented developmental study was conducted. Twelve inseminated rats were administered 0, 20, 40, or 80 mumol/kg MnDPDP on days 6-8, 9-11, 12-14, or 15-17 of gestation. Skeletal malformations, identical to those seen in the previous study, were increased in a dose-dependent manner with the highest incidence occurring in fetuses from females dosed from days 15-17 of gestation. A third study, in which 15 rats/group were dosed intravenously with 0, 5, 20, or 40 mumol/kg MnCl2 on days 6-17 of gestation, produced identical skeletal malformations to those seen with MnDPDP, indicating that manganese is the active moiety responsible for these specific malformations.

Abnormalities, Drug-Induced↗
PubMed1996

Developmental toxicity study of mangafodipir trisodium injection (MnDPDP) in New Zealand white rabbits.

Mangafodipir trisodium injection (MnDPDP) is an intravenously administered manganese chelate undergoing clinical evaluation for magnetic resonance imaging contrast enhancement of the hepatobiliary system. The anticipated single clinical dose for adults is 5 micromol/kg body wt. MnDPDP, as well as the inorganic salt, MnCl2, was previously shown to induce a specific syndrome of skeletal abnormalities in rats. The syndrome malformations included angulated or irregularly shaped clavicle, femur, fibula, humerus, ilium, radius, scapula, tibia, and/or ulna. The objective of the present study was to assess the developmental toxicity of MnDPDP in a second mammalian species, the New Zealand White rabbit. MnDPDP was intravenously administered daily to groups of rabbits (22 per group) on Days 6 through 18 of pregnancy at doses of 0 (saline), 5, 20, 40, and 60 micromol/kg MnDPDP. Fetuses were examined on Day 29 of pregnancy for external, visceral, and skeletal abnormalities. Treatment with MnDPDP did not result in overt symptoms of maternal toxicity, and there were no significant effects on maternal body weight gains or feed consumption. The maternal no-observed-adverse-effect level (NOAEL), therefore, was 60 micromol/kg MnDPDP. Treatment with MnDPDP resulted in a significant increase in postimplantation loss at 60 micromol/kg, but there was no significant increase in external, visceral, or skeletal abnormalities at any dose. The developmental NOAEL for MnDPDP, therefore, was 40 micromol/kg. These results indicate that the developmental toxicity profile of MnDPDP differs considerably in the rat and rabbit. In the rat, this compound induces specific skeletal abnormalities, whereas in the rabbit, embryo/fetal toxicity is the most sensitive developmental endpoint with no evidence for the induction of specific skeletal abnormalities.

Abnormalities, Drug-Induced↗