Data from subjects receiving intrathecal laronidase for cervical spinal stenosis due to mucopolysaccharidosis type I.

Five subjects with mucopolysaccharidosis type I and symptomatic cervical spinal stenosis received intrathecal laronidase in a 4-month pilot study and/or a 12-month extension study [1]. Clinical descriptions of study subjects, nonserious adverse events, individual data tables, and scoring system methods are provided. There were ten nonserious adverse events that occurred in more than one study subject. Somatosensory evoked potentials were absent in two subjects and normal in two subjects, limiting their utility as an endpoint. There were no significant changes in magnetic resonance imaging of cervical spinal cord or brain, pulmonary function tests, or cerebrospinal fluid opening pressure. These data are presented along with the scoring methods used in evaluation of the study subjects.

Continuous infusion of enzyme replacement therapy is inferior to weekly infusions in MPS I dogs.

Intravenous enzyme replacement therapy with recombinant human α-L-iduronidase (rhIDU) is used weekly to treat mucopolysaccharidosis (MPS) I. We tested continuous administration of rhIDU at two dosing levels (0.58 mg/kg per week and 2 mg/kg per week) in MPS I dogs, and compared the efficacy of continuous infusion with the clinically used 0.58 mg/kg weekly three-hour infusion. Peak plasma concentrations of rhIDU were much higher in weekly-treated dogs (mean 256 units/ml) than steady-state concentrations in dogs treated with continuous infusion (mean 1.97 units/ml at 0.58 mg/kg per week; 8.44 units/ml at 2 mg/kg per week). Dogs receiving continuous IV rhIDU, even at a higher (2 mg/kg per week) dose, had consistently lower iduronidase levels in tissues than dogs receiving a weekly (0.58 mg/kg per week) dose. GAG storage was also less improved by continuous intravenous infusion. Adverse events were similar in all dosing groups. We found that continuous administration of 2 mg/kg per week rhIDU to MPS I dogs was insufficient to achieve GAG storage reduction comparable to 0.58 mg/kg weekly dosing.

Monosomy 7 syndrome associated with congenital adrenal hypoplasia and male pseudohermaphroditism.

BACKGROUND: Bone marrow monosomy 7 is an uncommon disorder of the pluripotent stem cells that leads to frequent childhood infections and leukemia. Primary adrenal hypoplasia occurs very rarely and is incompatible with life. Male pseudohermaphroditism results from inadequate androgen secretion or inappropriate androgen action. We report a case of monosomy 7, adrenal hypoplasia, and male pseudohermaphroditism. CASE: An infant was born with sexual ambiguity and bilateral inguinal masses. Bone marrow karyotype was 45, XY,-7. Serum testosterone level was low normal. The infant died on the fourth day of life. Autopsy revealed severely hypoplastic adrenal glands, inguinal testes, and a vaginal pouch. CONCLUSION: Monosomy 7 and male sexual ambiguity are reported in association with primary adrenal hypoplasia of the cytomegalic (X-linked) type.

Role of extracellular calcium and calcium channels in the response of human placental venous smooth muscle to endothelin-1.

OBJECTIVE: Our purpose was to evaluate the role of calcium and calcium channels in endothelin-1-induced contraction of the smooth muscle of human placental veins. STUDY DESIGN: Placentas were collected after vaginal delivery at term. After their removal from the chorionic plate, placental veins were divided into rings that were suspended in organ chambers and stretched to optimal tension. In the first part of the study, vessels from six women were initially suspended in calcium-poor modified Krebs-Ringer solution. They were then treated with either EGTA [ethylene glycol-bis(beta-aminoethyl ether)N,N,N',N'-tetraacetic acid; calcium chelator, 0.5 mmol/L] or calcium chloride 2.5 mmol/L (control). Endothelin-1 was then added cumulatively (10(-10) to 10(-7) mol/L), and the resulting changes in isometric tensions were recorded. In the second part of the study vessels from six other women were treated with either (1) normal modified Krebs-Ringers solution (control), (2) calcium-poor modified Krebs-Ringers solution, or (3) nicardipine (dihydropyridine calcium channel inhibitor, 10(-7) mol/L) in separate organ chambers. Endothelin-1 was then added cumulatively. RESULTS: Endothelin-1 produced concentration-dependent contractions in placental veins, with maximal tension reached at 10(-7) mol/L. Substitution of calcium-poor for standard Krebs-Ringers solution in the organ chamber abolished contractions to low endothelin-1 concentrations (< or = 10(-9) mol/L, p < 0.001) but did not affect the contractile response to higher concentrations. EGTA abolished contractions to all concentrations tested (p < 0.02). Nicardipine significantly, but incompletely, inhibited the contractile responses to all endothelin-1 concentrations tested (p < 0.05). CONCLUSIONS: Endothelin-1 induces contraction of the smooth muscle of human placental veins, which requires the influx of extracellular calcium. Dihydropyridine-sensitive calcium channels represent a major route of entry, but other pathways participate. The fetal effects of nifedipine and other calcium-channel blockers deserve specific evaluation in intrauterine growth retardation and other pregnancies complicated by elevated fetal levels of endothelin-1.

Contractile effect of endothelin in human placental veins: role of endothelium prostaglandins and thromboxane.

OBJECTIVE: The aim was to study the effects of endothelin-1 on human placental veins and the role of cyclooxygenase products as mediators of these effects. STUDY DESIGN: Rings of placental veins with and without endothelium were suspended in organ chambers filled with physiologic salt solution. After a period of stabilization at optimal basal tension, isometric tensions in the control group were recorded at increasing concentrations of endothelin-1 (10(-10) to 10(-7) mol/L). Rings in the experimental groups were treated with either indomethacin (cyclooxygenase inhibitor, 10(-5) mol/L), dazoxiben (thromboxane synthetase inhibitor, 10(-4) mol/L), or SQ29548 (thromboxane receptor antagonist, 10(-6) mol/L) before addition of endothelin-1. To demonstrate the presence of functional thromboxane receptors in the rings, contractile responses to U-46619 (10(-9) to 10(-6) mol/L), a thromboxane A2 analog were measured. The effectiveness of SQ29548 blockade was tested in rings treated with SQ29548 (10(-6) mol/L) before addition of U-46619. The concentration-response curves of the treated and control groups were compared with the Student paired t test. RESULTS: Endothelin-1 in doses of 10(-10) to 10(-7) mol/L caused concentration-dependent contraction of placental veins. Indomethacin significantly reduced the response of veins with endothelium to low endothelin-1 concentrations (10(-9.5) to 10(-9) mol/L), (p < 0.05). However, it had no effect at higher endothelin-1 concentrations or in vessels without endothelium. The presence of functional thromboxane A2 receptors was confirmed by the vasoconstrictor effect of U-46619 and its blockade by treatment with SQ29548. Neither SQ29548 nor the thromboxane A2 synthesis inhibitor dazoxiben significantly influenced the response to endothelin-1. CONCLUSIONS: These results demonstrated that endothelin-1 is a potent vasoconstrictor in the human placental vein. Although functional thromboxane A2 receptors exist in this vessel, endothelin-1's action is independent of thromboxane A2. Prostaglandins may mediate part of the endothelin-1-induced placental vasoconstriction. However, endothelin-1 acts primarily by a direct effect on vascular smooth muscle cells.

Endothelins 1 and 3 and big endothelin-1 contract isolated human placental veins.

Experiments were designed to investigate the reactivity of vascular smooth muscle to endothelins (ETs) in veins taken from human placentas immediately after delivery. The placental veins were cut into rings and suspended between two stirrups in conventional organ chambers (filled with aerated, modified Krebs-Ringer bicarbonate solution) for isometric recording of tension. ET-1 and ET-3 caused concentration-dependent contractions of the isolated human placental veins. The responses induced by ET-1 were greater than those evoked by ET-3 and were not significantly affected by BQ-123, a selective inhibitor of ETA receptors. Contractions to big ET-1 were obtained in rings both with and without endothelium; they were inhibited by phosphoramidon, an inhibitor of endothelin-converting enzyme. These findings indicate that the conversion of the precursor of ET-1 can occur in human placental veins. The receptors mediating the contraction of human placental veins to endothelins do not belong to the ETA subtype; the response to the peptides is probably mediated in part by an uncharacterized ET-receptor subtype and in part by ETB receptors. The output of big ET-1 in the vascular wall or from surrounding tissues in the placenta could be involved in the regulation of venous tone in this organ.