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H Mulder

Publications and source records attributed to H Mulder.

At least 55 records · Page 3Linked to original sources
PubMed1997

Analysis of atrial sensed far-field ventricular signals: a reassessment.

Accurate detection of the spontaneous far-field ventricular signal may be used to determine the ventricular activation, and hence, the interval from atrial stimulus to the ventricular R wave (AR interval) using a standard atrial pacing lead. This can be useful in developing a physiological atrial rate responsive (AAIR) pacemaker and in further improving DDD(R) pacing algorithms. In order to better characterize the atrial sensed far-field ventricular signal, 200 consecutive patients undergoing pacemaker implantation were studied. The amplitude of the far-field ventricular signal was significantly smaller than that of the atrial deflection. In all recordings, the slew rate of the atrial deflection was larger than that of the far-field ventricular signal. Subdivision of the recordings by electrode position, pocket location, or QRS duration on the surface ECG resulted in significantly different signal characteristics. The amplitude and slew rate of the far-field ventricular signal were significantly smaller in bipolar versus unipolar sensing. Atrial sensed far-field ventricular recordings could also be obtained in the case of ventricular pacing. Our results indicate that accurate sensing of the far-field ventricular signal from an atrial pacing lead is conceivable in most patients. The different signal characteristics in relation to parameters, such as electrode position, sensing mode, and pocket location, may be useful in determining the optimal conditions for signal sensing.

Cardiac Pacing, Artificial↗
PubMed1997

Pituitary adenylate cyclase activating polypeptide and nitric oxide synthase are expressed in the rat ciliary ganglion.

AIMS: To study the distribution in the rat ciliary ganglion of neurons synthesising and storing the recently discovered neuropeptide pituitary adenylate cyclase activating polypeptide (PACAP) and neuronal nitric oxide synthase (NOS), the neuronal marker of the novel gaseous transmitter nitric oxide. METHODS: Neurons expressing PACAP and neuronal NOS mRNA were identified in the rat ciliary ganglion by in situ hybridisation with radiolabelled oligonucleotide probes. Immunocytochemistry was used to demonstrate immunoreactive neuropeptides and NOS. RESULTS: Immunocytochemistry demonstrated immunoreactivity for PACAP and NOS in a small number of neuronal cell bodies. In situ hybridisation revealed that NOS and PACAP were expressed in numerous ganglion cell somata. The well established ciliary messengers vasoactive intestinal peptide and neuropeptide Y were found in a large number of neuronal cell bodies. CONCLUSION: These results demonstrate that PACAP and NOS are synthesised and stored in the ciliary ganglion. These findings further illustrate the mixed nature of the ciliary ganglion and may provide a basis for the understanding of the diverse physiological functions of this ganglion.

Animals↗
PubMed1997

Differential effect of insulin treatment on islet amyloid polypeptide (amylin) and insulin gene expression in streptozotocin-induced diabetes in rats.

Islet amyloid polypeptide (IAPP) is a beta cell hormone, which forms islet amyloid in non-insulin-dependent diabetes mellitus and may oppose insulin action and release. Therefore, the previously observed relative overexpression of IAPP compared with insulin in streptozotocin-treated rats could be unfavourable if it occurs in diabetes. Using quantitative in situ hybridization, we examined whether insulin treatment affected IAPP and insulin gene expression and their ratio at day 8 and 20 after induction of streptozotocin diabetes (plasma glucose approximately 30 mM). Total islet IAPP mRNA levels were less reduced than those of insulin at both time points. Differential regulation of the two hormones was further reflected by mean IAPP mRNA levels in the remaining islet cells being unaffected by streptozotocin treatment, whereas those of insulin were reduced. At both time points, insulin treatment decreased total islet levels of IAPP and insulin mRNA even more, IAPP mRNA levels being less reduced. Mean insulin mRNA levels, but not IAPP mRNA levels, in the remaining islet cells were reduced by insulin treatment. Between time points, total islet mRNA levels were higher at day 20, while mean mRNA levels in the remaining islet cells were unchanged, suggesting that regeneration of beta cells had occurred. In contrast, insulin gene expression was the same at both time points in insulin-treated rats, suggesting that insulin impaired insulin expression. To summarize, we found that IAPP and insulin were differentially expressed in experimental diabetes and that insulin treatment inhibited insulin, but not IAPP, gene expression. It is therefore unlikely that insulin will protect against amyloid formation and metabolic perturbations which may arise as a consequence of IAPP overexpression.

Amyloid↗
PubMed1996

Molecular cloning, genomic organization, and expression of a testicular isoform of hormone-sensitive lipase.

By catalyzing the rate-limiting step in adipose tissue lipolysis, hormone-sensitive lipase (HSL) is an important regulator of energy homeostasis. The role and importance of HSL in tissues other than adipose are poorly understood. We report here the cloning and expression of a testicular isoform, designated HSLtes. Due to an addition of amino acids at the NH2-termini, rat and human HSLtes consist of 1068 and 1076 amino acids, respectively, compared to the 768 and 775 amino acids, respectively, of the adipocyte isoform (HSLadi). A novel exon of 1.2 kb, encoding the human testis-specific amino acids, was isolated and mapped to the HSL gene, 16 kb upstream of the exons encoding HSLadi. The transcribed mRNA of 3.9 kb was specifically expressed in testis. No significant similarity with other known proteins was found for the testis-specific sequence. The amino acid composition differs from the HSLadi sequence, with a notable hydrophilic character and a high content of prolines and glutamines. COS cells, transfected by the 3.9-kb human testis cDNA, expressed a protein of the expected molecular mass (M(r) approximately 120,000) that exhibited catalytic activity similar to that of HSLadi. Immunocytochemistry localized HSL to elongating spermatids and spermatozoa; HSL was not detected in interstitial cells.

Amino Acid Sequence↗
PubMed1996

Vasoactive intestinal peptide expression in enteric neurons is upregulated by both colchicine and axotomy.

Axotomy is known to induce changes in neuropeptide expression in several types of neurons. Colchicine blocks the axonal transport and may mimic axotomy. The effects of colchicine-treatment and axotomy (local nerve crush by clamping of the gut) on enteric neurons expressing vasoactive intestinal peptide, neuropeptide Y and nitric oxide synthase were studied in rat small intestine by immunocytochemistry and in situ hybridization. Colchicine treatment significantly increased the number of submucous and myenteric neurons expressing vasoactive intestinal peptide and its mRNA. In contrast, an increase in the number of neuropeptide Y or nitric oxide synthase expressing neurons could not be detected. Axotomy markedly increased the number of myenteric vasoactive intestinal peptide-immunoreactive neurons in the segment located orally to the lesion, but not in the segment anally to the lesion, whereas that of nitric oxide synthase and neuropeptide Y expressing neurons was not affected. Double immunostaining revealed that the myenteric neurons containing nitric oxide synthase were induced by colchicine and axotomy to express vasoactive intestinal peptide. The present data indicate that colchicine and axotomy may induce marked changes in the neuropeptide expression of enteric neurons.

Animals↗
PubMed1996

Procolipase is produced in the rat stomach--a novel source of enterostatin.

Procolipase was identified in the stomach by in situ hybridisation. A strong autoradiographic labelling of chief cells was seen in the fundus region, declining more distally and being almost absent in antrum. There was no labelling seen in the intestine. Colipase activity was estimated in rat gastric juice following pentagastrin stimulation and was found to average 2 microM. Furthermore, enterostatin, the N-terminal pentapeptide of procolipase, has been identified in the rat gut and pancreas. Extracts from gastric mucosa, intestinal mucosa and pancreas were purified by gel filtration (Sephadex G25), ion-exchange chromatography (CM-Sepharose) and HPLC (C18 reverse phase). Using an ELISA assay with antibodies directed against enterostatin, two forms of the peptide were identified both in the gut and in the pancreas, with the amino-acid sequences APGPR and VPGPR, respectively. APGPR was found to be the predominant form of enterostatin, whereas only a small amount had the structure VPGPR. Enterostatin in the form of APGPR, when injected intracerebroventricularly in female Sprague-Dawley rats, significantly reduced high-fat food intake in a two-choice situation of low-fat (14% fat by energy) and high-fat (38% fat) food. It is concluded that procolipase is produced in the stomach and secreted into the gastric juice. This is also a novel source of enterostatin.

Amino Acid Sequence↗
PubMed1996

Adrenomedullin: localization in the gastrointestinal tract and effects on insulin secretion.

Adrenomedullin is a novel hypotensive adrenal polypeptide originally isolated from a human pheochromocytoma and is structurally related to calcitonin gene-related peptide and islet amyloid polypeptide. Using immunocytochemistry, the occurrence of adrenomedullin in the adrenal gland and gastro-entero-pancreatic region in the rat was examined and its effect on insulin secretion from isolated rat islets was determined. Adrenomedullin-like immunoreactivity occurred in noradrenaline- and adrenaline-producing cells in the adrenal gland. Gastrointestinal endocrine cells, with increased density distally, displayed adrenomedullin-like immunoreactivity; these cells constituted a subpopulation of the enterochromaffin (serotonin-containing) cells. Co-localization of adrenomedullin with somatostatin, glicentin, gastrin/cholecystokinin, peptide YY or islet amyloid polypeptide was not encountered. Adrenomedullin-immunoreactive cells were not observed in the pancreatic islets. At 1, 10 and 100 nmol/l, adrenomedullin stimulated insulin release from isolated rat islets in the presence of 3.3 mmol/l glucose (P < 0.05) and at 100 nmol/l, the peptide potentiated insulin secretion also in the presence of 8.3 mmol/l glucose (P < 0.05). These findings suggest that, besides being an adrenal hypotensive peptide, adrenomedullin may be a gut hormone with a potential insulinotropic function.

Adrenal Glands↗
PubMed1996

Blockade of muscarinic transmission increases the frequency of diabetes after low-dose alloxan challenge in the mouse.

The diabetogenic action of the beta-cell toxin, alloxan, is transient when administered to mice at a dosage of 50 mg/kg. We examined whether increased cholinergic activity is involved in the compensatory mechanisms. Therefore, following administration of alloxan, methylatropine (32 mumol/kg) was given intraperitoneally once daily for 5 consecutive days. Methyl atropine worsened the degree of hyperglycaemia during the first week after alloxan administration. Recovery from the diabetes mellitus was observed in a substantial number of animals given alloxan without methyl atropine, whereas the risk of developing manifest diabetes was markedly enhanced by methyl atropine. At 35 days after alloxan administration, 33% of the animals, which were given alloxan alone and were diabetic after 4 days, still had diabetes. In contrast, of the animals rendered diabetic by alloxan with concomitant atropinization, 92% remained diabetic throughout the study (p = 0.0145 vs alloxan alone). Glucose-stimulated insulin secretion and pancreatic insulin content were markedly reduced in animals with diabetes while being less reduced in alloxan-injected animals without diabetes. Moreover, in situ hybridization and immunocytochemistry revealed markedly decreased levels of insulin mRNA and number of insulin cells in alloxan-treated animals. With regard to insulin secretion, pancreatic insulin content, insulin mRNA and insulin cell number, the reduction was the same irrespective of whether methyl atropine had been given. Thus, 5 days of atropinization increases the incidence of diabetes following alloxan at 50 mg/kg in mice. We suggest that cholinergic activity protects insulin cells from glucotoxicity during the first week after alloxan administration and therefore, reduces the frequency of diabetes.

Alloxan↗
PubMed1996

Islet amyloid polypeptide (amylin) and insulin are differentially expressed in chronic diabetes induced by streptozotocin in rats.

Islet amyloid polypeptide (IAPP) is overexpressed relative to insulin under several experimental conditions relevant to diabetes mellitus, including the immediate phase (7 days) following induction of streptozotocin diabetes. In the present study, IAPP and insulin gene expression were examined in chronic streptozotocin diabetes (3 weeks) in rats. Quantitative in situ hybridization, determining grain areas and optical densities of mRNA labelling, revealed that IAPP and insulin expression were reduced at the islet level at both low and high streptozotocin doses, partly due to reduced beta-cell mass. In contrast, the cellular levels of IAPP mRNA were either increased or unaffected at the low and high streptozotocin doses, respectively, whereas those of insulin mRNA were unaffected or reduced. When dexamethasone was administered to rats given the low streptozotocin dose, IAPP expression was increased, whereas that of insulin was markedly reduced. Immunocytochemistry revealed that IAPP predominantly occurred in insulin cells and to a lesser extent in somatostatin cells at all treatments examined. Our findings demonstrate that IAPP and insulin gene expression are differentially regulated; the over-expression of IAPP relative to insulin is augmented when the beta-cell insult is aggravated, in our experiments represented by massive beta-cell destruction (high streptozotocin dose) or a combination of moderate beta-cell damage and peripheral insulin resistance (low streptozotocin dose and dexamethasone). An over-expression of IAPP relative to insulin may therefore be involved in diabetes pathogenesis, contributing to its metabolic perturbations, possibly through the capacity of IAPP to restrain insulin release and action and to form islet amyloid.

Amyloid↗
PubMed1996

Identification of a GDP-Fuc:Gal beta 1-3GalNAc-R (Fuc to Gal) alpha 1-2 fucosyltransferase and a GDP-Fuc:Gal beta 1-4GlcNAc (Fuc to GlcNAc) alpha 1-3 fucosyltransferase in connective tissue of the snail Lymnaea stagnalis.

Connective tissue of the freshwater pulmonate Lymnaea stagnalis was shown to contain fucosyltransferase activity capable of transferring fucose from GDP-Fuc in alpha 1 -2 linkage to terminal Gal of type 3 (Gal beta 1-3GalNAc) acceptors, and in alpha 1-3 linkage to GlcNAc ot type 2 (Gal beta 1-4GlcNAc) acceptors. The alpha 1-2 fucosyltransferase was active with Gal beta 1-3GalNAc beta 1-OCH2CH=CH2 (Km = 12mM, V(max) = 1.3 mUml-1) and Gal beta 1-3GalNAc (km =20 mM, V(max) = 2.1 mUml-1), whereas the alpha 1-3 fucosyltransferase was active with Gal beta 1-4GlcNAc (Km = 23 mM, V(max) = 1.1 mUml-1). The products formed from from Gal beta 1-3GalNAc beta 1-OCH2CH=CH2 and Gal beta 1-4GlcNAc were purified by high performance liquid chromatography, and identified by 500 MHz 1H-NMR spectroscopy and methylation analysis to be Fucalpha1-2Gal beta 1-3GalNAc beta 1-OCH2CH=CH2 and Gal beta 1-4(Fucalpha1-3)GlcNAc, respectively. Competition experiments suggest that the two fucosyltransferase activities are due to two distinct enzymes.

Animals↗
PubMed1996

Diminished effect of etidronate in vitamin D deficient osteopenic postmenopausal women.

OBJECTIVE: The effects of vitamin D deficiency in osteopenic postmenopausal women treated with intermittent cyclical etidronate have been studied. Bone mass and biochemical parameters as bone markers were measured before and after one year of therapy with intermittent cyclical etidronate. RESULTS: In 30 patients without vitamin D deficiency, bone mass in the lumbal spine and femoral neck was significantly increased compared to 28 vitamin D deficient patients. After cyclical intermittent etidronate therapy, serum osteocalcin and PTH were significantly increased in the vitamin D deficient patients, whereas in non-vitamin D deficient patients they did not change. CONCLUSION: It is worthwhile measuring serum vitamin D before starting etidronate therapy and, in case of deficiency, to give vitamin D.

Absorptiometry, Photon↗
PubMed1996

Islet amyloid polypeptide and insulin gene expression are regulated in parallel by glucose in vivo in rats.

Islet amyloid polypeptide (IAPP) is a novel amyloid-forming beta-cell hormone with putative roles in glucose metabolism and non-insulin-dependent diabetes mellitus (NIDDM) pathogenesis. To study how IAPP and insulin expression are regulated by glucose, rats were fasted for 48h followed by administration of glucose at repeated 4-h intervals; IAPP and insulin mRNA levels were determined by quantitative in situ hybridization. Fasting markedly reduced IAPP and insulin mRNA levels. Two (6 h) and four (14 h) glucose injections dose dependently increased both mRNA levels; the effects were matched by similar changes in plasma glucose levels. Actinomycin D blocked the glucose-induced increase in IAPP expression. IAPP and insulin mRNA levels were significantly correlated over the range of glucose levels. The parallel regulation of IAPP and insulin gene expression by glucose is consistent with a role for IAPP in glucose homeostasis. Thus, under hyperglycemic conditions such as NIDDM, IAPP gene expression is likely to increase. Hence, IAPP could, by elevated local concentrations, contribute to amyloid formation and/or affect metabolism unfavorably by inhibition of insulin release and action.

Amyloid↗
PubMed1995

Differential expression of islet amyloid polypeptide (amylin) and insulin in experimental diabetes in rodents.

An increased ratio of islet amyloid polypeptide (IAPP) to insulin for mRNA and peptide content in pancreatic extracts and for secretion has been observed in experimental diabetes, suggesting a differentially regulated IAPP and insulin expression. Therefore, we investigated the islet expression of IAPP and insulin in streptozotocin and alloxan diabetic rats and mice, using in situ hybridization and immunocytochemistry. A low dose of streptozotocin equivalently reduced IAPP and insulin mRNA levels to approximately 45% of controls. In contrast, a high dose of streptozotocin or alloxan reduced IAPP mRNA levels significantly less than those of insulin mRNA (streptozotocin: 24 vs. 15%, P = 0.011; alloxan: 15 vs. 6%, P < 0.0001). In situ hybridization and immunocytochemistry revealed expression of IAPP in experimental diabetes to occur predominantly in insulin cells. Thus, IAPP and insulin gene expression are differentially regulated in experimental diabetes in rodents and IAPP is predominantly expressed in insulin cells.

Amyloid↗
PubMed1995

Pituitary adenylate cyclase activating polypeptide is expressed in autonomic neurons.

Pituitary adenylate cyclase activating polypeptide (PACAP) is a novel vasoactive intestinal peptide (VIP)-like peptide, which is present in neuronal elements of several peripheral organs, and thus a putative neurotransmitter/modulator. In the present study, the expression of PACAP in two parasympathetic ganglia (otic, sphenopalatine) and one mixed parasympathetic/sensory ganglion (jugular-nodose) in rat was characterized by use of in situ hybridization and immunocytochemistry and compared to that of VIP and calcitonin gene-related peptide (CGRP). PACAP and VIP were expressed in virtually all nerve cell bodies in the otic and sphenopalatine ganglia; PACAP and VIP were also expressed in subpopulations of nerve cell bodies in the jugular-nodose ganglion. CGRP was expressed in numerous nerve cell bodies in the jugular-nodose ganglion and in a few, scattered, nerve cell bodies in the sphenopalatine ganglion. In the otic and sphenopalatine ganglia, PACAP- and VIP-like immunoreactivities were frequently co-localized; in the jugular-nodose ganglion, PACAP-like immunoreactivity was frequently co-localized with CGRP-like immunoreactivity in presumably sensory neurons and to a lesser extent with VIP in parasympathetic neurons. Thus, PACAP is synthesized and stored in autonomic parasympathetic neurons as well as in vagal sensory neurons, which provides an anatomical basis for the diverse effects of PACAP previously described.

Animals↗
PubMed1995

In the biosynthesis of N-glycans in connective tissue of the snail Lymnaea stagnalis of incorporation GlcNAc by beta 2GlcNAc-transferase I is an essential prerequisite for the action of beta 2GlcNAc-transferase II and beta 2Xyl-transferase.

Using a series of relevant substrates, connective tissue of the snail Lymnaea stagnalis was shown to contain beta 1-2 xylosyltransferase (beta 2Xyl-T), beta 1-2 N-acetylglucosaminyltransferase I (beta 2GlcNAc-T I), and beta 1-2 N-acetylglucosaminyltransferase II (beta 2GlcNAc-T II) activities. These enzymes are probably involved in the biosynthesis of the N-linked carbohydrate chains, like those present in hemocyanin. The products formed by incubation of GlcNAc beta 1-2Man alpha 1-6(GlcNAc beta 1-2Man alpha 1-3)Man beta 1-R [where R = -4GlcNAc beta 1-4GlcNAc or O-(CH2)7CH3] with UDP-Xyl and connective tissue microsomes have been purified and characterized by 1H-NMR spectroscopy in conjunction with methylation analysis to be GlcNAc beta 1-2Man alpha 1-6(GlcNAc beta 1-2Man alpha 1-3)(Xyl beta 1-2)Man beta 1-R. Substrate specificity studies focused on connective tissue beta 2Xyl-T show that the minimal structure requirements are fulfilled in GlcNAc beta 1-2Man alpha 1-3Man beta 1-O-(CH2)7CH3. The enzyme activity can therefore be characterized as UDP-Xyl:Glc-NAc beta 1-2Man alpha 1-3Man beta-R (Xyl to Man beta) beta 1-2 xylosyltransferase. In substrate-specificity studies directed to connective tissue beta 2GlcNAc-T I, it could be demonstrated that the enzyme is active towards acceptors having at the minimum a Man alpha 1-3Man beta-R sequence, and that introduction of a beta Xyl residue at C2 of beta Man totally abolishes the enzyme activity. Xylose-containing oligosaccharides are not acceptors for beta 2GlcNAc-T I. In combination with the substrate specificity of beta Xyl-T, this shows that in snail connective tissue beta 2GlcNAc-T I must act before beta 2Xyl-T. The connective tissue beta 2GlcNAc-T II activity follows the earlier established biosynthetic routes. Based on the substrate specificities of the various connective tissue glycosyltransferases known so far, and the structures isolated from L. stagnalis hemocyanin, a partial biosynthetic scheme for N-glycosylation in snail connective tissue is proposed.

Animals↗
PubMed1995

Identification of a novel UDP-GalNAc:GlcNAc beta-R beta 1-4 N-acetylgalactosaminyltransferase from the albumen gland and connective tissue of the snail Lymnaea stagnalis.

Both the albumen gland, one of the female accessory sex glands, and connective tissue of the freshwater snail Lymnaea stagnalis contain N-acetylgalactosaminyltransferase activity, capable of transferring GalNAc from UDP-GalNAc in beta 1-4 linkage to the terminal GlcNAc residue of GlcNAc beta-R. The albumin gland enzyme was partially purified by affinity chromatography on UDP-hexanolamine-Sepharose 4B. Using GlcNAc beta 1-2Man alpha 1-6(GlcNAc beta 1-2Man alpha 1-3)Man beta 1-4GlcNAc beta 1-4GlcNAc or GlcNAc beta 1-OMe as substrates, the enzyme showed an absolute requirement for Mn2+ with an optimum concentration of 12.5-50 mM. The optimal pH was approximately pH 7.0. The enzyme activity was independent of the Triton X-100 concentration in the range 0.25-2.5%, and no activation effect was found. The more labile connective tissue microsomal enzyme, subjected to the same optimization procedure, gave comparable results. Both enzyme activities have similar substrate specificities towards GlcNAc or GlcNAc beta 1-OMe, and towards oligosaccharides or glycopeptides with a non-reducing terminal beta-GlcNAc unit, but cannot act on GlcNAc alpha 1-OMe. Saccharides with non-reducing terminal Gal or GalNAc residues, and free GalNAc, Gal or Glc residues are not acceptors. Product analysis was carried out for albumen gland N-acetylgalactosaminyltransferase and four acceptors having GlcNAc beta 1-R as the terminal non-reducing unit, and for connective tissue N-acetylgalactosaminyltransferase with GlcNAc beta 1-OMe as acceptor. In all instances, products with GalNAc beta 1-4-linked to GlcNAc were obtained, showing that the connective tissue and the albumen gland activities are probably from one enzyme. This enzyme activity can be identified as UDP-GalNAc:GlcNAc beta-R beta 1-4 N-acetylgalactosaminyltransferase, and is probably involved in the biosynthesis of N,N'-diacetyllactosediamine-containing glycoproteins, like hemocyanin, in the snail L. stagnalis.

Animals↗
PubMed1995

Comparative prospective, double-blind, multicenter study of the efficacy of tiludronate and etidronate in the treatment of Paget's disease of bone.

OBJECTIVE: To compare the efficacy and safety of tiludronate and etidronate at the same dosage (400 mg/day) for the treatment of active Paget's disease of bone. METHODS: We studied 234 patients with radiologic lesions characteristic of Paget's disease of bone and serum alkaline phosphatase (AP) concentrations at least twice the upper limit of normal, in a prospective, randomized, double-blind, multicenter clinical trial lasting 6 months. Patients were randomly allocated into 1 of 3 treatment groups: tiludronate for 3 months followed by placebo for 3 months, tiludronate for 6 months, or etidronate for 6 months. Serum AP levels and urinary hydroxyproline excretion were measured at baseline and after 3 months and 6 months. Patients with a reduction of at least 50% in the serum AP concentration were considered to be responders. RESULTS: After 3 months, the proportion of responders was higher in the tiludronate group (57.4%) than in the etidronate group (13.9%) (P < 0.0001). In the etidronate group, this percentage was lower among patients who had received previous treatment with a bisphosphonate (2.3%) than among those who had not (28.6%) (P < 0.01). Previous bisphosphonate treatment was not associated with response in the tiludronate group. After 6 months, the proportion of responders did not differ between the 2 tiludronate groups (60.3% and 70.1%), but was lower in the etidronate group (25.3%) (P < 0.0001). There was a higher proportion of patients with treatment-resistant disease (< 25% reduction of serum AP) in the etidronate group (51.9%) than in the tiludronate 3-month group (17.9%) or the tiludronate 6-month group (19.5%) (P < 0.0001). Gastrointestinal disturbances were more common, and occurred earlier, with tiludronate, but they were mostly mild, requiring no treatment. CONCLUSION: Tiludronate at 400 mg/day for 3 months or 6 months is more effective than the same dosage of etidronate for 6 months in the treatment of Paget's disease.

Adult↗