Re-alignment and intramedullary rodding of the humerus and forearm in children with osteogenesis imperfecta: revision rate and effect on fracture rate.

PURPOSE: Intramedullary rodding is indicated for patients with osteogenesis imperfecta (OI) to manage deformity and help treat recurrent fractures. Historically, the focus of intramedullary stabilisation has been the lower extremity. Here we report our experience of intramedullary rodding of the humerus and forearm in children with OI and its impact on the fracture rate of those bone segments. PATIENTS AND METHODS: This is a retrospective chart review of all OI patients who have undergone re-alignment and intramedullary rodding of the humerus or forearm between October 1994 and February 2016. Patient demographics, surgical information, complications and pre-operative and post-operative fracture rates were gathered. RESULTS: A total of 45 upper extremity segments (26 humeri, 19 forearms) were rodded at an average age of 8.7 years (3.1 to 19.2). Of these, 15 (33.3%) of the bone segments required a return to the operating room at a mean 30.8 months (1 to 90) post-operatively. Fracture data was available for 24 of the bone segments. The average number of pre-operative and post-operative fractures was 3.58 (SD 2.84) and 0.46 (SD 0.72) respectively. The average pre-operative and post-operative fracture rates were 0.87 fractures/year (SD 0.47) and 0.10 fractures/year (SD 0.16) respectively. CONCLUSION: In this OI population, re-alignment and rodding appeared to reduce the fracture rate of the humerus and forearm. Among our population, one third returned to the operating room and one fifth required revision to a new intramedullary implant. This data may help families better understand the potential outcomes of upper extremity realignment and rodding and its effect on the rate of upper extremity fractures.

Periodate oxidized ATP (oATP) reduces hyperalgesia in mice: involvement of P2X7 receptors and implications for therapy.

Some inflammatory mediators play an important role not only in the pathogenesis of the inflammatory pain, but also in that of neuropathic and visceral pain. We previously showed the antihyperalgesic effect of oATP, the inhibitor of the P2X7 receptors for the pro-nociceptive ATP, in experimental inflammation. Here we show the antihyperalgesic effect of oATP in mouse models of neuropathic and visceral pain, other than in a model of arthritic pain mimicking rheumatoid arthritis in humans. We also show that mice lacking P2X7 receptors (KO) are resistant to hyperalgesic thermal stimuli following the induction of arthritic, neuropathic and visceral pain. Local (injection into the right hind paw) pre-treatment with oATP is able to prevent the successive induction of ATP-dependent hyperalgesia in wild type mice. In addition, KO mice are not insensitive to intraplantar treatment with ATP. Our data suggest that, even if oATP is able to inhibit purinoceptors different from P2X7, the latter are the more important involved in pain transmission.

A randomized, controlled study of thymosin-alpha1 therapy in patients with anti-HBe, HBV-DNA-positive chronic hepatitis B.

No consistently effective therapy is yet available for the treatment of chronic HBsAg, anti-HBe, HBV-DNA-positive hepatitis. A multicenter trial has shown that the response rates are not significantly different when patients with anti-HBe-positive hepatitis are treated with six-month course of thymosin-alpha1 or of interferon-alpha. However, since among these patients, interferon's real efficacy is still debated, with sustained biochemical response achieved in only a few of the treated patients, we conducted this controlled study to investigate the safety and efficacy of thymosin-alpha1 as compared with no treatment. Forty-four chronic hepatitis B virus (HBV) carriers, who were anti-HBe- and HBV-DNA-positive, were randomized, with stratification for the presence of cirrhosis at baseline liver biopsy, to receive either thymosin-alpha1 at a dose of 900 microg/m2 twice a week for six months or no treatment. At entry, both groups of patients were comparable for sex, age, liver histology, ALT, IgM anti-HBc, and HBV-DNA levels. Forty-two patients were followed-up for 20 months (median; range 12-32 months) after completion of therapy: one dropped out, and one developed hepatocellular carcinoma at six months. Thymosin-alpha1 treatment had no side effects. Six months after the end of the therapy, HBV-DNA was negative and ALT had normalized in 14% of treated cases and in 4.5% of control group, while IgM anti-HBc was negative (<0.200) in 14% of the treated patients and in 4.5% of the controls. Among the treated patients, the median ALT levels stayed significantly lower compared to the pretreatment values during the treatment period and six months of follow-up. During the first year, there were six flares of hepatitis in the control group and five among the treated patients (P = NS), yielding a per year average of 0.3 and 0.23 flares per patient, respectively. Among the treated patients, median IgM anti-HBc levels were low with respect to baseline values 4-10 months after treatment started. None became HBsAg negative. In conclusion, these results indicate that, in anti-HBe, HBV-DNA-positive chronic hepatitis B, thymosin-alpha1 therapy alone does not increase the response rate, but may contribute to reduce the immune-mediated liver cell necrosis as indirectly assessed by ALT and IgM anti-HBc levels.

A randomized controlled trial of thymosin-alpha1 versus interferon alfa treatment in patients with hepatitis B e antigen antibody--and hepatitis B virus DNA--positive chronic hepatitis B.

It has recently been shown that thymosin-alpha1(T-alpha1), a synthetic polypeptide of thymic origin, is able to promote disease remission and inhibition of hepatitis B virus (HBV) replication in patients affected by hepatitis B e antigen (HBeAg)-positive chronic active hepatitis. We evaluated the efficacy and safety of T-alpha1 treatment in patients with hepatitis B e antibody (anti-HBe) and HBV-DNA-positive chronic hepatitis. Thirty-three patients were randomly assigned to receive either T-alpha1 900 microg/m2 body surface area twice weekly (17 patients) or 5 MU of interferon alfa (IFN-alpha) three times weekly (16 patients) for 6 months. At baseline, both groups were comparable concerning age, sex, liver histology, and alanine transaminase (ALT) levels. At the end of treatment, complete response (defined as ALT normalization and HBV-DNA loss) occurred in 5 of 17 (29.4%) in the T-alpha1 group and in 7 of 16 (43.8%) in the IFN-alpha group (P = not significant). After a follow-up period of 6 months, a complete response was observed in 7 of 17 (41.2%) in the T-alpha1 group and in 4 of 16 (25%) in the IFN-alpha group (P = n.s.). Compared with the results observed in a group of 15 patients never treated with IFN-alpha and followed for 12 months, the rate of complete response was significantly higher in the IFN-alpha group at the end of therapy (1 of 15 vs. 7 of 16, respectively; P < .05) and in the T-alpha1 group at the end of follow-up (1 of 15 vs. 7 of 17, respectively; P < .05). Unlike IFN-alpha, T-alpha1 was well tolerated by all patients. The only side effect, reported by some, was local discomfort at injection sites. The results of this trial suggest that T-alpha1 is able to reduce HBV replication in patients affected by anti-HBe-positive chronic hepatitis. Furthermore, compared with IFN-alpha, T-alpha1 is better tolerated and seems to induce a gradual and more sustained ALT normalization and HBV-DNA loss. In conclusion, T-alpha1 appears to be a safe and effective alternative treatment for anti-HBe-positive chronic hepatitis. The benefit of this agent in producing long-term inhibition of HBV replication must be confirmed by future trials.

Pharmacological studies in animals of beta-hydroxyethyltheophylline, the major metabolite of doxofylline in humans.

beta-HET (beta-Hydroxyethyltheophylline), the major metabolite of the antibronchospastic, antiasthmatic drug doxofylline was studied in several in vitro and in vivo trials to characterize its pharmaco-toxicological profile. When compared to the parent compound, beta-HET was found to be significantly less active. It was also discovered to be a very weak inhibitor of phosphodiesterase activity. Its affinity for A1- and A2-adenosine receptors was even lower than that of doxofylline, which was quite low. The oral toxicity of beta-HET was about three times lower than that of doxofylline. The pharmacological activity of doxofylline is due to the drug in its original form and not to its major metabolite.

Metabolism of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine by rat liver microsomes. Diastereoselective metabolism of the 1,3-dithiolane ring.

The metabolic transformation of the antibronchospastic compound ABC-99 [7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine] was studied in vitro with a rat liver microsomal preparation containing an NADPH-generating system. Thirty percent of the ABC-99 was metabolized and the only metabolic pathway observed as the oxidation of the 1,3-dithiolane ring. Two distinct sulfoxides were formed diastereoselectively, the trans isomer being the major product in the ratio 7:3. In contrast to the 1,3-dioxolane ring of doxophylline, the 1,3-dithiolane ring of ABC-99 did not undergo oxidative opening through acetal carbon oxidation. Furthermore no N-dealkylation to theophylline was observed. This high regioselectivity in in vitro metabolism was most likely due to the nucleophilicity of the sulfur atom. The diastereoselective sulfoxidation was apparently catalyzed by flavin-dependent monooxygenases, as no effect was observed with CO treatment, whereas selective thermal inactivation significantly reduced the rate of sulfoxidation.

Doxofylline differs from methylxanthines in its movement of cytosolic calcium.

This paper contributes to the pharmacological profile of doxofylline (Ansimar), a new xanthine derivative with high antibronchospastic activity and no extrapulmonary or cardiac side-effects, clearly demonstrating its inability to mobilize intracellular calcium stores, unlike other xanthines. In vitro, doxofylline does not cause rabbit ear artery contraction under Ca(++)-free conditions. In vivo, doxofylline does not induce a decrease in the calcium concentration of rabbit washed blood platelets. In the same trials theophylline showed opposite results. Furthermore, doxofylline does not antagonize receptors of Ca-antagonists, and does not interfere with the influx of calcium into the cell. Doxofylline also has a very low affinity for adenosine receptors inhibiting cAMP-phosphodiesterase as does theophylline. The absence of typical methylxanthine side-effects is undoubtedly due to doxofylline's low affinity for adenosine receptors, although this does not explain the absence of cardiovascular effects. The present study presents clear evidence that the inability of doxofylline to cause positive inotropism can be linked to its inability to induce calcium movement from intracellular stores.

Synthesis of a new anti-anaemic iron lysozyme glutarate complex and pharmacological studies in animals.

Iron lysozyme glutarate (ABC 1020) is a new soluble complex with an anti-anaemic activity superior to that of ferritin, ferrous sulphate and iron succinyl protein. Iron serum concentrations after treatment with ABC 1020 are higher than after ferritin and iron succinyl protein and lower than after ferrous sulphate treatment. Anaemic adult rats and rats born from dams with anaemia induced by an iron-deficient diet and by repeated bleeding showed considerable, dose-related improvement when treated with ABC 1020, which gave markedly better results than ferritin, iron succinyl protein and ferrous sulphate. Treatment with all four compounds improved the hematological and blood chemistry parameters considered, and reversed cardio- and splenomegaly. Preliminary data show that ABC 1020 is well tolerated, does not induce gastric lesions and has a high bioavailability.

In vivo anti-inflammatory activity of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine.

A new methylxanthine derivative [7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine, ABC 99] with mucoregulatory and antibronchospastic properties has been studied. ABC 99 was observed to have marked anti-inflammatory activity in a series of experimental trials involving the principal mediators of inflammation (PAF, histamine, serotonin, LTC4-like substances, etc). It inhibits the formation of oedemas induced both by carrageenin and PAF in the rat paw, and reduces the increase in vascular permeability induced by histamine and serotonin. ABC 99 was also found to inhibit PAF-induced pleurisy, reducing the volume of pleural exudate and the presence of LTC4-like substances in the pleural cavity. When administered subacutely, ABC 99 checks the formation of granulation tissue caused by the subcutaneous implantation of cotton pellets in the rat. These experimental results indicate ABC 99 may be of particular interest in the treatment of respiratory disorders involving obstructive inflammation and bronchial hypersensitivity.

Kinetic and metabolic studies of 7-(1,3-dithiolan-2-ylmethyl)-1,3-dimethylxanthine in the rat.

The kinetics (absorption, tissue distribution and excretion) of 7-(1,3-dithiolan-2-ylmethyl)-1, 3-dimethylxanthine(ABC 99) were studied in the rat. ABC 99 was administered orally at doses of 10, 30 and 100 mg/kg for the serum kinetic studies. Only the 30 mg/kg dose was used for the tissue distribution and excretion kinetic studies. ABC 99 is rapidly absorbed, metabolized in the liver and partially excreted in the urine. It is equally distributed in the tissues, including the brain, although in much lower amounts than those absorbed. Three metabolites were identified: theophylline, which forms in very small quantities, and two isomers (cis and trans) of the sulfoxide. The latter two compounds form in larger amounts with respect to theophylline, and the trans-isomer predominates. The metabolites are distributed to the tissues, but do not accumulate. Elimination is virtually complete at 24 h. The pharmacological activity of ABC 99 (antibronchospastic, mucoregulatory and anti-inflammatory) can be attributed the compound, which is absorbed in its original form. Similar activity of the two sulfoxides (met 1 and 2) cannot be excluded at present as they have a structure analogous to ABC 99.

Pharmacological and toxicological activities of a new methylxanthine derivative [7-(1,3-dithiolan-2-ylmethyl)1,3-dimethylxanthine] with antibronchospastic and mucoregulatory properties.

7-(1,3-Dithiolan-2-ylmethyl)-1,3-dimethylxanthine (ABC 99) has been studied in the animal to evaluate its pharmacological activity. This compound was found to have antibronchospastic activity in vitro and in vivo markedly greater than aminophylline. The new compound also had moderate antitussic properties and was an active mucoregulator. ABC 99 acts as an intestinal muscle relaxant, but it has no cardiovascular, urinary, or CNS side effects. The mechanism of ABC 99 could be explained by its inhibition of guinea-pig lung phosphodiesterases and affinity for adenosine receptors, particularly A2 receptors. ABC 99 had a low acute toxicity in animals, indicating it may be useful for treating asthma and chronic bronchitis.

Doxofylline in rat brain in relation to locomotor activity.

Doxofylline is a new xanthine derivative with significant bronchodilatatory activity. We have studied in HPLC the distribution of doxofylline in various areas of rat brain (cortex, cerebellum, limbic system) and its activity on the central nervous system by using a spontaneous motility test comparing it with aminophylline administered orally in equimolar doses (4.7 - 9.4 - 19 x 10(-5) mol/kg). Doxofylline is absorbed 3 or 4 times less than aminophylline at the same doses. Nevertheless, the quantity of doxofylline that goes to the brain is equivalent to that absorbed, whereas the quantity of aminophylline is about one-third. This is due to the greater liposolubility of doxofylline in comparison to aminophylline. In spite of the fact that doxofylline is easily distributed in the brain, spontaneous motility in animals is not modified, whereas aminophylline increases this activity significantly. The low affinity of doxofylline with adenosine receptors (A1 and A2) in comparison with aminophylline explains the lack of side effects on the central nervous system which has been amply documented for theophylline and for other methylxanthine derivatives.

Doxofylline, an adenosine-nonblocking xanthine, does not induce cardiostimulant effects.

Doxofylline (ANSIMAR) is a new adenosine-nonblocking anti-asthmatic drug with potent bronchodilator activity that does not display the typical extrapulmonary side effects of theophylline--a potent adenosine antagonist. The cardiac activity of doxofilline and theophylline was investigated in guinea pig right and left atrial preparations and in anestetized cat. In spontaneously beating right atria doxofylline slightly increased the atrial rate only at 0.3 mM, while theophylline induced a concentration-dependent positive chronotropic effect starting at 0.03 mM. The contractile force of electrically stimulated left atria was affected by doxofylline starting at 0.3 mM. Theophylline induced the same effect already at 0.03 mM. In the anesthetized cat, doxofylline (1-30 mg/kg.i.v.) did not affect the diastolic blood pressure, but the heart rate increased slightly at a dose of 30 mg/kg i.v. On the contrary, theophylline induced a marked dose-dependent hypotensive and positive chronotropic effect. Doxofylline was 10 times less potent that theophylline is its ability to antagonize the cardiodepressant activity induced by adenosine in isolated guinea pig atria. The pharmacodynamic differences between doxofylline and theophylline may bring new insights to the understanding of the mechanisms underlying the positive chronotropic effects of xanthines, and the functional importance of endogenous adenosine. Additionally, the lack of cardiostimulant effects makes doxofylline highly suitable for the treatment of chronic obstructive lung disease particularly in combination with beta 2-adrenergic agonists.

Doxofylline exerts a prophylactic effect against bronchoconstriction and pleurisy induced by PAF.

The effect of doxofylline, a new xanthine drug with a low incidence of side-effects in the central nervous, renal and gastroenteric system, on the actions of PAF-acether on bronchopulmonary functions was studied. Doxofylline inhibited: (1) PAF-induced bronchoconstriction in vitro, and the concomitant generation of TXA2-like activity in perfused guinea-pig lungs; (2) PAF-induced bronchoconstriction in vivo and the concomitant release of TXA2-like activity into the circulation; (3) PAF-acether-induced pleurisy and the liberation of type C4 leukotriene into the rat pleural cavity. The results suggest that doxofylline, like theophylline, is able to counteract the bronchoconstriction induced by PAF-acether and, in addition, displays anti-inflammatory properties. These pharmacological data support the notion that doxofylline exerts a prophylactic effect against the respiratory damage induced by mediators, such as PAF-acether, of lung bronchial hyperreactivity; its mechanism of action is unusual, it has slight antagonistic activity at A1- and A2-adenosine receptors.

[Histologic evaluation of gastric tolerability in rats of ferritin compared with ferrous sulfate]. / Valutazione istologica della tollerabilità gastrica nel ratto della ferritina in confronto col solfato ferroso.

The gastric tolerance of ferritin has been studied in Wistar rats and compared with a conventional antianaemic product (ferrous sulphate). The oral administration of the same amount of elementary iron (10-50-100 mg/kg 3 times in 24 h) from each compound produces different anatomopathological results. The treatment with ferritin caused only a moderate gastritic process. In contrast, the administration of ferrous sulphate induced a dose-dependent progression from incipient gastritis to intense gastritis, focal haemorrhagic gastritis and focal necrotizing gastritis. Ferritin did not produce other secondary effects, and is well tolerated even at the highest dosages.

Synthesis, antilipidemic and platelet antiaggregatory activity of 2-aminobenzimidazole amide derivatives.

The synthesis and preliminary pharmacological evaluation of 2-aminobenzimidazole amide derivatives are reported. None of these compounds showed antilipidemic or platelet antiaggregatory activity comparable to that of drugs used in therapy.

Treatment of reversible chronic airways obstruction with doxofylline compared with slow-release theophylline: a double-blind, randomized, multicentre trial.

A multicentre, double-blind, randomized trial was carried out in 11 Italian Pneumologic Clinics to investigate the therapeutic efficacy and tolerability of doxofylline compared with slow-release theophylline in 139 patients (86 males, 53 females) aged 17-77 years suffering from reversible chronic airways obstruction. The two groups of 69 patients on doxofylline and 70 patients on theophylline did not differ in their baseline clinical and functional parameters. After one week of wash-out, the two drugs were administered orally at a dose of 400 mg twice daily of doxofylline and 300 mg twice daily of theophylline. The treatment and follow-up lasted 28 days. Inhaled salbutamol on demand was allowed in the wash-out week and throughout the trial. The average serum levels at day 14 and 28 were: doxofylline 7.5 and 8.5 micrograms/ml; theophylline 10.4 and 7.95 micrograms/ml respectively. Both drugs significantly increased spirometric parameters (p less than 0.001 for all tests) and significantly reduced salbutamol consumption (p less than 0.001 for both drugs). Doxofylline was better tolerated than theophylline considering either the number of unwanted side-effects: (doxofylline 12; theophylline 37) or number of drop-outs due to side-effects (doxofylline 5; theophylline 10). From these results doxofylline seemed to be a good alternative to theophylline in the treatment of reversible chronic airway obstruction in view of its better safety profile.

Doxofylline, an antiasthmatic drug lacking affinity for adenosine receptors.

In the present study the interaction of doxofylline, a new antiasthmatic drug, with A1- and A2-adenosine receptors of the guinea-pig brain and rat striatum was investigated in comparison with known methylxanthine derivatives. Inhibition studies of N6-cyclohexyl-3H-adenosine (3H-CHA), 1,3-diethyl-8-3H-phenylxanthine (3H-DPX) binding and 3H-5'-N-ethylcarboxamidoadenosine (3H-NECA) binding showed how doxofylline did not bind to adenosine receptors in a pharmacological fashion, since doxofylline affinity for A1- and A2-adenosine receptors lies in a 10(-4) M range, a concentration which is too high to have any pharmacological meaning or predictability. However, saturation binding studies demonstrate that doxofylline behaves as a competitive inhibitor of the 3 radioligands used to label adenosine receptors. These data seem to corroborate the theory that antagonism to adenosine receptors is not necessarily associated with bronchodilator activity of methylxanthines, and explain the lack of the typically unwanted side effects induced by methylxanthine derivatives after doxofylline administration.

Biological properties of pancreatic elastase in relation to atherosclerotic disease.

The inhibitory effect of elastase on experimental atherosclerosis has been reported in numerous studies. In our investigation, performed in the rat, a pancreatic extract provided with elastolytic activity has been shown to possess an anti-aggregative effect in vitro and ex vivo and anti-thrombotic properties. In addition, the elastase was capable of inhibiting endothelial exfoliation induced by the desquamatory agent sodium citrate. This agent was tested for its microhaemorrhoeological activity in acute and subacute experiments. In both these conditions, elastase was able to increase the flexibility of red blood cells and their resistance to lysis provoked by hypotonic solutions. In animals fed on an atherogenic diet, this substance limited the lipoprotein accumulation in the aorta wall. Moreover, it reduced the enhanced calcium content, induced by vitamin D administration, in the tissue of arteries. These data indicate that elastase can counteract some pathobiological aspects that characterize atherosclerotic events.