Tahir Ahmed

Mometasone furoate: efficacy and safety in moderate asthma compared with beclomethasone dipropionate

BACKGROUNDnMometasone furoate (MF) is a new inhaled glucocorticoid administered by dry powder inhaler (DPI).nnnOBJECTIVEnMF-DPI was evaluated for safety and efficacy and compared with placebo DPI and beclomethasone dipropionate (BDP) administered by metered dose inhaler (MDI) in the treatment of patients with moderate persistent asthma.nnnMETHODSnEligible patients (n = 227), 13 to 75 years of age, maintained on inhaled glucocorticoids before entering the trial, were randomized to receive: MF-DPI, 100 microg, twice daily, MF-DPI, 200 microg, twice daily, BDP MDI, 168 microg, twice daily, or placebo in a 12-week, multicenter, double-blind study.nnnRESULTSnAt endpoint, FEV1 (primary efficacy variable) significantly improved for all three active treatments compared with placebo (P < .01, all comparisons). The response to MF-DPI, 200 microg, twice daily treatment was approximately twice as large as the response to MF-DPI, 100 microg, twice daily or BDP MDI treatment, although the differences between these groups did not reach statistical significance. Secondary efficacy variables including PEFR, asthma symptoms, nocturnal awakenings, and albuterol use showed similar trends. The MF-DPI, 100 microg, twice daily and BDP MDI, 168 microg, twice daily treatment groups produced comparable results for all efficacy variables.nnnCONCLUSIONSnMF-DPI, 100 microg and 200 microg, twice daily were well-tolerated and significantly improved lung function and symptom control in the treatment of patients with moderate persistent asthma. In this study, MF-DPI, 200 microg, twice daily seemed to be the most effective dosage.

Pulmonary Edema with Nifedipine in Primary Pulmonary Hypertension

Despite occasional case reports, vasodilator therapy of primary pulmonary hypertension remains unsatisfactory. Nifedipine, a calcium channel antagonist, has recently been recommended for the treatment of primary pulmonary hypertension. Transient mild side effects to this drug have been known. In this report we describe a case of primary pulmonary hypertension in whom oral nifedipine use was followed by fatal pulmonary edema. We suggest that nifedipine has the potential of causing life-threatening complications of pulmonary edema in patients with severe primary pulmonary hypertension, and in this condition it should be used cautiously.

Increased Serum Copper in Primary Pulmonary Hypertension: A Possible Pathogenic Link?

In conscious sheep, we showed that intravenous infusion of copper sulfate produced a marked increase in pulmonary vascular resistance which was prevented by alpha-adrenergic blockade or catecholamine depletion. Because of these observations, we measured serum copper in 7 patients with primary pulmonary hypertension, and in 6 normal women. The 5 female patients had taken contraceptive and appetite-suppressant medication in the past. The mean serum copper level was significantly higher in patients with pulmonary hypertension, indicating that increased serum copper may be a cause or a marker of this entity.

Functional depression of H2 histamine receptors in sheep with experimental allergic asthma

We tested the hypothesis that airway hyperresponsiveness to histamine in the allergic sheep is related to functional depression of H2 histamine receptors. Thirteen of 32 sheep responded with bronchoconstriction to inhaled Ascaris suum antigen (allergic sheep), and the remainder served as controls (nonallergic sheep). In the allergic sheep, 50 and 100 breaths of 5% histamine solution increased mean pulmonary resistance (RL) to 235% and 438% of baselines, respectively. The corresponding values in nonallergic sheep were 200% and 211%, indicating a greater response to the higher dose of histamine in allergic sheep. Selective H1-receptor stimulation with 50 breaths of histamine (pretreatment with the H2-receptor antagonist metiamide) failed to enhance the effect of histamine in allergic sheep (mean RL increased to 239% of baseline) whereas it enhanced the histamine response in nonallergic sheep (RL increased to 438% of baseline). Selective H2-receptor stimulation (pretreatment with the H1-receptor antagonist chlorpheniramine) caused histamine to decrease RL by 31% in the nonallergic sheep group; it blocked but did not reverse the histamine effect in the allergic sheep. Similar observations were made in a different group of animals when selective H1- or selective H2-receptor stimulation was produced by 100 breaths of histamine. The cutaneous wheal response to intradermal histamine dilutions of 0.0001. 0.001, 0.01, and 1 mg/ml was similar in both groups. In nonallergic sheep, both chlorpheniramine and metiamide blunted the cutaneous wheal response. In allergic animals, only chlorpheniramine blunted the cutaneous wheal response, whereas metiamide was without effect. We conclude that airway hyperresponsiveness to histamine in allergic sheep is related to a functional depression of H2 receptors and that such a defect is observed both in the airways as well as in the skin.

Inhibition of allergic airway responses by heparin derived oligosaccharides: identification of a tetrasaccharide sequence

BackgroundPrevious studies showed that heparins anti-allergic activity is molecular weight dependent and resides in oligosaccharide fractions of <2500 daltons.ObjectiveTo investigate the structural sequence of heparins anti-allergic domain, we used nitrous acid depolymerization of porcine heparin to prepare an oligosaccharide, and then fractionated it into disaccharide, tetrasaccharide, hexasaccharide, and octasaccharide fractions. The anti-allergic activity of each oligosaccharide fraction was tested in allergic sheep.MethodsAllergic sheep without (acute responder) and with late airway responses (LAR; dual responder) were challenged with Ascaris suum antigen with and without inhaled oligosaccharide pretreatment and the effects on specific lung resistance and airway hyperresponsiveness (AHR) to carbachol determined. Additional inflammatory cell recruitment studies were performed in immunized ovalbumin-challenged BALB/C mice with and without treatment.ResultsThe inhaled tetrasaccharide fraction was the minimal effective chain length to show anti-allergic activity. This fraction showed activity in both groups of sheep; it was also effective in inhibiting LAR and AHR, when administered after the antigen challenge. Tetrasaccharide failed to modify the bronchoconstrictor responses to airway smooth muscle agonists (histamine, carbachol and LTD4), and had no effect on antigen-induced histamine release in bronchoalveolar lavage fluid in sheep. In mice, inhaled tetrasaccharide also attenuated the ovalbumin-induced peribronchial inflammatory response and eosinophil influx in the bronchoalveolar lavage fluid. Chemical analysis identified the active structure to be a pentasulfated tetrasaccharide ([IdoU2S (1→4)GlcNS6S (1→4) IdoU2S (1→4) AMan-6S]) which lacked anti-coagulant activity.ConclusionsThese results demonstrate that heparin tetrasaccharide possesses potent anti-allergic and anti-inflammatory properties, and that the domains responsible for anti-allergic and anti-coagulant activity are distinctly different.

Inhibition of antigen-induced bronchoconstriction by methylprednisolone succinate☆

We investigated whether the glucocorticoid methylprednisolone succinate mg/kg) could prevent antigen-induced bronchoconstriction in conscious sheep. Ten allergic ewes were subjected to inhalation challenge with Ascaris suum antigen, with and without methylprednisolone pretreatment, administered intravenously either 20 min or 3 hr before antigen challenge. Antigen challenge alone resulted in increased airflow resistance, pulmonary hyperinflation, and decreases in dynamic lung compliance and arterial oxygen tension. Methylprednisolone administered 20 min before antigen challenge had no effect on these antigen-induced changes. In contrast, administration of methylprednisolone 3 hr before antigen challenge effectively prevented all the responses to antigen challenge. We suggest that pretreatment with glucocorticoids can attenuate airway anaphylaxis if sufficient time is allowed between the pretreatment and the antigen challenge.

Airway responses to antigen challenge in allergic rhinitis and allergic asthma

The density dependence of the maximum expiratory flow-volume curve, functional residual capacity (FRC), and specific airway conductance (SGaw) were determined before and during bronchial provocation with ragweed extract in 27 subjects with ragweed hypersensitivity and a history of either bronchial asthma (16 subjects) or allergic rhinitis (11 subjects). Mean baseline SGaw was significantly lower while mean volume of isoflow (Visov) and FrC were significantly higher in subjects with bronchial asthma. During antigen challenge, 10 of 16 subjects with bronchial asthma (63%) and five of 11 subjects with allergic rhinitis (45%) showed a greater than 35% decrease in SGaw (reactors): mean relative decreases in SGaw from baseline were 46% and 53%, respectively. The remaining subjects showed a less than 35% decrease in SGaw (nonreactors) with mean relative decreases of 9% (allergic asthma) and 6% (allergic rhinitis). Mean Visov increased in all subjects with bronchial asthma and in eight of 11 subjects with allergic rhinitis. A significant increase in FRC (6%) was seen only in the reactors with bronchial asthma. Following antigen challenge, the beta adrenergic agonist, isoetharine, increased SGaw and decreased Visov. We conclude that in asymptomatic subjects with ragweed hypersensitivity, (1) central and peripheral airway function is more abnormal in subjects with bronchial asthma than in subjects with allergic rhinitis, (2) subjects of both groups show quantitatively and qualitatively comparable airway responses during antigen challenge with a decrease in SGaw or an increase in Visov, possibly representing increase in central and/or peripheral airflow resistance, respectively, (3) Visov may be a more sensitive indicator of airway response to antigen challenge than SGaw, and (4) the bronchodilator effects of a beta adrenergic agonist on antigen-induced bronchospasm are similar in both groups.

Modification of airway histamine-receptor function with methylprednisolone succinate

The purpose of the present study was to investigate whether glucocorticosteroids alter airway histamine-receptor function. We measured pulmonary resistance in six conscious sheep before and after inhalation challenge with 100 breaths of 5% histamine solution, without and with intravenous pretreatment with the specific H1- and H2-receptor antagonists. Inhalation of histamine (combined H1 and H2 stimulation) increased mean pulmonary resistance (RL) to 290% of baseline (p less than 0.05). Pretreatment with the H2 antagonist, metiamide (selective H1 stimulation), enhanced the effect of histamine, with a mean RL increase to 760% of baseline (p less than 0.05). Histamine challenge after pretreatment with the H1 antagonist, chlorpheniramine (selective H2 stimulation), decreased RL to 40% of chlorpheniramine value (p less than 0.05). A single intravenous bolus injection of methylprednisolone succinate (30 mg/kg) 30 min before histamine challenge suppressed the airway responsiveness to histamine, with a mean RL increase to only 186% of baseline. After methylprednisolone, selective H1-receptor stimulation with histamine elicited a blunted H1-receptor response; mean RL increased to only 248% of baseline. Both changes were significantly lower than that with histamine alone (p less than 0.05). Methylprednisolone per se blunted the chlorpheniramine-induced increase in RL which made it difficult to evaluate H2-receptor function (RL decreased to 67% of postchlorpheniramine value). However, in the presence of increased airway tone with carbachol, selective H2 stimulation with histamine decreased RL to 26% of postcarbachol value (p less than 0.05), thus excluding suppression of H2 receptors. Methylprednisolone had no effect on carbachol-induced increase in RL. In conscious sheep, methylprednisolone blunts airway responsiveness to histamine by suppressing H1 receptors without significantly altering H2 receptors or cholinergic-receptor function.

Effect of oral and intravenous heparin tetrasaccharide on allergic airway responses: critical role of N-sulfation.

We have shown that inhaled heparin (hep) oligosaccharides attenuate allergic airway responses in sheep and that this anti-allergic activity resides in a tetrasaccharide sequence. Here we determined: (a) the anti-allergic activity of oral and intravenous hep-tetrasaccharide on allergic airway responses in the sheep model of asthma; and (b) the role of N-sulfation in mediating this anti-allergic activity. Ascaris suum-induced early (EAR) and Late (LAR) airway responses and airway hyperresponsiveness (AHR) to carbachol were measured in allergic sheep without and after treatment with different doses of oral or intravenous hep-tetrasaccharide. At doses of 0.06xa0mg/kg, 0.125xa0mg/kg, and 0.25xa0mg/kg, oral hep-tetrasaccharide caused a dose-dependent inhibition of EAR and LAR. Post-antigen AHR was also inhibited dose dependently. The same doses of intravenous hep-tetrasaccharide yielded comparable inhibition of EAR, LAR and AHR, confirming that orally delivered hep-tetrasaccharide has good bioavailability. The protection by hep-tetrasaccharide on EAR and LAR was dependent on N-sulfation, as N-desulfated/N-acetylated tetrasaccharide had a markedly reduced effect. However, inhibition of the post-antigen AHR was independent of N-sulfation. These results demonstrate that orally administered hep-tetrasaccharide inhibits allergic airway responses in the sheep model of asthma. Hep-tetrasaccharide has good oral bioavailability and its anti-allergic activity is critically dependent on N-sulfation of the glucosamine ring.

Heparin-derived supersulfated disaccharide inhibits allergic airway responses in sheep

The tetrasaccharide sequence of heparin oligosaccharides is the minimum chain length possessing anti-allergic activity, as the disaccharide fraction is inactive. Since sulfation pattern can modify the biological actions of heparin, we hypothesized that supersulfation of the inactive heparin disaccharide could confer anti-allergic activity to this molecule. To test this, we produced a supersulfated heparin disaccharide (Hep-SSD) and evaluated its anti-allergic activity in sheep with documented antigen-induced early and late airway responses (EAR and LAR) and airway hyperresponsiveness (AHR). Porcine intestinal heparin was depolymerized with nitrous acid, the disaccharide fraction separated by size exclusion chromatography, and then treated with pyridine-sulfur trioxide complex to yield Hep-SSD. Its chemical structure [IdoU2,3,4S (1→4) AMan1,3,6S] was confirmed by HPLC, Mass Spectrometry and NMR analysis. Inhaled doses of 5 mg, 10 mg and 20 mg Hep-SSD produced inhibition of EAR (8%, 35% and 35%), LAR (50%, 80%, and 77%) and AHR (67%, 100% and 75%), respectively. A single oral dose of 2 mg/kg Hep-SSD given 90 min before challenge significantly inhibited EAR, LAR and AHR, but 1 mg/kg was ineffective. Multi dose oral treatment with Hep-SSD had a cumulative effect, as a once daily dose of 2 mg/kg for 3 days (last dose, 16 h before antigen) inhibited EAR, LAR and AHR by 30%, 75% and 74%, respectively. Finally, the oral activity of Hep-SSD could be enhanced 4 fold by formulating it with Carbopol(®)934P, in an enteric coated capsule. These data demonstrate that supersulfation can confer biological activity to the inactive heparin disaccharide. Both inhaled and oral Hep-SSD demonstrate significant anti-allergic activity and, therefore, may have therapeutic potential.