Synthesis, pharmacological activity and nitric oxide generation by nitrate derivatives of theophylline.

Nitrates of theophylline derivatives - potential nitric oxide (NO) donors - were synthesized by esterification of 7-hydroxyalkyl theophylline derivatives with fuming nitric acid. The nitrates obtained were tested in-vitro in reactions with sulfydryl compounds at appropriately adjusted pH and temperature. Under the applied conditions, the synthesized compounds underwent decomposition to release NO, quantified using a polarographic method using a selective isolated (ISO-NO) sensor. The effects of dyphylline and proxyphylline and their new synthesized nitrates on arterial blood pressure (BP) were measured in spontaneously hypertensive (SH) rats. BP was measured in conscious SH rats using the tail-cuff method. Both short- and long-term administration of the xanthines tested significantly decreased systolic, diastolic and mean BP. The hypotensive effect of a single dose of nitrate dyphylline on mean BP was greater than that of the parent compound (P = 0.000012; P=0.000472 at 30 and 60 min post-dose, respectively), whereas proxyphylline and its nitrate derivative had similar activity. In rats treated with the tested compounds for 9 days twice daily, the decrease in BP persisted for at least 16 h after the last dose. Proxyphylline produced the most marked decrease in diastolic and mean BP. Among the xanthines examined, proxyphylline nitrate had the strongest hypotensive effect when administered in a single dose to animals pretreated with the same compound for 9 days. These results indicate that insertion of a nitrate group weakly modifies the hypotensive action of the studied xanthines in SH rats.

[Clinical observation on shufei granule in improving right ventricular function of patients with chronic pulmonary heart disease].

OBJECTIVE: To observe the effect of Shufei Granule (SG) on right ventricular function in patients with chronic pulmonary heart disease (CPHD). METHODS: One hundred CPHD patients were randomly divided into two groups, the control group (n = 40) treated with fleroxacin 0.2 g twice per day by intravenous dripping and diprophylline 0.2 g 3 times per day orally, the treatment group (n = 60) treated with SG 10 g 3 times a day orally additionally besides the treatment given to the control group. The therapeutic course for both groups was 3 weeks. The changes of the cardiac function, the right ventricular function [A peak velocity (VA), E peak velocity (VE), VA/VE, systolic pulmonary artery pressure (SPAP), pre-ejection period (PEP), right ventricular ejection time (RVET), PEP/RVET], and blood-gas analysis were investigated, the condition of clinical symptoms and signs as well as tongue pictures were observed also. RESULTS: The total effective rate was 91.6% in the treated group, significantly higher than that in the control group (70.0%, P < 0.01); the improvements in symptom score, cardiac function and the other laboratory indexes were all superior in the treatment group to those in the control group (P < 0.05, P < 0.01). CONCLUSION: SG is an effective drug for improving right ventricular function in CPHD patients.

[Effects of diprophylline on pulmonary hypertension in patients with chronic pulmonary disease].

The present study was undertaken to evaluate the short-term effects of diprophylline on hemodynamic and gases exchange in 10 patients in stable condition with chronic pulmonary disease. Diprophylline decreased the pulmonary vascular resistance by markedly reducing the mean pulmonary arterial pressure but didn't change cardiac output significantly. Diprophylline also caused a significant decrease in arterial carbon dioxide tension, but there was no significant difference between the level of PaO2, SaO2 and A-aDo2 before and after the administration of diprophylline.

Hypolipemic and potential antiatherosclerotic properties of diprophyllinyl-4-benzyloxybenzoate.

To assess the hypolipemic and antiatherosclerotic activity of diprophyllinyl-4-benzyloxybenzoate guinea-pigs were kept on a high-lipid diet alone or with the tested compound for 21 days, and rabbits--for 3 months. It was found that diprophyllinyl-4-benzyloxybenzoate displays a distinct hypolipemic activity, particularly with respect to cholesterol, both in guinea-pigs and rabbits. It also depresses the cholesterol and the trigliceride content in liver homogenates and shows a tendency to normalize the low-density-lipoprotein fraction in guinea-pigs, as well as cholesterol of the high-density lipoprotein fraction, and malon dialdehyde in rabbits. The area of intima covered with atheromatous plaques was smaller in rabbits receiving the high-lipid diet with diprophyllinyl-4-benzyloxybenzoate than in those receiving that diet alone.

Protective effect of methylxanthines against carbachol-induced bronchoconstriction in normal subjects.

The bronchoprotective effect of bioequivalent doses of theophylline (TH; 234 mg) and a combination of TH, proxyphylline (PPH) and diprophylline (DPH) in the proportion 2:3:3 (Neo-Biphyllin, NB; 600 mg) against carbachol-induced bronchoconstriction was studied in 10 healthy non-smokers in a randomised controlled double-blind cross-over trial. The subjects were on a methylxanthine-free diet 4 days prior to and during each study day. Bronchial provocation tests were conducted in the morning and afternoon of the three separate study days--control and two medication days--using a standardised technique. On the control day, the dose of carbachol required to reduce the partial expiratory flow volume at 25% of vital capacity (V25p) by at least 25% was established. A significant protective effect was achieved with both TH (p less than 0.05) and NB (p less than 0.001) as measured by V25p. Bronchoprotection was achieved with low maintenance serum levels of TH.

Dyphylline versus theophylline: a double-blind comparative evaluation.

This study was a randomized double-blind evaluation of three doses of dyphylline, theophylline, and placebo for blocking exercise-induced bronchospasm (EIB). Twenty patients aged 12 to 17 years took one of the following on five separate days prior to an exercise challenge: 10, 15, or 20 mg/kg dyphylline; 6 mg/kg anhydrous theophylline; or placebo. Linear relationships were found between the log of dyphylline doses and per cent changes from baseline for PEFR, FEV1 and FEF25-75%. The 15 and 20 mg/kg doses differed significantly from placebo in preventing declines in PEFR, FEV1, and FEF25-75%. While significant, these changes were one half to one third those found with 6 mg/kg theophylline. Tremor was twice as common with theophylline. While dyphylline has therapeutic effectiveness compared to placebo for blocking EIB, its benefit is small. Further evaluations are needed to elucidate optimal dosaging for maximal effectiveness.

Dyphylline aerosol can induce bronchospasm in human asthmatics.

Dihydroxypropyl theophylline (dyphylline) was administered by aerosol in a single dose of 250 mg aerosolized over five minutes to two asthmatic volunteers and in a single dose of 375 mg aerosolized over ten minutes to two other asthmatic volunteers. Serial spirometry was then performed. Marked bronchospasm occurred within ten minutes in two of the subjects, and developed more slowly in another. One subject demonstrated no significant change. Aerosolized dyphylline solution was not an effective bronchodilator, using the methods described in this study.

[Comparison of the bronchodilatatory efficacy of oral methylxanthines (author's transl)]. / Vergleich der bronchodilatatorischen Wirksamkeit oraler Methylxanthine.

Two tablets of aminophylline (each 350 mg) or of a mixture (75 mg theophylline, 112,5 mg diprophylline, 112,5 mg proxyphylline per tablet) were given to 12 patients with reversible air-flow obstruction and their effects on lung function, blood pressure and pulse rate were surveyed for eight hours as an intra-individual randomized cross-over experiment. A three-day wash-out period was allowed between the studies on each patient. Statistical evaluation of the data shows that, on the average, the bronchodilator effects were comparable. Unwanted side-effects were seen in three patients after aminophylline. There were none after the mixture.

Utilization of intravenous dihydroxypropyl theophylline (dyphylline) in an aminophylline-sensitive patient, and its pharmacokinetic comparison with theophylline.

The pharmacokinetics and urinary excretion of intravenously administered 7-(2,3-dihydroxypropyl) theophylline (dyphylline), were studied in a 37-yr-old asthmatic woman with ethylene diamine sensitivity who manifested intolerance to intravenous aminophylline on three separate occasions. In this subject, intravenously administered dyphylline was tolerated very well and was effective in the subsequent management of acute bronchospastic episodes. Dyphylline was significantly concentrated in the urine. This, coupled with its rapid clearance, suggests potential clinical application in patients with hepatic dysfunction. Though aminophylline sensitivity is rare, ethylene diamine sensitivity should be considered in untoward reactions to this drug.

[Bronchodilator effect of methylxanthine derivatives (author's transl)]. / Zur bronchodilatatorischen Wirkung von Methylxanthinderivaten.

The bronchodilator effect of theophylline ethylenediamine was compared with that of a combination of the methylxanthines theophylline, diprophylline and proxyphylline, after administration of slow-release capsules. At an initial dose of twice two capsules the two drug preparations produced similar, therapeutically significant, effects. When reducing the dose to twice one capsule, during long-term treatment, there was a clinically and statistically significantly greater bronchodilator effect among those patients receiving the combined methylxanthine preparation.