Doxofylline: The next generation methylxanthine.

Methylxanthines are widely used in the treatment of asthma. Being one of the few drugs that can be administered orally, they are especially helpful in resource restricted settings. Theophylline, the commonly used methylxanthine drug is associated with a wide range of adverse effects accounting for the poor compliance and high drop-out rates. Moreover, a narrow therapeutic index warrants routine monitoring of its levels in the blood. Doxofylline, a new methylxanthine derivative, is shown to have similar efficacy with significantly less side effects in both animal studies as well as human adults. However, there is a paucity of studies in children with asthma. Retrospective data suggest that 11% patients experienced some side effects, but only 5% reported moderate side effects. Available evidence suggests that it improves spirometric parameters in children with asthma as compared to placebo. Extrapolating data from adult patients, it may be used in place of theophylline as an add on therapy in step 3 and step 4 in children with asthma. Dosage recommended for children> 6 yrs of age is 6 mg/Kg/dose BID. Doxofylline produces stable serum concentrations, hence plasma monitoring is required only in patients with hepatic insufficiency and intolerance to xanthine drugs.

Simultaneous determination of multi drug components theophylline, etofylline, guaiphenesine and ambroxol hydrochloride by validated RP-HPLC method in liquid dosage form

The RP-HPLC [reverse phase high performance liquid chromatography] method was developed and validated for simultaneous determination of Multi drug components i.e., Theophylline, Etofylline, Guaiphenesine and Ambroxol Hydrochloride in a liquid dosage form. Chromatographic separation of the four drugs was performed on a Hypersil Phenyl BDS [25cmX4.6mm, 5um]. The mobile phase constituted of triethylamine pH 3.0 buffer: methanol [85:15] v/v was delivered at the flow rate 1.5 mL/min. Detection was performed at 235 nm. The peak purity of Theophylline, Etofylline, Guaiphenesine and Ambroxol Hydrochloride were 0.99970, 0.99979, 0.99986 and 0.99949 respectively. Calibration curves were linear with correlation coefficient between 0.99995 to 0.99997 over a concentration range of 5 to 37 micro g/mL for Theophylline, 19 to 140 micro g/mL for Etofylline, 20 to 149 micro g/mL for Guaiphenesine and 6 to 45 micro g/mL for Ambroxol hydrochloride. The relative standard deviation [RSD] was found < 2.0%. The percentage recovery was found between th e range of 98.6% and 100.5% at three different levels. Robustness and ruggedness were performed and result found within the RSD of 2%. All the parameters of validation were found in the acceptance range of ICH guideline

Influence of adenosine, dipyridamole, adenosine antagonists and antiepileptic drugs on EEG after discharge following cortical stimulation.

The effects of adenosine (100 nM, icv), dipyridamole (DPM, 5 mg/kg, i.p.), adenosine A1 receptor antagonist 8-cyclopentyl-theophylline (8-CPT, 10 mg/kg, i.p.), and aminophylline (AMP) and caffeine (CAF) (at equivalent doses of 35 mg/kg, i.p.), were examined in rats. Anti-epileptic drugs (AEDs) were also administered i.p., viz, carbamazepine (CBZ, 10 mg/kg); phenobarbitone (PB, 10 mg/kg); phenytoin (PHT, 20 mg/kg); valproic acid (VPA, 300 mg/kg); and diazepam (DZP, 10 mg/kg), to study their effects on EEG after discharge (AD) and postictal depression (PID) induced by cortical stimulation. The AD parameters: (1) duration of EEG-AD (sec) and (2) number of spikes was noted both during pre and post drug treatment sessions. Adenosine and DPM had no special effects on AD parameters but showed significant prolongation of PID. All the adenosine antagonists, 8-CPT, AMP and CAF produced significant prolongation of AD duration, increase in number of spikes and reduced the duration of PID to a significant extent. Interestingly, some of the AEDs, viz. CBZ, VPA and DZP showed abolition of all the EEG-AD parameters whereas PB and PHT failed to show any significant effect. The results confirm previous findings on involvement of adenosine in postictal events.

Involvement of adenosine in postictal events in rats given electroshock.

The effect of a selective adenosine antagonist, 8-cyclopentyl 1,3-dimethylxanthine (8-CPT) was used to examine involvement of adenosine in ictal and postictal events in rats subjected to maximal electroshock (MES). MES induces the ictal event of hindlimb tonic extension (HLTE) followed by postictal depression (PID). 8-CPT 10 mg/kg, ip produced maximal significant reduction of PID without affecting HLTE, further confirming involvement of adenosine in PID. Carbamazepine and sodium valproate were studied independently and were coadministered with 8-CPT to determine if their anticonvulsant activity was modulated by adenosine and if they altered PID. 8-CPT did not antagonize the seizure protection afforded by CBZ or SV. CBZ significantly reduced postictal events whereas SV had no significant effect. These observations further confirm a role for adenosine in postictal phenomena.

Effect of drugs used in pulmonary edema (frusemide and combination of etofylline and theophylline) on surfactant system of lung.

Pulmonary surfactant activity of healthy male albino rats was estimated in terms of the maximum and minimum surface tension values of alveolar washings and the phospholipid content of the extract. The results obtained in these (control) animals were compared with those in two groups of animals treated with therapeutic doses of frusemide and a combination of etofylline and theophylline. A significant increase in surfactant activity in terms of surface tension values and phospholipid content was observed with frusemide, whereas a significant increase in phospholipid content without a change in surface tension values was observed in the case of combination of etofylline and theophylline. These findings suggest that frusemide in addition to its diuretic action, increases the surfactant activity of lung. This might be another mechanism by which it provides relief in pulmonary edema patients. The study also indicates that phospholipid concentration need not always reflect surfactant activity of lung.