Prolongation of pentoxifylline aliphatic side chain positively affects the reversal of P-glycoprotein-mediated multidrug resistance in L1210/VCR line cells.

We reported previously that derivatives of pentoxifylline (PTX) reverse multidrug resistance (MDR) in P-glycoprotein (P-gp) positive L1210/VCR cells. Based on the results of a recent study using 25 N-alkylated methylxanthines with carbohydrate side-chains of various lengths, we formulated the following design criteria for a methylxanthine molecule to effectively reverse P-gp mediated MDR: i) a massive substituent at the N1 position is crucial for MDR reversal potency; ii) elongation of the substituents at the N3 and N7 positions (from methyl to propyl) increases the efficacy of a xanthine to reverse MDR; iii) elongation of the substituent at the C8 position (from H to propyl) decreases the efficacy of a xanthine to reverse MDR. Based on these criteria, we synthesized and tested for potency to reverse MDR a new PTX derivative, 1-(10-undecylenyl)-3-heptyl-7-methyl xanthine (PTX-UHM), with prolonged substituents at the N1 and N3 positions. The derivative was obtained by alkylation of 3-heptyl-7-methyl xanthine with 1-methylsulfonyloxy-10-undecylenyl. NMR and IR structural analyses proved the identity of the product. Cytotoxicity study showed that PTX-UHM is only slightly more toxic to L1210/VCR cells than PTX. We found that both PTX-UHM and PTX were able to reverse vincristine resistance of L1210/VCR cells, yet PTX-UHM was significantly more efficient in the reversal than PTX.

Carbonyl group of aliphatic side chain of pentoxifylline does not play role for P-glycoprotein antagonizing effect of pentoxifylline.

Previously we have found that pentoxifylline (PTX), but not caffeine, theophylline, or 1-methyl-3-isobutylxanthine, affects sensitivity of L1210/VCR cells, a line with multidrug resistance mediated by P-glycoprotein (P-gp) to vincristine (VCR) and doxorubicine. Comparison of chemical structure of PTX with other above xanthines has revealed only one marked difference. PTX contains extended aliphatic chain containing reactive electrophilic carbonyl group in the position N1. The investigation of possibility that this group is crucial for PTX-induced MDR reversal represents the aim of the current paper. To prove this hypothesis, we used the new synthesized PTX derivative in which the carbonyl group is modified by a substance containing amino-group and the product of reaction is the respective Schiff base (SB). Successful reaction was observed when PTX reacted with 3,5-diaminobenzenesulfonyl acid (DABS). The product of reaction of DABS with carbonyl group of aliphatic part of PTX was proved using NMR and IR spectroscopy. We found that the resulting PTX derivative PTX-SB revealed higher cytotoxicity on both sensitive L1210 and multidrug resistant L1210/VCR cells than PTX. Moreover, PTX-SB exerts more pronounced MDR reversal effect on L1210/VCR cells than PTX. These results indicate that electrophilic carbonyl group on aliphatic chain located in position N1 of PTX is not essential for MDR reversal effects of PTX.

Midodrine hydrochloride in the treatment of vasovagal syncope.

Therapy of vasovagal syncope is still a subject of debate. Various pharmacotherapies were proposed. However, they are often not tolerated or ineffective. The purpose of this prospective, nonrandomized study was to evaluate the usefulness of alpha-agonist midodrine hydrochloride in the treatment of vasovagal syncope. Forty-one patients (mean age 34 years, 18 men) with history of recurrent syncope and positivity of head-up tilt testing were included (28 patients with type 1, 10 patients with type 2, 3 patients with type 3 according to VASIS classification). In all patients oral therapy with midodrine was started. Initial dose was 2.5 mg two times daily. When necessary, the dose was increased to 5 mg two times daily. Efficacy of treatment was assessed by repeated head-up tilt testing after 1-2 weeks of therapy and by long-term follow-up. After midodrine hydrochloride treatment, 39 of 41 patients (95%) had no inducible presyncope or syncope on repeated tilt table testing. Effective dose was 2.5 mg two times daily in 25 patients and 5 mg two times daily in 16 patients. During a mean follow-up period 19+/-9 months, 38 of 39 patients (97%) with negative repeated tilt table test remained free of syncope recurrence.

[The antitussive effect of theophylline]. / Sledovanie antitusického úcinku teofylínu.

Theophylline belongs to a group of medicaments used in asthma therapy. It yields an antiinflammatory effect, reduces allergic reactions, and in respiratory airways it improves the mucociliary clearance and eminently dilates smooth muscles. Therefore, the main aim of our interest is its effect on the cough reflex. Cough was evoked by mechanical irritation of the airways in cats with chronic tracheal cannula. It has been discovered that theophylline, when dosed 10 mg per kg of body weight i.p. achieved a more intensive effect than dextromethorphane, namely in evaluation of cough parameters, but it had a lower suppressive effect than codeine. (Fig. 3, Ref. 13.)