Mechanism of multidrug resistance in relation to passive membrane permeation.

Passive uptake of drugs into cells is described in terms of the following steps: (1) massive immediate binding of the drugs to the outer leaflet of the plasma membrane resulting in practical equilibrium between extremely high drug concentrations at the cell surface compared to the drug concentration in the medium. (2) Due to their amphipathic nature, anticancer drugs are practically excluded from the lipid core of the membrane. They cross the lipid core by distinct flip-flop events that occur in the case of doxorubicin and daunorubicin after an average period of 0.7 and 0.15 min, respectively. (3) The drug reaching the inner leaflet of the plasma membrane is in practical equilibrium with the drug present in the cytoplasm. (4) Almost all the amounts of anticancer drugs present in the cells are bound by molecular sinks, such as DNA or cytoskeleton elements. The resistance afforded to multidrug resistant (MDR) cells by extrusion pumps, such as P-glycoprotein, is negatively correlated with the affinity of the drugs to the membranes and with their flip-flop rates across membranes. Binding rates of the drugs to membranes and intracellular sinks have no effect on drug concentration in the cytoplasm once equilibrium is reached between the passive uptake of drugs and their active extrusion.     

Antiviral activity of natural and recombinant human leukocyte interferons in tobacco protoplasts

Several purified species of human leukocyte interferon, including recombinant interferons, inhibit the multiplication of tobacco mosaic virus (TMV) in tobacco protoplasts derived from various cultivars. Viral RNA accumulation was determined by dot-blot hybridization to specific cDNA probes, and virus antigen was determined serologically. Interferon apparently inhibited both TMV-RNA replication and its expression into coat protein. However, these effects were of limited duration. Maximum effect was obtained when interferon was applied to the cells either prior to inoculation or within the first hour after inoculation. Antibodies to interferon abolished its antiviral activity in protoplasts. Tobacco protoplasts were about 1000 times more responsive to interferon than the reference animal viral-cell system and showed an "antiviral state" at a ratio of 1 molecule of interferon per cell.     

Hepatic capillariasis

The clinico-pathologic features of Capillaria hepatica infection in a 27-year-old Nigerian woman are discussed. This animal parasite has been encountered only rarely in humans. Less than 30 cases of human infection, mostly in children, having been recorded as far as the present authors are aware. This is the first case of hepatic capillariasis reported in West Africa. The pathologic features of this patient is marked by severe hepatic fibrosis, and this is correlated with disordered liver function. The possibility of histopathologic confusion with schistosomiasis mansoni is discussed.     

GTR with three different types of membranes in the treatment of intrabony periodontal defects: three-year results in sixty consecutive cases

The aim of the present study was to evaluate the clinical results at 3 years following treating intrabony periodontal defects with different nonresorbable and bioabsorbable membrane barriers. Sixty intrabony periodontal defects were treated according to the principles of guided tissue regeneration (GTR). Twenty pockets were treated with Gore Resolut, a bioabsorbable membrane; 20 were treated with Gore-Tex, a titanium-reinforced membrane; and 20 with nonresorbable Gore-Tex membrane (all manufactured by Gore Regenerative Technologies, Flagstaff, AZ). The therapeutic results were evaluated by assessing probing pocket depth (PPD), recession of the gingival margin (GR), and clinical attachment level (CAL) at baseline, at 1 and at 3 years after therapy. The postoperative phase was uneventful in all cases. At 1 year after surgery, the results showed a mean PPD reduction from 9.42 mm to 3.35 mm (p < 0.0001) with Resolut; from 10.30 mm to 4.00 with titanium-reinforced Gore-Tex (p < 0.0001); and from 8.40 mm to 3.73 mm (p < 0.0001) with Gore-Tex membranes. The mean GR increased from 1.92 mm to 3.70 mm (p < 0.001) with Resolut; from 0.47 mm to 2.85 mm (p < 0.0001) with titanium-reinforced Gore-Tex; and from 0.73 mm to 2.15 mm (p < 0.0001) with Gore-Tex membranes. The mean CAL changed from 11.35 mm to 6.92 mm (p < 0.001) with Resolut; from 10.78 mm to 6.85 mm (p < 0.0001) with titanium-reinforced Gore-Tex; and from 9.13 mm to 5.87 mm (p < 0.0001) with Gore-Tex membranes. The clinical results at 3 years were not significantly different when compared with the 1-year results (p > 0.05). No significant differences existed between the mean changes in PPD, GR, and CAL in the three different test groups. Furthermore, one tooth scheduled for extraction for periodontal and prosthodontic reasons was treated with Resolut. Histological analysis 6 months after treatment demonstrated the neoformation of a connective tissue attachment and of new alveolar bone. This additional evidence thus proved that treatment with bioabsorbable membranes according to GTR principles delivers not only clinical improvement, but also histological periodontal regeneration.     

Consensus guidelines on pediatric acute rheumatic fever and rheumatic heart disease

JUSTIFICATION: Acute rheumatic fever and rheumatic chronic valvular heart disease is an important preventable cause of morbidity and mortality in suburban and rural India. Its diagnosis is based on clinical criteria. These criteria need verification and revision in the Indian context. Furthermore, there are glaring differences in management protocols available in literature. These facts prompted Indian Academy of Pediatrics to review the management of rheumatic fever. PROCESS: Management of Rheumatic fever was reviewed and recommendation was formulated at national consultative meeting on 20th May 2007 at New Delhi. OBJECTIVES: To formulate uniform guidelines on management of acute rheumatic fever and rheumatic heart disease in the Indian context. Guidelines were formulated for the management of streptococcal pharyngitis, acute rheumatic fever and its cardiac complication as well as secondary prophylaxis for recurrent episodes. RECOMMENDATIONS: (1) Streptococcal eradication with appropriate antibiotics (Benzathine penicillin single dose or penicillin V oral or azithromycin). (2) Diagnosis of rheumatic fever based on Jones criteria. (3) Control inflammatory process with aspirin with or without steroids (total duration of treatment of 12 weeks). (4) Treatment of chorea according to severity (therapy to continue for 2-3 weeks after clinical improvement). (5) Protocol for managing cardiac complication like valvular heart disease, congestive heart failure and atrial fibrillation. (6) Secondary prophylaxis with benzathine penicillin and management of anaphylaxis.     

The additive miotic effects of dapiprazole and pilocarpine

Background: Since dapiprazole on alpha-adrenergic agent, produces miosis by paralyzing the dilator muscle, and pilocarpine, a parasympathetic drug, causes miosis by affecting the sphincter, we speculated that the two drugs might have additive effects. Methods: The additive miotic actions of pilocarpine 2% and dapiprazole 0.5% were evaluated by comparing the effects of two drugs given together and alone on the reversal of mydriasis induced by tropicamide (0.5%) and phenylephrine (10%) in one eye each of 60 healthy volunteers. Results: Dapiprazole and pilocarpine together induced miosis significantly faster than each drug alone, showing additive effects. Conclusion: Co-administration of dapiprazole and pilocarpine at the end of the eye examination will induce fast pupillary constriction, which might be useful in preventing the development of an acute attack of angle-closure glaucoma in patients with anatomically narrow angles.     

Pregnancy outcome after gestational exposure to the new macrolides: a prospective multi-center observational study

Objectives

To determine whether the use of the new macrolides (azithromycin, clarithromycin, roxithromycin) during the first trimester of pregnancy is associated with an increased risk of major malformations.

Study design

In a prospective multi-center study, pregnancy outcome was compared between pregnant women exposed to one of the new macrolides during the first trimester of pregnancy and two comparison groups one exposed to other antibiotics and the other to other non-teratogenic medications. All women enrolled in the study called one of the three participating teratogen information services (TIS). Group 1 macrolides (n = 161), group 2 other antibiotics (n = 213) and group 3 non-teratogens (n = 740).

Results

A total of 161 women exposed to the new macrolides (118 were exposed in the first trimester of pregnancy) and 953 from a comparison groups were followed up. The rate of major malformations in the study group was 4.1% compared to 2.1% in the other antibiotics exposed group (OR = 1.41, 95% CI 0.47–4.23) and 3.0% in the non-teratogens exposed group. The rate of elective terminations of pregnancy was significantly higher in the exposed group in compare to both comparison groups.

Conclusion

Our study, although relatively small sized, suggests that the use of the new macrolides during the first trimester of pregnancy does not represent an increased risk for congenital malformations strong enough for an induced abortion after such an exposure. Elective terminations of pregnancy because of early exposure to these medications should be reconsidered.