Low-frequency sonophoresis: current status and future prospects

Application of ultrasound enhances skin permeability to drugs, a phenomenon referred to as sonophoresis. Significant strides have been made in sonophoresis research in recent years, especially under low-frequency conditions (20 kHz相似文献   

Altered levels of sex and stress steroid hormones assessed daily over a 28-day cycle in early abstinent cocaine-dependent females

Rationale There is growing evidence of alterations in brain stress and reward circuits associated with cocaine dependence. Sex differences are also documented and sex steroid hormones have been linked to cocaine reinforcement. Objectives The current study therefore assessed daily fluctuations in stress and sex hormones in cocaine-dependent females compared with healthy females. Method Daily salivary samples of cortisol, progesterone, and estradiol were collected at waking across 28 days from 12 cocaine-dependent females receiving inpatient treatment and 10 healthy females. Participants also completed mood-rating scales each week corresponding to four phases of the menstrual cycle and cocaine craving was monitored in cocaine patients at each phase. Results Cocaine-dependent females in their first month of abstinence demonstrated significantly higher levels of both cortisol and progesterone across the menstrual cycle and significantly lower estradiol/progesterone (E2/P) ratios compared to healthy controls. They also showed significantly increased negative mood compared with controls, but no variation in cocaine craving across the menstrual cycle. Conclusions Findings indicate altered stress and sex hormones suggestive of an overactive stress system during the first month of cocaine abstinence after chronic cocaine abuse. These increased levels of cortisol and progesterone could impact both abstinence-related symptoms such as negative mood and susceptibility to drug-seeking behavior in cocaine-dependent females.     

Stereoselective,competitive, and nonlinear plasma protein binding of ibuprofen enantiomers as determinedin vivo in healthy subjects

The plasma protein binding and competitive inhibition parameters of R(–)- and S(+)-ibuprofen were determined in vivo in 12 healthy subjects. Subjects participated in a 4×4 Latin square design in which oral solutions of drug were administered as 300 mg R (–)-ibuprofen, 300 mg S (+)-ibuprofen, 300 mg R (–)-+300 mg S (+)-ibuprofen, and 300 mg R(–)-+600 mg S (+)-ibuprofen. Unlabeled ibuprofen enantiomers were quantitated using a stereospecific reversed-phase HPLC assay, and plasma protein binding experiments were performed using radiolabeled¹⁴C-enantiomers and an ultrafiltration method at 37C. At therapeutic drug concentrations, the protein binding of each enantiomer was greater than 99%. Furthermore, the binding of ibuprofen enantiomers was Stereoselective and mutually competitive, as well as nonlinear. The bound-free data were fitted to a model in which the non-linearity of plasma protein binding and competition between enantiomers for binding sites could be accommodated. There were substantial differences in the affinity of ibuprofen enantiomers for protein binding sites (RP2=0.358±0.185 vs. SP2=0.979 ±0.501 g/ml; X±SD) but no differences in their binding capacity (RP1=160±86 vs. SP1=161 ±63 g/ml). Although statistically significant, the differences in competitive inhibition parameters were more modest (SKI=0.661 ±0.363 vs. RKI=0.436 ±0.210 g/ml). As a result, the intrinsic binding (i.e.), P1/P2J of R(–)-ibuprofen was greater than S(±)-ibuprofen, and the unbound fraction was significantly greater for S-enantiomer vs. R-enantiomer after a given dose of R-ibuprofen or racemate.This work was supported in part by a grant from The Upjohn Company, and by grants R01 GM 35498 and MO1 RR00042 from the National Institutes of Health. During the course of this work, J. K. Paliwal was supported by a CONRAD Fellowship.     

Novel molecular targets for antimalarial chemotherapy

The emergence and spread of drug-resistant malaria parasites is a serious public health problem in the tropical world. Malaria control has relied upon the traditional quinoline, antifolate and artemisinin compounds. Very few new antimalarials were developed in the last quarter of the 20th century. An alarming increase in drug-resistant strains of the malaria parasite poses a significant problem for effective control. Recent advances in our knowledge of parasite biology as well as the availability of the genome sequence provide a wide range of novel targets for drug design. Gene products involved in controlling vital aspects of parasite metabolism and organelle function could be attractive targets. It is expected that the application of functional genomic tools in combination with modern approaches such as structure-based drug design and combinatorial chemistry will lead to the development of effective new drugs against drug-resistant malaria strains. This review discusses novel molecular targets of the malaria parasite available to the drug discovery scientist.     

Immunogenicity and reactogenicity of a combined high dose hepatitis A and hepatitis B vaccine, compared to that of Twinrix in healthy Indian children

BACKGROUND AND AIMS: Hepatitis A virus (HAV) and hepatitis B virus (HBV) are vaccine preventable important childhood acquired infectious diseases in developing countries. In the changing epidemiology of HAV, the utility of such a vaccine in India needs urgent attention. Further, the efficacy of two versus three dose schedule needs to be assessed to improve compliance. SUBJECTS AND METHODS: One hundred healthy school children, aged 1-15 years were recruited in a randomised open study to receive either vaccination schedule: Group I: combined high-dose hepatitis A and B vaccine to be administered on a 0, 6 month schedule intramuscularly; Group II: to be administered on 0, 1, 6 month Twinrix (GlaxoSmithKline Biologicals, Rixensart, Belgium) schedule intramuscularly. The seroconversion (> or =1MIU/ml for anti-HBs antibodies and > or =33MIU/ml for anti-HAV antibodies) and seroprotection (anti-HBs > or =10MIU/ml after the third dose of vaccine) rates were determined at months 1, 2, and 7. RESULTS: The mean age and gender was similar between groups: 7.9+/-2.6 years (range 3-15 years). At month 7 all subjects (100%) in both groups were seropositive for anti-HAV antibodies, Group I had higher anti-HAV titres at months 1 or 2 compared to Group II (P=0.025, P=0.040). Group II developed higher seroprotection rates (month 2, P=0.002, month 6, P=0.003) compared to Group I and higher titres (month 2, P=0.001, month 6 P=0.001) compared to Group I. At month 7, the geometric mean titres (GMTs) were comparable between groups and seroprotection reached 100% in both the groups. The incidence of any symptom per dose analysis reported during a 4-day follow-up period was significantly higher in Group I, 53% (52/98) of the documented doses compared to 37% (54/146) in Group II (P=0.018). CONCLUSION: Twinrix vaccine is safe and highly immunogenic in Indian children. Further study of the high dose vaccine would determine if its two dose regimen is a feasible advantage.     

Cationic transfection lipids in gene therapy: successes,set-backs,challenges and promises

The clinical success of gene therapy is critically dependent on the development of efficient and safe gene delivery reagents, popularly known as "Transfection Vectors". The transfection vectors commonly used in gene therapy are mainly of two types: viral and non-viral. The efficiencies of viral transfection vectors are, in general, superior to their non-viral counterparts. However, the myriads of potentially adverse immunogenic aftermaths associated with the use of viral vectors are increasingly making the non-viral gene delivery reagents as the vectors of choice. Among the existing arsenal of non-viral gene delivery reagents, the distinct advantages associated with the use of cationic transfection lipids include their: (a) robust manufacture; (b) ease in handling & preparation techniques; (c) ability to inject large lipid:DNA complexes and (d) low immunogenic response. The present review will highlight the successes, set-backs, challenges and future promises of cationic transfection lipids in non-viral gene therapy.     

Oral cancer in Southern India: the influence of body size, diet, infections and sexual practices.

Between 1996 and 1999, we carried out a study in Southern India on risk factors for oral cancer. The study included 591 incident cases of cancer of the oral cavity (282 women) and 582 hospital controls (290 women). Height was unrelated to oral cancer risk. Body mass index (weight in kilograms/height in metres squared) was inversely associated with risk (P for trend<0.001). Paan chewers with low BMI were at particularly high risk. Risk was increased among subjects consuming meat (odds ratio (OR) 1.54, 95% confidence interval (CI) 1.00-2.37), ham and salami (OR 4.40, 95% CI 2.88-6.71) two or more times per week. Frequent consumption of fish, eggs, raw green vegetables, cruciferous vegetables, carrots, pulses, apples or pears, citrus fruit, and overall consumption of vegetables and fruit decreased oral cancer risk (P for trend for each of these items less than or equal to 0.001). The risk associated with low consumption of vegetables was higher among smokers than among non-smokers. Men, but not women, who practised oral sex had an increased oral cancer risk (OR 3.14, 95% CI 1.15-8.63). Women with more than one sexual partner during life were at increased oral cancer risk (OR 9.93, 95% CI 1.57-62.9).     

Summated chemotherapy dose-intensity versus loco-regional response in locally advanced breast cancer: its possible implications

BACKGROUND: Summated dose-intensity (SDI) of chemotherapy regimen could influence the outcome in malignancies. AIMS: To evaluate the implication of SDI and identify key drugs for loco-regional response in locally advanced breast cancer (LABC). Settings and design: This retrospective study was based on audit of records of LABC patients who had received neoadjuvant chemotherapy (NACT). MATERIAL AND METHODS: Actual unit dose-intensity (UDI) of each drug and corresponding SDI of every doxorubicin (n=116 cycles) or non-doxorubicin (n=110 cycles) based NACT received by 42 patients of LABC were summated. Cumulative dose-intensity (CDI) for individual drugs and cumulative SDI (CSDI) for the entire course of NACT were estimated and correlated with quantum of primary tumor, axillary and supraclavicular nodal responses. STATISTICAL ANALYSIS USED: Two-sided chi-square, t-test, step-wise regression was used. RESULTS: Dose-response curve between CSDI and corresponding responses for both primary and lymph nodes were sigmoid in shape for both doxorubicin or non-doxorubicin based NACT. Curves were best fitted using a cubic fit for all patients (r2 = 0.82, 0.84 and 0.93 for primary tumor, axillary and supraclavicular lymph nodes respectively). CSDI emerged as an important prognosticators for both primary (P<0.001) and nodal (P<0.001) responses. Individually, CDI of 5-fluorouracil for primary (P<0.001), CDIs of doxorubicin (P<0.001) and methotrexate (P=0.006) for axillary nodes and CDI of cyclophosphamide (P=0.001) for supraclavicular nodes were significant. CONCLUSIONS: Loco-regional responses in LABC are dependent on CSDI of NACT regimen. Drugs for high-dose intensification protocols could be identified and chosen based on the impact of CDI of individual drugs in NACT.