Bactericidal activities of single or multiple doses of various combinations of new antileprosy drugs and/or rifampin against M. leprae in mice.

The bactericidal activities against Mycobacterium leprae of single or multiple doses of various combinations of new antileprosy drugs [minocycline (MINO), clarithromycin (CLARI), ofloxacin (OFLO), and sparfloxacin (SPFX)] and/or rifampin (RMP) were titrated in immunocompetent mice by the proportional bactericidal method. Drugs were administered by gavage at the following dosages (mg/kg) per dose: RMP 10, MINO 25, CLARI 100, OFLO 150, and SPFX 50. All 15 regimens exerted significant bactericidal activities, at least 96% of viables were killed. The activity of a single dose MINO + CLARI was only slightly inferior to that of RMP, and the activities of a single dose OFLO/SPFX + MINO + CLARI were similar to that of RMP. This suggests that either MINO + CLARI or OFLO/SPFX + MINO + CLARI may be administered once monthly together with RMP 600 mg for the treatment of multibacillary (MB) leprosy, and monthly administration of MINO + CLARI or OFLO/SPFX + MINO + CLARI may also be employed for the treatment of RMP-resistant MB leprosy. Because the killing effects of multiple doses of the combinations were so powerful, comparison of the bactericidal activities of these regimens was beyond the sensitivity of the immunocompetent mouse model, and are being tested in the nude mouse model. Although SPFX is more active against M. leprae than OFLO on a weight-to-weight basis, when both drugs were administered in mice at dosages equivalent to clinically tolerated dosages in humans, SPFX did not show more superiority than OFLO, and its real advantage over OFLO in the treatment of leprosy remains unclear.     

Clinical trial of pefloxacin and ofloxacin in the treatment of lepromatous leprosy

Twenty-one previously untreated lepromatous patients were randomized into two groups and treated with either 800 mg pefloxacin (PEFLO) or 400 mg ofloxacin (OFLO) once daily. The trial consisted of two parts: monotherapy from day 0 to day 56; and combined with the World Health Organization multidrug therapy (WHO/MDT) regimen for multibacillary (MB) leprosy from day 57 to day 180. Four patients were removed from the trial because the organisms recovered from their pretreatment biopsies failed to infect mice. Among the remaining 17 cases, four (23.5%) had primary resistance to dapsone but all of them were susceptible to rifampin. The initial (day 0) proportion of viable organisms, as measured by mouse foot pad inoculation, varied tremendously from patient to patient despite randomization during admission. Definite clinical improvement was noticed in virtually all patients after 22 doses of treatment with either PEFLO or OFLO. A significant fall in the morphological index (MI) occurred as early as after 8 doses of PEFLO or after 22 doses of OFLO; the bacterial load also showed a moderate degree of reduction during the period of monotherapy. Although single-dose PEFLO or OFLO displayed only a modest degree of bactericidal effect against Mycobacterium leprae, about 99.9%, or 4 logs, of organisms viable on day 0 were killed by 22 doses of either PEFLO or OFLO. No significant difference in the therapeutic effect was detected between the two regimens. During PEFLO or OFLO monotherapy, except in one patient (case no. 10), the side effects were few and mild. Case no. 10 developed a psychic disorder after 27 days of PEFLO monotherapy, presumably due to the treatment with PEFLO. All of the patients tolerated the period of combined therapy extremely well, although some asymptomatic and transient laboratory abnormalities were observed. Because both PEFLO and OFLO displayed rapid bactericidal activities in human leprosy and were well tolerated by the patients, further clinical trials and field trials in evaluating the therapeutic effects of combined regimens containing both rifampin and PEFLO or OFLO are being organized. Since this is the first clinical trial in leprosy employing nude mice, in combination with normal mice, for monitoring the therapeutic effects of antimicrobials, the advantages, limitations and appropriate timing in using nude mice are discussed.     

Antimycobacterial activities of two newer ansamycins, R-76-1 and DL 473

The antimycobacterial activities of two newer ansamycins, isobutylpiperazinylrifamycin SV (R-76-1) and cyclopentylrifamycin SV (DL 473), were compared with those of rifampin (RMP) both in vitro and in vivo. In terms of minimal inhibitory concentrations against a number of cultivable mycobacteria, R-76-1 was about eight times more active in vitro than RMP; whereas DL 473 was only slightly more active than RMP. Therapeutic activities of R-76-1 versus RMP and DL 473 versus RMP were compared, respectively, in the experimental infection of mice with Mycobacterium lepraemurium by different treatment schedules (immediate and delayed) and dosage regimens. R-76-1 appeared to have been three times more effective than RMP; DL 473 was also more effective than RMP in that an equivalent therapeutic effect could be obtained by fewer doses of DL 473 than of RMP, and in that DL 473 exerted a more prolonged activity than RMP. With the kinetic method and a dosage of 0.001% in the diet, R-76-1 demonstrated a bactericidal-type effect against M. leprae whereas RMP did not; with the proportional bactericidal method, R-76-1 possessed about three times the bactericidal activity of RMP against M. leprae. When drugs were administered once in 4 weeks, the RMP dose required to prevent multiplication of M. leprae in the foot pads of half of the mice was in the range of 1.25 to 2.5 mg/kg; whereas that of DL 473 was less than 0.625 mg/kg. With the proportional bactericidal method, even a single dose of 1.25 mg DL 473 per kg was active against M. leprae; whereas the smallest single active dose of RMP was 10 mg/kg. DL 473 in single doses of 5 mg/kg and 10 mg/kg was significantly more effective than RMP in equal doses and, among the intermittent regimens administered four times, once every 4 weeks, no significant differences of bactericidal activity were observed between RMP at 20 mg/kg and DL 473 at 0.625 mg/kg. A preliminary clinical trial of R-76-1 in 20 patients with lepromatous leprosy showed that the compound, administered in a dosage of 150 mg daily, was very effective.     

Study of 39 documented relapses of multibacillary leprosy after treatment with rifampin

Among 39 strains of Mycobacterium leprae isolated from patients with multibacillary leprosy who relapsed after treatment with rifampin (RMP), 22 strains were resistant to RMP and 17 were susceptible. All of the RMP-resistant strains were recovered from patients who had been treated with more than 50 doses of RMP, usually given as monotherapy. RMP-susceptible strains were recovered from only six patients who had received more than 50 doses of RMP, and from 11 patients who had received no more than seven doses. The median time to relapse after the beginning of RMP therapy was 9 years (range 1-12 years) among the patients harboring RMP-resistant strains of M. leprae, and the median time to relapse after discontinuation of RMP treatment was 7 years (range 1-11 years) among the patients harboring RMP-susceptible strains. These data suggest that monotherapy with more than a few doses of RMP can be responsible for the emergence of RMP-resistant strains of M. leprae, thus emphasizing the need to employ RMP only in combination with other effective drugs in the chemotherapy of multibacillary leprosy.     

4种药物单用或联用治疗大鼠华支睾吸虫感染的实验研究

目的观察三苯双脒(TBD)、青蒿琥酯(AS)、阿苯达唑(ABZ)、甲苯咪唑(MBZ)单用或联用治疗感染华支睾吸虫大鼠的疗效。方法 140只大鼠各感染华支睾吸虫囊蚴100个,于感染后第5周开始分组治疗,均采用灌胃给药。感染大鼠随机分为药物治疗组同批感染对照组(每组5～10只),将TBD、AS、ABZ与MBZ分别按照高、低剂量单剂用药和两两配伍给药,顿服,观察疗效。治疗后10d处死大鼠,解剖,收集胆管和肝组织内的华支睾吸虫,计算平均虫数和减虫率,对相应组间的平均虫数进行单因素方差分析。结果感染华支睾吸虫大鼠用75mg/kg体重TBD、MBZ、ABZ单剂治疗后,平均减虫率分别为98.04%、100%和86.67%,30mg/kg体重AS治疗后减虫率为87.25%;当给药剂量均降低1/3时,上述各药物治疗组的平均减虫率分别降至78.3%、46.02%、31.94%和62.07%。50mg/kg体重TBD分别与50mg/kg体重MBZ、ABZ配伍用组平均减虫率为98.43%和100%,检虫数与75mg/kg体重TBD、MBZ、ABZ单用药组比较,差异有统计学意义(P<0.05)。20mg/kg体重AS分别与50mg/kg体重ABZ、50mg/kg体重MBZ配伍用,平均减虫率为89.22%和97.55%,检虫数与75mg/kg体重ABZ、MBZ,30mg/kg体重AS单用药组比较,差异有统计学意义(P<0.05)。结论联合用药可降低给药剂量,并具有增效作用,50mg/kg体重TBD分别与50mg/kg体重MBZ、ABI配伍用对治疗大鼠华支睾吸虫病疗效较好。     

Hydroxychloroquine sulphate in the treatment of rheumatoid arthritis: a double blind comparison of two dose regimens.

A controlled, double blind, parallel group, long term study of hydroxychloroquine sulphate in the treatment of rheumatoid arthritis, comparing daily doses of 200 mg and 400 mg, is described. The trial involved 54 patients with moderate disease activity who had not previously received antimalarial drugs. Forty three patients completed the one year treatment. The groups receiving different doses were homogeneous and did not differ in any of the 25 monitored indicators. Both dose regimens were effective, and a significant reduction of disease activity was observed after one year's treatment. Of the nine laboratory and 11 clinical indices of efficacy monitored, no statistically significant differences were reported, but in the group of patients treated with the 400 mg daily dose the number of side effects was three times greater. As there have been no reports of retinopathy with hydroxychloroquine at daily doses of 200 mg the effectiveness of this dose is of practical importance.     

Low serum concentrations of anti-tuberculosis drugs and determinants of their serum levels.

SETTING: Low serum concentrations of anti-tuberculosis drugs have occasionally been associated with treatment failure. OBJECTIVE: To determine the prevalence of low serum concentrations of anti-tuberculosis drugs and to identify the determinants of drug concentrations. DESIGN: Venous blood was obtained 2 h after drug ingestion, and serum levels of isoniazid (INH), rifampicin (RMP), ethambutol (EMB), pyrazinamide (PZA), acetyl INH and 25-desacetyl RMP were analysed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Patients with human immunodeficiency virus co-infection and gastrointestinal disease or diarrhoea were excluded. RESULTS: Among 69 enrolled TB patients, the prevalence of a low 2 h serum concentration of at least one anti-tuberculosis drug was 46.4%. Prevalences of a low concentration of INH, RMP, EMB or PZA were 15.2%, 23.5%, 22.4% and 4.5%, respectively. By multivariate linear regression analysis, the serum concentrations of INH, RMP and PZA were positively associated with dose per kg of body weight (P < 0.05). Moreover, INH concentration was associated with acetyl INH/INH ratio (beta = -8.588, P < 0.001) and EMB concentration was associated with calculated creatinine clearance (beta = -0.025, P < 0.001). CONCLUSION: Low concentrations of anti-tuberculosis drugs are common, and although the clinical significance of low concentrations remains uncertain, it may be necessary to optimise drug doses by therapeutic drug monitoring, especially in patients with an inadequate clinical response to chemotherapy.     

Comparison between the efficacy of oxamniquine and praziquantel in the treatment of Schistosoma mansoni infections on a sugar estate in Ethiopia

The efficacy of the antischistosomal drugs praziquantel and oxamniquine was tested on four groups of Ethiopian sugar estate workers. The cure rates, determined by the absence of eggs in stools, were 96, 93 and 74% at one, three and six months post-treatment for patients receiving a single dose (40 mg kg-1 body weight) of praziquantel, and 82, 78 and 78% for patients on a single dose (15 mg kg-1 body weight) of oxamniquine. When split doses of these drugs were used, praziquantel achieved cure rates of 96, 95 and 89%, while the corresponding cure rates for oxamniquine were 98, 96 and 88% at one, three and six months post-treatment. In general, there were no statistically significant differences within the single and split doses of each drug, nor between the two drugs except that single doses of praziquantel had significantly higher cure rates than oxamniquine at one and three months post-treatment. Although both drugs produced mild and transient side-effects such as dizziness, abdominal discomfort and diarrhoea, serious side-effects such as seizures were seen only among patients on oxamniquine. As praziquantel is also effective against other forms of schistosomiasis as well as against cestodes, we recommended the use of this drug in mass chemotherapy and in the ambulatory treatment of schistosomiasis in Ethiopia.     

Radioiodine treatment of hyperthyroidism-prognostic factors for outcome

There is little consensus regarding the most appropriate dose regimen for radioiodine (131I) in the treatment of hyperthyroidism. We audited 813 consecutive hyperthyroid patients treated with radioiodine to compare the efficacy of 2 fixed-dose regimens used within our center (185 megabequerels, 370 megabequerels) and to explore factors that may predict outcome. Patients were categorized into 3 diagnostic groups: Graves' disease, toxic nodular goiter, and hyperthyroidism of indeterminate etiology. Cure after a single dose of 131I was investigated and defined as euthyroid off all treatment for 6 months or T4 replacement for biochemical hypothyroidism in all groups. As expected, patients given a single dose of 370 megabequerels had a higher cure rate than those given 185 megabequerels, (84.6% vs. 66.6%, P < 0.0001) but an increase in hypothyroidism incidence at 1 yr (60.8% vs. 41.3%, P < 0.0001). There was no difference in cure rate between the groups with Graves' disease and those with toxic nodular goiter (69.5% vs. 71.4%; P, not significant), but Graves' patients had a higher incidence of hypothyroidism (54.5% vs. 31.7%, P < 0.0001). Males had a lower cure rate than females (67.6% vs. 76.7%, P = 0.02), whereas younger patients (<40 yr) had a lower cure rate than patients over 40 yr old (68.9% vs. 79.3%, P < 0.001). Patients with more severe hyperthyroidism (P < 0.0001) and with goiters of medium or large size (P < 0.0001) were less likely to be cured after a single dose of 131I. The use of antithyroid drugs, during a period 2 wk before or after 131I, resulted in a significant reduction in cure rate in patients given 185 megabequerels 131I (P < 0.01) but not 370 megabequerels. Logistic regression analysis showed dose, gender, goiters of medium or large size, and severity of hyperthyroidism to be significant independent prognostic factors for cure after a single dose of 131I. We have demonstrated that a single fixed dose of 370 megabequerels 131I is highly effective in curing toxic nodular hyperthyroidism as well as Graves' hyperthyroidism. Because male patients and those with more severe hyperthyroidism and medium or large-sized goiters are less likely to respond to a single dose of radioiodine, we suggest that the value of higher fixed initial doses of radioiodine should be evaluated in these patient categories with lower cure rates.     

A study with cumulative doses of formoterol and salbutamol in children with asthma.

In a double-blind, cross-over study, 9 children (7-13 yrs old) with stable, moderate asthma inhaled formoterol (6, 18 and 54 micrograms) and salbutamol (100, 300 and 900 micrograms) at hourly intervals, in order to compare the peak effect of cumulative doses of the two drugs. One hour after the last dose, 1 mg salbutamol was inhaled to ensure that maximum bronchodilatation was obtained. The forced expiratory volume in one second (FEV1), peak expiratory flow rate (PEFR), forced vital capacity (FVC), pulse rate, blood pressure and tremor were measured regularly after each dose and the PEFR 5, 7, 9 and 20 h after the last dose. The first dose of each drug improved the FEV1, PEFR and FVC substantially while the following doses only gave minor improvement. The final addition of 1 mg salbutamol produced no further improvement. No statistically significant difference in bronchodilating effect was seen between the two drugs at any point in time. Side-effects were minimal. Our data indicate that doses of 6-24 micrograms formoterol can be recommended for school children. For most patients with mild to moderate bronchial asthma higher doses will not add much to the bronchodilating effect.     

Hepatotoxicity of the combination of rifampin-ethionamide in the treatment of multibacillary leprosy

During treatment of multibacillary leprosy with the combination rifampin (RMP) 600 mg, ethionamide (ETH) 500 mg, and either dapsone (DDS) or clofazimine (CLO) 100 mg, hepatotoxicity was observed in 4.5% of 596 patients. Hepatitis appeared after 5-186 days, with a mean of 93 days and a median of 76 days. Mortality was 26%. ETH and DDS or CLO were administered daily in all regimens in which hepatitis occurred. RMP was given either daily or daily during the first two weeks or eight weeks, followed by a once-weekly dose. It is concluded that the combination RMP + ETH is the toxic component. In some patient groups there was a high correlation of toxicity with age. A regimen in which RMP was administered only twice a week during three months was not accompanied by hepatotoxicity. Future studies should show if reduction of the daily dose of ETH or reduction of the duration of the administration of RMP + ETH might reduce the incidence of hepatotoxicity while conserving the efficacy.     

Prospective study on the relationship between intensive bactericidal therapy and leprosy reactions

A systematic study was performed on the reactions occurring during several short-course therapy regimens for the treatment of paucibacillary and multibacillary patients. Most type 1 upgrading reactions in paucibacillary (PB) leprosy were mild to moderate and of short duration, while the time of onset was extremely variable. Their incidence was higher in the regimen rifampin (RMP) 900 mg once weekly for ten weeks than when a single dose of RMP 40 mg/kg body weight was given or 1500 mg in one dose followed by one year of dapsone (DDS) 100 mg daily. In multibacillary (MB) leprosy, three regimens were compared: MB-WHO regimen; regimen C, consisting of daily RMP 600 mg, ethionamide (ETH) 500 mg, and DDS or clofazimine (CLO) 100 mg for six months, followed by six months of daily DDS or CLO; and regimen D, identical to regimen C but comprising daily DDS or CLO plus ETH 500 mg during the second semester. Type 1 upgrading reactions occurred more frequently in MB patients and were more severe than in PB patients. They occurred more frequently and were more severe in regimens C and D than in the MB-WHO regimen. CLO 100 mg daily prevented type 1 reactions in MB patients and rendered them less severe. ENL was also more frequent in regimens C and D and was not prevented by CLO in the dosage used. Although there is some correlation between type 1 reactions and the total amount of RMP administered, other aspects of RMP administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of single daily dose of methimazole and propylthiouracil in the treatment of Graves' hyperthyroidism

OBJECTIVE: The present study was to compare the efficacy of a single daily dose of methimazole (MMI) and propylthiouracil (PTU) in the treatment of Graves' hyperthyroidism. BACKGROUND: Antithyroid drugs, MMI and PTU, are widely used in the treatment of hyperthyroidism. Previous studies in the treatment of hyperthyroidism with a single daily dose of antithyroid drugs have demonstrated a more favourable result with MMI. However, the efficacy of a single daily dose of PTU was inconsistent. In this study, we examined the therapeutic efficacy of single daily doses of MMI and PTU on the change of thyroid hormones and thyrotropin receptor antibodies (TRAb) levels. METHODS: Thirty patients with newly diagnosed Graves' hyperthyroidism were randomly divided into two groups, each receiving a single dose of either 15 mg MMI or 150 mg PTU daily for 12 weeks. The therapeutic efficacy was determined by serum total triiodothyronine (TT3), total thyroxine (TT4), thyrotropin (TSH), free thyroxine (FT4), and TRAb levels at baseline and at the end of 4, 8 and 12 weeks during the study period. RESULTS: There was no significant difference in baseline thyroid function parameters. Serum TT3, TT4 and FT4 levels in the MMI-treated group were significantly lower than those of the PTU-treated group after 4 weeks and through the end of the study. MMI also has superior effect on reducing serum TRAb levels than PTU after 8 weeks and at the end of the study. CONCLUSION: During the 12-week treatment of Graves' hyperthyroidism, a single daily dose of 15 mg MMI was much more effective in the induction of euthyroidism than a single daily dose of 150 mg PTU. In the doses used in this study, MMI is preferable to PTU when a once-daily regimen of antithyroid drug is considered for the treatment of Graves' hyperthyroidism.     

Efficacy of nisoldipine combined with beta-adrenergic-blocking drugs in the treatment of chronic stable angina

A double-blind, placebo-controlled study was performed to assess whether a new calcium antagonist, nisoldipine, in doses of either 5 mg or 10 mg daily, in combination with beta-adrenergic-blocking drugs (combination therapy) was more effective than beta-adrenergic-blocking drugs alone (single therapy) in the treatment of chronic stable angina. Treatments were assessed at two-week intervals, using exercise electrocardiography and patients' anginal diaries. A significant improvement in exercise capacity and reduction in anginal attacks occurred only during nisoldipine (10 mg daily) combination therapy compared with single therapy. Mean exercise time increased from 419 +/- 146 s (single) to 454 +/- 158 s (p less than 0.02) after combination therapy. Exercise time to onset of 1 mm ST-segment depression improved from 326 +/- 145 s (single) to 331 +/- 139 s after combination therapy, although the change was not significant. Mean number of anginal attacks decreased from 21 +/- 22 (single to 15 +/- 19 (p less than 0.01) during combination treatment, with an associated significant reduction in glyceryl trinitrate consumption. Adverse effects during combined therapy were minor and tolerable. Thus patients limited by exertional angina despite beta-adrenergic-blocking drugs may obtain supplemental relief of angina and myocardial ischemia with the addition of nisoldipine in a dose of 10 mg daily.     

Intravenous gammaglobulins in refractory polymyositis: lower dose for maintenance treatment is effective

OBJECTIVES: To test lower dose immunoglobulins as a maintenance treatment in a patient with refractory polymyositis. METHODS: In a patient with longstanding refractory polymyositis, intravenous (IV) immunoglobulin treatment was introduced at a standard dose (2 g/kg monthly). After a few treatment courses, doses were reduced to 0.8 g/kg monthly, allowing perfusion over one single day. RESULTS: Although response to the standard dose was only partial, reduction of subsequent doses did not alter the evolution. On the contrary, the evolution was marked by further improvement, which has been sustained over the following year. CONCLUSION: Lower dose IV immunoglobulins as a maintenance treatment were used with excellent results in a case of refractory polymyositis allowing considerable reduction in treatment costs. Further trials should be undertaken to evaluate this interesting alternative.     

Vilanterol trifenatate,a novel inhaled long-acting beta2 adrenoceptor agonist,is well tolerated in healthy subjects and demonstrates prolonged bronchodilation in subjects with asthma and COPD

Vilanterol (VI; GW642444M) is a novel inhaled long-acting β2-agonist with inherent 24 h activity in vitro in development as a combination with the inhaled corticosteroid fluticasone furoate for both COPD and asthma. These studies were conducted to determine the safety, tolerability, pharmacodynamics and pharmacokinetics of VI in healthy subjects and subjects with mild to moderate persistent asthma and moderate to severe COPD.Single doses of VI (25–100 μg) were given once daily to subjects with asthma and COPD and repeat doses once daily for 14 days to healthy subjects. Adverse events (AEs), vital signs, ECGs, pharmacodynamic endpoints, FEV₁ and VI plasma pharmacokinetics (AUC, Cmax and Tmax) were determined following dosing.VI (25–100 μg) was well tolerated. The incidence and severity of AEs were comparable to placebo. Following VI administration there were no clinically significant abnormalities in vital signs, 12-lead ECG, Holter ECG, blood glucose or potassium. There were no statistically significant effects on QTc of single and repeat VI doses up to 50 μg; some differences were seen following the 100 μg VI dose after single and repeat dose in healthy subjects and single dose in asthmatic subjects. All VI doses produced increases in FEV₁ from as early as 5 min after dosing which were maintained up to 24 h post-dose in subjects with asthma and COPD. In all subjects VI was rapidly absorbed (healthy subjects median Tmax at 5 min; asthma and COPD subjects median Tmax at 10 min) with systemic exposure increasing in an approximately dose proportional manner across the VI dose range. Marginal accumulation was seen on repeat dosing.Single doses of inhaled VI in subjects with asthma and COPD and repeat doses in healthy subjects were well tolerated with no clinically significant unwanted systemic effects. VI produced a rapid and prolonged bronchodilation over 24 h suggesting the potential for once daily administration.     

不同剂量美托洛尔联合胺碘酮对轻中度高血压患者颈动脉内膜中层厚度的影响

目的：探讨不同剂量美托洛尔联合胺碘酮对轻中度高血压患者颈动脉内膜中层厚度的影响。方法：2012年8月到2015年2月选择在我院进行诊治的轻中度高血压患者120例,根据随机抽签原则分为治疗组与对照组各60例,对照组给予小剂量美托洛尔联合胺碘酮治疗,治疗组给予大剂量美托洛尔联合胺碘酮,都治疗2个月。结果：治疗组的美托洛尔每天平均剂量为77.33±10.34mg,而对照组为23.09±8.92mg;同时治疗组与对照组的治疗总有效率分别为98.3%和86.7%,治疗组的治疗总有效率明显高于对照组(P<0.05)。两组治疗后的收缩压与舒张压、LVEDD和LVESD值都明显下降,同时治疗后治疗组的收缩压与舒张压、LVEDD和LVESD值也都明显低于对照组(P<0.05)。治疗后治疗组与对照组的颈动脉内膜中层厚度分别为0.87±0.32mm和1.21±0.45mm,都明显低于治疗前的1.88±0.41mm和1.84±0.54mm(P<0.05),同时组间对比差异也有统计学意义(P<0.05)。结论：相对于小剂量,大剂量美托洛尔联合胺碘酮对轻中度高血压患者能更加有效发挥降低作用,能促进心功能的恢复,有利于颈动脉内膜中层厚度降低,从而提高总体治疗疗效。     

Dose-response effect of perfluorocarbon administration on lung microvascular permeability in rats

The effect of various perflubron doses on overdistension lung injury was evaluated. Rats were given perflubron at 0 ml/kg (control) to 20 ml/kg and ventilated with a VT of 33 ml/kg without or with 5 cm H2O of positive end-expiratory pressure (PEEP). High (20 ml/kg), but not lower, perflubron doses aggravated lung capillary leak in the absence of PEEP. PEEP application aggravated capillary leak in controls, had no effect in those given a low (10 ml/kg) dose, but decreased the leak in rats ventilated with a large dose compared with zero end-expiratory pressure. In the presence of PEEP, this low dose decreased capillary leak compared with controls or with rats given the large dose. Lung computerized tomography scans showed that the large dose increased functional residual capacity by 68% and produced gas trapping that was reduced by PEEP. Thus, large doses predispose to overdistension injury whereas low doses do not and may even have a protective effect in the presence of PEEP. The paradoxical beneficial effect of PEEP when large doses are given may be due to gas trapping reduction. These findings confirm that liquid ventilation does not aggravate volutrauma provided perflubron doses are adjusted. They provide a lead to further investigate partial liquid ventilation in the clinical setting.     

Does Digoxin Provide Additional Hemodynamic and Autonomic Benefit at Higher Doses in Patients With Mild to Moderate Heart Failure and Normal Sinus Rhythm?

Objectives. This study sought to examine the hemodynamic and autonomic dose response to digoxin.Background. Previous studies have demonstrated an increase in contractility and heart rate variability with digitalis preparations. However, little is known about the dose-response to digoxin, which has a narrow therapeutic window.Methods. Nineteen patients with moderate heart failure and a left ventricular ejection fraction <0.45 were studied hemodynamically using echocardiography and blood pressure at baseline and after 2 weeks of low dose (0.125 mg daily) and 2 weeks of moderate dose digoxin (0.25 mg daily). Loading conditions were altered with nitroprusside at each study. Autonomic function was studied by assessing heart rate variability on 24-h Holter monitoring and plasma norepinephrine levels during supine rest.Results. Low dose digoxin provided a significant increase in ventricular performance, but no further increase was seen with the moderate dose. Low dose digoxin reduced heart rate and increased heart rate variability. Moderate dose digoxin produced no additional increase in heart rate variability or reduction in sympathetic activity, as manifested by heart rate, plasma norepinephrine or low frequency/high frequency power ratio. In addition, we did not find that either low or moderate dose digoxin increased parasympathetic activity.Conclusions. We conclude that moderate dose digoxin provides no additional hemodynamic or autonomic benefit for patients with mild to moderate heart failure over low dose digoxin. Because higher doses of digoxin may predispose to arrhythmogenesis, lower dose digoxin should be considered in patients with mild to moderate heart failure.(J Am Coll Cardiol 1997;29:1206–13)     

Serious side effects of rifampin on the course of WHO/MDT: a case report

A male born in 1935 was diagnosed as having lepromatous leprosy when he was 17 years old. In addition to dapsone (DDS) monotherapy, he had been treated with rifampin (RMP) for 2 terms: first with 450 mg a day for 2 years when he was 39 years old; second with 150 mg a day for 2 months after a 1-year interval from the first regimen. During these entire courses with RMP, no complication was noted. When he was 64 years old in 1999, a diagnosis of relapsed borderline tuberculoid (BT) leprosy was made, and he was started on the multibacillary (MB) regimen of the World Health Organization multidrug therapy (WHO/MDT). After the third dose of monthly RMP, he developed a flu-like syndrome and went into shock. A few hours later, intravascular hemolysis occurred followed by acute renal failure. He was placed on hemodialysis for 7 series and recovered almost completely about 2 months later. The immune complexes with anti-RMP antibody followed by complement binding may have accounted for these symptoms. Twenty-four reported cases of leprosy who had developed side effects of RMP under an intermittent regimen were analyzed; 9 of the cases had had prior treatment with RMP but 15 had not. Adverse effects were more likely to occur in MB cases and were more frequent during the first 6 doses of intermittent regimens. The cases with prior treatment with RMP had had a higher incidence of serious complications such as marked hypotension, hemolysis and acute renal failure. However, many exceptions were also found, and we could not verify any fully dependable factor(s) to predict the side effects of RMP. More field investigation is desirable, and monthly administration of RMP must be conducted under direct observation through the course of WHO/MDT.