Lopinavir plasma levels in salvage regimes by a population of highly active antiretroviral therapy-treated HIV-1-positive patients.

Increased lopinavir (LPV) exposure obtained in vivo through combination with low-dose ritonavir may overcome a certain grade of resistance but not all. We sought to analyze LPV variability and possible risk factors. LPV trough plasma concentrations were determined by high-performance liquid chromatography after 1, 4, and 12 weeks from salvage regimens and tested in both univariate and multivariate regression analyses with age, gender, weight, risk factors for HIV acquisition, hepatitis C virus reactivity, hepatitis B surface antigen positivity, baseline aspartate transferase (AST) or alanine transferase (ALT) levels, creatinine, non-nucleoside reverse transcriptase inhibitors (NNRTIs) or tenofovir as concomitant drugs, and NNRTIs administered in the previous regimen. Fifty-six patients were included into the study. Among them, 8 of 56 (14.3%) at week 1, 12 of 56 (21.4%) at week 4, and 9 of 56 (16.1%) at week 12 had suboptimal LPV plasma concentrations, defined as trough concentration less than 4 microg/mL. No correlation was found between LPV trough concentrations and assessed variables. In conclusion, pharmacokinetic variability and low LPV concentrations have been found, supporting the use of therapeutic drug monitoring in those starting this drug.

Biological activity of all-trans-retinoic acid with and without tamoxifen and alpha-interferon 2a in breast cancer patients.

In addition to suppressing breast cancer cell growth, retinoids potentiate growth inhibition in human breast cancer when tested in vitro and in vivo with tamoxifen and/or interferon. The purpose of this study was to ascertain the biologic effects of all-trans-retinoic acid (ATRA) administered alone and with tamoxifen +/- interferon and to identify the relationship between ATRA plasma concentrations and optimal biological dose (the lowest dose that produces a biological response). Three consecutive groups of 15 patients with locally advanced operable breast cancer were treated, in accordance with good clinical practice (GCP) requirements, with ATRA at 3 dose levels alone or with tamoxifen +/- alpha-interferon 2a at flat doses. After 3 weeks, the tumors were surgically removed. Biological parameters measured at the beginning (in biopsy tissue) and end (in surgical tissue) of the study were compared. The optimal biological dose for ATRA was 15 mg/m2/day. Treatments influenced tumor grade but not cell cycle kinetics (G0-G1 phase) or proliferation (Ki67 levels). ATRA induced progesterone receptors independent of dose level and co-administered drugs, but did not induce estrogen receptors when administered alone. Retinoic acid receptor (RAR)-alpha was not affected by treatment and RAR-alpha was moderately influenced whereas RAR-beta (concomitantly with transforming growth factor-beta) was induced in 33% of patients by ATRA alone. ATRA pharmacokinetics were dose- and time-dependent. Neither the ATRA + tamoxifen nor the ATRA + tamoxifen + interferon combinations potentiated the ATRA-induced biological changes. Future studies evaluating the role of RAR-beta as a biological marker of retinoid activity are warranted.

[Modification in some nasal function parameters after metacholine stimulation and pretreatment with ipratropium bromide]. / Modificazioni di alcuni parametri di funzionalità nasale dopo stimolazione con metacolina e pretrattamento con ipratropio bromuro.

Experimental research conducted on normal subjects and on perennial rhinitis sufferers demonstrates that the application of metacholine stimulates nasal secretions and that this effect is inhibited by pretreatment with ipratropium bromide. Using the Baroody et al. method, a group of 20 healthy volunteers was used to check the effect metacholine and ipratropium/metacholine had on nasal secretions. At the same time a study was performed to determine whether these treatments modify other nasal functions: turbinate blood flow, nasal resistance, mucociliar transport. The data confirm earlier observations regarding the effect of metacholine and ipratropium on nasal secretions. A parallel effect is also seen in mucociliary transport time, most likely linked to modifications in the rheological characteristics of the mucous. On the other hand, no significant difference was found in the other functions studied: turbinate blood flow and nasal resistance. We can consider metacholine and ipratropium selective and specific, acting on the secretory function of the nasal mucosa.

Effect of lidocaine on neutrophil chemotaxis in newborn infants.

Anesthetic drugs can influence the immune system, particularly granulocyte function. The goal of the present study was to evaluate if lidocaine used for epidural anesthesia during cesarean section can influence neonatal neutrophil chemotaxis. We measured chemotaxis and plasma cord lidocaine and cortisol levels in (A) 15 infants born by cesarean section with epidural anesthesia, (B) 15 infants born by vaginal delivery, and (C) 20 infants born by cesarean section with general anesthesia. Chemotaxis levels were significantly lower in group A infants (35.5 +/- 16.1 microns) compared to groups B (54.6 +/- 10.5 microns) and C (71.4 +/- 23 microns). The highest cortisol levels were observed in vaginally delivered infants. A significant inverse relationship was observed between chemotaxis and lidocaine levels (r = -0.6, P = 0.016) in infants born by cesarean section after epidural anesthesia, while no significant correlation was observed between chemotaxis and cortisol level. In conclusion, lidocaine, transferred through the placenta to the fetus during epidural anesthesia, may have an inhibitory effect on chemotaxis.

Effect of passive smoking on thyroid function in infants.

OBJECTIVE: To evaluate the effect of passive smoking on thyroid function in infants. DESIGN AND METHODS: Cord serum tri-iodiothyronine (T3), free T3 (fT3), thyroxine (T4), free T4 (fT4), TSH, thyroxine binding globulin (TBG), thyroglobulin (TG) and cord plasma thiocyanate were measured at birth, and serum TG and thiocyanate after 1 year of life, in 18 infants born from parents who did not smoke (group A), in 18 infants with a father who smoked (group B) and in 18 infants with parents both being smokers (group C). RESULTS: No significant differences were observed in cord serum concentrations of T3, fT3, T4, fT4, TSH and TBG among the three groups. Median (range) TG concentrations (ng/ml) were 30.2 (5.0-102.0), 56.3 (20.5-208.0) and 76.0 (26.0-199.0) at birth (P=0.009 for groups A and B compared; P=0.0002 for groups A and C compared), and 14.9 (5.4-32.0), 19.5 (10.0-57.5) and 20.0 (14.0-40.7) at 1 year (P=0.017 for groups A and C compared), in the three groups respectively, and thiocyanate concentrations (mmol/l) were 3.3 (0.0-51.4), 12.9 (0.0-122.2) and 27.8 (3.3-184.5) at birth (P=0.015 for groups A and C compared), and 3.1 (0.0-32.7), 6.0 (0.0-47.3) and 20.3 (0.0-230.8) at 1 year (P=0.01 for groups A and C compared) in the three groups respectively. CONCLUSIONS: TG and thiocyanate concentrations at birth and at 1 year of age in infants of smoking parents are greater than in infants with non-smoking parents. These results indicate that the change in thyroid function as evaluated by serum TG concentrations observed at birth can persist at least for 1 year if the exposure to passive smoking from both parents is continued. Increased TG concentrations may be due to a direct effect of thiocyanate on the thyroid gland.

Central nervous system (CNS) leukemia: the role of high dose cytarabine (HDAra-C).

Knowing the good penetration of systemic HDara-C into the CNS, we treated with this approach overt meningeal leukemia, either isolated or with bone marrow (BM) disease, in 31 adults: 18 ALL, 4 ANLL, 1 lymphoid blast crisis of CGL (LBC-CGL), and 8 non-Hodgkin's lymphoma (NHL). Treatment consisted of Ara-C, 3 g/m2 i.v. q 12 h, by 3 h infusion for 8 doses, followed by 4 doses at day 21. Complete remitters received consolidation with four monthly 4-dose courses of HDara-C. Additional multidrug consolidation and direct CNS therapy with intrathecal (i.t.) methotrexate (MTX) or Ara-C +/- cranial RT was administered to the 11 remitters last treated. Twenty of 31 patients (64%) achieved CR: 10/10 with isolated meningeal leukemia and 10/21 with concurrent CNS and BM disease. Of the remaining 11 patients, 8 had cerebrospinal fluid (CSF) clearing with persistent BM disease. In all cases but one CNS symptoms resolved promptly. CR median duration was 6 months (range 2 to 20). The main toxicity was myelosuppression requiring intensive support. There was no neurologic toxicity. These results show that systemic HDara-C is highly effective in acute leukemias and NHL with CNS involvement, and suggest the utility of this regimen for sanctuary chemoprophylaxis in patients at high risk for CNS disease.

Ventricular arrhythmias during acute myocardial ischaemia in man. The role and significance of R-ST-T alternans and the prevention of ischaemic sudden death by medical treatment.

Malignant ventricular arrhythmias appearing during acute myocardial ischaemia, are the most frequent mechanism of sudden death. ST-T alternans is the result of an intraischaemic conduction delay and is frequently associated with those potentially lethal arrhythmias. In fact, such a phenomenon was seen in 35% of 46/86 patients with Prinzmetal's variant angina who showed ventricular arrhythmias during ischaemia, while it was never observed in the remaining 40 patients without arrhythmias during ischaemia. Therefore ST-segment alternans should be considered a reliable marker of the possible occurrence of ventricular arrhythmias during myocardial ischaemia. ST-T-segment alternans is associated with R alternans, as clearly demonstrated by thoracic maps, and this phenomenon is due to a 2:1 intraischaemic block. The patients with Prinzmetal's variant angina who present ventricular arrhythmias during ischaemia, show a more prominent increase of the positive area of the QRS (411.75 +/- 102.5 vs 294.05 +/- 80.3 mu volts ms), that is, a more relevant intraischaemic conduction delay. The effects of different pretreatments (lidocaine, propranolol and diltiazem) on arrhythmias related to vasospastic myocardial ischaemia induced by ergonovine maleate, were evaluated in four patients with Prinzmetal's variant angina. As in experimental observations, neither a 'pure' antiarrhythmic agent like lidocaine, nor a betablocking agent like propranolol, prevented acute ischaemic ventricular arrhythmias. Only the calcium antagonist, diltiazem, seemed to prevent such arrhythmias. However, these findings necessitate further confirmation.

Dihydroquinidine versus disopyramide: efficacy in patients with chronic stable ventricular ectopy.

Dihydroquinidine (DQ) is contained in substantial amounts in quinidine salts, but its direct antiarrhythmic action has not been studied. The efficacy of oral DQ (300 mg t. i. d.) compared to disopyramide (D) (200 mg t.i.d.) was thus investigated using a double-blind crossover placebo-controlled protocol in 12 patients, aged 13 to 67 years, with chronic stable high frequency premature ventricular beats (PVB), defined as greater than 100 PVB/h during 48-72-h control Holter monitoring. The protocol included three 72-h treatment periods: DQ, D, and placebo at random. On days 2 and 3 of each period a 24-h Holter recording was carried out; drug blood levels were determined at peak (days 2 and 3) and trough time (day 3). No significant difference in the mean PVB/h was found between control (735 +/- 400) and placebo periods (564 +/- 388), or between the two Holter recordings of each period. Compared to placebo both DQ (106 +/- 113, p less than 0.005) and D (240 +/- 263, p less than 0.05) reduced the mean PVB/h, but the decrease was significantly higher with DQ (78 versus 53%, p less than 0.02). Nine patients (75%) on DQ and 5 (42%) on D had a greater than 70% decrease in mean PVB/h; complex PVBs were abolished in 3 of 6 patients on both treatments. On day 3, DQ plasma levels were 1.31 +/- 0.44 (peak) and 0.92 +/- 0.45 (trough) mg/l; D plasma levels were 2.88 +/- 0.64 (peak) and 2.02 +/- 0.31 (trough) mg/l; no significant difference was found between day 2 and day 3 samples.(ABSTRACT TRUNCATED AT 250 WORDS)

The bioavailability and kinetics of dihydroquinidine in patients with heart disease.

The absolute bioavailability of dihydroquinidine chloride (normal tablet and sustained-release capsule) was studied in 12 hospitalized patients with heart disease. A 300-mg dose of dihydroquinidine gluconate was administered to each patient by short intravenous infusion. After a single dose of two tablets of dihydroquinidine chloride (300 mg), the average peak concentration was 0.74 +/- 0.43 mg/l (+/- SD); following administration two capsules of the sustained-release form (500 mg dihydroquinidine chloride) the average peak concentration was 0.55 +/- 0.25 mg/l. Tmax was approximately 5 h with the dihydroquinidine tablet and 7 h with the dihydroquinidine capsule. The mean absolute bioavailability was 89 +/- 9% for the conventional tablet and 52 +/- 15% for the sustained-release capsule. After intravenous infusion of dihydroquinidine (2.63 +/- 0.29 mg/kg), the disposition of the drug is described by a two-compartment open model. The volume of distribution (Vd) was 4.67 l/kg. Distribution (t1/2 alpha = 18.63 +/- 15.2 h) and the apparent elimination half-life (t1/2 beta = 10.8 +/- 4.7 h) were longer than the corresponding values reported by Ueda et al. [1976]. These discrepancies are presumably due to the different sampling period that was extended to 24 h in our study, consequently evidencing a slower rate of elimination from 12 to 24 h. Mean total body clearance (Cl) was 0.28 +/- 0.057 l/h/kg. Urine sample collection for 48 h showed 21% of the dose was excreted unchanged. The renal clearance (Clr) was 0.062 +/- 0.018 l/h/kg.