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Sperm DNA damage may have adverse effects on reproductive outcome. Sperm DNA breaks can be detected by several tests, which evaluate DNA integrity from different and complementary perspectives and offer a new class of biomarkers of the male reproductive function and of its possible impairment after environmental exposure. The remodeling of sperm chromatin produces an extremely condensed nuclear structure protecting the nuclear genome from adverse environments. This nuclear remodeling is species specific, and differences in chromatin structure may lead to a dissimilar DNA susceptibility to mutagens among species. In this study, the capacity of the comet assay in its two variants (alkaline and neutral) to detect DNA/chromatin integrity has been evaluated in human, mouse, and bull sperm. The hypothesis that chromatin packaging might influence the amount of induced and detectable DNA damage was tested by treating sperm in vitro with DNAse I, whose activity is strictly dependent upon its DNA accessibility. Furthermore, hydrogen peroxide (H 2 O 2 ) was used to assess whether spermatozoa of the three species showed a different sensitivity to oxidative stress. DNAse I-induced damage was also assessed by the sperm chromatin structure assay and the TUNEL assay, and the performances of these two assays were compared and correlated with the comet assay results. Results showed a different sensitivity to DNAse I treatment among the species with human sperm resulting the most susceptible. On the contrary, no major differences among species were observed after H 2 O 2 treatment. Furthermore, the three tests show a good correlation in revealing sperm with DNA strand breaks.

Rifampicin (RIF) decreases serum concentrations of several antiretroviral drugs. We carried out a prospective, comparative study to define efavirenz (EFV) pharmacokinetics in 16 cases and 13 controls. Cases were HIV and tuberculosis (TB) co-infected adults assuming RIF 600 mg once daily and EFV 800 mg once daily. Patients on EFV at standard 600 mg dose without RIF were taken as controls. EFV levels in plasma were assayed by high-performance liquid chromatography (HLPC) predose (C(trough)) and at 1, 2, 3, 4, 5, 6, 8, 10, 11, 12, 13, 14, 16, 18, 22 and 24 hours post-dose, and pharmacokinetic parameters were determined by non-compartmental methods. Among cases, 81% were males, mean age was 37 years, 50% were Caucasians, mean weight was 64 kg, mean CD4 cell counts and log HIV RNA copies were 160/microl and 5.2 /microl, respectively. Cases had a significantly higher Cl/F/kg if compared with controls (0.269 +/- 0.12 versus 0.167 + 0.05 L/h/kg, p<0.01). Otherwise, dose-dependent pharmacokinetic parameters of EFV were similar between cases and controls. Interindividual variability was consistently higher among TB cases compared to controls for all considered parameters. All cases completed combined treatment and no increased EFV toxicity was observed. These results suggest that a dose of 800 mg of EFV in association with rifampicin may be appropriate for patients of weight > 60 kg in Europe. Therapeutic drug monitoring may be beneficial for patients on combination therapy with RIF.

This study was performed to assess oral valganciclovir V-GCV (GCV pro-drug), 15 mg/kg bid for 6 weeks to 13 neonates with symptomatic congenital cytomegalovirus (CMV). We monitored plasma levels of GCV within 30 days of therapy: C(trough), and C(2h) (before and the 2 hours after administration), we performed viral assessment in plasma and urine and tolerability at baseline, and every fortnight. Pharmacokinetics showed GCV stable and effective plasma concentrations: mean C(trough) = 0.51 +/- 0.3 and C(2h) : 3.81 +/- 1.37 microg/ml. No significant variability was seen neither intra-patient nor inter-patients. One newborn discontinued therapy because of thrombocytopenia, another finished with a neutrophils count of 1,000/microl. At the end of therapy 6 out of 12 and 8 out of 12 newborns were negative for CMV in urine and plasma. The 4 newborns positive for CMV DNA showed a 90% reduction of pre-therapy values. Clinically, the 4 patients reporting hepatic disease and the 3 with thrombocytopenia recovered after 6 weeks of therapy. Eight newborns suffered from SNHL; at the 6-month follow-up no patients had worsened, 2 had improved, and no deterioration was reported in 3 newborns with chorioretinitis scarring. The paucity of adverse events, and the effectiveness and stability of drug plasma concentrations are the important findings of our study.

Aims To define the pharmacokinetic profile of efavirenz (EFV) in HIV‐1 infected patients, when administered alone or with nelfinavir (NFV). Methods Eleven HIV‐positive patients, in steady‐state treatment with EFV and 11 patients in steady‐state treatment with EFV+NFV, were evaluated. Blood samples for pharmacokinetic analysis were obtained during a dosage interval. Plasma concentrations of EFV were determined by h.p.l.c. Results No significant difference was found between the principal pharmacokinetic parameters of EFV when administered alone or in combination with NFV (mean AUC: 57.1–7727.3 vs 60.9±12.3 μg ml−1 h; mean CL/F: 0.18±0.072 vs 0.16±0.04 l h−1 kg−1; mean Cmax: 4.0±1.7 vs 4.3±1.2 μg ml−1, and mean tmax: 4.1±1.7 vs 3.5±0.5 h) Mean trough plasma concentrations (C0) of EFV were 1.64±0.93 μg ml−1, with and without NFV. A good correlation was found between C0 and AUC(0,24h) (r=0.96; P<0.01). Conclusions Despite the common metabolic pathway, there was no significant influence of NFV on the pharmacokinetics of EFV. EFV exhibits a relatively low interindividual variability and a dosing regimen of 600 mg day−1 assures plasma concentrations that are adequate for inhibition of viral replication.

Tuberculosis (TB) and HIV continue to be two of the major causes of morbidity and mortality in the world, and together are responsible for the death of millions of people every year. There is overwhelming evidence to recommend that patients with TB and HIV co-infection should receive concomitant therapy of both conditions regardless of the CD4 cell count level. The principles for treatment of active TB disease in HIV-infected patients are the same as in HIV-uninfected patients. However, concomitant treatment of both conditions is complex, mainly due to significant drug-drug interactions between TB and HIV drugs. Rifamycins are potent inducers of the cytochrome P450 (CYP) pathway, leading to reduced (frequently sub-therapeutic) plasma concentrations of some classes of antiretrovirals. Rifampicin is also an inducer of the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzymes and interferes with drugs, such as integrase inhibitors, that are metabolized by this metabolic pathway. Rifampicin is also an inducer of the adenosine triphosphate (ATP) binding cassette transporter P-glycoprotein, which may also lead to decreased bioavailability of concomitantly administered antiretrovirals. On the other side, rifabutin concentrations are affected by the antiretrovirals that induce or inhibit CYP enzymes. In this review, the pharmacokinetic interactions, and the relevant clinical consequences, of the rifamycins-rifampicin, rifabutin, and rifapentine-with antiretroviral drugs are reviewed and discussed. A rifampicin-based antitubercular regimen and an efavirenz-based antiretroviral regimen is the first choice for treatment of TB/HIV co-infected patients. Rifabutin is the preferred rifamycin to use in HIV-infected patients on a protease inhibitor-based regimen; however, the dose of rifabutin needs to be reduced to 150 mg daily. More information is required to select optimal treatment regimens for TB/HIV co-infected patients whenever efavirenz cannot be used and rifabutin is not available. Despite significant pharmacokinetic interactions between antiretrovirals and antitubercular drugs, adequate clinical response of both infections can be achieved with an acceptable safety profile when the pharmacological characteristics of drugs are known, and appropriate combination regimens, dosing, and timing of initiation are used. However, more clinical research is needed for newer drugs, such as rifapentine and the recently introduced integrase inhibitor antiretrovirals, and for specific population groups, such as children, pregnant women, and patients affected by multidrug-resistant TB.

AimsTo compare steady-state nelfinavir (NFV) pharmacokinetics in pregnant and nonpregnant HIV-infected women. MethodsTwenty-five pregnant HIV-infected women were selected from an ongoing observational study evaluating the pharmacokinetics of antiretroviral agents during pregnancy. Twenty of them were in the third and five in the second trimester. Data for the control group of 21 HIV-infected nonpregnant women were taken from a previous multicentre pharmacokinetic trial. All the participating women achieved steady-state plasma concentrations while on a highly active antiretroviral therapy (HA ART) regimen including NFV (1250 mg bid) and two nucleoside reverse transcriptase inhibitors (N RTIs). Blood samples for NFV measurement were collected predose ( C trough ) and at 0.5, 1, 2, 3, 4, 5, 6, 8 and 12 h post dose. ResultsDuring the third trimester of pregnancy NFV AUC 0 − 12 h median (range) values were 25.76 (12.61-42.74) µ g h − 1 ml − 1 , and were 32. 49 (19.16-63.81) µ g h − 1 ml − 1 in the control group [mean difference − 9.30 µ g h − 1 ml − 1 ; 95% confidence interval (CI) − 15.76, − 2.83; P < 0.05). Median oral clearance (CL/F) was significantly higher in pregnant women than in the control group (48.5 l h − 1 , range 29.3-99.1 l h − 1 vs. 38.5 l h − 1 , range 19.6-65.2 l h − 1 ; mean difference 12.6 l h − 1 ; 95% CI 3.3, 21.9) but the difference disappeared when CL/F was adjusted for body weight. C trough was significantly ( P < 0.01) lower in pregnant compared with nonpregnant women (median 0.8 µ g ml − 1 , range 0-2.6 µ g ml − 1 vs. 1.5 µ g ml − 1 , range 0.5-4.9 µ g ml − 1 ; mean difference − 1.0 µ g ml − 1 ; 95% CI − 1.7, − 0.31). The median elimination half-life of NFV observed during pregnancy was 3.7 h (range 1.4-6.6 h), compared with 5.2 (range 3.1-10.1 h) in the control group (mean difference − 1.7; 95% CI − 2.8, − 0.51). ConclusionsOur results indicate that women in the later stages of pregnancy may be exposed to subtherapeutic concentrations of NFV. Thus, adjustments in drug dosage or frequency of administration may be required. P. Villani et al. 31062 :3 Br J Clin Pharmacol