Dolutegravir and pregnancy outcomes in women on antiretroviral therapy in Brazil: a retrospective national cohort study.

BACKGROUND: Dolutegravir has been widely available in Brazil since 2017. Following the signal that infants born to women with dolutegravir exposure at conception in Botswana had a higher risk of neural tube defects (NTDs), public health leaders initiated a national investigation to evaluate periconception dolutegravir exposure among all pregnant Brazilian women with HIV and its potential association with risk of NTDs, stillbirth, or miscarriage before 22 weeks (also called spontaneous abortion). METHODS: In this retrospective, observational, national, cohort study, we identified all women with pregnancies and possible dolutegravir exposure within 8 weeks of estimated date of conception between Jan 1, 2017, and May 31, 2018, and approximately 3:1 matched pregnant women exposed to efavirenz between Jan 1, 2015, and May 31, 2018, using the Brazilian antiretroviral therapy database. We did detailed chart reviews for identified women. The primary outcomes were NTD and a composite measure of NTD, stillbirth, or miscarriage. NTD incidences were calculated with 95% CI. The composite outcome was examined with logistic regression using propensity score matching weights to balance confounders. FINDINGS: Of 1427 included women, 382 were exposed to dolutegravir within 8 weeks of estimated date of conception. During pregnancy, 183 (48%) of 382 dolutegravir-exposed and 465 (44%) of 1045 efavirenz-exposed women received folic acid supplementation. There were 1452 birth outcomes. There were no NTDs in either dolutegravir-exposed (0, 95% CI 0-0·0010) or efavirenz-exposed groups (0, 95% CI 0-0·0036). There were 23 (6%) stillbirths or miscarriages in 384 dolutegravir-exposed fetuses and 28 (3%) in the 1068 efavirenz-exposed fetuses (p=0·0037). Logistic regression models did not consistently indicate an association between dolutegravir exposure and risk of stillbirths or miscarriages. After study closure, two confirmed NTD outcomes in fetuses with periconception dolutegravir exposure were reported to public health officials. An updated estimate of NTD incidence incorporating these cases and the estimated number of additional dolutegravir-exposed pregnancies between Jan 1, 2015 and Feb 28, 2019, is 0·0018 (95% CI 0·0005-0·0067). INTERPRETATION: Neither dolutegravir nor efavirenz exposure was associated with NTDs in our national cohort; incidence of NTDs is probably well under 1% in dolutegravir-exposed HIV-positive women but still slightly above HIV-uninfected women (0·06%) in Brazil. FUNDING: The Brazilian Ministry of Health and the United States' National Institutes of Health.

Successful use of once-daily high-dose darunavir and dolutegravir in multidrug-resistant HIV.

WHAT IS KNOWN AND OBJECTIVE?: Antiretroviral (ARV) resistance may result during periods of consistently poor adherence. We report the successful use of a novel once-daily (QD) ARV regimen in a patient with multidrug-resistant (MDR) HIV. CASE SUMMARY: Once-daily darunavir 1200 mg/ritonavir 100 mg, dolutegravir and emtricitabine/tenofovir alafenamide was initiated with directly observed therapy. With the assistance of therapeutic drug monitoring, dolutegravir dosing was increased to 150 mg daily. The patient maintained virologic suppression for 18 months. WHAT IS NEW AND CONCLUSIONS?: In this case, QD darunavir/ritonavir achieved similar trough concentrations to twice daily dosing with dolutegravir dose titration necessitated and resulted in HIV virologic control.

Defining the Contribution of CYP1A1 and CYP1A2 to Drug Metabolism Using Humanized CYP1A1/1A2 and Cyp1a1/Cyp1a2 Knockout Mice.

Cytochrome P450s CYP1A1 and CYP1A2 can metabolize a broad range of foreign compounds and drugs. However, these enzymes have significantly overlapping substrate specificities. To establish their relative contribution to drug metabolism in vivo, we used a combination of mice humanized for CYP1A1 and CYP1A2 together with mice nulled at the Cyp1a1 and Cyp1a2 gene loci. CYP1A2 was constitutively expressed in the liver, and both proteins were highly inducible by 2,3,7,8-tetrachlorodibenzodioxin (TCDD) in a number of tissues, including the liver, lung, kidney, and small intestine. Using the differential inhibition of the human enzymes by quinidine, we developed a method to distinguish the relative contribution of CYP1A1 or CYP1A2 in the metabolism of drugs and foreign compounds. Both enzymes made a significant contribution to the hepatic metabolism of the probe compounds 7-methoxy and 7-ehthoxyresorufin in microsomal fractions from animals treated with TCDD. This enzyme kinetic approach allows modeling of the CYP1A1, CYP1A2, and non-CYP1A contribution to the metabolism of any substrate at any substrate, inhibitor, or enzyme concentration and, as a consequence, can be integrated into a physiologically based pharmacokinetics model. The validity of the model can then be tested in humanized mice in vivo. SIGNIFICANCE STATEMENT: Human CYP1A1 and CYP1A2 are important in defining the efficacy and toxicity/carcinogenicity of drugs and foreign compounds. In light of differences in substrate specificity and sensitivity to inhibitors, it is of central importance to understand their relative role in foreign compound metabolism. To address this issue, we have generated mice humanized or nulled at the Cyp1a gene locus and, through the use of these mouse lines and selective inhibitors, developed an enzyme kinetic-based model to enable more accurate prediction of the fate of new chemicals in humans and which can be validated in vivo using mice humanized for cytochrome P450-mediated metabolism.

Baloxavir marboxil, a novel cap-dependent endonuclease inhibitor potently suppresses influenza virus replication and represents therapeutic effects in both immunocompetent and immunocompromised mouse models.

Baloxavir marboxil (BXM) is an orally available small molecule inhibitor of cap-dependent endonuclease (CEN), an essential enzyme in the initiation of mRNA synthesis of influenza viruses. In the present study, we evaluated the efficacy of BXM against influenza virus infection in mouse models. Single-day oral administration of BXM completely prevented mortality due to infection with influenza A and B virus in mice. Moreover, 5-day repeated administration of BXM was more effective for reducing mortality and body weight loss in mice infected with influenza A virus than oseltamivir phosphate (OSP), even when the treatment was delayed up to 96 hours post infection (p.i.). Notably, administration of BXM, starting at 72 hours p.i. led to significant decrease in virus titers of >2-log10 reduction compared to the vehicle control within 24 hours after administration. Virus reduction in the lung was significantly greater than that observed with OSP. In addition, profound and sustained reduction of virus titer was observed in the immunocompromised mouse model without emergence of variants possessing treatment-emergent amino acid substitutions in the target protein. In our immunocompetent and immunocompromised mouse models, delayed treatment with BXM resulted in rapid and potent reduction in infectious virus titer and prevention of signs of influenza infection, suggesting that BXM could extend the therapeutic window for patients with influenza virus infection regardless of the host immune status.

SENS-401 Effectively Reduces Severe Acoustic Trauma-Induced Hearing Loss in Male Rats With Twice Daily Administration Delayed up to 96 hours.

HYPOTHESIS: SENS-401 (R-azasetron besylate) is effective against severe acoustic trauma-induced hearing loss. BACKGROUND: SENS-401 has calcineurin inhibiting properties and attenuates cisplatin-induced hearing loss in a rat model. Cisplatin-induced and acoustic trauma-induced hearing loss share common apoptotic pathways. METHODS: The dose-response relationship of SENS-401 (6.6 mg/kg BID, 13.2 mg/kg BID, 26.4 mg/kg QD) and treatment time-window (13.2 mg/kg BID starting 24, 72, and 96 h posttrauma) versus placebo for 28 days were evaluated in a male rat model of severe acoustic trauma-induced hearing loss (120 dB SPL, 2 h) using auditory brainstem response (ABR) and distortion product otoacoustic emissions (DPOAE) measures followed by cochlear outer hair cell (OHC) counting with myosin-VIIa immunolabeling. RESULTS: All SENS-401 doses improved ABR threshold shift and recovery, reaching statistical significance (p < 0.05) for ABR threshold recoveries after 28-days treatment. DPOAE amplitude loss and recovery improved markedly for 13.2 mg/kg BID SENS-401, reaching significance after 14 days (p < 0.05). Significant improvements in ABR threshold shifts/recovery and DPOAE amplitude loss occurred with up to 96-hours delay in initiating SENS-401 (p < 0.05), and in DPOAE amplitude recovery with up to 72-hours delay (p < 0.05). Significantly more surviving OHCs were present after SENS-401 treatment compared with placebo after 24 to 96-hours delay posttrauma, with up to 5.3-fold more cells in the basal cochlea turn. CONCLUSIONS: In vivo data support the otoprotective potential of twice daily oral SENS-401. Improvements in hearing loss recovery make SENS-401 a promising clinical candidate for acoustic trauma-induced hearing loss, including when treatment is not initiated immediately.

Clinical pharmacokinetics and pharmacodynamic target attainment of pazufloxacin in prostate tissue: Dosing considerations for prostatitis.

The present study examined the clinical pharmacokinetics of pazufloxacin in prostate tissue and estimated the probability of target attainment for tissue-specific pharmacodynamic goals related to treating prostatitis using various intravenous dosing regimens. Patients with prostatic hypertrophy received prophylactic infusions of pazufloxacin (500 mg, n = 23; 1000 mg, n = 25) for 0.5 h prior to transurethral prostate resection. Drug concentrations in plasma (0.5-5 h) and prostate tissue (0.5-1.5 h) were measured by high-performance liquid chromatography and used for subsequent noncompartmental and three-compartmental analysis. Monte Carlo simulation was performed to evaluate the probability of target attainment of a specific minimum inhibitory concentration (MIC) in prostate tissue: the proportion that achieved both area under the drug concentration over time curve (AUC)/MIC = 100 and maximum concentration (Cmax)/MIC = 8. Prostatic penetration of pazufloxacin was good with mean Cmax ratios (prostate tissue/plasma) of 0.82-0.99 and for AUC, 0.80-0.98. The probability of reaching target MIC concentrations in prostate tissue was more than 90% for dosing schedules of 0.25 mg/L for 500 mg every 24 h (500 mg daily), 0.5 mg/L for 500 mg every 12 h (1000 mg daily), 1 mg/L for 1000 mg every 24 h (1000 mg daily), and 2 mg/L for 1000 mg every 12 h (2000 mg daily). Importantly, the 2000 mg daily regimen of pazufloxacin produced a profile sufficient to have an antibacterial effect in prostate tissue against clinical isolates of Escherichia coli and Klebsiella pneumonia with MIC values less than 2 mg/L.

Discovery of BI 135585, an in vivo efficacious oxazinanone-based 11ß hydroxysteroid dehydrogenase type 1 inhibitor.

A potent, in vivo efficacious 11ß hydroxysteroid dehydrogenase type 1 (11ß HSD1) inhibitor (11j) has been identified. Compound 11j inhibited 11ß HSD1 activity in human adipocytes with an IC50 of 4.3nM and in primary human adipose tissue with an IC80 of 53nM. Oral administration of 11j to cynomolgus monkey inhibited 11ß HSD1 activity in adipose tissue. Compound 11j exhibited >1000× selectivity over other hydroxysteroid dehydrogenases, displays desirable pharmacodynamic properties and entered human clinical trials in 2011.

[Effectiveness of switch therapy for peritonitis].

The usefulness of switch therapy, from injection to oral medicine, for the treatment of peritonitis was evaluated. Thirty-five patients, who agreed to enroll the study, were randomly assigned to four treatment groups; one group treated with carbapenem antibacterial agent alone and three groups treated with switch therapy, in which injectable quinolone was switched to oral quinolone. For the intravenous administration group, if the patient showed the tendency of improvement by the third day, the intravenous injection was continued. However, if the patient did not show any improvement, the medication was changed to other medicine. For the switch therapy group, if the body temperature dropped to 37.5 degrees C or lower for at least 8 hours and if blood findings and clinical findings showed the tendency of improvement by the fourth day, the medication was switched to oral medicine. There was no difference in therapeutic effects among treatment groups. However, both duration of hospitalization and total medical costs were significantly reduced in the switch therapy groups comparing to those in the intravenous administration group. The results of this study showed that the switch therapy, from injection to oral medicine, was one of useful treatments in treating peritonitis.

Preclinical pharmacokinetics and interspecies scaling of ragaglitazar, a novel biliary excreted PPAR dual activator.

Allometric scaling has been used as an effective tool for the prediction of human pharmacokinetic parameters. Allometry has been a useful approach for the analysis of compounds that are eliminated unchanged in the urine and/or exhibit similar metabolic patterns across species. However, it has been a challenging issue to correctly predict human pharmacokinetic parameters for drugs that are eliminated intact and/or as conjugates in the bile. Ragaglitazar is a novel, non-thiazolidinedione peroxisome proliferator-activated receptor (PPAR) alpha- and gamma-agonist. In our investigation, preclinical pharmacokinetic data on ragaglitazar were gathered for several animal species (mice, rats, rabbits and dogs). Ragaglitazar when administered orally has shown a low clearance rate (Cl/F; < 5% of hepatic blood flow) in mice, rats and rabbits and a moderately high Cl/F in dogs (> 15% of hepatic blood flow). A qualitative estimation of rat bile has unequivocally confirmed the elimination of ragaglitazar in the bile. The human pharmacokinetic data are also indicative of the involvement of enterohepatic biliary recycling. In order to predict key parameters such as Cl/F and volume of distribution (V/F), simple allometry was the approach adopted at the onset. Although V/F scaled adequately, it failed to accurately predict human Cl/F. Therefore, standard correction factors such as maximum life span potential (MLP) and brain weight were also included. Although such modifications improved the linearity (r2 > 0.9), they failed to predict the investigated values. Further incorporation of correction factors particularly relevant to biliary excreted drugs improved the prediction of these values. Interestingly, the exclusion of dog data from the interspecies scaling considerably improved the prediction of both Cl/F and V/F.

Toxicity and antiviral activity of cinnabarin obtained from Pycnoporus sanguineus (Fr.) Murr.

This work describes the cytopathic effect on cells, cytotoxic action on mice, and antiviral activity of cinnabarin. This substance had no effect on mouse neuroblastoma cells (NA cell, ATCC clone C-1300) at a concentration of 0.31 mg/ml, it was not able to cause toxic effects in mice at concentrations of 1000 mg/kg, and reduced by four times the titers of the rabies virus at concentrations of 0.31 mg/ml.

Therapeutic effects of an injectable new quinolone, pazufloxacin, against polymicrobial infections in the uterine endometritis model.

Polymicrobial infections with aerobes and anaerobes are common in female genital tract infections. We evaluated the efficacy of an injectable new quinolon, pazufloxacin, using a uterine endometritis model. Rats were infected with a mixed inoculation of Escherichia coli plus Bacteriodes fragilis (MIC of pazufloxacin and ceftazidime: E. coli: 0.05 and 1.56 micrograms/ml, respectively, B. fragilis: 3.13 and 3.13 micrograms/ml, respectively). After inoculating 10(7) cfu/rat of each organism, pazufloxacin or ceftazidime (10 or 20 mg/kg, respectively, i.v., b.i.d., 3 days) was administered and compared with the nontreated group. The viable cell counts of the uterine corpus and uterine cervix in pazufloxacin-treated and ceftazidime-treated groups were decreased, compared with the nontreated group. The viable cell counts of the adnexa in the pazufloxacin-treated group were significantly decreased, compared with the ceftazidimetreated group. These results suggest that pazufloxacin would be useful for the treatment of polymicrobial infections, especially adnexitis.

[Use of ofloxacin in otorhinolaryngologic infections]. / Impiego dell'ofloxacina nelle infezioni del distretto O.R.L.

Ofloxacin, a new fluoroquinolonic synthetic compound with broad antibacterial spectrum, was used in per os therapy of 15 ear, nose and throat infected patients. The antibiotic was then compared with other eight antimicrobial agents against the Gram-positive and Gram-negative isolates. Either in vitro than in vivo the god antibacterial activity and tolerance of ofloxacin, particularly against Gram-positive infections, was demonstrated. Results point out the possibility of utilization of ofloxacin per os against ear, nose and throat infections.

Testing of 2,3-dihydro-1,3-6H-oxazine-dione (3-oxauracil) in mouse L1210 leukemia and 37 sarcoma.

The antimetabolite 2,3-dihydro-1,3-6H-oxazine-dione (3-oxauracil) has been investigated in an attempt to elucidate its effects on survival time of DBA/2 and B6D2F1 mice with L1210 leukemia and of outbred albino mice with 37 sarcoma. A significant increase in survival time was observed in mice with 37 sarcoma and slight effects were observed in mice with L1210 leukemia when treated with 3 x 12.5 or 3 x 25 mg/kg of 3-oxauracil. No toxic side effects were observed when large therapeutic doses of the drug were given.

[Bronchopulmonary aminochlorthenoxycycline levels in experimental burns of the respiratory tree]. / Ricerche sul tropismo degli antibiotici a livello broncopolmonare nella ustione sperimentale dell'albero respiratorio.

A special technique was employed to obtain burns of the respiratory tree in 24 male rabbits, Increased bronchial secretion was observed during the burning. Aminochlorthenoxycycline values were higher in the secretion after 90' than in the controls, while blood and lung concentrations displayed a similar pattern. The usefulness of the drug in the prevention and treatment of infectious complications following burns in this area is stressed.

[Aminochlorthenoxycycline levels in experimental acute inflammation of the respiratory tree]. / Ricerche sulla distribuzione dell'aminoclortenoxiciclina nell'infiammazione sperimentale acuta dell'albero respiratorio.

A special technique used to obtain acute respiratory inflammation in the rabbit produced a considerable increase in expectorate by comparison with the controls. Bronchial, lung and blood aminochlorthenoxycycline levels were much higher than in the controls, showing that this antibiotic has a marked affinity for inflamed lung tissue.