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1.
Am J Perinatol ; 2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38423119

ABSTRACT

OBJECTIVE: To assess the association between use of an oxytocin decision support checklist with oxytocin usage and clinical outcomes. STUDY DESIGN: We conducted a retrospective cohort study of patients with singleton gestations at 370/7 weeks or greater who received oxytocin during labor from October 2012 to February 2017 at an integrated community health care system during three exposure periods: (1) pre-checklist; (2) after paper checklist implementation; and (3) after checklist integration into the electronic medical record (EMR). The checklist was a clinical decision support tool to standardize the dosing and management of oxytocin. Thus, our primary outcomes included oxytocin infusion rates and cumulative dose. Secondary outcomes included maternal and neonatal outcomes. We controlled for maternal risk factors with multivariable regression analysis and stratified by mode of delivery. RESULTS: A total of 34,269 deliveries were included. Unadjusted analyses showed that compared with pre-checklist, deliveries during the paper and EMR-integrated periods had a lower cumulative dose (4,670 ± 6,174 vs. 4,318 ± 5,719 and 4,286 ± 5,579 mU, p < 0.001 for both), lower maximal infusion rate (9.9 ± 6.8 vs. 8.7 ± 5.8 and 8.4 ± 5.6 mU/min, p < 0.001 for both), and longer duration of oxytocin use (576 ± 442 vs. 609 ± 476 and 627 ± 488 minutes, p < 0.001 and p = 0.01, respectively). The unadjusted rates of cesarean, 5-minute Apgar <7, mechanical ventilation, and neonatal hospital length of stay were similar between periods. The adjusted mean difference in time from admission to delivery was longer during the EMR-integrated period compared with pre-checklist (3.0 [95% confidence interval: 2.7-3.3] hours, p < 0.001). CONCLUSION: Oxytocin checklist use was associated with decreased oxytocin use patterns at the expense of longer labor times. Findings were more pronounced with EMR integration. KEY POINTS: · An oxytocin decision support checklist is associated with reduced amounts of oxytocin used.. · However, checklists were associated with longer duration of oxytocin use and of labor.. · Results were more pronounced in the EMR-integrated checklist compared with paper checklist..

2.
J Matern Fetal Neonatal Med ; 36(1): 2199344, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37031970

ABSTRACT

OBJECTIVE: Though misoprostol is commonly used for inpatient cervical ripening, its use in outpatient settings has been limited by safety concerns. This study was conducted to assess the association between early fetal heart tracing (FHT) and maternal tocodynamometry patterns and the incidence of adverse fetal and pregnancy outcomes after the administration of oral misoprostol for cervical ripening. METHODS: We conducted a retrospective cohort study of 9908 low-risk patients at ≥37 weeks gestation who received oral misoprostol for cervical ripening prior to rupture of membranes between 01/01/2012 and 12/31/2017 at Kaiser Permanente Northern California hospitals as inpatients. We excluded patients who received a different agent for cervical ripening or had any need for additional inpatient monitoring, including hypertensive disorders of pregnancy, diabetes, or intrauterine growth restriction. Abnormal FHT, abnormal uterine activity, and adverse pregnancy or fetal-related events documented in the electronic health record in the four hours after administration of the first and second doses of misoprostol were assessed using descriptive statistics. RESULTS: We found that 0.9% of patients experienced tachysystole after the first dose of misoprostol (0.6% without decelerations; 0.3% with decelerations). The incidence of variable decelerations only and other FHT abnormalities (i.e. bradycardia, late or prolonged decelerations, or absent or minimal variability) in the first hour after misoprostol administration were 7.1% and 6.7% respectively, and diminished over time. The need for tocolytic use was 0.2% in the first hour and declined over time to 0.03% in the fourth hour after the first dose. Urgent cesarean delivery occurred in 0.1% of patients after receiving the first dose of misoprostol. Patients who did not experience variable, prolonged, or late decelerations in the first hour after the initial misoprostol dose were less likely to have such FHT abnormalities in the subsequent three hours compared to patients who had other FHT abnormalities (11.8% among patients with no FHT abnormalities vs. 43.7% among patients with other FHT abnormalities; p <.001). The overall trends in outcomes over time were similar after the second dose of misoprostol. CONCLUSION: The risk of short-term adverse outcomes associated with misoprostol is low among relatively low-risk patients. FHT abnormalities occurred in up to 32% of patients in the first four hours of monitoring post-misoprostol. Patients with no FHT abnormalities in the first hour after receiving misoprostol had a low risk of developing adverse outcomes and FHT abnormalities on continued monitoring, while patients with any type of deceleration in the first hour were at higher risk of adverse outcomes and FHT abnormalities. Our data may inform the development of protocols for cervical ripening that allow reduced monitoring for a subset of low-risk patients, however, more research is needed to validate findings and develop clinical protocols.


Subject(s)
Misoprostol , Oxytocics , Pregnancy , Female , Humans , Misoprostol/adverse effects , Oxytocics/adverse effects , Cervical Ripening , Incidence , Heart Rate, Fetal , Retrospective Studies , Labor, Induced/adverse effects , Labor, Induced/methods , Administration, Intravaginal , Administration, Oral
3.
Am J Perinatol ; 2022 Nov 15.
Article in English | MEDLINE | ID: mdl-36130669

ABSTRACT

OBJECTIVE: In 2012, two Kaiser Permanente Northern California (KPNC) hospitals began offering outpatient cervical ripening with oral misoprostol under a study protocol. We evaluated inpatient time from admission to delivery and adverse maternal and neonatal outcomes associated with outpatient use of misoprostol for cervical ripening among low-risk women with term pregnancies. STUDY DESIGN: We conducted a retrospective cohort study comparing three groups: women who received misoprostol (1) outpatient, under a study protocol; (2) inpatient, at the study sites; and (3) inpatient, at all KPNC hospitals. Data were obtained from between 2012 and 2017. The primary outcome was time from inpatient admission to delivery. Secondarily, we evaluated maternal and neonatal outcomes, including the duration and maximum rate of oxytocin administered, rate of cesarean delivery, incidence of chorioamnionitis and blood transfusion, Apgar scores, and neonatal intensive care unit admissions. Demographic and clinical characteristics and outcomes of the outpatient group were compared with both inpatient misoprostol groups using the appropriate statistical test. Variables included in the regression analysis were either statistically significant in the bivariate analyses or have been reported in the literature to be potential confounders: maternal age at admission, race/ethnicity, body mass index, cervical dilation at initial misoprostol, and parity. RESULTS: We analyzed data from 10,253 patients: (1) 345 outpatients, under a study protocol; (2) 1,374 inpatients, at the study sites; and (3) 9,908 inpatients, at all the Kaiser hospitals. Women in the outpatient group were more likely to be white than both inpatient groups (63.3 vs. 56.3% at study sites and 47.1% in all hospitals, p = 0.002 and <0.001, respectively); other demographics were clinically comparable. Most women undergoing labor induction were nulliparous; however, a greater proportion in the outpatient group were nulliparous compared with inpatient groups (70.8 vs. 61.8% and 64.3%, p = 0.002 and 0.01). On inpatient admission for delivery, women who received outpatient misoprostol were more likely to have a cervical dilation of ≥3 cm (39.8 vs. 12.5% at study sites and 9.7% at all KPNC hospitals, p < 0.001 for both). The outpatient group had a shorter mean time between admission and delivery (23.6 vs. 29.4 at study sites and 29.8 hours at all KPNC, p < 0.001 for both). The adjusted estimated mean difference between the outpatient and inpatient group at all the Kaiser hospitals in time from admission to delivery was -6.48 hours (p < 0.001), and the adjusted estimated mean difference in cervical dilation on admission was +1.02 cm (p < 0.001). There was no difference in cesarean delivery rates between groups. The rate of chorioamnionitis in the outpatient group was higher compared with inpatients at all hospitals (17.7 vs. 10.6%, p < 0.001), but similar when compared with the inpatients at the study sites (17.7 vs. 15.4%, p = 0.29). CONCLUSION: Outpatient use of misoprostol for cervical ripening under the study protocol was associated with reduced inpatient time from admission to delivery compared with inpatient misoprostol. Although there was a higher rate of chorioamnionitis among outpatients under the study protocol compared with inpatients at all hospitals, there was no difference when compared with inpatients at the study sites. There was no difference in rates of cesarean delivery or maternal or neonatal complications with outpatient misoprostol. KEY POINTS: · Outpatient misoprostol patients had 6.46 fewer hours from admission to delivery compared with inpatients at all hospitals.. · There was no difference in the rate of cesareans between the outpatient versus inpatient misoprostol groups.. · Other maternal and neonatal complications were low and comparable among outpatients and inpatients who received misoprostol; this study was not large enough to assess rare safety outcomes..

4.
Med J Malaysia ; 73(2): 106-109, 2018 04.
Article in English | MEDLINE | ID: mdl-29703874

ABSTRACT

BACKGROUND: Leptospirosis is a zoonotic disease with symptoms ranging from a mild, febrile illness to a severe form with multiorgan failure. Severe leptospirosis may require medical interventions in the form of dialysis and/or mechanical ventilation and often leads to mortality. An exaggerated host immune response-in particular, a "cytokine storm"-that causes endothelial and organ damage is associated with the disease severity and mortality. METHODS: Microscopic agglutination test (MAT)-positive and MAT-negative human serum samples (n=30) from patients with leptospirosis were obtained from the Public Health Laboratory, Kota Kinabalu, Sabah, Malaysia and control serum samples (n=10) were obtained from healthy student volunteers. We estimated the levels of IL-1ß, IL-6, IL-8, IL-10, and TNF-α in serum samples by a Luminex assay. RESULTS: The levels of IL-6, IL-8, and IL1-ß were significantly higher in 13% of the patients with leptospirosis compared to the healthy controls, while the levels of IL-10 and TNF-α were not elevated in either group. CONCLUSION: Our data suggest that elevated levels of IL-6, IL- 8, and IL1-ß may be associated with leptospirosis disease severity, which requires patient follow-up for confirmation.


Subject(s)
Cytokines/blood , Leptospirosis/blood , Agglutination Tests , Case-Control Studies , Humans , Interleukin-10/blood , Interleukin-1beta/blood , Interleukin-6/blood , Interleukin-8/blood , Malaysia , Tumor Necrosis Factor-alpha/blood
5.
Med J Malaysia ; 70(6): 351-5, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26988208

ABSTRACT

OBJECTIVE: The aim of this article was to review published research articles on leptospirosis, in particular the recent incidence of leptospirosis in Malaysia and the currently available diagnostic methods for the detection of leptospirosis. METHODS: PubMed, Google Scholar and Google Search databases were searched using the key words Leptospira and leptospirosis. A total of seventy-six references were reviewed including sixty-seven research articles, three annual reports from Ministry of Health and six online newspaper articles. This review includes the following five sub-headings: introduction, leptospirosis transmission, leptospirosis incidents, laboratory diagnosis of leptospirosis and treatment and prevention of leptospirosis. RESULTS: An increase in incidents of leptospirosis cases has been seen in recent years in Malaysia. The recent floods have contributed to the rise in the number of reported cases. Current diagnostic approaches such as dark field microscopy, microscopic agglutination test (MAT), Polymerase chain reaction and serological tests are inadequate as the organism is a slow grower. CONCLUSION: There is an urgent need to develop newer techniques for rapid detection of leptospirosis. The combination of PCR and ELISA are suggested for rapid and accurate diagnosis of leptospirosis. Studies on the mechanism of pathogenesis of Leptospira are needed for the development of vaccines that are safe for human use.

6.
Pak J Pharm Sci ; 22(3): 282-6, 2009 Jul.
Article in English | MEDLINE | ID: mdl-19553175

ABSTRACT

Flavonoids which were reported as having many pharmacological activities, antimicrobial, antioxidant, cytotoxic, chemoprevention activities and they possess strong antiproliferative effects related to inhibition of cell cycle progression and apoptosis induction. On the basis of this Thespesia populnea (L.) Sol. Ex Correa (Family-Malvaceae) was selected and it is having the major composition of flavonoids and the antibacterial activity of methanolic extract of Thespesia populnea flowers was investigated by agar well diffusion method. Furthermore our phytochemical studies indicated that methanolic extract of Thespesia populnea flowers contains flavonoids, alkaloids, tannins and anthroquinone glycosides. Moreover the individual components were identified by thin layer chromatography and Rf value was compared with standard flavonoid quercetin. The total phenolic and flavonoid content studies were also quantified. The bacteria used for antibacterial study were Shigella flexneri (NCIM 4924), Rhodococcus terrae (NCIM 5126), Escherichiae coli (ATCC 11775), Streptococcus faecalis (NCIB 2406), Klebsiella pneumoniae (ATCC 13883),Brevibacterium luteum (NCIM 2923), Micrococcus flavum (NCIM 2376), Proteus mirabilis (NCIB 8268), Bacillus licheniformis (NCIM 2468), Micrococcus luteus (ATCC 2984), Flavobacterium devorans (NCIM 2581), Shigella sonei(ATCC 29930), Shigella boydii (ATCC 8700) and Shigella dysentriae (ATCC 13313).According to our results in the lowest tested concentration of 62.5 microg/ml and 125mug/ml 7.2% of the plant extract were active, 5% active in the concentration of 250 microg/ml, 75.7% active in the concentration of 500 microg/ml and 92.8% active at the concentration of 1000 microg/ml in a dose dependent manner.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteria/drug effects , Flavonoids/pharmacology , Flowers/chemistry , Malvaceae/chemistry , Phenols/pharmacology , Alkaloids/isolation & purification , Alkaloids/pharmacology , Anthraquinones/isolation & purification , Anthraquinones/pharmacology , Anti-Bacterial Agents/chemistry , Chromatography, High Pressure Liquid , Flavonoids/isolation & purification , Glycosides/isolation & purification , Glycosides/pharmacology , Microbial Sensitivity Tests , Phenols/isolation & purification , Plant Extracts/chemistry , Plant Extracts/pharmacology , Tannins/isolation & purification , Tannins/pharmacology
7.
Antivir Ther ; 13(4): 563-9, 2008.
Article in English | MEDLINE | ID: mdl-18672535

ABSTRACT

BACKGROUND: An open-label, randomized, crossover study was performed to investigate the effect of multiple doses of darunavir co-administered with low-dose ritonavir (DRV/r) on the steady-state pharmacokinetics of the oral contraceptives ethinyl estradiol (EE) and norethindrone (NE) (commercial name of the combined drug Ortho-Novum 1/35) in 19 HIV-negative healthy women. METHODS: In session 1, participants received 35 microg EE and 1.0 mg NE from days 1 to 21. In session 2, participants received the same oral contraceptive treatment as in session 1 on days 1 to 21 plus DRV/r (600 mg/100 mg twice daily) on days 1 to 14. Pharmacokinetic assessments were performed on day 14 for each session. RESULTS: Steady-state systemic exposure to EE and NE decreased when DRV/r was co-administered, based on the ratio of least square means of the minimum plasma concentration (Cmin), the maximum plasma concentration (Cmax), and the area under the curve (AUC24h) of EE (which decreased by 62%, 32% and 44%, respectively) and NE (which decreased by 30%, 10% and 14%, respectively) compared with administration of EE and NE alone. Five participants discontinued the study due to grade 2 cutaneous events, as required per protocol, during treatment with EE and NE in combination with DRV/r. There were no clinically relevant findings for laboratory and cardiovascular parameters. CONCLUSIONS: The pharmacokinetic interaction observed here is considered to be clinically relevant as EE concentrations are considerably reduced when DRV/r is co-administered with EE and NE. Alternative or additional contraceptive measures should be used when oestrogen-based contraceptives are co-administered with DRV/r.


Subject(s)
Contraceptives, Oral/pharmacokinetics , Ethinyl Estradiol/pharmacokinetics , HIV Protease Inhibitors/pharmacokinetics , Norethindrone/pharmacokinetics , Ritonavir/pharmacokinetics , Sulfonamides/pharmacokinetics , Adolescent , Adult , Contraceptives, Oral/adverse effects , Cross-Over Studies , Darunavir , Drug Interactions , Drug Therapy, Combination , Ethinyl Estradiol/administration & dosage , Ethinyl Estradiol/adverse effects , Female , HIV Protease Inhibitors/administration & dosage , HIV Protease Inhibitors/adverse effects , HIV Seronegativity , Humans , Norethindrone/administration & dosage , Norethindrone/adverse effects , Ritonavir/administration & dosage , Ritonavir/adverse effects , Sulfonamides/administration & dosage , Sulfonamides/adverse effects
8.
Br J Clin Pharmacol ; 66(2): 215-21, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18460033

ABSTRACT

AIMS: To investigate the interaction between ketoconazole and darunavir (alone and in combination with low-dose ritonavir), in HIV-healthy volunteers. METHODS: Volunteers received darunavir 400 mg bid and darunavir 400 mg bid plus ketoconazole 200 mg bid, in two sessions (Panel 1), or darunavir/ritonavir 400/100 mg bid, ketoconazole 200 mg bid and darunavir/ritonavir 400/100 mg bid plus ketoconazole 200 mg bid, over three sessions (Panel 2). Treatments were administered with food for 6 days. Steady-state pharmacokinetics following the morning dose on day 7 were compared between treatments. Short-term safety and tolerability were assessed. RESULTS: Based on least square means ratios (90% confidence intervals), during darunavir and ketoconazole co-administration, darunavir area under the curve (AUC(12h)), maximum plasma concentration (C(max)) and minimum plasma concentration (C(min)) increased by 155% (80, 261), 78% (28, 147) and 179% (58, 393), respectively, compared with treatment with darunavir alone. Darunavir AUC(12h), C(max) and C(min) increased by 42% (23, 65), 21% (4, 40) and 73% (39, 114), respectively, during darunavir/ritonavir and ketoconazole co-administration, relative to darunavir/ritonavir treatment. Ketoconazole pharmacokinetics was unchanged by co-administration with darunavir alone. Ketoconazole AUC(12h), C(max) and C(min) increased by 212% (165, 268), 111% (81, 144) and 868% (544, 1355), respectively, during co-administration with darunavir/ritonavir compared with ketoconazole alone. CONCLUSIONS: The increase in darunavir exposure by ketoconazole was lower than that observed previously with ritonavir. A maximum ketoconazole dose of 200 mg day(-1) is recommended if used concomitantly with darunavir/ritonavir, with no dose adjustments for darunavir/ritonavir.


Subject(s)
Antifungal Agents/pharmacokinetics , HIV Infections/metabolism , HIV Protease Inhibitors/pharmacokinetics , Ketoconazole/pharmacokinetics , Ritonavir/pharmacokinetics , Sulfonamides/pharmacokinetics , Adolescent , Adult , Antifungal Agents/administration & dosage , Area Under Curve , Cross-Over Studies , Darunavir , Dose-Response Relationship, Drug , Drug Combinations , Drug Interactions , Female , HIV Infections/drug therapy , HIV Protease Inhibitors/administration & dosage , Humans , Ketoconazole/administration & dosage , Male , Middle Aged , Ritonavir/administration & dosage , Sulfonamides/administration & dosage , Treatment Outcome
9.
J Clin Pharmacol ; 48(1): 60-5, 2008 Jan.
Article in English | MEDLINE | ID: mdl-18094220

ABSTRACT

This study investigated the steady-state pharmacokinetic interaction between the HIV protease inhibitor, darunavir (TMC114), administered with low-dose ritonavir (darunavir/ritonavir), and clarithromycin in HIV-negative healthy volunteers. In a 3-way crossover study, 18 individuals received darunavir/ritonavir 400/100 mg bid, clarithromycin 500 mg bid, and darunavir/ritonavir 400/100 mg bid plus clarithromycin 500 mg bid in 3 separate sessions for 7 days, with a washout period of at least 7 days between treatments. Pharmacokinetic assessment was performed on day 7. Safety and tolerability of the study medication were monitored throughout. Coadministration of darunavir/ritonavir with clarithromycin resulted in a reduction in darunavir maximum plasma concentration (Cmax) and area under the curve from administration until 12 hours postdose (AUC12 h) of 17% and 13%, respectively. Ritonavir Cmax and AUC12 h were unchanged. During coadministration with darunavir/ritonavir, clarithromycin Cmax and AUC12 h increased by 26% and 57%, respectively; 14-hydroxy-clarithromycin plasma concentrations were reduced to below the lower limit of quantification (<50 ng/mL). The study medication was generally well tolerated. Based on these pharmacokinetic findings, neither clarithromycin nor darunavir/ritonavir dose adjustments are necessary when clarithromycin is coadministered with darunavir/ritonavir.


Subject(s)
Clarithromycin/pharmacokinetics , Ritonavir/pharmacokinetics , Sulfonamides/pharmacokinetics , Adolescent , Adult , Anti-Bacterial Agents/metabolism , Anti-Bacterial Agents/pharmacokinetics , Area Under Curve , Chromatography, High Pressure Liquid , Clarithromycin/analogs & derivatives , Clarithromycin/blood , Clarithromycin/metabolism , Cross-Over Studies , Darunavir , Dose-Response Relationship, Drug , Drug Combinations , Female , HIV Protease Inhibitors/blood , HIV Protease Inhibitors/pharmacokinetics , Humans , Male , Middle Aged , Ritonavir/blood , Sulfonamides/blood , Time Factors
10.
Ther Drug Monit ; 29(6): 795-801, 2007 Dec.
Article in English | MEDLINE | ID: mdl-18043478

ABSTRACT

This was an open-label, crossover study to investigate the pharmacokinetic interaction between darunavir (TMC114), coadministered with low-dose ritonavir (darunavir/ritonavir), and the protease inhibitor saquinavir in HIV-negative healthy volunteers. Thirty-two volunteers were randomized into two cohorts (panel 1 and panel 2). In two separate sessions, panel 1 received 400/100 mg darunavir/ritonavir twice a day and 400/1000/100 mg darunavir/saquinavir/ritonavir twice a day; panel 2 received 1000/100 mg saquinavir/ritonavir twice a day and 400/1000/100 mg darunavir/saquinavir/ritonavir twice a day. All treatments were administered orally under fed conditions for 13 days with an additional single morning dose on day 14. Treatment sessions were separated by a washout period of at least 14 days. Twenty-six volunteers completed the study (n=14, panel 1; n=12, panel 2), whereas six discontinued as a result of adverse events. Coadministration of saquinavir with darunavir/ritonavir resulted in decreases of darunavir area under the curve and maximum and minimum plasma concentrations of 26%, 17%, and 42%, respectively, compared with administration of darunavir/ritonavir alone. Relative to treatment with saquinavir/ritonavir alone, saquinavir exposure was not significantly different with the addition of darunavir. Ritonavir area under the curve12h increased by 34% when saquinavir was added to treatment with darunavir/ritonavir. The coadministration of darunavir/saquinavir/ritonavir was generally well tolerated. Similar findings are expected with the approved 600/100 mg darunavir/ritonavir twice-a-day dose. The combination of saquinavir and darunavir/ritonavir is currently not recommended.


Subject(s)
Anti-HIV Agents/pharmacokinetics , HIV Seronegativity , Saquinavir/pharmacokinetics , Sulfonamides/pharmacokinetics , Adolescent , Adult , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Area Under Curve , Cross-Over Studies , Darunavir , Dose-Response Relationship, Drug , Drug Interactions , Drug Monitoring , Drug Therapy, Combination , Humans , Middle Aged , Ritonavir/administration & dosage , Ritonavir/adverse effects , Ritonavir/pharmacokinetics , Saquinavir/administration & dosage , Saquinavir/adverse effects , Sulfonamides/administration & dosage , Sulfonamides/adverse effects
11.
Antivir Ther ; 12(4): 509-14, 2007.
Article in English | MEDLINE | ID: mdl-17668559

ABSTRACT

BACKGROUND: This open-label, crossover study investigated the pharmacokinetic interaction between TMC114 (darunavir [Prezista]), administered with low-dose ritonavir (TMC114/r) and efavirenz (EFV) in HIV-negative, healthy volunteers. METHODS: Volunteers received TMC114/r 300/100 mg twice daily for 6 days, and once daily on day 7 (session 1). After a 7-day washout period volunteers received EFV 600 mg once daily for 18 days (session 2), with coadministration of TMC114/r 300/100 mg twice daily from day 11-day 16 and TMC114/r once daily on day 17. RESULTS: When coadministered with TMC114/r, plasma concentrations of EFV were slightly increased. In the presence of TMC114/r, EFV minimum (Cmin) and maximum (Cmax) plasma concentrations increased by 15-17%, and by 21% for EFV area under the curve (AUC24h). TMC114/r and EFV coadministration resulted in TMC114 Cmin, Cmax and AUC12h decreases of 31%, 15% and 13%, respectively. No serious adverse events (AEs) or AEs leading to withdrawal were reported in this trial. Overall, TMC114/r and EFV coadministration was well tolerated. CONCLUSIONS: The clinical significance of the changes in AUC and Cmin seen with TMC114/r and EFV coadministration has not been established; this combination should be used with caution. Similar findings are expected with the approved TMC114/r 600/100 mg twice daily dose.


Subject(s)
Anti-HIV Agents/pharmacokinetics , Benzoxazines/pharmacokinetics , Reverse Transcriptase Inhibitors/pharmacokinetics , Ritonavir/pharmacokinetics , Sulfonamides/pharmacokinetics , Adult , Alkynes , Anti-HIV Agents/administration & dosage , Anti-HIV Agents/adverse effects , Benzoxazines/administration & dosage , Benzoxazines/adverse effects , Cyclopropanes , Darunavir , Drug Interactions , Drug Therapy, Combination , HIV Seronegativity , Humans , Middle Aged , Reverse Transcriptase Inhibitors/administration & dosage , Reverse Transcriptase Inhibitors/adverse effects , Ritonavir/administration & dosage , Ritonavir/adverse effects , Sulfonamides/administration & dosage , Sulfonamides/adverse effects , Treatment Outcome , Volunteers
12.
Drugs R D ; 8(4): 241-8, 2007.
Article in English | MEDLINE | ID: mdl-17596110

ABSTRACT

BACKGROUND AND OBJECTIVE: To investigate the potential for pharmacokinetic interactions between the protease inhibitors darunavir (DRV, TMC114) coadministered with low-dose ritonavir (darunavir/r), and atazanavir in HIV-negative, healthy volunteers. METHODS: This was an open-label, randomised, three-period, crossover study. Darunavir/r (400/100mg twice daily), atazanavir/r (300/100mg once daily) or darunavir/r (400/100mg twice daily) plus atazanavir (300mg once daily) were administered in three separate sessions, with a washout period of at least 7 days between regimens. The follow-up lasted 30 days. Twenty-three healthy volunteers participated. Pharmacokinetic assessments were performed at steady-state on day 7. Plasma drug concentrations were determined by liquid chromatography-tandem mass spectrometry and pharmacokinetic parameters were compared between treatments. The safety and tolerability of the study medications were monitored throughout. RESULTS: Darunavir pharmacokinetics were unaffected by atazanavir. No change in overall exposure to atazanavir was observed during coadministration with darunavir/r. However, there was a 52% increase in minimum atazanavir plasma concentration (least squares mean ratio [90% CI 0.99, 2.34]). Mean systemic exposure to ritonavir was increased by 65% and 106%, respectively, with the combination treatment compared with darunavir/r alone or atazanavir/r alone. There were no apparent differences in mean changes in lipids between the darunavir/r, atazanavir/r or darunavir/r plus atazanavir regimens. Hyperbilirubinaemia and ocular icterus were reported with atazanavir-containing regimens. CONCLUSION: Atazanavir at a dose of 300mg once daily can be coadministered with a darunavir/r twice-daily regimen without any dose adjustment if there is a clinical need to combine darunavir/r and atazanavir in HIV-1-infected patients.


Subject(s)
Oligopeptides/pharmacokinetics , Pyridines/pharmacokinetics , Adolescent , Adult , Area Under Curve , Atazanavir Sulfate , Chromatography, Liquid , Cross-Over Studies , Darunavir , Dose-Response Relationship, Drug , Drug Interactions , Female , HIV Protease Inhibitors/adverse effects , HIV Protease Inhibitors/blood , HIV Protease Inhibitors/pharmacokinetics , Half-Life , Humans , Hyperbilirubinemia/chemically induced , Male , Middle Aged , Nausea/chemically induced , Oligopeptides/adverse effects , Oligopeptides/blood , Pyridines/adverse effects , Pyridines/blood , Sulfonamides/adverse effects , Sulfonamides/blood , Sulfonamides/pharmacokinetics , Tandem Mass Spectrometry , Time Factors , Vomiting/chemically induced
13.
Antimicrob Agents Chemother ; 51(3): 958-61, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17210768

ABSTRACT

Darunavir (DRV; TMC114; Prezista) is a human immunodeficiency virus (HIV) protease inhibitor used in combination with low-dose ritonavir (RTV) (DRV/r) as a pharmacokinetic enhancer. Protease inhibitor absorption may be decreased during coadministration of drugs that limit stomach acid secretion and increase gastric pH. This study was conducted to investigate the effect of ranitidine and omeprazole on the plasma pharmacokinetics of DRV and RTV in HIV-negative healthy volunteers. Sixteen volunteers completed the study and received DRV/r, DRV/r plus ranitidine, and DRV/r plus omeprazole, in three separate sessions. Treatment was given for 4 days with an additional morning dose on day 5, and regimens were separated by a washout period of 7 days. Samples were taken over a 12-h period on day 5 for the assessment of DRV and RTV plasma concentrations. Pharmacokinetic parameters assessed included DRV area under the curve, maximum plasma concentration, and trough plasma concentration. The least-squares mean ratios and 90% confidence intervals are reported with treatment of DRV/r alone as a reference. Compared with DRV/r alone, no significant changes in DRV pharmacokinetic parameters were observed during coadministration of DRV/r and either ranitidine or omeprazole. Treatment regimens were generally well tolerated, and no serious adverse events were reported. In conclusion, coadministration of DRV/r and ranitidine or omeprazole was well tolerated by the volunteers. Ranitidine and omeprazole did not have a significant influence on DRV pharmacokinetics. No dose adjustments are required when DRV/r is coadministered with omeprazole or ranitidine.


Subject(s)
Anti-HIV Agents/pharmacology , Anti-HIV Agents/pharmacokinetics , Anti-Ulcer Agents/pharmacology , Anti-Ulcer Agents/pharmacokinetics , Antiviral Agents/pharmacology , Antiviral Agents/pharmacokinetics , Histamine H2 Antagonists/pharmacology , Histamine H2 Antagonists/pharmacokinetics , Omeprazole/pharmacology , Omeprazole/pharmacokinetics , Ranitidine/pharmacology , Ranitidine/pharmacokinetics , Ritonavir/pharmacology , Ritonavir/pharmacokinetics , Sulfonamides/pharmacology , Sulfonamides/pharmacokinetics , Adolescent , Adult , Anti-HIV Agents/adverse effects , Anti-Ulcer Agents/adverse effects , Antiviral Agents/adverse effects , Area Under Curve , Darunavir , Drug Interactions , Female , Histamine H2 Antagonists/adverse effects , Humans , Male , Middle Aged , Omeprazole/adverse effects , Ranitidine/adverse effects , Ritonavir/adverse effects , Sulfonamides/adverse effects
14.
Diagn Microbiol Infect Dis ; 49(3): 179-82, 2004 Jul.
Article in English | MEDLINE | ID: mdl-15246507

ABSTRACT

Fifty-one clinical isolates and 5 clarithromycin-resistant mutants of Mycobacterium avium complex (MAC) were tested for their susceptibility to clarithromycin by microplate Alamar blue assay (MABA). The susceptibility results were compared with the results obtained by the BACTEC 460 method. All clinical isolates were susceptible, while all mutants were resistant to clarithromycin by BACTEC. Eighty-six percent of the clinical isolates were susceptible by MABA, and one of the resistant mutants was misclassified as susceptible by this method. The overall agreement between MABA and BACTEC was 86%, indicating the usefulness of MABA in drug susceptibility testing of MAC.


Subject(s)
Antibiotics, Antitubercular/pharmacology , Antitubercular Agents/pharmacology , Microbial Sensitivity Tests/methods , Mycobacterium avium Complex/drug effects , Oxazines , Xanthenes , Clarithromycin/pharmacology , Coloring Agents , Culture Media , Drug Resistance, Bacterial , Female , Humans , Male , Mycobacterium avium Complex/growth & development , Mycobacterium avium Complex/isolation & purification , Reproducibility of Results , Sensitivity and Specificity
15.
Curr Med Chem ; 11(11): 1423-30, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15180575

ABSTRACT

The current practice of ingesting phytochemicals to support the immune system or to fight infections is based on centuries-old tradition. We review reports on seven Chinese herbs, (Aloe vera Mill. (Aloaceae), Angelica species (Umbelliferae), Astragalus membranaceus Bunge. (Leguminosae), Ganoderma lucidum (Fr.) Karst. (Ganodermataceae), Panax ginseng C.A Mey. (Araliaceae), Scutellaria species (Lamiaceae) and Zingiber officinale Rosc. (Zingiberaceae) with emphasis to their immunomodulatory and antimicrobial activities. While some of these herbaceous plants have a direct inhibitory effect on microbial organisms, we observe that each plant has at least one compound that selectively modulates cells of the immune system. The successful derivation of pure bioactive compounds from Ganoderma lucidum, ginseng and Zingiber officinale supports the traditional practice of using these plants to stimulate the immune system. As many modern drugs are often patterned after phytochemicals, studying the influence of each compound on immune cells as well as microbes can provide useful insights to the development of potentially useful new pharmacological agents.


Subject(s)
Anti-Infective Agents/pharmacology , Drugs, Chinese Herbal/pharmacology , Immunosuppressive Agents/immunology , Animals , Anti-Infective Agents/chemistry , Anti-Infective Agents/isolation & purification , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/classification , Forecasting , History, Ancient , Humans , Immunosuppressive Agents/chemistry , Immunosuppressive Agents/isolation & purification , Medicine, Chinese Traditional/trends
16.
Appl Environ Microbiol ; 69(7): 4337-41, 2003 Jul.
Article in English | MEDLINE | ID: mdl-12839827

ABSTRACT

Mycobacterium chelonae and Mycobacterium terrae were reported to be frequently present in the environment of the Mycobacterium bovis BCG trial area in south India. Six isolates of M. chelonae and four isolates of M. terrae obtained from different sources in this area were analyzed by pulsed-field gel electrophoresis (PFGE) to examine large-restriction-fragment (LRF) polymorphism using the chromosomal DNA digested with DraI and XbaI restriction enzymes. With the exception of one isolate of M. terrae, DNA from all other isolates could be digested with DraI and XbaI and resulted in separable fragments. Visual comparison of the LRFs showed a unique pattern for each of the isolates tested. A computer-assisted dendrogram of the percent similarity demonstrated a high degree of genetic diversity in this group of isolates. This study demonstrates that species of nontuberculous mycobacteria, particularly M. chelonae and M. terrae, can be successfully typed by their LRF pattern using PFGE, which does not require species-specific DNA probes.


Subject(s)
Bacterial Typing Techniques , Mycobacterium chelonae/classification , Nontuberculous Mycobacteria/classification , Polymorphism, Restriction Fragment Length , BCG Vaccine/administration & dosage , Deoxyribonucleases, Type II Site-Specific/metabolism , Electrophoresis, Gel, Pulsed-Field , Humans , Mycobacterium Infections, Nontuberculous/microbiology , Mycobacterium chelonae/genetics , Nontuberculous Mycobacteria/genetics , Tuberculosis/prevention & control
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