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1.
In Vitro Exposure to PC-1005 and Cervicovaginal Lavage Fluid from Women Vaginally Administered PC-1005 Inhibits HIV-1 and HSV-2 Infection in Human Cervical Mucosa.
Villegas, G, Calenda, G, Zhang, S, Mizenina, O, Kleinbeck, K, Cooney, ML, Hoesley, CJ, Creasy, GW, Friedland, B, Fernández-Romero, JA, et al
Antimicrobial agents and chemotherapy. 2016;(9):5459-66
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Abstract
Our recent phase 1 trial demonstrated that PC-1005 gel containing 50 μM MIV-150, 14 mM zinc acetate dihydrate, and carrageenan (CG) applied daily vaginally for 14 days is safe and well tolerated. Importantly, cervicovaginal lavage fluid samples (CVLs) collected 4 or 24 h after the last gel application inhibited HIV-1 and human papillomavirus (HPV) in cell-based assays in a dose-dependent manner (MIV-150 for HIV-1 and CG for HPV). Herein we aimed to determine the anti-HIV and anti-herpes simplex virus 2 (anti-HSV-2) activity of PC-1005 in human cervical explants after in vitro exposure to the gel and to CVLs from participants in the phase 1 trial. Single HIV-1BaL infection and HIV-1BaL-HSV-2 coinfection explant models were utilized. Coinfection with HSV-2 enhanced tissue HIV-1BaL infection. In vitro exposure to PC-1005 protected cervical mucosa against HIV-1BaL (up to a 1:300 dilution) in single-challenge and cochallenge models. CG gel (PC-525) provided some barrier effect against HIV-1BaL at the 1:100 dilution in a single-challenge model but not in the cochallenge model. Both PC-1005 and PC-525 at the 1:100 dilution inhibited HSV-2 infection, pointing to a CG-mediated protection. MIV-150 and CG in CVLs inhibited HIV (single-challenge or cochallenge models) and HSV-2 infections in explants in a dose-dependent manner (P < 0.05). Stronger inhibition of HIV-1 infection by CVLs collected 4 h after the last gel administration was observed compared to infection detected in the presence of baseline CVLs. The anti-HIV and anti-HSV-2 activity of PC-1005 gel in vitro and CVLs in human ectocervical explants supports the further development of PC-1005 gel as a broad-spectrum on-demand microbicide.
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A comparative phase 1 clinical trial to identify anti-infective mechanisms of vitamin D in people with HIV infection.
Lachmann, R, Bevan, MA, Kim, S, Patel, N, Hawrylowicz, C, Vyakarnam, A, Peters, BS
AIDS (London, England). 2015;(10):1127-35
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Abstract
OBJECTIVES To determine if there is a biological mechanism that explains the association between HIV disease progression and increased mortality with low circulating vitamin D levels; specifically, to determine if restoring vitamin D levels induced T-cell functional changes important for antiviral immunity. DESIGN This was a pilot, open-label, three-arm prospective phase 1 study. METHODS We recruited 28 patients with low plasma vitamin D (<50 nmol/l 25-hydroxyvitamin D3), comprising 17 HIV+ patients (11 on HAART, six treatment-naive) and 11 healthy controls, who received a single dose of 200 000 IU oral cholecalciferol. Advanced T-cell flow cytometry methods measured CD4 T-cell function associated with viral control in blood samples at baseline and 1-month after vitamin D supplementation. RESULTS One month of vitamin D supplementation restored plasma levels to sufficiency (>75 nmol/l) in 27 of 28 patients, with no safety issues. The most striking change was in HIV+ HAART+ patients, where increased frequencies of antigen-specific T cells expressing macrophage inflammatory protein (MIP)-1β - an important anti-HIV blocking chemokine - were observed, with a concomitant increase in plasma MIP-1β, both of which correlated significantly with vitamin D levels. In addition, plasma cathelicidin - a vitamin D response gene with broad antimicrobial activity - was enhanced. CONCLUSION Vitamin D supplementation modulates disease-relevant T-cell functions in HIV-infected patients, and may represent a useful adjunct to HAART therapy.
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Exopolysaccharides and antimicrobial biosurfactants produced by Paenibacillus macerans TKU029.
Liang, TW, Wu, CC, Cheng, WT, Chen, YC, Wang, CL, Wang, IL, Wang, SL
Applied biochemistry and biotechnology. 2014;(2):933-50
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Abstract
Paenibacillus macerans TKU029 can produce exopolysaccharides (EPSs; 3.46 g/L) and a biosurfactant (1.78 g/L) in a medium with 2 % (w/v) squid pen powder as the sole carbon/nitrogen source. The biosurfactant can reduce the surface tension of water from 72.30 to 35.34 mN/m at a concentration of 2.76 g/L and reach an emulsification index of 56 % after a 24-h reaction with machine oil. This biosurfactant is stable at 121 °C for 20 min, over a pH range from 3 to 11, and in <5 % salt solutions. It also shows significant antimicrobial activity, which remains active after treatment at 121 °C and at pH values from 4 to 10, against Escherichia coli BCRC13086, Staphylococcus aureus BCRC10780, Fusarium oxysporum BCRC32121 and Aspergillus fumigatus BCRC30099. Furthermore, human skin shows from 37.3 to 44.3 % hydration after being treated with TKU029 EPSs for 180 min. These results imply that EPSs and the biosurfactant from this strain have potential in cosmetics, for removal of oil contamination, and as antimicrobial agents.
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Pharmacokinetics of single-dose morinidazole in patients with severe renal impairment.
Zhang, H, Huang, L, Huang, YY, Yi, B, Pei, Q, Tan, HY, Huang, J, Liu, JS, Yuan, H, Yang, GP
International journal of clinical pharmacology and therapeutics. 2014;(2):159-65
Abstract
OBJECTIVE To evaluate the pharmacokinetics of morinidazole in individuals with severe renal impairment (RI). METHODS This open-label Phase I study enrolled healthy volunteers and patients with severe RI aged 18 - 65 years. All subjects received a single infusion of sodium chloride injection with 500 mg morinidazole. Plasma and urine concentration of morinidazole and one of its metabolites (M4-1) were evaluated by using HPLC-UV and HPLC-MS/MS respectively. Pharmacokinetic parameters were calculated by Phoenix WinNonlin 6.0 software. RESULTS 22 individuals (healthy: n = 11, severe RI: n = 11) received morinidazole. In both groups, maximum plasma concentration of morinidazole was reached within 1 hour, while the tmax of M4-1 differed greatly. Both AUC0-t and AUC0-∞ of morinidazole were 1.4 times higher in patients with severe RI, while M4-1 were over 7 times higher than healthy groups. Renal excretion of unchanged morinidazole was decreased by 65% in patients with RI, and M4-1 was decreased by 72%. Apparent correlation between CLcr and CL, AUC, t1/2 and CLr were seen in two groups. CONCLUSIONS A single dose of 500 mg morinidazole is well tolerated. Changes in pharmacokinetic parameters of morinidazole and M4-1 are seen in patients with RI and may be clinically important.
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Atovaquone versus trimethoprim-sulfamethoxazole as Pneumocystis jirovecii pneumonia prophylaxis following renal transplantation.
Gabardi, S, Millen, P, Hurwitz, S, Martin, S, Roberts, K, Chandraker, A
Clinical transplantation. 2012;(3):E184-90
Abstract
Pneumocystis pneumonia (PCP) is associated with significant morbidity and mortality in renal transplant recipients (RTR). Trimethoprim-sulfamethoxazole (TMP-SMZ) is considered the prophylactic agent-of-choice. Some patients require an alternative owing to TMP-SMZ intolerance. This is the first evaluation of full-dose atovaquone vs. TMP-SMZ for PCP prevention in RTR. One hundred and eighty-five RTR were evaluated in this single-center, retrospective analysis. Patients received either single-strength TMP-SMZ daily (group I; n = 160) or 1500 mg/d of atovaquone and of a fluoroquinolone for one month (group II; n = 25). The primary endpoint was the incidence of PCP at 12 months post-transplant. There were no cases of PCP in either group. There were comparable rates of infections from bacterial pathogens and cytomegalovirus, but rates of BK viremia were significantly higher in group I (22.5%) vs. group II (4%; p = 0.03). The incidence of leukopenia was similar in both groups. Higher mean potassium levels were seen in group I at three months post-transplant but were comparable at all other time points. The need for dose reduction and/or premature discontinuation of therapy secondary to adverse events was more prevalent in TMP-SMZ-treated patients. In our experience, atovaquone appears to be effective in preventing PCP post-renal transplant and also demonstrates good tolerability.
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Evaluation of the effects of rifampicin, ketoconazole and erythromycin on the steady-state pharmacokinetics of the components of a novel oral contraceptive containing estradiol valerate and dienogest in healthy postmenopausal women.
Blode, H, Zeun, S, Parke, S, Zimmermann, T, Rohde, B, Mellinger, U, Kunz, M
Contraception. 2012;(4):337-44
Abstract
BACKGROUND We evaluated the effects of cytochrome P450 3A4 (CYP3A4) induction and inhibition on steady-state pharmacokinetics of the components of a novel oral contraceptive (OC) containing estradiol valerate (E₂V) and dienogest (DNG). STUDY DESIGN CYP3A4 induction was assessed in an open-label, one-arm study. Sixteen healthy postmenopausal women received E₂V 2 mg/DNG 3 mg (days 1-17) and concomitant rifampicin (600 mg, days 12-16). Ratios of the area under the serum concentration-time curve between 0 and 24 h [AUC(0-24 h)] and maximum serum concentration (C(max)) of E₂ and DNG on days 17 and 11 (after and before rifampicin intervention) are presented. CYP3A4 inhibition was investigated in an open-label, parallel-group study in 24 healthy postmenopausal women receiving E₂V 2 mg/DNG 3 mg (days 1-14) and concomitant ketoconazole (400 mg, n=12) or erythromycin (500 mg three times daily, n=12) on days 8-14. Mean ratios of AUC(0-24 h) and C(max) of E₂ and DNG on days 7 and 14 are presented. RESULTS Concomitant administration of rifampicin decreased systemic drug exposure and yielded geometric mean ratios for E₂C(max) and AUC(0-24 h) of 75% and 56%, respectively. Corresponding mean ratios for DNG were 48% and 17%, respectively. Ketoconazole coadministration increased systemic drug exposure and yielded ratios of E₂ of 165% and 157%, respectively, and ratios of DNG of 194% and 286%, respectively. Erythromycin coadministration also resulted in increased mean C(max) and AUC(0-24 h) of both E₂ and DNG. Geometric mean ratios of C(max) and AUC(0-24 h) for E₂ were 151% and 133%, respectively. Corresponding ratios for DNG were 133% and 162%, respectively. CONCLUSIONS Significant drug-drug interactions are apparent when CYP3A4 modulators are coadministered with the components of a novel OC containing E₂V/DNG. Coadministration of CYP3A4 modulators should be avoided where possible, and another type of contraception should be used when coadministration of CYP3A4 inducers like rifampicin is unavoidable.
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Trimethoprim-sulfamethoxazole exposure alters ex vivo function of B lymphocytes isolated from human immunodeficiency virus-infected patients receiving Zidovudine.
Venugopalan, V, Thornton, AC, Steinke, DT, Rapp, RP, Romanelli, F, Feola, DJ
Pharmacotherapy. 2009;(4):373-82
Abstract
STUDY OBJECTIVE To determine if exposure to trimethoprim-sulfamethoxazole (TMP-SMX) causes a defect in peripheral B-cell function among patients with the human immunodeficiency virus (HIV) who are receiving zidovudine antiretroviral therapy. DESIGN Prospective, single-center, single-group, case-crossover design with a 4-week exposure period. SETTING University-affiliated infectious diseases outpatient clinic. PATIENTS Fourteen HIV-infected adult men receiving zidovudine, who had CD4(+) cell counts above 350 cells/mm(3) and undetectable viral loads. INTERVENTION Patients were administered a 28-day course of TMP 160 mg-SMX 800 mg/day (one double-strength tablet/day). Peripheral blood mononuclear cells (PBMCs) were obtained and isolated before and after exposure to TMP-SMX. Cells were cultured ex vivo with three mitogens of differing immunologic properties: pokeweed mitogen ([PWM] T-cell-dependent B-cell mitogen), Staphylococcus aureus Cowan ([SAC] T-cell-independent B-cell mitogen), and phytohemagglutinin A ([PHA] T-cell mitogen). Functionality of the B and T lymphocytes was then assessed. MEASUREMENTS AND MAIN RESULTS Proliferative capacity, cytokine secretion, and antibody production were measured and compared before and after TMP-SMX exposure. Reduced proliferative capacities of both PBMC and B cells stimulated with mitogens were observed at the 3-day culture time point in response to PWM, PHA, and SAC (p=0.029, 0.028, and 0.026, respectively). Proliferative capacity at day 7 of culture was not significantly different for any condition examined. Cytokine production was not altered by combination drug exposure after 10 days of culture when cells were stimulated with either PWM or PHA. Although antibody responses to PWM and PHA were similar, total immunoglobulin G concentration was lower in cells stimulated with SAC in samples obtained after TMP-SMX regimen completion compared with those obtained before exposure (p=0.005). CONCLUSION Although these data were affected by limitations in power and study design, they suggest that peripheral B-lymphocyte function is altered as a result of TMP-SMX exposure in HIV-infected patients concurrently receiving zidovudine. Further study of this effect is warranted.
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Urticaria unresponsive to antihistaminic treatment: an open study of therapeutic options based on histopathologic features.
Criado, RF, Criado, PR, Martins, JE, Valente, NY, Michalany, NS, Vasconcellos, C
The Journal of dermatological treatment. 2008;(2):92-6
Abstract
BACKGROUND The non- or low-sedating H1 receptor antagonists represent the basic therapy for urticaria. OBJECTIVE To test an alternative approach to patients unresponsive to conventional treatment. MATERIALS AND METHODS A total of 22 patients with chronic urticaria unresponsive to conventional antihistamine treatment were enrolled for this study. They had uncontrolled urticaria even using multiple combinations of antihistamines on maximum doses and corticosteroids in short cycles (prednisone 20-40 mg, per os once a day, 3-7 days per month). Cutaneous biopsies of the urticaria lesions were taken. These findings were classified as: (I) a mixture of perivascular dermal inflammatory infiltrate composed of lymphocytes, monocytes and neutrophils and/or eosinophils; (II) inflammatory infiltrate composed chiefly of neutrophils; and (III) inflammatory infiltrate composed mainly of eosinophils. According to histology, the patients were submitted to one of the following therapeutic schemes: class A - antihistamine treatment plus dapsone; class B - colchicine or dapsone; class C - montelukast. RESULTS Four patients in class A, 08 in class B and seven in class C displayed complete control of urticaria after 12 weeks of treatment; one patient in class B and two in class C did not respond to treatment. Two years after discontinuation, 16 patients are still free of urticaria. CONCLUSIONS This study suggests an alternative approach for treating unresponsive chronic urticaria.
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Maintenance therapy with a probiotic in antibiotic-dependent pouchitis: experience in clinical practice.
Shen, B, Brzezinski, A, Fazio, VW, Remzi, FH, Achkar, JP, Bennett, AE, Sherman, K, Lashner, BA
Alimentary pharmacology & therapeutics. 2005;(8):721-8
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Abstract
BACKGROUND Management of antibiotic-dependent pouchitis is often challenging. Oral bacteriotherapy with probiotics (such as VSL #3) as maintenance treatment has been shown to be effective in relapsing pouchitis in European trials. However, this agent has not been studied in the US, and its applicability in routine clinical practice has not been evaluated. AIM: To determine compliance and efficacy of probiotic treatment in patients with antibiotic-dependent pouchitis. METHODS Thirty-one patients with antibiotic-dependent pouchitis were studied. VSL #3 is a patented probiotic preparation of live freeze-dried bacteria. All patients received 2 weeks of ciprofloxacin 500 mg b.d. followed by VSL #3 6 g/day for 8 months. Baseline Pouchitis Disease Activity Index scores were calculated. Patients' symptoms were reassessed at week 3 when VSL #3 therapy was initiated and at the end of the 8-month trial. Some patients underwent repeat pouch endoscopy at the end of the trial. RESULTS All 31 patients responded to the 2-week ciprofloxacin trial with resolution of symptoms and they were subsequently treated with VSL #3. The mean duration of follow-up was 14.5+/-5.3 months (range: 8-26 months). At the 8-month follow-up, six patients were still on VSL #3 therapy, and the remaining 25 patients had discontinued the therapy due to either recurrence of symptoms while on treatment or development of adverse effects. All six patients who completed the 8-month course with a mean treatment period of 14.3+/-7.2 months (range: 8-26 months) had repeat clinical and endoscopic evaluation as out-patients. At the end of 8 months, these six patients had a mean Pouchitis Disease Activity Index symptom score of 0.33+/-0.52 and a mean Pouchitis Disease Activity Index endoscopy score of 1.83+/-1.72, which was not statistically different from the baseline Pouchitis Disease Activity Index endoscopy score of 2.83+/-1.17 (P=0.27). CONCLUSION This study was conducted to evaluate bacteriotherapy in routine care. The use of probiotics has been adopted as part of our routine clinical practice with only anecdotal evidence of efficacy. Our review of patient outcome from the treatment placebo showed that only a minority of patients with antibiotic-dependent pouchitis remained on the probiotic therapy and in symptomatic remission after 8 months.
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Rifaximin in patients with lactose intolerance.
Cappello, G, Marzio, L
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver. 2005;(5):316-9
Abstract
BACKGROUND Abdominal symptoms linked to lactose malabsorption may be caused by metabolic activity of colonic bacteria. Rifaximin, a non-absorbable rifampycin derivative, is active against colonic bacteria, it may be useful in the treatment of lactose intolerance. AIM: The aim of this study has been to evaluate short-term rifaximin therapy in patients with lactose intolerance. METHODS Thirty-two patients with lactose intolerance diagnosed using the hydrogen lactose breath test were studied. Fourteen patients received rifaximin 800 mg/day for 10 days, 13 patients followed a diet without milk for 40 days and 5 patients received a placebo for 10 days. Total breath H(2) excretion expressed as area under the curve, and the symptom score were evaluated in all patients at the start, and subsequently after 10 and 40 days. RESULTS In the 14 patients who received rifaximin for 10 days, area under the curve at day 10 and day 40 was statistically significantly lower than the one computed at basal (P<0.01). Diet reduced area under the curve progressively reaching statistical significance at day 40, while the placebo did not change area under the curve throughout the study. The total symptom score significantly improved after rifaximin and diet. CONCLUSION In patients with lactose intolerance, a 10-day therapy with rifaximin as well as 40-day diet without lactose reduces the area under the curve and the symptom score.