79 research outputs found
Pharmacokinetic study of saquinavir hard gel caps/ritonavir in HIV-1-infected patients: 1600/100 mg once-daily compared with 2000/100 mg once-daily and 1000/100 mg twice-daily
Objectives: A pharmacokinetic comparison of three dosing regimens of saquinavir/ritonavir was carried out: 1600/100 mg once-daily with 1000/100 mg twice-daily, and 1600/100 mg once-daily with 2000/100 mg once-daily. Methods: Twenty patients on saquinavir hard gel caps/ritonavir 1600/100 mg once-daily in combination with two nucleoside reverse transcriptase inhibitors for at least 4 weeks were enrolled and randomized to either saquinavir hard gel caps/ritonavir 1000/100 mg twice-daily or 2000/100 mg once-daily. Two pharmacokinetic curves were plotted, at baseline (day 0) and 7 days after the switch. Plasma concentrations were measured at 0, 2, 4, 6, 8, 10, 12 (and 24 for once-daily dosing) hours after drug intake by validated high-performance liquid chromatographic assay (HPLC). The area under the plasma concentration-time curve (AUC0-24 or AUC0-12), maximum and minimum concentration (Cmax and Cmin) and elimination half-life were calculated using a non-compartmental model. Results: Compared with saquinavir/ritonavir 1600/100 mg once-daily dosing, the saquinavir AUC and Cmin improved significantly when dosed as 1000/100 mg twice-daily (53% and 299%, respectively), and as 2000/100 mg once-daily (71% and 65%, respectively). Low Cmin in three subjects at baseline was corrected after switch to the other dosages. Saquinavir/ritonavir 2000/100 mg once-daily was also associated with a significant increase in saquinavir Cmax (52%) compared with saquinavir/ritonavir 1600/100 mg once-daily. Conclusions: Saquinavir/ritonavir when dosed as 2000/100 mg once-daily or 1000/100 mg twice-daily achieves higher saquinavir plasma levels compared with saquinavir/ritonavir 1600/100 mg once-daily. Taking the convenience of once-daily dosing into consideration, dosage of 2000/100 mg once-daily may be preferre
Renal Clearance of the Thyrotropin-Releasing Hormone-Like Peptide Pyroglutamyl-Glutamyl-Prolineamide in Humans
Renal clearance of the thyrotropin-releasing hormone-like peptide pyroglutamyl-glutamyl-prolineamide in humans
TRH-like peptides have been identified that differ from TRH
(pGlu-His-ProNH2) in the middle amino acid. We have estimated TRH-like
immunoreactivity (TRH-LI) in human serum and urine by RIA with
TRH-specific antiserum 8880 or with antiserum 4319, which binds most
peptides with the structure pGlu-X-ProNH2. TRH was undetectable in serum
(< 25 pg/mL), but TRH-LI was detected with antiserum 4319 in serum of 27
normal subjects, 21 control patients, and 12 patients with carcinoid
tumors (range 17-45, 5-79, and 18-16,600 pg/mL, respectively). Because
serum was kept for at least 2 h at room temperature, which causes
degradation of TRH, pGlu-Phe-ProNH2, and pGlu-Tyr-ProNH2, serum TRH-LI is
not caused by these peptides. On high-performance liquid chromatography,
serum TRH-LI coeluted with pGlu-Glu-ProNH2 (< EEP-NH2), a peptide produced
in, among others, the prostate. Urine of normals and control patients also
contained TRH-LI (range 1.14-4.97 and 0.24-5.51 ng/mL, respectively), with
similar levels in males and females. TRH represented only 2% of urinary
TRH-LI, and anion-exchange chromatography and high-performance liquid
chromatography revealed that most TRH-LI in urine was < EEP-NH2. In
patients with carcinoid tumors, increased urinary TRH-LI levels were noted
(range 1.35-962.4 ng/mL). Urinary TRH-LI correlated positively with
urinary creatinine, and the urinary clearance rate of TRH-LI was similar
to the glomerular filtration rate. In addition, serum TRH-LI was increased
in 17 hemodialysis patients (43-373 pg/mL). This suggests that serum <
EEP-NH2 is cleared by glomerular filtration with little tubular
resorption. The possible role of the prostate as a source of urinary
TRH-LI was evaluated in 11 men with prostate cancer, showing a 25%
decrease in urinary TRH-LI excretion after prostatectomy (0.19 +/- 0.02
vs. 0.15 +/- 0.01 ng/mumol creatinine, mean +/- SEM). However, TRH-LI was
similar in spontaneously voided urine and in urine obtained through a
nephrostomy cannula from 16 patients with unilateral urinary tract
obstruction (0.15 +/- 0.01 vs. 0.14 +/- 0.01 ng/mumol creatinine). These
data indicate that: 1) TRH-LI in human serum represents largely < EEP-NH2,
which is cleared by renal excretion; 2) part of urinary < EEP-NH2 is
derived from prostatic secretion into the blood and not directly into
urine; and 3) urinary < EEP-NH2 can be used as marker for carcinoid
tumors
Renal clearance of the thyrotropin-releasing hormone-like peptide pyroglutamyl-glutamyl-prolineamide in humans
TRH-like peptides have been identified that differ from TRH
(pGlu-His-ProNH2) in the middle amino acid. We have estimated TRH-like
immunoreactivity (TRH-LI) in human serum and urine by RIA with
TRH-specific antiserum 8880 or with antiserum 4319, which binds most
peptides with the structure pGlu-X-ProNH2. TRH was undetectable in serum
(< 25 pg/mL), but TRH-LI was detected with antiserum 4319 in serum of 27
normal subjects, 21 control patients, and 12 patients with carcinoid
tumors (range 17-45, 5-79, and 18-16,600 pg/mL, respectively). Because
serum was kept for at least 2 h at room temperature, which causes
degradation of TRH, pGlu-Phe-ProNH2, and pGlu-Tyr-ProNH2, serum TRH-LI is
not caused by these peptides. On high-performance liquid chromatography,
serum TRH-LI coeluted with pGlu-Glu-ProNH2 (< EEP-NH2), a peptide produced
in, among others, the prostate. Urine of normals and control patients also
contained TRH-LI (range 1.14-4.97 and 0.24-5.51 ng/mL, respectively), with
similar levels in males and females. TRH represented only 2% of urinary
TRH-LI, and anion-exchange chromatography and high-performance liquid
chromatography revealed that most TRH-LI in urine was < EEP-NH2. In
patients with carcinoid tumors, increased urinary TRH-LI levels were noted
(range 1.35-962.4 ng/mL). Urinary TRH-LI correlated positively with
urinary creatinine, and the urinary clearance rate of TRH-LI was similar
to the glomerular filtration rate. In addition, serum TRH-LI was increased
in 17 hemodialysis patients (43-373 pg/mL). This suggests that serum <
EEP-NH2 is cleared by glomerular filtration wit
In vitro induction of NETosis: Comprehensive live imaging comparison and systematic review
__Background__ Multiple inducers of in vitro Neutrophil Extracellular Trap (NET) formation (NETosis) have been described. Since there is much variation in study design and results, our aim was to create a systematic review of NETosis inducers and perform a standardized in vitro study of NETosis inducers important in (cardiac) wound healing.
__Methods__ In vitro NETosis was studied by incubating neutrophils with PMA, living and dead bacteria (S. aureus and E. coli), LPS, (activated) platelets (supernatant), glucose and calcium ionophore Ionomycin using 3-hour periods of time-lapse confocal imaging.
__Results__ PMA is a consistent and potent inducer of NETosis. Ionomycin also consistently resulted in extrusion of DNA, albeit with a process that differs from the NETosis process induced by PMA. In our standardized experiments, living bacteria were also potent inducers of NETosis, but dead bacteria, LPS, (activated) platelets (supernatant) and glucose did not induce NETosis.
__Conclusion__ Our systematic review confirms that there is much variation in study design and results of NETosis induction. Our experimental results confirm that under standardized conditions, PMA, living bacteria and Ionomycin all strongly induce NETosis, but real-time confocal imaging reveal different courses of events
Angiographic and Optical Coherence Tomography Insights into Bioresorbable Scaffold Thrombosis: Single-Center Experience
Background - As bioresorbable vascular scaffolds (BVSs) are being increasingly used in complex real-world lesions and populations, BVS thrombosis cases have been repo
Risk factors for virological failure and subtherapeutic antiretroviral drug concentrations in HIV-positive adults treated in rural northwestern Uganda
ABSTRACT: BACKGROUND: Little is known about immunovirological treatment outcomes and adherence in HIV/AIDS patients on antiretroviral therapy (ART) treated using a simplified management approach in rural areas of developing countries, or about the main factors influencing those outcomes in clinical practice. METHODS: Cross-sectional immunovirological, pharmacological, and adherence outcomes were evaluated in all patients alive and on fixed-dose ART combinations for 24 months, and in a random sample of those treated for 12 months. Risk factors for virological failure (>1,000 copies/mL) and subtherapeutic antiretroviral (ARV) concentrations were investigated with multiple logistic regression. RESULTS: At 12 and 24 months of ART, 72% (n=701) and 70% (n=369) of patients, respectively, were alive and in care. About 8% and 38% of patients, respectively, were diagnosed with immunological failure; and 75% and 72% of patients, respectively, had undetectable HIV RNA (<400 copies/mL). Risk factors for virological failure (>1,000 copies/mL) were poor adherence, tuberculosis diagnosed after ART initiation, subtherapeutic NNRTI concentrations, general clinical symptoms, and lower weight than at baseline. About 14% of patients had low ARV plasma concentrations. Digestive symptoms and poor adherence to ART were risk factors for low ARV plasma concentrations. CONCLUSIONS: Efforts to improve both access to care and patient management to achieve better immunological and virological outcomes on ART are necessary to maximize the duration of first-line therapy
Dose adjustment of the non-nucleoside reverse transcriptase inhibitors during concurrent rifampicin-containing tuberculosis therapy: one size does not fit all
Importance of the field: HIV/tuberculosis (TB) co-infection is common and
associated with high mortality. Simultaneous highly active antiretroviral
therapy during TB treatment is associated with substantial survival benefit
but drug–drug interactions complicate NNRTI dosing.
Areas covered in this review: We reviewed the impact of rifampicin-containing
TB therapy on the NNRTIs pharmacokinetics and clinical outcome. PubMed
database was searched from 1966 to July 2009 using the terms efavirenz,
rifampicin, nevirapine, pharmacokinetics, pharmacogenetics, HIV, TB, CYP2B6,
CYP3A4 and metabolism. References from identified articles and abstracts
from meetings were also reviewed.
What the reader will gain: A comprehensive review of the literature on this
subject including pharmacokinetic and clinical studies. Most studies were
small, observational or underpowered to detect the true effect of rifampicin
on NNRTI-based therapy. None of the studies were controlled for genetic
factors and there were limited data on children.
Take home message: There were insufficient data to make definitive recommendations
about dose adjustment of the NNRTIs during rifampin-containing
therapy. Current data suggest that the standard dose of efavirenz or nevirapine
is adequate in most HIV/TB co-infected adults. However, more research is
needed in pediatric populations as well as to define role of drug–gene
interactions
A review of the evidence for the efficacy of Anti-Embolism Stockings (AES) in Venous Thromboembolism (VTE) prevention
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