Efavirenz plasma concentrations and efficiency.
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Biomedical subjects
Publications and source records attributed to L F López-Cortés.
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In order to assess whether complete inactivation of retinitis at the end of induction therapy leads to delayed progression during maintenance therapy with weekly intravitreal ganciclovir, the time to the first progression to retinitis was evaluated in 27 AIDS patients (34 eyes) with stable cytomegalovirus retinitis. Data were censored before the introduction of protease inhibitors. Overall, retinitis progressed in 22 of 34 eyes in a median time of 12 weeks (mean +/- SD, 33 +/- 9 weeks). However, retinitis progressed in 15 of 19 eyes in which only partial inactivation was achieved following induction therapy (median time, 10 weeks; mean +/- SD, 17 +/- 4 weeks) but in only 7 of 15 eyes when complete inactivation was obtained (median time, 59 weeks; mean +/- SD, 56 +/- 19 weeks) (P= 0.02). There were no differences between the groups in CD4+ cell counts, drugs, route of induction treatment, or length of induction therapy. Induction therapy should be prolonged until complete inactivation of retinitis is obtained, since achieving only a partial response appears to be a factor in earlier progression when patients are switched to maintenance therapy with intravitreal ganciclovir.
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PURPOSE: To perform a detailed pharmacokinetic study and to evaluate the drug levels reached in the retina after the intravitreal administration of ganciclovir and foscarnet to rabbits. METHODS: Retinal and vitreal levels of both drugs were measured by high-performance liquid chromatography at 1, 6, 12, 24, 36, 48, 60, and 72 hours after a single intravitreal injection of 196 microg and 800 microg of ganciclovir and 960 microg of foscarnet to three groups of 24 pigmented rabbits. A noncompartmental pharmacokinetic analysis was used. RESULTS: Both drugs incorporated rapidly into the retina, but no equilibrium was observed between the drug levels in the vitreous humor and retina. Mean ganciclovir levels in vitreous and retina were 179.6 microg/g and 131.3 microg/g (dose of 196 microg), 755.7 microg/g and 381.6 microg/g (dose of 800 microg) at 1 hour after administration, decreasing to 0.1 microg/g, 0.6 microg/g, 0.8 microg/g, and 0.7 microg/g, respectively, by 72 hours. Mean foscarnet levels in vitreous and retina were 944 microg/g and 217.1 microg/g at 1 hour after administration, decreasing to 74 microg/g and 17.1 microg/g, respectively, by 72 hours. Whereas both doses of ganciclovir yielded retinal levels above the mean inhibitory concentration (IC50) of most human cytomegalovirus (CMV) isolates for more than 60 hours, foscarnet retinal levels were lower than the CMV IC50 before 36 hours had elapsed after administration. CONCLUSIONS: The results suggest that the intravitreal administration of ganciclovir has a better pharmacokinetic profile than foscarnet for the treatment of retinitis caused by CMV and other herpes viruses and support the administration of intravitreal ganciclovir twice a week as a treatment for CMV retinitis.
OBJECTIVE: To evaluate whether cerebrospinal fluid concentrations of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, or IL-8 may be used as diagnostic markers for the differential diagnosis of aseptic vs. bacterial meningitis and/or ventriculitis in neurosurgical patients. DESIGN: Prospective, observational study. SETTING: University teaching hospital. SUBJECTS: A total of 112 cerebrospinal fluid samples from 14 asymptomatic patients with normal cerebrospinal fluid after neurosurgery, 27 asymptomatic and 19 symptomatic patients with postneurosurgical aseptic meningitis, 32 patients with postneurosurgical cerebrospinal fluid infection, and 20 with severe subarachnoid and/or cerebral hemorrhage. MEASUREMENTS AND MAIN RESULTS: Specific ELISA kits were used to analyze TNF-alpha, IL-1beta, IL-6, and IL-8 concentrations on cerebrospinal fluid samples. Elevations in cerebrospinal fluid concentrations of TNF-alpha, IL-1beta, IL-6, and IL-8 were induced by different diseases or neurosurgical procedures, but cerebrospinal fluid bacterial infection induced the highest concentrations. To discriminate between aseptic cerebrospinal fluid pleocytosis and cerebrospinal fluid infection with a specificity of 95%, cerebrospinal fluid leukocyte count >1700/mL, TNF-alpha >150 pg/mL, and IL-1beta >90 pg/mL showed sensitivities of 51%, 74%, and 90%, respectively. Sufficiently sensitive and specific cutoff points could not be found for cerebrospinal fluid IL-6 or IL-8. CONCLUSION: Cerebrospinal fluid IL-1beta appears to be the best biochemical marker of cerebrospinal fluid infection in neurosurgical patients.
Retinal, vitreous humor, brain, and cerebrospinal fluid (CSF) foscarnet levels were measured by high-performance liquid chromatography after administration of an intravenous dose of 120 mg/kg of body weight to 32 pigmented rabbits. A pharmacokinetic analysis was done using a two-compartment model. The penetration ratios, defined as ratios of retinal, vitreous humor, brain, and CSF areas under the concentration-time curve from 0 to 2 h were 110% +/- 1%, 12.3% +/- 0.7%, 118% +/- 1%, and 20.2% +/- 2.2%, respectively. These results suggest a good penetration of foscarnet into the retinal and brain tissues, reaching higher concentrations than those estimated from vitreous humor and CSF levels.
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BACKGROUND: Fever of intermediate duration (FID), characterized by a febrile syndrome lasting from 7 to 28 days, is a frequent condition in clinical practice, but its epidemiological and etiologic features are not well described. Murine typhus (MT) is a worldwide illness; nevertheless, to our knowledge, no studies describing its epidemiological and clinical characteristics have been performed in the south of Spain. Also, its significance as a cause of FID is unknown. OBJECTIVE: To determine the epidemiological features, clinical characteristics, and prognosis of MT and, prospectively, its incidence as a cause of FID. DESIGN: Prospective study of cases of MT over 17 years (1979-1995) and of all cases of FID treated in a tertiary teaching hospital in Seville, Spain. RESULTS: One hundred and four cases of MT were included, and MT was the cause in 6.7% of 926 cases of FID. Insect bites were reported in only 3.8% of the cases of MT previous to the onset of illness. Most cases (62.5%) occurred in the summer and fall. A high frequency of rash (62.5%) was noted. Arthromyalgia (77%), headache (71%), and respiratory (25%) and gastrointestinal (23%) symptoms were also frequent. Laboratory findings were unspecific. Organ complications were uncommon (8.6%), but they were severe in 4 cases. The mean duration of fever was 12.5 days. Cure was achieved in all cases, although only 44 patients received specific treatment. CONCLUSIONS: Murine typhus is prevalent in the south of Spain and is a significant cause of FID. Clinical signs are benign, but some patients may develop severe complications. A high degree of clinical suspicion is required for diagnosis.
A prospective study was conducted to determine the etiology, clinical features, and outcome in a series of 32 consecutively enrolled HIV-infected patients with prolonged fever in whom high resolution (7.5 Mhz) sonography revealed multiple splenic microabscesses. Conventional (3.5 Mhz) sonography showed no splenic abnormalities in any patients. The diagnoses were: tuberculosis (14), visceral leishmaniasis (7), disseminated Mycobacterium avium complex infection (5), Salmonella spp. bacteremia (2), lymphoma (2), disseminated Rhodococcus equi infection (1), disseminated Candida krusei infection (1) and Pneumocystis carinii pneumonia (1). Twenty-eight patients were followed up for six months and four were lost to follow-up. In 16 patients with a clinical cure and microbiological eradication, the findings on follow-up high resolution sonography were normal, and in two patients the microabscesses persisted; ten patients died. In conclusion, the findings suggest splenic microabscesses may be a frequent condition in HIV-infected patients with prolonged fever, being an unspecific manifestation of the opportunistic diseases causing fever of unknown origin in this population. They cannot be detected by conventional abdominal sonography, whereas high resolution sonography is a useful technique for their detection and follow-up.
OBJECTIVE: To review a serie of patients with cryptococcal meningitis and immunodeficiency syndrome (AIDS) treated in our hospital in the last two years. PATIENTS AND METHODS: Retrospective study of 25 patients infected with the human immunodeficiency virus (HIV) and affected by Cryptococcus neoformans meningitis. The factors analysed were epidemiological data, clinical manifestations, biochemical and microbiological characteristics of cerebrospinal fluid (CSF), radiological abnormalities, treatment, adverse reactions and outcomes. RESULTS: Eighty-four percent of patients had less than 200 CD4/microliter. Cryptococcal infection was the AIDS defining illness in 24% of cases. Patients typically presented with neurologic symptoms such as: headache (88%), fever (68%) and somnolence (68%); 20% presented seizures and 28% focal deficits. There were no CSF biochemical alterations in 25% of them. CSF culture and indian ink stain were positive in 76%. CSF cryptococcal antigen test was positive in 68% of the cases. TC showed abnormalities in 48%. CSF of all patients treated with amphotericin B (AB) plus flucytosine (5FC) whose CSF culture was monitored became negative in the first two weeks, meanwhile those treated only with AB or fluconazol had negative control culture in 60% and 50% respectively. Six patients died within the initial 10 weeks. Death was due to bacterian sepsis in 3 patients and high intracranial pressure was the cause in 2 cases. One happened before treatment was administered. CONCLUSIONS: It's essential to consider the possibility of cryptococcal meningitis in patients infected with HIV and any compatible symptom regardless of CSF biochemical results and immunodepression level (CD4). Although our study was non randomized and so we can't propose a therapeutical schedule based on it, we can say that patients treated with AB plus 5FC showed an earlier conversion from positive to negative CSF cultures without more adverse reactions.
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We compared two techniques for detecting delayed-type hypersensitivity (DTH) skin responses in 359 patients infected with human immunodeficiency virus (HIV) (mean CD4+ lymphocyte count, 387/microL). DTH responses were assessed with use of two antigenic panels administered simultaneously: tuberculin purified protein derivative (PPD) plus three control antigens (Candida albicans, mumps antigen, and tetanus toxoid) administered by the Mantoux method and by a multiple-puncture device delivering seven antigens percutaneously (MULTITEST CMI; Institut Mérieux, Lyon, France). Eighty-three patients (23%) were anergic, 216 (60%) reacted to both panels, 55 (15%) did not react to MULTITEST CMI but did react to the antigens administered by Mantoux method, and only five (1%) reacted to MULTITEST CMI without reacting to antigens administered by the Mantoux method (P < .001, McNemar's test). Each of the three possible combinations of PPD plus two control antigens administered by the Mantoux method were also superior to MULTITEST CMI for classifying patients as nonanergic (P < .001, McNemar's test). We conclude that the application of antigens by the Mantoux method is more efficient than MULTITEST CMI for detecting DTH skin responses in HIV-infected patients.
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During the last two years important advances in the diagnosis and treatment of cytomegalovirus (CMV) disease have occurred. Several studies have suggested that biologic markers of CMV viremia (PCR, branched DNA and pp65 antigenemia) might be useful both to stratify the risk of developing CMV disease and to follow the response of CMV retinitis to therapy. It has been shown that patients who are plasma CMV PCR positive have a risk of developing CMV disease three times higher than patients who are plasma CMV PCR negative. In addition, for each log10 increase of the CMV viral load there is a 3-fold higher risk of developing CMV disease. Currently, therapeutic options for induction treatment of CMV retinitis (CMVR) are: i.v. ganciclovir (GCV), i.v. foscarnet, i.v. cidofovir or GCV intraocular implant combined with oral GCV. For maintenance therapy options are: i.v. GCV (3, 5 or 7 days per week), oral GCV (only for peripheral retinitis), i.v. foscarnet (daily), i.v. cidofovir (biweekly) and GCV intraocular implant (replaced every 6-8 months) combined with oral GCV. There is currently enough evidence to allow the diagnosis of progressive multifocal leukoencephalopathy (PML) based on the finding of JC virus DNA in CSF by PCR. There are still no drugs with proven clinical efficacy against JC virus but the possibility that HAART treatments might improve the control of this disease appear promising.
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We assayed interleukin 6 (IL-6) concentrations in cerebrospinal fluid (CSF) from patients affected by meningitis of different aetiologies, and verified whether IL-6 can be used as a diagnostic marker in the differential diagnosis of meningitis. We used a monoclonal antibody enzyme immunoassay to test 98 CSF samples classified as pyogenic (15), viral (15), self-resolving aseptic meningitis (20), other infectious meningitis (9), neoplastic (4) and normal CSF from patients with (20) and without (15) non-infectious neurological diseases. CSF IL-6 concentrations were increased in pyogenic meningitis (100%) and in more than 50% of viral and other subarachnoid space infections, and rarely in patients without central nervous system infections. Though patients affected by pyogenic meningitis showed the highest levels of CSF IL-6, only a cut-off point > or = 10000 pg/mL was able to discriminate pyogenic meningitis from those of other aetiologies with a specificity > or = 94% and a positive predictive value of > or = 0.75 but the sensitivity was < or = 60%. Therefore, CSF IL-6 concentration is not a good diagnostic marker in the differential diagnosis of meningitis.