RESUMO
OBJECTIVES: To describe the course of symptoms reported by patients with symptoms attributed to Lyme borreliosis (LB) without being subsequently diagnosed with LB. METHODS: We performed a prospective cohort study with patients presenting at the outpatient clinic of two clinical LB centres. The primary outcome was the prevalence of persistent symptoms, which were defined as clinically relevant fatigue (CIS, subscale fatigue), pain (SF-36, subscale bodily pain), and cognitive impairment (CFQ) for ≥ 6 months and onset < 6 months over the first year of follow-up. Outcomes were compared with a longitudinal cohort of confirmed LB patients and a general population cohort. Prevalences were standardised to the distribution of pre-defined confounders in the confirmed LB cohort. RESULTS: Participants (n = 123) reported mostly fatigue, arthralgia, myalgia, and paraesthesia as symptoms. The primary outcome could be determined for 74.8% (92/123) of participants. The standardised prevalence of persistent symptoms in our participants was 58.6%, which was higher than in patients with confirmed LB at baseline (27.2%, p < 0.0001) and the population cohort (21.2%, p < 0.0001). Participants reported overall improvement of fatigue (p < 0.0001) and pain (p < 0.0001) but not for cognitive impairment (p = 0.062) during the follow-up, though symptom severity at the end of follow-up remained greater compared to confirmed LB patients (various comparisons p < 0.05). CONCLUSION: Patients with symptoms attributed to LB who present at clinical LB centres without physician-confirmed LB more often report persistent symptoms and report more severe symptoms compared to confirmed LB patients and a population cohort.
Assuntos
Fadiga , Doença de Lyme , Humanos , Doença de Lyme/epidemiologia , Doença de Lyme/diagnóstico , Masculino , Estudos Prospectivos , Feminino , Pessoa de Meia-Idade , Fadiga/etiologia , Fadiga/epidemiologia , Seguimentos , Adulto , Inquéritos e Questionários , Idoso , Prevalência , Disfunção Cognitiva/epidemiologia , Disfunção Cognitiva/etiologia , Dor/etiologia , Dor/epidemiologia , Artralgia/microbiologia , Artralgia/epidemiologia , Artralgia/etiologia , Adulto JovemRESUMO
Lyme borreliosis is caused by spirochetes belonging to the Borrelia burgdorferi sensu lato group, which are transmitted by Ixodes tick species living in the temperate climate zones of the Northern Hemisphere. The clinical manifestations of Lyme borreliosis are diverse and treated with oral or intravenous antibiotics. In some patients, long-lasting and debilitating symptoms can persist after the recommended antibiotic treatment. The etiology of such persisting symptoms is under debate, and one hypothesis entails persistent infection by a subset of spirochetes after antibiotic therapy. Here, we review and appraise the experimental evidence from in vivo animal studies on the persistence of B. burgdorferi sensu lato infection after antibiotic treatment, focusing on the antimicrobial agents doxycycline and ceftriaxone. Our review indicates that some in vivo animal studies found sporadic positive cultures after antibiotic treatment. However, this culture positivity often seemed to be related to inadequate antibiotic treatment, and the few positive cultures in some studies could not be reproduced in other studies. Overall, current results from animal studies provide insufficient evidence for the persistence of viable and infectious spirochetes after adequate antibiotic treatment. Borrelial nucleic acids, on the contrary, were frequently detected in these animal studies and may thus persist after antibiotic treatment. We put forward that research into the pathogenesis of persisting complaints after antibiotic treatment for Lyme borreliosis in humans should be a top priority, but future studies should most definitely also focus on explanations other than persistent B. burgdorferi sensu lato infection after antibiotic treatment.
Assuntos
Grupo Borrelia Burgdorferi , Ixodes , Doença de Lyme , Animais , Humanos , Antibacterianos/uso terapêutico , Doença de Lyme/diagnóstico , Doença de Lyme/tratamento farmacológico , Modelos AnimaisRESUMO
OBJECTIVE: To investigate which preventive measures runners use when preparing for a half- or full-marathon and whether the use of these measures at baseline and during the preparation-period differs between runners who sustained no/non-substantial running-related injuries (NSIRs) or substantial running-related injuries (SIRs). DESIGN: Prospective cohort study. SETTING: 16-week period before the Utrecht Marathon. PARTICIPANTS: Runners who subscribed for the half- or full-marathon. MAIN OUTCOME MEASURES: The occurrence of RRIs was registered every 2-weeks, using the Dutch version of the Oslo Sport Trauma Research Center (OSTRC) questionnaire on Health Problems. The OSTRC was used to differentiate between runners with SIRs (question 2/3 score>12) and NSIRs (question 2/3 score<13). The use of different preventive measures, was registered every 4-weeks. RESULTS: 51.6% of the runners reported at least one RRI in the 12-months prior to this study (history of RRIs). The SIRs with a history of RRIs more often asked for running shoe advice than NSIRs with a history of RRIs (67.9%vs43.4%, P < 0.05); 18.9% of the SIRs with a history of RRIs used supportive materials for knee and/or ankle versus 0% of NSIRs with a history of RRIs (P < 0.05). CONCLUSION: SIRs with a history of RRIs might be using their preventive measures for symptom reduction or secondary prevention.
Assuntos
Traumatismos em Atletas/prevenção & controle , Resistência Física , Corrida/lesões , Adulto , Traumatismos em Atletas/epidemiologia , Bandagens , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Estudos Prospectivos , Sapatos , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: There has been an increase in testing of vitamins in patients in general practice, often based on irrational indications or for non-specific symptoms, causing increasing healthcare expenditures and medicalisation of patients. So far, there is little evidence of effective strategies to reduce this overtesting in general practice. Therefore, the aim of this qualitative study was to explore the barriers and facilitators for reducing the number of (unnecessary) vitamin D and B12 laboratory tests ordered. DESIGN AND SETTING: This qualitative study, based on a grounded theory design, used semistructured interviews among general practitioners (GPs) and patients from two primary care networks (147 GPs, 195 000 patients). These networks participated in the Reducing Vitamin Testing in Primary Care Practice (REVERT) study, a clustered randomized trial comparing two de-implementation strategies to reduce test ordering in primary care in the Netherlands. PARTICIPANTS: Twenty-one GPs, with a maximum of 1 GP per practice who took part in the REVERT study, and 22 patients (who were invited by their GP during vitamin-related consultations) were recruited, from which 20 GPs and 19 patients agreed to participate in this study. RESULTS: The most important factor hampering vitamin-test reduction programmes is the mismatch between patients and medical professionals regarding the presumed appropriate indications for testing for vitamin D and B12. In contrast, the most important facilitator for vitamin-test reduction may be updating GPs' knowledge about test indications and their awareness of their own testing behaviour. CONCLUSION: To achieve a sustainable reduction in vitamin testing, guidelines with clear and uniform recommendations on evidence-based indications for vitamin testing, combined with regular (individual) feedback on test-ordering behaviour, are needed. Moreover, the general public needs access to clear and reliable information on vitamin testing. Further research is required to measure the effect of these strategies on the number of vitamin test requests. TRIAL REGISTRATION NUMBER: WAG/mb/16/039555.
Assuntos
Técnicas de Laboratório Clínico , Medicina Geral , Uso Excessivo dos Serviços de Saúde/prevenção & controle , Vitamina B 12/sangue , Vitamina D/sangue , Atitude do Pessoal de Saúde , Técnicas de Laboratório Clínico/economia , Técnicas de Laboratório Clínico/métodos , Análise por Conglomerados , Feminino , Medicina Geral/economia , Medicina Geral/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Países Baixos , Avaliação de Resultados em Cuidados de Saúde , Padrões de Prática Médica , Pesquisa Qualitativa , Procedimentos Desnecessários/economiaRESUMO
Our objective was to describe clinical features and predisposing factors attributed to lactic acidosis in 4 HIV-infected patients on long-term nucleoside reverse transcriptase inhibitor (NRTI) therapy. All patients had received at least 6-20 months of NRTI-containing antiretroviral therapy: all used stavudine (d4T), in one combined with lamivudine (3TC), in the other 3 with didanosine (ddI); in one hydroxyurea was added. In all, the initial symptoms were gastrointestinal (nausea and vomiting), followed by tachypnoea preceding the lactic acidosis; death followed 6-22 days after admission (liver failure and uncontrollable arrhythmias). Treatment with riboflavin was unsuccessful in one patient. The only definite risk factor in all cases was NRTI-induced mitochondrial toxicity; one patient was concomitantly treated for Kaposi's sarcoma (with bleomycin and vinblastine) and one just recovered from pneumococcal sepsis. None of the patients had a history of chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. In all patients, some sort of toxicity to other previously used NRTIs had occurred earlier. Lactic acidosis occurred after months of NRTI therapy in patients who had already suffered other forms of NRTI toxicity. Concomitant diseases or comedication might have aggravated the mitochondrial toxicity of the NRTIs. Screening methods to detect mitochondrial toxicity are necessary, since lactic acidosis occurs rather unexpectedly, with a rapid, fatal course.
Assuntos
Acidose Láctica/induzido quimicamente , Fármacos Anti-HIV/efeitos adversos , Infecções por HIV/tratamento farmacológico , Inibidores da Transcriptase Reversa/efeitos adversos , Acidose Láctica/diagnóstico , Adulto , Fármacos Anti-HIV/administração & dosagem , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Evolução Fatal , Feminino , Humanos , Masculino , Inibidores da Transcriptase Reversa/administração & dosagem , Fatores de RiscoRESUMO
An indinavir oral liquid was developed and studied. Several oral liquids containing indinavir were prepared and taste tested in eight healthy volunteers. Physical and chemical stability over two weeks were examined, and a randomized, two-way-crossover, single-dose bioequivalence trial was performed in 12 healthy male volunteers. Indinavir 800 mg was given as two 400-mg indinavir capsules (Crixivan) on day 1 and as 80 mL of the indinavir liquid on day 2, or vice versa. A standard breakfast and lunch were given at fixed times, and blood and urine samples were collected at various intervals up to eight hours. The log-transformed area under the concentration-versus-time curve from zero to eight hours (AUC0-8) and maximum plasma concentration (Cmax) for the liquid versus the capsules were compared by using a 90% confidence interval (CI) test (limits, 80-125%), and the time to Cmax (tmax) was compared by using the nonparametric sign test. The liquid selected had an acceptable taste, contained indinavir 10 mg/mL, and was chemically stable for two weeks at 4 degrees C. The 90% CI for the AUC ratio (liquid versus capsules) was 92-99% (mean, 95%); for the Cmax ratio it was 95-106% (mean, 100%). There was no significant difference in tmax between the liquid and capsules. An oral liquid formulation of indinavir was developed that had an acceptable taste, was chemically stable, and was bioequivalent to the commercially available capsule.
Assuntos
Inibidores da Protease de HIV/administração & dosagem , Indinavir/administração & dosagem , Administração Oral , Adulto , Criança , Estabilidade de Medicamentos , Humanos , Indinavir/química , Masculino , Pessoa de Meia-Idade , Equivalência TerapêuticaRESUMO
The concentration of radon daughters has been determined in and around 80 dwellings located in the northern part of the Netherlands by using a one-filter method. Median values of 2.0 and 0.4 mWL were measured for the indoor and outdoor concentrations, respectively. The average outdoor concentration was about an order of magnitude higher for wind directions between SE and SW than for SW-NW. On the average, dwellings with double-pane windows and/or concrete floors were found to have significantly higher radon concentrations than those with single-pane windows and/or wooden floors. For the living room of a particular dwelling 18 measurements were carried out. The data for this dwelling indicate a linear relation between the concentration indoors and outdoors with a slope of 3.8 +/- 2.0. This unexpected behaviour is thought to be related to ventilation via the crawl space. Measurements of ventilation patterns and measurements of radon concentrations in the living room and the crawl space are consistent with this picture.
Assuntos
Poluentes Radioativos do Ar/análise , Poluentes Atmosféricos/análise , Bismuto/análise , Materiais de Construção , Habitação , Chumbo/análise , Polônio/análise , Ventilação , Países Baixos , Produtos de Decaimento de RadônioRESUMO
Three men aged 53, 25 and 34 years and 2 women aged 39 and 34 years with HIV infection had different courses with and without highly active antiretroviral therapy (HAART). Medication regimes were often complicated and adverse events occurred frequently, which led to adjustment of treatment. Since the introduction of HAART for treatment of HIV infection, a tremendous progress has been achieved, resulting in reduction of HIV related events and in reduction of fatality due to AIDS. However, besides the positive effects of this therapy, there is also a negative side of HAART. In addition to the complexity and adverse events, the medication has to be taken lifelong while non-compliance might result in resistance-mutation. If HAART might be indicated, it is necessary to weigh the pros and contras before starting with medication.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Cooperação do Paciente/psicologia , Inibidores da Transcriptase Reversa/administração & dosagem , Adulto , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Infecções por HIV/complicações , Infecções por HIV/mortalidade , Infecções por HIV/psicologia , Inibidores da Protease de HIV/efeitos adversos , HIV-1/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do TratamentoRESUMO
A 33-year-old HIV-infected man was given antiretroviral therapy with zidovudine and lamivudine. After ten months' treatment the patient had elevated hepatic transaminase levels. Severe hepatic steatosis was found in the biopsy. Clinical history, laboratory, microbiologic and X-ray examination revealed no other abnormalities. The transaminase levels remained high after withdrawal of zidovudine alone, but a decrease was observed when both zidovudine and lamivudine were stopped. Rechallenge of lamivudine therapy caused the levels to increase again. The hepatic steatosis was considered to be caused by the antiretroviral therapy, lamivudine having a synergistic influence on this side effect of zidovudine. Ten months after the therapy was changed to the protease inhibitor indinavir combined with zalcitabine and stavudine, two other nucleoside analogues, hepatic steatosis recurred.
Assuntos
Fármacos Anti-HIV/efeitos adversos , Fígado Gorduroso/induzido quimicamente , Soropositividade para HIV/tratamento farmacológico , Lamivudina/efeitos adversos , Zidovudina/efeitos adversos , Adulto , Quimioterapia Combinada , Fígado Gorduroso/enzimologia , Fígado Gorduroso/patologia , Humanos , Masculino , Transaminases/sangueAssuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , HIV-1 , Contagem de Linfócito CD4 , Esquema de Medicação , Infecções por HIV/imunologia , Infecções por HIV/virologia , Inibidores da Protease de HIV/uso terapêutico , HIV-1/genética , Humanos , Lamivudina/uso terapêutico , Nelfinavir/uso terapêutico , RNA Viral/sangue , Inibidores da Transcriptase Reversa/uso terapêutico , Saquinavir/uso terapêutico , Estavudina/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Carga ViralAssuntos
Terapia Antirretroviral de Alta Atividade/efeitos adversos , Infecções por HIV/tratamento farmacológico , Síndrome de Lipodistrofia Associada ao HIV/induzido quimicamente , Doenças Mitocondriais/induzido quimicamente , Inibidores da Transcriptase Reversa/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Síndrome de Lipodistrofia Associada ao HIV/tratamento farmacológico , Síndrome de Lipodistrofia Associada ao HIV/epidemiologia , Síndrome de Lipodistrofia Associada ao HIV/fisiopatologia , Humanos , Doenças Mitocondriais/diagnóstico , Doenças Mitocondriais/epidemiologia , Doenças Mitocondriais/fisiopatologia , Fatores de RiscoRESUMO
In antiretroviral therapy, to improve compliance the need is increasing to develop regimens that combine potency and safety with convenient dosing. The objective of our study was to find a once-daily dosing regimen of a HIV-protease inhibitor, indinavir (IDV), by combining it with ritonavir (RTV). In the study, 12 healthy volunteers took a single IDV dose of 800 mg on day 1. Plasma and urine sampling was done for 12 hours. From day 2 to day 21, participants took RTV liquid 200 mg (group A) or 400 mg (group B) once daily. Repeated pharmacokinetic sampling was performed over the course of 24 hours, after single doses of indinavir 400 mg (day 15), 800 mg (day 18), and 1200 mg (day 21). The best dosage regimen in this pharmacokinetic study was selected based on efficacy and tolerability criteria. The study comprised 10 male and 2 female healthy volunteers, mean age, 25 years (range, 18-50 years), mean weight, 70 kg (range, 52-83 kg). One male participant discontinued on day 8 due to influenza. All other participants completed the study without the occurrence of serious adverse events. RTV inhibited indinavir plasma clearance by 51% to 70%, leading to increased and prolonged IDV exposure. Renal clearance was influenced by the addition of RTV and dosage increments of IDV. The efficacy criterion was best fulfilled by 1200 mg IDV/400 mg RTV, whereas this combination performed most poorly on tolerability criteria. Based on the single dose data, a once-daily regimen of IDV with a low dose of RTV is possible. The best dosage regimen to start with among those studied here appears to be 1200 mg IDV/400 mg RTV, which could be decreased at steady state to 800 IDV/400 RTV or 1200 IDV/200 RTV if toxicity occurs. Steady-state pharmacokinetic data of once-daily IDV/RTV regimens in HIV-infected patients are warranted.
Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores da Protease de HIV/administração & dosagem , Indinavir/administração & dosagem , Ritonavir/administração & dosagem , Adolescente , Adulto , Creatinina/sangue , Quimioterapia Combinada , Feminino , Inibidores da Protease de HIV/efeitos adversos , Inibidores da Protease de HIV/farmacocinética , Humanos , Indinavir/efeitos adversos , Indinavir/farmacocinética , Absorção Intestinal , Masculino , Pessoa de Meia-Idade , Ritonavir/efeitos adversos , Ritonavir/farmacocinéticaRESUMO
OBJECTIVE: To report a case of antiretroviral therapy failure caused by an interaction between carbamazepine and indinavir. CASE SUMMARY: A 48-year-old HIV-positive white man was treated with antiretroviral triple therapy, consisting of indinavir, zidovudine, and lamivudine. His HIV-RNA (viral load) became undetectable (<400 copies/mL) less than two months after this therapy was started; this was confirmed one month later. Shortly after the start of antiretroviral therapy, the patient developed herpes zoster, which was treated with famciclovir. Tramadol was initially prescribed for postherpetic neuralgia; however, this was substituted with carbamazepine due to insufficient analgesic effect. Indinavir plasma concentrations decreased substantially during carbamazepine therapy. Carbamazepine was stopped after 2.5 months and, two weeks later, the HIV-RNA was detectable (6 x 103 copies/mL). Resistance for lamivudine was observed in that blood sample; resistance for zidovudine might have been present, and resistance to indinavir was not detected. A few months later, a further increase of the HIV-RNA occurred (300 x 103 copies/mL), after which the therapy was switched to a new antiretroviral regimen containing nevirapine, didanosine, and stavudine. DISCUSSION: Physicians may prescribe carbamazepine for HIV-infected patients to treat seizures or postherpetic neuralgia, which are complications of opportunistic infections such as herpes zoster or toxoplasmosis. Carbamazepine is a potent enzyme inducer, predominantly of the CYP3A enzyme system, while HIV-protease inhibitors such as indinavir are substrates for and inhibitors of CYP3A. Therefore, an interaction between these drugs could be expected. A low dose of carbamazepine (200 mg/d) and the usual dose of indinavir (800 mg q8h) in our patient resulted in carbamazepine concentrations within the therapeutic range for epilepsy treatment; indinavir concentrations dropped substantially. The virologic, resistance, and plasma drug concentration data, as well as the chronology of events, are highly indicative of antiretroviral treatment failure due to the interaction between carbamazepine and indinavir. CONCLUSIONS: Concomitant use of carbamazepine and indinavir may cause failure of antiretroviral therapy due to insufficient indinavir plasma concentrations. Drugs other than carbamazepine should be considered to prevent this interaction. Amitriptyline or gabapentin are alternatives for postherpetic neuralgia; valproic acid or lamotrigine are alternatives for seizures. When alternate drug therapy is not possible, dosage adjustments, therapeutic drug monitoring, and careful clinical observation may help reduce adverse clinical consequences.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Anticonvulsivantes/uso terapêutico , Carbamazepina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Indinavir/uso terapêutico , Fármacos Anti-HIV/sangue , Inibidores das Enzimas do Citocromo P-450 , Interações Medicamentosas , Quimioterapia Combinada , HIV/efeitos dos fármacos , Humanos , Indinavir/sangue , Masculino , Pessoa de Meia-Idade , Convulsões/tratamento farmacológico , Falha de TratamentoRESUMO
The presence of the HIV-protease inhibitor indinavir in saliva was analyzed to investigate whether salivary indinavir concentrations are applicable to monitor compliance and/or predict plasma indinavir levels. Fourteen HIV-infected outpatients treated with indinavir and 24 healthy volunteers who ingested a single dose of indinavir were included. Paired plasma and citric-acid-stimulated saliva samples were analyzed by high-performance liquid chromatography (HPLC). Stimulated salivary indinavir concentrations showed a high correlation (r = 0.85, p < 0.01) with corresponding plasma levels. The median saliva/plasma ratio was 65% (P25 50%; P75 94%). The ratios were independent of the plasma concentration; however, a relation with time after ingestion was seen. The unbound fraction of indinavir in plasma was not significantly correlated with the saliva/plasma ratio after stimulated saliva collection, in contrast with a subset of nonstimulated saliva from healthy volunteers, where we did find a significant correlation. Although stimulated salivary indinavir concentrations are highly correlated with plasma concentrations, it is not possible to predict plasma indinavir levels by the salivary concentrations for purposes of therapeutic drug monitoring, due to large interindividual and intraindividual variation. Nevertheless, monitoring compliance by measuring the presence of indinavir in saliva is possible: ingestion of indinavir can be assessed with a sensitivity of 84.8% in the whole dosing interval or with 98.8% between 1 and 6 hours after the last dose, which is comparable with plasma.