Systematic review of drug–drug interactions between rifamycins and anticoagulant and antiplatelet agents and considerations for management

Rifamycins (rifampin, rifabutin, and rifapentine) play an essential role in the treatment of mycobacterial and some nonmycobacterial infections. They also induce the activity of various drug transporting and metabolizing enzymes, which can impact the concentrations and efficacy of substrates. Many anticoagulant and antiplatelet (AC/AP) agents are substrates of these enzymes and have narrow therapeutic indices, leading to risks of thrombosis or bleeding when coadministered with rifamycins. The objective of this systematic review was to evaluate the effects on AC/AP pharmacokinetics, laboratory markers, and clinical safety and efficacy of combined use with rifamycins. A systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidance was performed. The PubMed, Embase, and Web of Science databases were queried for English-language reports on combination use of rifamycins and AC/AP agents from database inception through August 2021. The 29 studies identified examined warfarin (n = 17), direct oral anticoagulants (DOACs) (n = 8), and antiplatelet agents (n = 4) combined with rifampin (n = 28) or rifabutin (n = 1). Eleven studies were case reports or small case series; 14 reported on pharmacokinetic or laboratory markers in healthy volunteers. Rifampin-warfarin combinations led to reductions in warfarin area under the curve (AUC) of 15%–74%, with variability by warfarin isomer and study. Warfarin dose increases of up to 3–5 times prerifampin doses were required to maintain coagulation parameters in the therapeutic range. DOAC AUCs were decreased by 20%–67%, with variability by individual agent and with rifampin versus rifabutin. The active metabolite of clopidogrel increased substantially with rifampin coadministration, whereas prasugrel was largely unaffected and ticagrelor saw decreases. Our review suggests most combinations of AC/AP agents and rifampin are problematic. Further studies are required to determine whether rifabutin or rifapentine could be safe alternatives for coadministration with AC/AP drugs.     

Evaluating the Cost-Effectiveness of Hydrogel Rectal Spacer in Prostate Cancer Radiation Therapy

Purpose

A hydrogel rectal spacer (HRS) is a medical device that is approved by the U.S. Food and Drug Administration to increase the separation between the prostate and rectum. We conducted a cost-effectiveness analysis of HRS use for reduction in radiation therapy (RT) toxicities in patients with prostate cancer (PC) undergoing external beam RT (EBRT).

Evaluation ofin vitro drug screening leads using experimental models of human ovarian cancer

Summary Five compounds which were identified as potential new anticancer drugs inin vitro screening with the human tumor colony forming assay were selected for further evaluation usingin vitro andin vivo models of human ovarian cancer. Three of five compounds were found to inhibitin vitro colony formation of ovarian cancer cell lines derived from both untreated and combination chemotherapy refractory patients. One compound was also found to prolong survival in a human ovarian carcinoma xenograft model system. This compound, chloroquinoxaline sulfonamide, was selected for development and has shown preliminary indication of activity in phase I clinical testing.     

Measurement of free and total hydroxyproline by automated flow injection of serum or urine samples from maintenance hemodialysis patients with renal osteodystrophy

An automated measurement of total and free hydroxyproline in serum or urine is presented that uses flow injection analysis. After exclusion of nonspecific substances, hydroxyproline was oxidized by chloramine- T and L-cysteine with Ehrlich's reagent. The linearity obtained was from 3.8μmole/ L to 1.22 mmole/L with good precision (CV <3%). Comparison of the proposed method with HPLC yielded r = 0.939 as the correlation coefficient. Reference intervals of free and total hydroxyproline are 1.4–9.7 μmole/L, 3.8–27.2 μmole/L for serum, and 10.0–72.5 μmole/L, 25.2–303.6 μmole/L for urine, respectively. Serum free and total hydroxyproline levels in renal osteodystrophy patients on maintenance hemodialysis (N = 71) were significantly higher than in controls (P<0.0001). This method is superior to the use of HPLC with regard to stability of the color reaction. The measurement of serum free and total hydroxyproline is a useful marker for therapeutic observation of renal osteodystrophy patients. © 1994 Wiley-Liss, Inc.     

Management of metastatic breast cancer

Systemic treatment almost certainly prolongs the median survival of women with metastatic breast cancer, and it may prolong the survival of a small number of patients substantially. Even with conventional therapy, 10% or more patients may live into the second decade after recurrence. However, the disease cannot be eradicated, and the primary goal of treatment remains palliation and improvement of the quality of life. Because of the great variability in the pattern and course of the disease from one patient to another, therapy should be selected judiciously to maximize response and minimize toxicity. In some clinical situations, such as pathologic fractures and brain metastases, local therapies alone, such as surgery or irradiation, are the treatments of choice. Patients who will respond to endocrine therapy are well defined, and all patients with the characteristics of an endocrine responder deserve a chance at palliation with this modality alone because of its limited toxicity. A number of new forms of endocrine therapy with more specific targets at estrogen and progesterone receptor sites are now in clinical trials. When used appropriately, chemotherapy significantly improves patient quality of life despite its toxicity. No drug combinations, schedules, or doses have been shown to prolong survival or provide better net palliation than classic CMF (oral cyclophosphamide with intravenous methotrexate and 5-fluorouracil) or CAF (intravenous cyclophosphamide, doxorubicin, and 5-fluorouracil). Treatment with these combinations in excess of 6 to 9 months provides only marginal additional benefits and no survival advantage. The role of high dose chemotherapy with autologous bone marrow transplantation remains a promising area of investigation, but the available survival data are entirely compatible with the possibility that this modality will eventually prove inferior to conventional therapy. Many new cytotoxic agents with unique mechanisms of action are currently under investigation, including taxol, taxotere, Topotecan, and amonafide. Taxol may be the most promising therapy now available for patients whose disease has become refractory to doxorubicin. Biologic therapies using monoclonal antibodies against a specific oncogene or its product have entered clinical trials, and novel drug delivery systems using liposomes are under evaluation.

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Resumen El tratamiento sistémico casi ciertamente prolonga la supervivencia media de las mujeres con cáncer mamario metastásico y logra prolongar la sobrevida de un muy pequeño número de pacientes en forma muy sustancial. Aún con terapia convencional, 10% o más de las pacientes sobreviven hasta la segunda década después de una recurrencia. Sin embargo, la enfermedad no puede ser erradicada y el objetivo primario del tratamiento sigue siendo paliativo para mejorar la calidad de vida. Teniendo en cuenta la gran variabilidad del patrón y de la evolución de la enfermedad entre una y otra paciente, la terapia debe ser cuidadosamente seleccionada a fin de lograr la máxima respuesta y minimizar la toxicidad. En algunas situaciones clínicas, tales como las fracturas patológicas y las metástasis cerebrales, las solas modalidades de terapia local, tales como la cirugía o la irradiación, constituyen los tratamientos de elección. Las pacientes que puedan responder a la terapia endocrina están bien definidas, y todas las pacientes con las características de ser una de las que responda al manejo endocrino merece la oportunidad de paliación con esta modalidad, en virtud de su limitada toxicidad. Variadas y nuevas formas de terapia endocrina con miras más específicas en cuanto a receptores de estrógeno y de progesterona se encuentran en ensayo. Cuando la quimioterapia es utilizada en forma apropiada, ésta mejora significativamente la calidad de vida a pesar de su toxicidad. Ninguna combinación de drogas, programas o dosificaciones ha demonstrado prolongar la sobrevida o lograr mejor paliación que el régimen clásico CMF (ciclofosfamida oral con metotrexato IV y 5-fluorouracilo). El tratamiento con estas combinaciones por más de 6–9 meses provee apenas beneficios adicionales marginales y ninguna ventaja en cuanto a sobrevida. El papel de la quimioterapia de altas dosis con trasplante autólogo de médula ósea permanece como una promisoria área de investigación, pero la información sobre supervivencia hasta ahora disponible es enteramente compatible con la posibilidad de que esta modalidad llegue a demostrar ser inferior a la terapia convencional. Muchos nuevos agentes citotóxicos con mecanismos de acción únicos están siendo investigados en la actualidad. Estos incluyen el taxol, el taxotere, el Topotecan y el amonafide. El taxol puede ser la forma más promisoria de terapia actualmente disponible para pacientes cuya enfermedad se ha hecho resistente a la doxorubicina. Las terapias biológicas usando anticuerpos monoclonales contra un oncogene específico o su producto han ingresado a los ensayos clínicos y novedosos sistemas de administración de drogas, utilizando liposomas, también se hallan en proceso de investigación.

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Résumé Le traitement par voie systémique prolonge la survie médiane des patientes ayant un cancer métastatique du sein et peut également prolonger, sans doute, la survie d'un petit nombre d'autres patientes quel que soit le dégréé de sévérité de la maladie. Même avec une thérapeutique conventionnelle, 10% ou plus des patientes peuvent espérer survivre plus de 10 ans après leur récidive. La maladie ne peut, dans ce cas cependant, être enrayée et le but de la thérapeutique restera palliatif et d'améliorer la qualité de vie. En raison de la grande variabilité du type et de l'évolutivité de la maladie d'une patiente à l'autre, chaque protocole thérapeutique se doit d'être élaboré de façon à maximaliser la réponse tout en minimisant la toxicité. Dans certaines situations cliniques, telles les fractures pathologiques ou les métastases cérébrales, les thérapeutiques locales, telles la chirurgie ou l'irradiation, sont de modalités thérapeutiques de choix. On connaît aussi une catégorie de patientes qui répondent bien au traitement hormonal, qui devraient toutes être traitées par cette modalité étant donnée le peu de toxicité. Un certain nombre de ces traitements hormonaux sont actuellement l'objet d'essais thérapeutiques. Utilisée judicieusement la chimiothérapie améliore de façon significative la qualité de vie, et ce souvent, malgré sa toxicité. Aucune combinaison de médicaments ni de régimes ou de doses ne se sont montrés plus efficaces pour prolonger la survie ou améliorer le confort mieux que la classique association CMF (cyclophosphamide per os, methotrexate et 5-Fluorouracil par voie intraveineuse) ou la CAF (cyclophosphamide, doxorubicine, 5-fluorouracil par voie intraveineuse). Un traitement par ces combinaisons pendant plus de 6–9 mois n'apporte guère d'avantages, sans prolonger la survie pour autant. Le rôle de la chimiothérapie à hautes doses combinée avec la greffe de moelle osseuse était une voie prometteuse mais pour le moment, il semble exister de preuves en faveur de son infériorìté par rapport aux traitements conventionnels. D'autres nouvelles substances cytotoxiques, faisant intervenir d'uniques mécanismes d'actions, sont actuellement en cours d'évaluation. Ces nouveaux médicaments comprennent le taxol, le taxotère, le Topotécane, et l'amonafide. Le taxol est probablement celuì qui a le plus d'intérêt, semble-t'il, e cas de résistance à la doxorubicine. Des traitements biologiques, utilisant des anticorps spécifiques dirigés contre tel on tel oncogèn ou son produit, ainsi que de nouveaux systèmes d'apport des médicaments sont également au stade d'évaluation clinique.

     

Early diagnosis of SARS: lessons from the Toronto SARS outbreak

The clinical presentation of SARS is nonspecific and diagnostic tests do not provide accurate results early in the disease course. Initial diagnosis remains reliant on clinical assessment. To identify features of the clinical assessment that are useful in SARS diagnosis, the exposure status and the prevalence and timing of symptoms, signs, laboratory and radiographic findings were determined for all adult patients admitted with suspected SARS during the Toronto SARS outbreak. Findings were compared between patients with laboratory-confirmed SARS and those in whom SARS was excluded by laboratory or public health investigation. Of 364 cases, 273 (75%) had confirmed SARS, 30 (8%) were excluded, and 61 (17%) remained indeterminate. Among confirmed cases, exposure occurred in the healthcare environment (80%) or in the households of affected patients (17%); community or travel-related cases were rare (<3%). Fever occurred in 97% of patients by the time of admission. Respiratory findings including cough, dyspnea and pulmonary infiltrates evolved later and were present in only 59, 37 and 68% of patients, respectively, at admission. Direct exposure, fever on the first day of illness, and elevated temperature, pulmonary infiltrates, lymphopenia and thrombocytopenia at admission were associated with confirmed cases. Rhinorrhea, sore throat, and an elevated neutrophil count at admission were associated with excluded cases. In the absence of fever or significant exposure, SARS is unlikely. Other clinical, laboratory and radiographic findings further raise or lower the likelihood of SARS and provide a rational basis for estimating the likelihood of SARS and directing initial management.     

Expression and characterization of the eaeA gene product of Escherichia coli serotype O157:H7.

In enteropathogenic Escherichia coli, the eaeA gene produces a 94-kDa outer membrane protein called intimin which has been shown to be necessary but not sufficient to produce the attaching-and-effacing lesion. The purpose of this study was to characterize the intimin specified by the eaeA allele of the enterohemorrhagic E. coli (EHEC) serotype O157:H7 strain CL8 and to determine its role in adherence. The carboxyl-terminal 266 amino acids of the CL8 intimin were expressed as a protein fusion with glutathione S-transferase, which was used to raise antiserum in rabbits. The antiserum reacted in Western immunoblots with a 97-kDa outer membrane protein of EHEC strains of serogroups O5, O26, O111, and O157 and enteropathogenic E. coli strains of serogroups O55 and O127. Surface labelling of CL8 with 125I showed that intimin was surface exposed. An eaeA insertional inactivation mutant of CL8 was produced and was designated CL8-KO1. Total adherence of CL8-KO1 to HEp-2 cells was not significantly different from that of CL8, but CL8-KO1 gave a negative result in the fluorescent actin staining test. The eaeA gene expressed alone in E. coli HB101 also gave a negative fluorescent actin staining test result. The eaeA gene of CL8 was able to complement the eaeA deletion mutation in CVD206. We conclude that the product of the EHEC eaeA gene is a 97-kDa surface-exposed protein and propose that it be designated intiminO157. Sherman et al. described a 94-kDa outer membrane protein which played an important role in adherence of E. coli O157:H7 (Infect. Immun. 59:890-899, 1991). Western immunoblotting and indirect fluorescent antibody studies showed that the protein described by Sherman et al. is not intimin.