A low-dose stimulation protocol using highly purified follicle-stimulating hormone can lead to high pregnancy rates in in vitro fertilization patients with polycystic ovaries who are at risk of a high ovarian response to gonadotropins.

OBJECTIVE: To study the benefits of a low-dose stimulation (LDS) protocol with purified urinary follicle-stimulating hormone in patients with polycystic ovaries who have presented previously with a very high ovarian response to a standard hMG stimulation. DESIGN: Cohort study. SETTING: Fertility center in a university hospital. PATIENT(S): Sixty-one patients involved in an IVF/ICSI program from January 1995 to December 1996. INTERVENTION(S): The patients were first stimulated with a standard protocol using hMG and presented with a very high ovarian response. These patients were then stimulated a second time using a low-dose protocol. Cryopreserved embryos were transferred in later artificial or natural cycles until to December 1999. MAIN OUTCOME MEASURE(S): Number of gonadotropin ampules; estradiol level on the day of ovulation induction; follicles, oocytes, and cryopreserved zygotes; fertilization, implantation, and pregnancy rates; and number of ovarian hyperstimulation syndromes (OHSS). RESULT(S): The number of ampules used, the estradiol level reached, and the number of oocytes obtained were significantly lower under the LDS than the standard protocol. High implantation (21.8%) and clinical pregnancy (38.4%) rates were obtained after LDS. The cumulated deliveries per cycle started and per patient were, respectively, 41.6% and 52.5%. Five patients suffered OHSS with the standard protocol, and none with the LDS. CONCLUSION(S): The LDS protocol offers a safe and efficient treatment for patients who present with echographic polycystic ovaries and are at risk of an excessive ovarian response to standard IVF stimulation protocols.

Oral administration of a low dose of midazolam (75 microg) as an in vivo probe for CYP3A activity.

OBJECTIVE: We investigated whether the oral administration of a low dose (75 micro g) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. METHODS: Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 micro g midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole (200 mg b.i.d.), a CYP3A inhibitor, and in four subjects pretreated for 4 days with rifampicin (450 mg q.d.), a CYP3A inducer. RESULTS: After oral administration of 75 micro g midazolam, the 30-min total (unconjugated + conjugated) 1'OH-midazolam/midazolam ratios measured in the groups without co-medication, with ketoconazole and with rifampicin were (mean+/-SD): 6.23+/-2.61, 0.79+/-0.39 and 56.1+/-12.4, respectively. No side effects were reported by the subjects taking this low dose of midazolam. Good correlations were observed between the 30-min total 1'OH-midazolam/midazolam ratio and midazolam clearance in the group without co-medication (r(2)=0.64, P<0.001) and in the three groups taken together (r(2)=0.91, P<0.0001). Good correlations were also observed between midazolam plasma levels and midazolam clearance, measured between 1.5 h and 4 h. CONCLUSION: A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.

Influence of the timing of low-dose aspirin on tolerability of prolonged-release nicotinic acid in patients at elevated cardiovascular risk

OBJECTIVES: To investigate the effect of low-dose aspirin administered in the morning or evening on the rate of discontinuation of prolonged-release nicotinic acid (Niaspan) due to flushing in patients at elevated cardiovascular risk. RESEARCH DESIGN AND METHODS: This was an observational, non-interventional study in patients at elevated cardiovascular risk due to cardiovascular disease or type 2 diabetes. Patients received prolonged-release nicotinic acid and aspirin under the usual care of their physician for 15 weeks. MAIN OUTCOME MEASURES: The main outcome measure was the rate of treatment discontinuation for flushing. Other adverse drug reactions (ADRs) were also recorded. Lipid parameters were also measured. RESULTS: The patient population included 539 subjects (70% male); 36% had type 2 diabetes, 80% had prior cardiovascular disease, and 37% had a family history of cardiovascular disease. The rate of treatment discontinuation due to flushing did not differ (p = 0.3375) between the morning aspirin group (10.6%) and the evening aspirin group (13.8%). The overall incidence of flushing was 57%. Most flushes were of mild or moderate severity and decreases occurred over time in both frequency and intensity. ADRs unrelated to flushing occurred in 6.6% of the morning aspirin group and 7.4% of the evening aspirin group. HDL-cholesterol increased by +21.3% in the overall population, together with moderate improvements in other lipid parameters. CONCLUSIONS: Flushing was the most common ADR with prolonged-release nicotinic acid treatment, as expected. The timing of aspirin administration did not influence the rate of treatment discontinuations for flushing. Marked increases in HDL-cholesterol were observed.

Low-dose, simple, and fast grating-based X-ray phase-contrast imaging.

Phase sensitive X-ray imaging methods can provide substantially increased contrast over conventional absorption-based imaging and therefore new and otherwise inaccessible information. The use of gratings as optical elements in hard X-ray phase imaging overcomes some of the problems that have impaired the wider use of phase contrast in X-ray radiography and tomography. So far, to separate the phase information from other contributions detected with a grating interferometer, a phase-stepping approach has been considered, which implies the acquisition of multiple radiographic projections. Here we present an innovative, highly sensitive X-ray tomographic phase-contrast imaging approach based on grating interferometry, which extracts the phase-contrast signal without the need of phase stepping. Compared to the existing phase-stepping approach, the main advantages of this new method dubbed "reverse projection" are not only the significantly reduced delivered dose, without the degradation of the image quality, but also the much higher efficiency. The new technique sets the prerequisites for future fast and low-dose phase-contrast imaging methods, fundamental for imaging biological specimens and in vivo studies.

Low-dose cidofovir for the treatment of polyomavirus-associated nephropathy: two case reports and review of the literature.

BACKGROUND: Polyomavirus-associated nephropathy (PVAN) is a serious complication and cause of graft loss in kidney transplant recipients. In the absence of specific antiviral drugs, early detection of the disease and reduction of immunosuppressive regimen is the cornerstone of therapy. Cidofovir, a nucleoside analogue, has been found to inhibit BK virus (BKV) replication in vitro and has been proposed as treatment of refractory PVAN at low doses; however, its efficacy has never been demonstrated in randomized controlled trials. METHODS: Cidofovir therapy (0.5 mg/kg at a 2-week interval for eight consecutive doses) was initiated in two patients with biopsy-proven PVAN and persistent BKV DNA viraemia (> or = 10,000 copies/ml despite sustained reduction of the immunosuppressive regimen). In addition to these two case reports, we performed a critical review of the literature on the use of cidofovir in PVAN. RESULTS: No significant decrease of BKV viral load in blood was observed during cidofovir therapy and in follow-up of the two patients treated with cidofovir. Our literature review identified 21 publications reporting the use of cidofovir for the treatment of PVAN. All were case reports or small series. The efficacy of cidofovir therapy could not be assessed in 17 of these publications because of lack of data or concomitant reduction of immunosuppressive regimen. The four remaining publications were case reports. CONCLUSIONS: In vitro and clinical data to support the efficacy of cidofovir in the treatment of PVAN are currently lacking. More promising compounds should be identified for further clinical studies.

Low-dose theophylline enhances the anti-inflammatory effects of steroids during exacerbations of chronic obstructive pulmonary disease

ABSTRACT Background: Chronic obstructive pulmonary disease (COPD) is characterised by an abnormal inflammatory response mainly to cigarette smoke that flares up during exacerbations of the disease (ECOPD). Reduced activity of histone deacetylases (HDAC) contributes to enhanced inflammation in stable COPD. It was hypothesised that HDAC activity is further reduced during ECOPD and that theophylline, an HDAC activator, potentiates the antiinflammatory effect of steroids in these patients. A study was performed to investigate HDAC activity during ECOPD and the effects of theophylline on the anti-inflammatory effects of steroids in a randomised single-blind controlled study. Methods: 35 patients hospitalised with ECOPD and treated according to international guidelines (including systemic steroids) were randomised to receive or not to receive low-dose oral theophylline (100 mg twice daily). Before treatment and 3 months after discharge, HDAC and nuclear factor-kB (NF-kB) activity in sputum macrophages, the concentration of nitric oxide in exhaled air (eNO) and total antioxidant status (TAS), tumour necrosis factor a (TNFa), interleukin (IL)-6 and IL8 levels in sputum supernatants were measured. Results: Patients receiving standard therapy showed decreased NF-kB activity, eNO concentration and sputum levels of TNFa, IL6 and IL8, as well as increased TAS during recovery of ECOPD, but HDAC activity did not change. The addition of low-dose theophylline increased HDAC activity and further reduced IL8 and TNFa concentrations. Conclusions: During ECOPD, low-dose theophylline increases HDAC activity and improves the anti-inflammatory effects of steroids.

Absence of BK viremia clearance after low-dose cidofovir therapy in kidney transplant recipients with BK virus associated nephropathy

Background: BK virus associated nephropathy occurs in 1-10% of kidney transplant recipients and may be a cause of graft loss. This infection is difficult to manage because of the absence of specific therapy. Cidofovir, a DNA polymerase inhibitor approved for the treatment of CMV retinitis, has shown in vitro activity against BK virus and some clinical efficacy when used at low-dose in uncontrolled series. Objective: To assess the efficacy of low-dose Cidofovir in the treatment of BK virus associated nephropathy. Method: Two adult kidney transplant recipients with biopsy-proven BK nephropathy and persistent high viremia (>10,000 copies/ml) despite 3-month reduction of immunosuppressive therapy were treated by Cidofovir 0.5 mg/kg fortnightly for a total of 16 weeks (8 doses). Clinical response was assessed by following BK viremia. Results: No decrease in BK viremia was observed at any point during cidofovir therapy (see figure). Creatinine clearance remained stable during therapy and no side-effects of Cidofovir were observed. Conclusions: Low-dose Cidofovir therapy was not associated with a clearance or with a significant decrease of BK viremia. This pilot study does not confirm previous reports suggesting clinical efficacy of Cidofovir for BK virus associated nephropathy.

Low-dose valganciclovir is efficacious and safe for prophylaxis of cytomegalovirus infection in kidney transplantation

Background: Optimal valganciclovir (VGC) dosage and duration for cytomegalovirus (CMV) prophylaxis in kidney transplant recipients remains controversial. This study aimed to determine GCV blood levels and efficacy/safety observed under low-dose oral VGC in kidney transplant recipients. Secondly, to quantify the variability of GCV blood levels, and its potential clinical impact. Methods: In this prospective study, each patient at risk for CMV undergoing kidney transplantation received low-dose VGC (450 mg qd) prophylaxis for 3 months, unless GFR was below 40 mL/min, in which case the dose was adapted to 450 mg every other day. GCV levels, at trough (Ctrough) and at peak (C3h) were measured monthly and CMV viremia was assessed during and after prophylaxis using real time quantitative Polymerase Chain Reaction. Adverse effects were recorded on each GCV sampling. Patients were followed up to one year after transplantation. Results: 38 kidney recipients (19 D+/R+, 11 D+/R-, 8 D-/R+) received 3-month VGC prophylaxis. Most patients (mean GFR of 59 mL/min) received 450 mg qd but the dose was reduced to 450 mg every other day in 6 patients with mean GFR of 22 mL/min. Average GCV C3h and Ctrough (regressed at 24h or 48h) were 3.9 mg/L (CV 33%, range: 1.3-8.2) and 0.4 mg/L (CV 111%, range 0.1-3.3). Population pharmacokinetic analysis showed a fair dispersion of the parameters mainly influenced by renal function. Despite this variability, patients remained aviremic during VGC prophylaxis. Neutropenia and thrombocytopenia (grade 2-4) were reported in 4% and 3% of patients respectively. During follow-up, asymptomatic CMV viremia was reported in 25% patients. One year after transplantation, 12% patients (all D+/R-) had developed a CMV disease, which was treated with a therapeutic 6-week course of oral VGC. Conclusion: Average GCV blood levels after oral administration of low-dose VGC in kidney transplant recipients were comparable to those previously reported with oral GCV prophylaxis, efficacious and well tolerated. Thus, a 3-month course of low-dose VGC is appropriate for the renal function of most kidney transplant recipients.

Low-dose radiotherapy (2x2 Gy) in indolent lymphoma

Dans la prise en charge des maladies oncologiques, la priorité est évidemment d'assurer le contrôle de la maladie (soit le taux de récidive local et la survie globale), surtout lorsque celle-ci est diagnostiquée tôt, à un stade précoce. Cependant, lorsque la maladie est plus avancée et que ce contrôle ne peut être assuré de façon raisonnable, l'accent de la prise en charge est surtout axé sur le confort du patient. Le principe est de fournir à celui-ci, dans la mesure du possible, une qualité de vie acceptable, avec notamment des douleurs bien contrôlées.Dans le cadre de ce travail de thèse, nous nous sommes intéressés à la prise en charge palliative des lymphomes non hodgkiniens (LNH) de bas grade. La survie de ces patients peut être relativement longue (de 5 à 10 ans selon les séries), cependant, le traitement est rarement à visée curative, contrairement aux lymphomes de haut grade, dont la survie est bien moindre, mais avec une chance de guérison après un traitement intensif.Plusieurs études cliniques, à la fois prospectives et rétrospectives, ont démontré l'intérêt d'une irradiation à faible dose {2x2 Gy) lors d'atteintes tymphomateuses à l'origine de symptômes gênants (douleurs, compression par une masse, dyspnée, entre autres). Etant donné la facilité d'administration de ce traitement (seulement 2 séances de radiothérapie sont nécessaires), et sa quasi absence de survenue d'effets secondaires avec cette faible dose totale (4 Gy), nous avons voulu y apporter une contribution suisse.Notre étude rétrospective a permis d'inclure 43 patients entre le CHUV et les HUG. Les résultats que nous avons obtenus sont également dans la ligne des autres études parues, avec un excellent contrôle local, soit un soulagement rapide et durable des symptômes dans la majorité des cas.Nous espérons que ce travail de thèse, publié sous forme d'un article dans « International Journal of Radiation Oncology, Biology, Physics », permettra une prise en charge plus optimale des ces patients en leur apportant un traitement facile à administrer, efficace, sans effets secondaires dans la majorité des cas, et pouvant être répété un grand nombre de fois si nécessaire.

Effect of low-dose chest irradiation before chemotherapy on the rate of local failure in small-cell lung cancer.

PURPOSE: To evaluate the rate of tumor recurrence within the irradiated volume after initial low-dose irradiation of limited-stage small-cell lung cancer (SCLC), to assess the tolerance of a sequential combination of low-dose chest irradiation followed by chemotherapy, and to confirm the responsiveness of limited-stage SCLC to low-dose irradiation. METHODS AND MATERIALS: In this pilot study, 26 patients with limited-stage SCLC were treated by first-line 20-Gy thoracic irradiation followed 3 weeks later by chemotherapy (cisplatin, doxorubicin, and etoposide for six cycles). RESULTS: We present our final results with a median follow-up of surviving patients of 7 years. The response rate to this low-dose irradiation was 83%, with an overall response rate to radiochemotherapy of 96% and a median survival of 21 months. No unexpected early or late toxicity was observed. The rate of initial isolated local failure was 8%, which compares favorably with other published series using higher doses of radiochemotherapy. CONCLUSION: An initial chest irradiation of 20 Gy before chemotherapy could be sufficient to reduce the risk of local failure during the time of survival of patients with limited-stage SCLC. Potential advantages of this treatment may be the prevention of resistance mechanisms to radiotherapy induced by preliminary chemotherapy and a reduced radiation-induced toxicity.

Mico-cocktail validation for CYP3A and CYP2D6 assessment using a low dose of midazolam (0.075 mg) and dextromethorphan (2.5 mg)

Background/Aim: Cocktail approach is generally preferred to individual administration of probes in order to characterize the activity of multiple enzymes. However, cocktail strategy has several drawbacks such as drug-drug interactions, tolerability and toxicity. Hence, there is a need to develop cocktails using low doses of probes. Our aim was to investigate whether the simultaneous oral administration of microdoses of midazolam (MDZ) and dextromethorphan (DEM) can be used to assess the simultaneous activities of CYP3A and CYP2D6. Methods: As part of a 5 arm randomized cross-over control trial on the analgesic efficacy of oxycodone, ten healthy young non-smoking males received the following combinations of drugs: Quinidine (Q)+ ketoconazole (K) or Q+placebo (P) or K+P or P+P. In all cases MDZ (0.075 mg) and DEM (2.5 mg) were administrated 1 hour after Q, K or P. CYP2D6 and CYP3A activities were determined after urine collection during 8 hours (ratio DEM/DOR), and a blood sample (EDTA) after 30 min (ratio 1-OH-MDZ/MDZ). DEM and DOR analysis was performed using LC-fluorescence. MDZ and 1-OH-MDZ determination was performed using GC-MS. Allele's variants of CYP2D6 were detected using the AmpliChipTMCYP450 (Roche). Results: CYP2D6 genotype predicted 1 poor (PM), 1 intermediate (IM), 7 extensive (EM) and 2 ultra rapid (UM) metabolizers. A good correlation was obtained between the predicted and the measured phenotypes except for 1 EM phenotyped as UM. Two duplications for alleles *41/*41xN and *1/*2xN were detected and the two volunteers were phenotyped as UM. A potent inhibition of CYP2D6 or CYP3A4 was obtained when Q or K were used. Mean metabolic ratio DEM/DOR in P and K groups were 0.015 (±0.028) and 0.015 (±0.019). It significantly increased in Q and QK groups (0.668 (±0.676) and 0.743 (±1.038)). Mean 1-OH-MDZ/MDZ in P, Q were 2.73 (±1.05) and 2.55 (±1.40) while it significantly decreased in K and QK groups (0.11 (±0.05), 0.10 (±0.05)). Moreover, there were no statistically significant differences between QK and K sessions for CYP3A and between QK and Q for CYP2D6 which indicate that there is no interaction between the two metabolic pathways. Conclusion: Simultaneous assessment of CYP3A and CYP2D6 activities can be obtained by low oral doses (micro-cocktail) of MDZ and DEM. Specific inhibitors such as Q or K modulates selectively CYP2D6 or CYP3A activities.

Combination of lentivector immunization and low-dose chemotherapy or PD-1/PD-L1 blocking primes self-reactive T cells and induces anti-tumor immunity.

In the last two decades, anti-cancer vaccines have yielded disappointing clinical results despite the fact that high numbers of self/tumor-specific T cells can be elicited in immunized patients. Understanding the reasons behind this lack of efficacy is critical in order to design better treatment regimes. Recombinant lentivectors (rLVs) have been successfully used to induce antigen-specific T cells to foreign or mutated tumor antigens. Here, we show that rLV expressing a murine nonmutated self/tumor antigen efficiently primes large numbers of self/tumor-specific CD8(+) T cells. In spite of the large number of tumor-specific T cells, however, no anti-tumor activity could be measured in a therapeutic setting, in mice vaccinated with rLV. Accumulating evidence shows that, in the presence of malignancies, inhibition of T-cell activity may predominate overstimulation. Analysis of tumor-infiltrating lymphocytes revealed that specific anti-tumor CD8(+) T cells fail to produce cytokines and express high levels of inhibitory receptors such as programmed death (PD)-1. Association of active immunization with chemotherapy or antibodies that block inhibitory pathways often leads to better anti-tumor effects. We show here that combining rLV vaccination with either cyclophosphamide or PD-1 and PD-L1 blocking antibodies enhances rLV vaccination efficacy and improves anti-tumor immunity.