Equal Total Dose Research Articles

Alternate day versus consecutive day oral iron supplementation in iron-depleted women: a randomized double-blind placebo-controlled study

Guidelines to treat iron deficiency recommend daily provision of oral iron, but this may decrease fractional iron absorption and increase side effects. Our objective was to compare consecutive-day versus alternate-day iron supplementation. In a double-masked, randomized, placebo-controlled trial, young Swiss women (n=150; serum ferritin ≤30μg/L) were assigned to: daily 100mg iron for 90d, followed by daily placebo for another 90d (consecutive-day group) or the same daily dose of iron and placebo on alternate days for 180d (alternate-day group). The study period was 24/11/2021-10/8/2022. Co-primary outcomes, at equal total iron doses, were serum ferritin and gastrointestinal side effects; secondary outcomes were iron deficiency and serum hepcidin. Compliance and side effects were recorded daily using a mobile application. Data were analysed using mixed models and longitudinal prevalence ratios (LPR). The trial was registered at ClinicalTrials.gov (NCT05105438). 75 women were assigned to each group and included in the intention-to-treat analysis. Capsule adherence and side effect reporting was >97% in both groups. At equal total iron doses, comparing consecutive-day and alternate-day groups, median serum ferritin was 43.8μg/L (31.7-58.2) versus 44.8μg/L (33.8-53.6) (P=0.98), the LPR for gastrointestinal side effects on days of iron intake was 1.56 (95% CI: 1.38, 1.77; P<0.0001), and median serum hepcidin was 3.0nM (IQR 2.0-5.0) versus 1.9nM (1.4-2.9) (P<0.0001). Iron deficiency prevalence after 3 months was 5.5% versus 4.3% (P=0.74) and after 6 months was 11.4% and 3.0% (P=0.049). At equal total iron doses, compared to consecutive day dosing of iron, alternate day dosing did not result in higher serum ferritin but reduced iron deficiency at 6 months and triggered fewer gastrointestinal side effects. Swiss National Science Foundation, Bern, Switzerland.

Effects of four-year cyclic versus two-year daily teriparatide treatment on volumetric bone density and bone strength in postmenopausal women with osteoporosis.

To evaluate the effects of cyclic vs daily teriparatide treatment (TPTD) on volumetric bone mineral density (vBMD) and bone strength at the hip and spine in women who were previously untreated. A total of 86 women were randomized to a 24-month open label treatment of either daily TPTD (20μg daily) or cyclic TPTD (20μg daily for 3months followed by 3months off). During a 2-year extension, women in the daily TPTD group were switched to alendronate (ALN) and those in the cyclic TPTD group continued on cyclic TPTD (without any ALN). QCT images were acquired at baseline, 2-years (n=54) and 4-years (n=35) and analyzed for volumetric integral, cortical and trabecular bone mineral density (vBMD) and bone strength (by finite element analysis) at the hip and spine. The primary analysis presented here compared the responses across equal total TPTD doses (2years daily vs 4years cyclic). In the spine, integral vBMD and strength increased substantially after 2years daily and 4years cyclic TPTD, with no significant differences (vBMD +12% vs +11%, respectively, p=0.70; spine strength +21% vs +16%, respectively, p=0.35). At the hip, the gains were smaller, but again no significant differences were detected between the groups for the increases in either vBMD (+2% in both groups, p=0.97) or hip strength (3% vs 3%, p=0.91). In the spine, the vBMD increment was about twice as large in the trabecular vs peripheral compartment; in the hip, significant vBMD gain was seen only in the trabecular compartment. The gains in volumetric BMD and bone strength for an equivalent dose of TPTD did not depend on whether it was administered every day over two years or cyclically over four years.

Antiaging Effects of Oleuropein Combined with Helichrysum Italicum or Kumquat Essential Oils in Cosmetic Lotions

Skin aging as a complex process involves innumerable genetic, biochemical, and environmental mechanisms. This in vitro study delves deep into whether topical cosmetic formulations containing oleuropein combined with essential oils of Helichrysum italicum or kumquat prevent skin aging. Two separate cosmetic lotions were formulated and evaluated by their physical and bioactive properties. The oil-in-water emulsions were prepared, antiaging lotions were formulated with the addition of oleuropein combined with either of the two essential oils as active components with the equal total doses of 1.5%, and lotions containing vitamin C or only oleuropein were used as controls. Findings revealed that pH, viscosity, and appearance of the lotions were stable and that the essential oils did not influence the physical properties. The lotion containing the combination of oleuropein and H. italicum exhibited the highest antioxidant and antimicrobial properties. In contrast, the oleuropein and kumquat combination exposed the highest inhibitory effect on all three hyaluronidase, lipoxygenase, and tyrosinase enzymes. It can be inferred that the combination of oleuropein and H. italicum is the most potent active ingredient of antioxidant in skin care products and that the oleuropein and kumquat combination is the better candidate as an active ingredient against skin inflammation, pigmentation, and loss of collagen.

A mathematical study of the impact of cell plasticity on tumour control probability.

The tumour control probability (TCP) is a treatment planning tool that evaluates the probability of tumour eradication and helps in the assessment of the relative efficacy of different radiotherapy regimens. The response of tumours to radiation differs greatly even between patients with same types of cancers. Tumour heterogeneity or cellular diversity among cancer cells has a pronounced impact on the success of administered radiotherapy protocols. Tumour heterogeneity can be explained using the cancer stem cells (CSCs) hypothesis, which posits that CSCs are responsible for tumour initiation and propagation as well as therapeutic resistance. Moreover, the existence of plasticity or bidirectional transition between CSCs and non-CSCs indicates that, sometimes, non-CSCs appear to mimic CSC phenotypes, resulting in an increase in resistance. Here, we have developed a stochastic model to investigate the impact of plasticity on the efficacy of radiotherapy. The effect of plasticity on TCP is explored by applying the model to standard and hyper-fractionated schedules for a three week period of treatment as well as standard, hyper-fractionated, and accelerated hyper-fractionated schedules with an equal total dose of 30 Gy. Our results confirm that tumour control becomes increasingly difficult in the presence of plasticity as well as for the most resistant tumours. For the case with equal total dose, it is observed that increasing fractionation, at first enhances the probability of CSCs and tumour removal, but ultimately results in lower TCPS+P and TCPS. In addition, the combination of radiotherapy and targeted therapy (with increasing CSC differentiation) improves both the probability of CSC and tumour removal, in the absence of plasticity. However, in the presence of plasticity, the impact of combination therapy is not significant.

The urinary cortisol metabolome in patients with adrenal insufficiency: Dual-release hydrocortisone is less deleterious than conventional hydrocortisone therapy

Introduction Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy provides a more physiological cortisol profile than conventional thrice-daily (TID) therapy and has demonstrated improved metabolic profile among patients with adrenal insufficiency (AI). The mechanisms by which this metabolic improvement occurs may be due to less total exposure, changed cortisol time exposure profile, but also modified metabolism of cortisol. Objective To study cortisol metabolism during DR-HC and TID. Methods Patients with primary AI received DR-HC or an equal total daily dose of TID in a crossover multi-center study. Cortisol metabolites were measured by gas chromatography/mass spectrometry on 24 h urinary collections after both treatments and in controls. Results Fifty patients (22 females, mean age 47 years) and 124 healthy controls (73 females, mean age 48 years) were included in the study. Total cortisol metabolites were significantly decreased during DR-HC [median: 6380 μg/24 h] compared to TID [8825 μg/24 h]; P Conclusion The urinary cortisol metabolome may be a more sensitive marker of “optimal cortisol replacement”. Abnormal cortisol metabolites excretion and cortisol metabolism are observed in patients receiving TID. This abnormal profile improves with DR-HC. Especially, reduced 11βHSD1 activity during DR-HC may mediate some of the beneficial metabolic effects previously observed with this treatment.

The urinary cortisol metabolome in patients with adrenal insufficiency: dual-release hydrocortisone is less deleterious than conventional hydrocortisone therapy

Introduction Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy provides a more physiological cortisol profile than conventional thrice-daily (TID) therapy and has demonstrated improved metabolic profile among patients with adrenal insufficiency (AI). The mechanisms by which this metabolic improvement occurs may be due to less total exposure, changed cortisol time exposure profile, but also modified metabolism of cortisol. Objective To study cortisol metabolism during DR-HC and TID. Methods Patients with primary AI received DR-HC or an equal total daily dose of TID in a crossover multi-center study. Cortisol metabolites were measured by gas chromatography/mass spectrometry on 24 h urinary collections after both treatments and in controls. Results Fifty patients (22 females, mean age 47 years) and 124 healthy controls (73 females, mean age 48 years) were included in the study. Total cortisol metabolites were significantly decreased during DR-HC [median: 6380 μg/24 h] compared to TID [8825 μg/24 h]; P Conclusion The urinary cortisol metabolome may be a more sensitive marker of “optimal cortisol replacement”. Abnormal cortisol metabolites excretion and cortisol metabolism are observed in patients receiving TID. This abnormal profile improves with DR-HC. Especially, reduced 11βHSD1 activity during DR-HC may mediate some of the beneficial metabolic effects previously observed with this treatment.

Routine habitat switching alters the likelihood and persistence of infection with a pathogenic parasite

AbstractAnimals switch habitats on a regular basis, and when habitats vary in suitability for parasitism, routine habitat switching alters the frequency of parasite exposure and may affect post‐infection parasite proliferation. However, the effects of routine habitat switching on infection dynamics are not well understood.We performed infection experiments, behavioural observations and field surveillance to evaluate how routine habitat switching by adult alpine newts (Ichthyosaura alpestris) influences infection dynamics of the pathogenic parasite,Batrachochytrium dendrobatidis(Bd).We show that when newts are exposed to equal total doses ofBdin aquatic habitats,differences in exposure frequency and post‐exposure habitat alter infection trajectories: newts developed more infections that persisted longer when doses were broken into multiple, reduced‐intensity exposures. Intensity and persistence of infections were reduced among newts that were switched to terrestrial habitats following exposure.When presented with a choice of habitats, newts did not avoid exposure toBd, but heavily infected newts were more prone to reduce time spent in water.Accounting for routine switching between aquatic and terrestrial habitat in the experiments generated distributions of infection loads that were consistent with those in two populations of wild newts.Together, these findings emphasize that differential habitat use and behaviours associated with daily movement can be important ecological determinants of infection risk and severity.Aplain language summaryis available for this article.

EFFECTIVENESS OF SODIUM DICHLOROACETATE AGAINST GLIOMA С6 DEPENDS ON ADMINISTRATION SCHEDULE AND DOSAGE

Anticancer action of sodium dichloroacetate (DCA) could be related to its ability to activate oxidative phosphorylation leading to enhanced generation of reactive oxygen species and induction of apoptosis. On the other hand, activation of oxidative phosphorylation could promote tumor cell survival, in particular, via increased ATP synthesis. Such ambiguous effects of DCA could influence its anticancer effectiveness, depending on biological properties of a tumor, schedule of DCA administration and its dosage. The aim of the study was to analyze anticancer effect of DCA against glioma С6 in rats under conditions of different schedules of its administration and various dosages. The study was carried out in Wistar rats with intracerebrally transplanted glioma С6 cells. Therapy with DCA was performed as follows: daily for 6 days starting from the second day after tumor cell transplantation (schedule І) or 7(th) day (schedule ІІ) at a dose of 1.0 g/kg, or daily for 13 days starting from the second day at doses of 1.0; 1.5 or 4.5 g/kg (schedule ІІІ). An influence of hypoxia on anticancer effect of DCA was studied using hypoxic chambers where oxygen content was maintained at a level of 12.5-13% for 3 h after DCA administration to glioma С6 bearing rats. The state of mitochondrial electron transport chain components in tumor cells was studied using electron paramagnetic resonance. It has been shown that therapy with DCA using schedule I resulted in 15% decrease of animals life span (LS; < 0.05), while the use of schedule II had no effect on this index. Prolonged administration of DCA (schedule ІІІ) resulted in significant antitumor effect and increased LS of rats by 25.5% (p < 0.05). Under hypoxic conditions, treatment with DCA resulted in a significant increase of animal LS by 15-22%. Dosage of DCA had a moderate effect of its anticancer action. Maximal effect, an increase of LS by 34.5% (p < 0.05) was detected at a dose of 1.5 g/kg. It has been shown that anticancer activity of DCA under all studied conditions is not related to its influence on a functional state of tumor cell mitochondria. Anticancer effect of DCA significantly depends on a schedule of its administration; being administered at equal total dose, but dependent on the schedule DCA could cause ambiguous effects varying from tumor growth stimulation to significant anticancer activity. Under hypoxic conditions, anticancer efficacy of DCA against glioma С6 is significantly enhanced.

Respons Superovulasi Sapi Peranakan Ongole terhadap Penyuntikan Tunggal Follicle Stimulating Hormone ke dalam Ruang Epidural (SUPEROVULATION RESPONSES IN ONGOLE CATTLE CROSSBREED TREATED WITH A SINGLE EPIDURAL INJECTION OF FOLLICLE STIMULATING HORMONE)

Super-ovulation is conventionally performed by injection of FSH twice daily for four days. Thistreatment needs frequent attention by farm-personnel and relatively increases the possibility of failuresdue to mishandling and errors in administration of the treatment. This study was conducted to evaluatethe responses of superovulation trough a single injection of FSH into epidural space in ongole cattlecrossbreed. In Experiment 1, a combination of single dose injection of FSH was applied into epidural spaceplus intramuscular (epi+i.m group) compared to the group of intramuscular injection of FSH, which wastreated twice daily for four days (intramuscular group), using equal total dose of FSH 400 mg. Superovulationresponse of epi+im group (n=4) was not significantly different compared with intramusculargroup (n=4). In experiment 2, it compared two treatmentof FSH in different concentration(280 mg versus160 mg) in a single dose applied into epidural space. Data of Epi+im group from experiment 1 was used ascontrol. Group of 280 mg FSH (n=4) resulted total collection of ova/embryo and transferable embryos(9,00+2,65 and 3,33+2,52 respectively) was significantly different compared to the 160 mg group (n=4)(which were 2,00+1,26 and 0,00) P <0,05, although they werenot significantly different compared to thecontrol (9,33+5,68 and 3,67+3,21). In conclusion, injection of a single dose of FSH at 280 mg into epiduralspace result in a comparable transferable embryo which similar to the conventional method that appliedintramuscular injection of FSH twice daily for four days.

Theoretical implications of incorporating relative biological effectiveness into radiobiological equivalence relationships

Earlier radiobiological equivalence relationships as derived for low-linear energy transfer (LET) radiations are revisited in the light of newer radiobiological models that incorporate an allowance for relative biological effectiveness (RBE). Linear-quadratic (LQ) radiobiological equations for calculating biologically effective dose at both low- and high-LET radiations are used to derive new conditions of equivalence between a variety of radiation delivery techniques. The theoretical implications are discussed. The original (pre-LQ) concept of equivalence between fractionated and continuous radiotherapy schedules, in which the same physical dose is delivered in each schedule, inherently assumed that low-LET radiation would be used in both schedules. LQ-based equivalence relationships that allow for RBE and are derived assuming equal total physical dose between schedules are shown to be valid only in limited circumstances. Removing the constraint of equality of total physical dose allows the identification of more general (and more practical) relationships. If the respective schedules under consideration for equivalence both involve radiations of identical LET, then the original equivalence relationships remain valid. However, if the compared schedules involve radiations of differing LET, then new (and more restrictive) equivalence relationships are found to apply. Theoretically derived equivalence relationships based on the LQ model provide a framework for the design and intercomparison of a wide range of clinical techniques including those involving high- and/or low-LET radiations. They also provide a means of testing for the validity of variously assumed tissue repair kinetics.

Recurrencias de malaria por Plasmodium vivax según el uso de primaquina: análisis de estudios descriptivos longitudinales

primaquine (PQ) is the only drug available in the market to prevent Plasmodium vivax malaria recurrence, but several aspects are still unknown. To compare PQ regimens to prevent recurrence of vivax malaria. systematic review and meta-analysis of data. 1. According to descriptive studies, is PQ effective in preventing recurrence of vivax malaria? Yes. The comparison of studies that did not use PQ to others that did, using any regimen, showed that if PQ is not used, recurrence is highly likely. 2. Are equal daily doses effective (mg/kg) but total doses different? The total dose of 75 mg is equally or more effective than 210 mg. 3. Does the efficacy depend on where the infection happens? Yes. There is variation by country and region. 4. Does the recurrence rate depend on the post-treatment time follow-up? The answer is not uniform everywhere. Although not 100%, PQ is effective in preventing recurrence. Total doses of 210 and 75 mg are equally effective, but 75 mg alone has been evaluated in India, where P. vivax seems to respond better to PQ than elsewhere. The effect of place in the proportion of recurrences seems evident, even using the same total dose. The role of follow-up time is not clear. Although the standard regimen has an average effectiveness of 90% or more, alternative regimens should be assessed.

Shorter Exposures to Harder X-Rays Trigger Early Apoptotic Events in Xenopus laevis Embryos

BackgroundA long-standing conventional view of radiation-induced apoptosis is that increased exposure results in augmented apoptosis in a biological system, with a threshold below which radiation doses do not cause any significant increase in cell death. The consequences of this belief impact the extent to which malignant diseases and non-malignant conditions are therapeutically treated and how radiation is used in combination with other therapies. Our research challenges the current dogma of dose-dependent induction of apoptosis and establishes a new parallel paradigm to the photoelectric effect in biological systems.Methodology/Principal FindingsWe explored how the energy of individual X-ray photons and exposure time, both factors that determine the total dose, influence the occurrence of cell death in early Xenopus embryo. Three different experimental scenarios were analyzed and morphological and biochemical hallmarks of apoptosis were evaluated. Initially, we examined cell death events in embryos exposed to increasing incident energies when the exposure time was preset. Then, we evaluated the embryo's response when the exposure time was augmented while the energy value remained constant. Lastly, we studied the incidence of apoptosis in embryos exposed to an equal total dose of radiation that resulted from increasing the incoming energy while lowering the exposure time.Conclusions/SignificanceOverall, our data establish that the energy of the incident photon is a major contributor to the outcome of the biological system. In particular, for embryos exposed under identical conditions and delivered the same absorbed dose of radiation, the response is significantly increased when shorter bursts of more energetic photons are used. These results suggest that biological organisms display properties similar to the photoelectric effect in physical systems and provide new insights into how radiation-mediated apoptosis should be understood and utilized for therapeutic purposes.

The Effects of Local Anesthetic Concentration and Dose on Continuous Infraclavicular Nerve Blocks: A Multicenter, Randomized, Observer-Masked, Controlled Study

It remains unclear whether local anesthetic concentration or total drug dose is the primary determinant of continuous peripheral nerve block effects. The only previous investigation, involving continuous popliteal-sciatic nerve blocks, specifically addressing this issue reported that insensate limbs were far more common with higher volumes of relatively dilute ropivacaine compared with lower volumes of relatively concentrated ropivacaine. However, it remains unknown if this relationship is specific to the sciatic nerve in the popliteal fossa or whether it varies depending on anatomic location. We therefore tested the null hypothesis that providing ropivacaine at different concentrations and rates, but at an equal total basal dose, produces comparable effects when used in a continuous infraclavicular brachial plexus block. Preoperatively, an infraclavicular catheter was inserted using the coracoid approach in patients undergoing moderately painful orthopedic surgery distal to the elbow. Patients were randomly assigned to receive a postoperative perineural ropivacaine infusion of either 0.2% (basal 8 mL/h, bolus 4 mL) or 0.4% (basal 4 mL/h, bolus 2 mL) through the second postoperative day. Both groups, therefore, received 16 mg of ropivacaine each hour with a possible addition of 8 mg every 30 min via a patient-controlled bolus dose. Our primary end point was the incidence of an insensate limb during the 24-h period beginning the morning after surgery. Secondary end points included analgesia and patient satisfaction. Patients given 0.4% ropivacaine (n = 27) experienced an insensate limb, a mean (sd) of 1.8 (1.6) times, compared with 0.6 (0.9) times for subjects receiving 0.2% ropivacaine (n = 23; estimated difference = 1.2 episodes, 95% confidence interval, 0.5-1.9 episodes; P = 0.001). Satisfaction with postoperative analgesia (scale 0-10, 10 = highest) was scored a median (25th-75th percentiles) of 10.0 (8.0-10.0) in Group 0.2% and 7.0 (5.3-8.9) in Group 0.4% (P = 0.018). Analgesia was similar in each group. For continuous infraclavicular nerve blocks, local anesthetic concentration and volume influence perineural infusion effects in addition to the total mass of local anesthetic administered. Insensate limbs were far more common with smaller volumes of relatively concentrated ropivacaine. This is the opposite of the relationship previously reported for continuous popliteal-sciatic nerve blocks. The interaction between local anesthetic concentration and volume is thus complex and varies among catheter locations.

Effects of Local Anesthetic Concentration and Dose on Continuous Interscalene Nerve Blocks: A Dual-Center, Randomized, Observer-Masked, Controlled Study

It is currently unknown if the primary determinant of continuous peripheral nerve block effects is simply total drug dose, or whether local anesthetic concentration and/or volume have an influence. We therefore tested the null hypothesis that providing ropivacaine at different concentrations and rates--but at an equal total basal dose--produces similar effects when used in a continuous interscalene nerve block. Preoperatively, an anterolateral interscalene perineural catheter was inserted using the anterolateral approach in patients undergoing moderately painful shoulder surgery. Subjects were randomly assigned to receive a postoperative perineural infusion of either 0.2% ropivacaine (basal 8 mL/h, bolus 4 mL) or 0.4% ropivacaine (basal 4 mL/h, bolus 2 mL) through the second postoperative day. Our primary endpoint was the incidence of an insensate hand/finger during the 24 hours beginning the morning following surgery. The incidence of an insensate hand/finger did not differ between the treatment groups (n = 50) to a statistically significant degree (0.2% ropivacaine, mean [SD] of 0.8 [1.3] times; 0.4% ropivacaine, mean 0.3 [0.6] times; estimated difference = 0.5 episodes, 95% confidence interval, -0.1 to 1.1 episodes; P = .080). However, this is statistically inconclusive given the confidence interval. In contrast, pain (P = .020) and dissatisfaction (P = .011) were greater in patients given 0.4% ropivacaine. For continuous interscalene nerve blocks, given the statistically inconclusive primary endpoint results and design limitations of the current study, further research on this topic is warranted. In contrast, providing a lower concentration of local anesthetic at a higher basal rate provided superior analgesia.

The Effects of Varying Local Anesthetic Concentration and Volume on Continuous Popliteal Sciatic Nerve Blocks: A Dual-Center, Randomized, Controlled Study

It remains unknown whether local anesthetic concentration, or simply total drug dose, is the primary determinant of continuous peripheral nerve block effects. We therefore tested the null hypothesis that providing different concentrations and rates of ropivacaine, but at equal total doses, produces comparable effects when used in a continuous sciatic nerve block in the popliteal fossa. Preoperatively, a perineural catheter was inserted adjacent to the sciatic nerve using a posterior popliteal approach in patients undergoing moderately painful orthopedic surgery at or distal to the ankle. Postoperatively, patients were randomly assigned to receive a perineural ropivacaine infusion of either 0.2% (basal 8 mL/h, bolus 4 mL) or 0.4% (basal 4 mL/h, bolus 2 mL) through the second postoperative day. Therefore, both groups received 16 mg of ropivacaine each hour with a possible addition of 8 mg every 30 min via a patient-controlled bolus dose. The primary end point was the incidence of an insensate limb, considered undesirable, during the 24-h period beginning the morning after surgery. Secondary end points included analgesia and patient satisfaction. Patients given 0.2% ropivacaine (n = 25) experienced an insensate limb with a mean (sd) of 1.8 (1.8) times, compared with 0.6 (1.1) times for subjects receiving 0.4% ropivacaine (n = 25; estimated difference = 1.2 episodes, 95% confidence interval, 0.3-2.0 episodes; P = 0.009). In contrast, analgesia and satisfaction were similar in each group. For continuous popliteal-sciatic nerve blocks, local anesthetic concentration and volume influence block characteristics. Insensate limbs were far more common with larger volumes of relatively dilute ropivacaine. During continuous sciatic nerve block in the popliteal fossa, a relatively concentrated solution in smaller volume thus appears preferable.

Brown Norway rat asthma model of diphenylmethane-4,4′-diisocyanate (MDI): Impact of vehicle for topical induction

The development of this Brown Norway (BN) rat asthma model was focused on the duplication of at least some hallmarks of human diisocyanate asthma using the skin as the initial priming route of exposure. Equal total doses of polymeric diphenylmethane-diisocyanate (MDI) were applied to similar surface areas either dissolved in di- n-octyl sebacic acid ester (20%) (SEBA), in acetone:olive oil (20%) (AOO) or undiluted. The elicitation of respiratory allergy utilized four repeated nose-only inhalation challenges of 30 min with 39 mg/m 3 MDI–aerosol approximately every 2 weeks. Emphasis was directed towards the analysis of respiratory responses delayed in onset. Endpoints suggestive of an allergic inflammatory response were examined by bronchoalveolar lavage (BAL) 1 day after the last inhalation challenge and comprised protein, LDH, cytodifferentiation of BAL cells, MCP-1, and some Th1 and Th2 cytokines. MCP-1 and cytokines were comparatively determined in three compartments: BAL fluid, BAL cells, and lung-associated lymph nodes (LALN). In all groups sensitized topically to MDI typical delayed-onset respiratory responses occurred. The lung and LALN weights, BAL-protein and -LDH were significantly increased as compared to the naïve control group challenged identically. There was compelling evidence of a neutrophilic rather than an eosinophilic inflammatory response. The patterns of interleukin (IL) IL-1α, TNF-α, IFN-γ, GM-CSF, and IL-4 differed appreciably from one compartment to another and were essentially maximal in BAL cells. In contrast, MCP-1 was increased to the same extent in all compartments measured. Collectively, changes were slightly, although consistently more pronounced when using SEBA as vehicle when compared with the vehicle AOO or undiluted MDI. Notable was a discordance of cytokine profiles and respiratory responses. In conclusion, the priming potency of topically administered MDI and subsequent asthma-like responses following repeated inhalation exposures appear to be dependent on multiple factors, one of them appears to be associated with the type of matrix used to dissolve MDI. This animal model provides a versatile and robust experimental tool to evaluate and assess at least some features of MDI-related asthma.

Single-mode optical waveguides fabricated in LiNbO 3 by multienergy C 2+ implantations

Single-mode waveguides in LiNbO 3 are demonstrated by use of prism coupling method. The waveguides are fabricated by three different energies and single energy C 2+ implantations at the equal total doses, respectively. Dark modes and propagation loss are measured by use of prism coupling and moving fiber methods, respectively. Damages produced by implantation are measured by RBS/channeling technique. The waveguide structures are investigated in two different implantation cases. The results of analysis indicate that the heavy ion-implanted waveguides are still defined by synergetic characteristics from both the raised-index region and the low-index barrier. The broadened barrier from multienergy implantation is demonstrated to play a significant role in reducing propagation loss.

Pharmacokinetic/Pharmacodynamic (PK/PD) Evaluation of a Once-Daily Treatment Using Ciprofloxacin in an Extended-Release Dosage Form*

To evaluate the suitability of a once-a-day dosing regimen of ciprofloxacin using a new extended-release dosage form based on PK/PD principles. Ciprofloxacin's serum concentrations were measured after administration of 500 mg immediate-release twice-daily, and 1,000 mg extended-release once-daily to 19 healthy volunteers. Pharmacokinetic parameters were determined using non-compartmental and compartmental data analysis. Measured serum concentration profiles were linked to ciprofloxacin's effect against Escherichia coli (MIC 0.013 mg/l) from in vitro kill curve studies where the pharmacokinetics of ciprofloxacin were simulated and change in number of bacteria (CFU/ml) versus time was monitored. Resulting parameters were used to compare expected kill curves for the two dosing regimens based on measured ciprofloxacin concentrations. Fitting the data using an appropriate PK/PD model resulted in a set of mean pharmacodynamic parameters (bacterial growth rate constant, k0, maximum kill rate constant, Kmax, and EC50). The model included a novel term to account for a change in kill rate after approximately 4 h when Kmax decreased in concentration-dependent matter. The model allowed excellent curve fits of all ciprofloxacin concentrations investigated. Comparison of expected kill curves with the immediate-release versus extended-release treatments showed similar outcome. Both treatments resulted in a decrease in CFU/ml > 5 log units over 24 h. Results indicate that once-a-day dosing of equal total daily doses with the new and more compliance-friendly extended-release dosing form will be therapeutically equivalent to once-a-day dosing with traditional immediate-release dosage forms for treatment of infections with this microorganism.

Antiepileptic Drugs: All Ages

Antiepileptic Drugs: All Ages

Improved tolerability and efficacy in epilepsy patients with extended-release carbamazepine

The authors conducted a 3-month, prospective, open-label study assessing the effects of switching from immediate-release carbamazepine formulations to an equal total daily dose of carbamazepine extended-release capsules (CBZ-ERC) in adolescents and adults with epilepsy. Using validated, epilepsy-specific measures the authors found that switching to CBZ-ERC significantly improved patients' adverse events and quality-of-life measures. Switching to CBZ-ERC also improved seizure control.