Biomedical subjects

D W Miller

Publications and source records attributed to D W Miller.

At least 19 recordsLinked to original sources

PubMed2003

[The molecular mechanisms of neovascular age-related macular degeneration].

Age-related macular degeneration is the leading cause of irreversible vision loss in industrialized countries. While early forms of this disease with drusen and focal pigment alterations generally do not lead to relevant functional limitations, later forms of the disease, either through atrophy or choroidal neovascularization, are associated with significant visual impairment. A significant increase in knowledge about the molecular mechanisms of new vessel formation from the choriocapillaries has occurred over the past few years. This has already allowed for the clinical testing of pharmacological agents which inhibit the formation of new vessels in AMD. This article describes current research in the pathophysiology of choroidal neovascularization secondary to age-related macular degeneration.

Aged↗

PubMed2003

[Pharmacological therapy for age-related macular degeneration. Current developments and perspectives].

Current therapeutic options for age-related macular degeneration are very limited and are, at best, only capable of slowing visual loss. Because of this an intensive search for prophylactic agents capable of inhibiting the progression of this disease from early into late forms, as well as for new therapeutic approaches has been undertaken. While neuroprotective substances are hoped to prevent cellular death in this disease process, multiple substances capable of inhibiting neovascularization, such as VEGF inhibitors, are in clinical trials. Inhibitors of matrix-metalloproteinases (MMP) and chemotherapeutic agents are also being clinically tested as novel therapies for AMD. Other targets include the inhibition of toxic compound formation in lipofuscin granules such as AZ-E. What follows is an overview of different substances and their stages of development in clinical trials.

Adrenal Cortex Hormones↗

PubMed2003

Digital analysis of choroidal neovascularisation in consecutive fluorescein angiograms for use in longitudinal clinical trials.

BACKGROUND/AIMS: To document the natural history and to assess the efficacy of interventional therapies in neovascular age related macular degeneration (AMD), an accurate and reproducible method is required for analysis of consecutive fluorescence angiograms. The development and evaluation of an image analysis software for this purpose is described here. It allows for the quantitative analysis of changes in CNV and/or leakage area over time. METHODS: In digitised angiograms, a mouse driven arrow was used to delineate the CNV border. The ratio of the CNV area to the square of the distance between two vessels was automatically calculated by pixel count to compensate for variation in image sizes at different examination times. These results were directly transferred and stored in a database. To assess reproducibility, CNV areas in 20 patients with occult and 20 patients with classic CNV were determined independently by two readers. RESULTS: There was only marginal variability between observers with this method: the mean deviation was 0.01 pixels for classic CNV (95% CI -0.17 to +0.15, SD 0.35) and 0.55 pixels for occult CNV (95% CI -1.06 to -0.04, SD 1.14). CONCLUSIONS: This practical PC based method allows for quantification of angiographic features such as CNV size in early frames and area of leakage in late frames. Limitations include non-readily defined borders in angiograms of poor image quality or indistinct borders of the hyperfluorescent areas of interest. The software is applicable to future clinical trials where the analysis of neovascular complex changes is required, for example, following therapeutic intervention.

Choroidal Neovascularization↗

PubMed2002

The effects of undernutrition, in utero, on reproductive function in adult male and female sheep.

The aim of this study was to determine the effects of maternal undernutrition during pregnancy on adult reproductive function in male and female offspring. Groups of ewes were fed rations providing either 100% (High, H) or 50% (Low, L) of estimated metabolisable energy (ME) requirements for pregnancy, from mating until day 95 of gestation, and thereafter were conventionally managed. At 20 months of age, LH and FSH profiles, and LH responses to exogenous GnRH were measured in male and female offspring and, in males, testicular responses to exogenous LH (as measured by testosterone concentrations) were also measured. Undernutrition had no effect on the mean birth weights of lambs of either sex, or on testicular size in male animals at either 6 weeks or 20 months of age. L males exhibited significantly higher FSH concentrations than H males (P < 0.05) but there were no differences with treatment in FSH profiles in females, basal LH profiles or gonadotrophin responses to GnRH in offspring of either sex, and no difference in basal testosterone concentrations or in the testosterone response to exogenous LH administration in males. Semen quality at 20 months of age was unaffected by pre-natal undernutrition but ovulation rate was significantly reduced in L compared to H female offspring (P < 0.05). It is concluded that pre-natal undernutrition had no effect on male reproductive development and adult function, but reduced ovulation rate in female progeny. This effect was not associated with a change in gonadotrophin profiles or pituitary responsiveness.

Analysis of Variance↗

PubMed2002

Maternal undernutrition alters triiodothyronine concentrations and pituitary response to GnRH in fetal sheep.

The aims of this study were to determine which hormones may have a role in the expression of maternal undernutrition effects on reproductive function, in both the developing fetus and the adult offspring. This was undertaken by measuring the effects of long-term maternal undernutrition on metabolic hormone profiles and pituitary responses to single doses of GnRH and GH-releasing factor (GRF) in fetal sheep. From mating, groups of ewes were fed rations providing either 100% (HIGH) or 50% (LOW) of estimated metabolisable energy requirements for pregnancy throughout the experiment until slaughter at approximately 119 days of gestation. Fetal and maternal blood samples were collected from 113 until 119 days of gestation, via carotid and jugular catheters respectively, and assayed for insulin, IGF-I, GH, thyroxine and triiodothyronine (T(3)). Undernutrition had no effects on fetal weight, fetal gonad weight of either sex, fetal insulin or IGF-I concentrations. Male LOW fetuses exhibited a significantly attenuated response (P<0.05) to a bolus challenge of GnRH compared with HIGH fetuses. Basal fetal GH concentrations and the response to exogenous GRF were similar in both treatment groups, although LOW fetuses exhibited more secretory episodes (P<0.01). Mean T(3) concentrations were significantly lower in both the maternal (P<0.01) and fetal (P<0.05) plasma of LOW animals compared with HIGH animals. It is concluded that pituitary function was altered in fetal males and could influence male reproductive development. On the other hand, in female sheep, fetal gonadal abnormalities and reductions in reproductive capacity in adult life which are associated with fetal undernutrition are unlikely to be attributable to altered pituitary function. Additionally, these studies raise the possibility that thyroid hormones may have a role in the expression of maternal undernutrition effects on fetal development.

Analysis of Variance↗

PubMed2002

Seasonal and dose-dependent effects of intracerebroventricular leptin on lh secretion and appetite in sheep.

The role of leptin in neuroendocrine appetite and reproductive regulation remains to be fully resolved. A series of three experiments was conducted using adequately nourished oestradiol-implanted castrated male sheep. In a cross-over design (n=6), responses to a single i.c.v. (third ventricle) injection of leptin (0.5, 1.0 and 1.5 mg ovine leptin (oLEP) and 1.0 mg murine leptin (mLEP)), N-methyl-D-aspartate (NMDA, 20 micro g) or 0.9% saline (control) were measured in terms of LH secretion (4 h post-injection compared with 4 h pre-injection) and appetite (during 2 h post-injection) in autumn (Experiment 1). NMDA and 1.0 mg oLEP treatments were repeated in the same sheep in the following spring (Experiment 2). With an additional 12 sheep (n=18 in cross-over design), responses to low-dose 'physiological' i.c.v. infusion of leptin (8 ng/h for 12 h daily for 4 days), insulin (0.7 ng/h) and artificial cerebrospinal fluid were measured in the next spring (Experiment 3). LH was studied over 8 h and appetite over 1 h on days 1 and 4 of infusion. In Experiment 1 (autumn), oLEP overall increased LH pulse frequency by up to 110% (P<0.05), decreased LH pulse amplitude (P<0.05) and decreased appetite (P<0.05). mLEP reduced LH pulse amplitude (P<0.05) without significant effect on appetite, while NMDA reduced appetite (P<0.05) but had no effect on LH. In Experiment 2 (spring), LH responses were 'surge-like' with highly significant increases in the moving average LH concentration after 1.0 mg oLEP (P<0.001) and after NMDA (P<0.001). Compared with similar analysis of experiment 1 results, the LH response in spring was greater than that in autumn for both 1.0 mg oLEP (P<0.05) and NMDA (P<0.005). Conversely, unlike in autumn (Experiment 1), there was no effect of 1.0 mg oLEP or NMDA on appetite in the spring (Experiment 2). In Experiment 3 (spring), 'physiological' i.c.v. infusion of oLEP or insulin increased LH pulse frequency by up to 100% (P<0.001) compared with the control infusion on both days 1 and 4, but there were no effects on appetite. These results indicate that intracerebral leptin both stimulates reproductive neuroendocrine output and decreases appetite in adequately nourished sheep. However, the responses of these two axes were dose-dependent and differentially affected by the time of year, suggesting dissociation of the neural pathways involved.

Animals↗

PubMed2002

Effect of maternal undernutrition on fetal testicular steroidogenesis during the CNS androgen-responsive period in male sheep fetuses.

The aim of this study was to determine the effects of maternal undernutrition, applied during physiologically relevant stages of development of the reproductive system, on reproductive development in male sheep fetuses. Groups of ewes (n = 11-19) were fed rations providing either 100% (high; H) or 50% (low; L) of metabolizable energy requirements for live weight maintenance during selected 'windows', bounded by days 0, 30, 50, 65 and 110 after mating. Ewes of control groups (HH (Expts 1 and 2) and HHH (Expt 3)) were fed the H ration from mating until they were killed at day 50 (Expt 1), day 65 (Expt 2) or day 110 (Expt 3) of gestation, whereas ewes of other groups were fed the L ration for the periods days 0-30 of gestation (LH and LHH), days 31-50 or days 31-65 of gestation (HL and HLH), days 65-110 of gestation (HHL), or day 0 to day 50, day 65 or day 110 of gestation (LL and LLL) when the animals were killed. At day 50 of gestation, there was no effect of nutritional treatment on mean fetal mass or fetal testicular mass, but there was increased expression of mRNA for steroidogenic acute regulatory protein (StAR) in the testes of LL animals (P < 0.05) compared with HH controls. Compared with HH animals, the mean plasma testosterone concentrations of LL fetuses tended to be higher, but this result did not reach significance. At day 65 of gestation there were no significant differences between treatments in mean fetal masses, testicular masses, mean plasma testosterone concentrations or StAR mRNA content. At day 110 of gestation, fetal masses in the LLL group were lower (P < 0.01) than those of control fetuses, although no differences in testicular size or fetal plasma testosterone concentrations were recorded. It is concluded that the effects of undernutrition on reproductive development of male sheep fetuses are dependent on the timing of the period of undernutrition.

Analysis of Variance↗

PubMed2001

Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion.

This paper, for the first time, demonstrates that exposure of cells to the poly(ethylene oxide)-poly(propylene oxide) block copolymer, Pluronic P85, results in a substantial decrease in ATP levels selectively in MDR cells. Cells expressing high levels of functional P-glycoprotein (MCF-7/ADR, KBv; LLC-MDR1; Caco-2, bovine brain microvessel endothelial cells [BBMECs]) are highly responsive to Pluronic treatment, while cells with low levels of P-glycoprotein expression (MCF-7, KB, LLC-PK1, human umbilical vein endothelial cells [HUVECs] C2C12 myoblasts) are much less responsive to such treatment. Cytotoxicity studies suggest that Pluronic acts as a chemosensitizer and potentiates cytotoxic effects of doxorubicin in MDR cells. The ability of Pluronic to inhibit P-glycoprotein and sensitize MDR cells appears to be a result of ATP depletion. Because many mechanisms of drug resistance are energy dependent, a successful strategy for treating MDR cancer could be based on selective energy depletion in MDR cells. Therefore, the finding of the energy-depleting effects of Pluronic P85, in combination with its sensitization effects is of considerable theoretical and practical significance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Transport of fluorescein in MDCKII-MRP1 transfected cells and mrp1-knockout mice.

The multidrug resistant-associated protein 1 (MRP1) is a membrane-bound transport protein that is involved in the efflux of organic anions and has been implicated in multidrug resistance in cancer. MRP1 has also been reported to be ubiquitously expressed in normal tissues, including the brain. The presence of functional organic anion transporters in the blood-brain and blood-CSF barriers that influence the distribution of various compounds to the brain has long been known. The purpose of this study was to examine the role of MRP1 in the brain distribution of a model organic anion, fluorescein. The substrate specificity of MRP1 for fluorescein was initially determined by examining the accumulation of fluorescein in MDCKII MRP1-transfected cells. The distribution of fluorescein in the brain was then examined in wild-type and mrp1 gene knockout mice. The results show that in MDCKII MRP1-transfected cells, the accumulation of fluorescein was significantly lower (about 40% lower) than that in wild-type MDCKII cells. MRP1 inhibitors such as probenecid, MK-571, and LY402913 enhanced fluorescein accumulation in MDCKII MRP1-transfected cells to a greater extent than in wild-type MDCKII cells. In an in vivo study, after intravenous injection of fluorescein, the fluorescein brain-to-plasma concentration ratio in mrp1 knockout mice was not significantly different than that in wild-type mice. However, when probenecid was co-administered with fluorescein in wild-type mice, the fluorescein brain-to-plasma ratio was significantly increased (1.5-fold). These findings suggest that fluorescein is a substrate for MRP1. Furthermore, the in vivo study also suggests that MRP1 has a limited role in the transport and distribution of fluorescein in the brain. Therefore, other organic anion transport proteins, including the various isoforms of the MRP family, may be responsible for the accumulation and transport of organic anions in the brain.

ATP-Binding Cassette Transporters↗

PubMed2001

Methodologies and tools for proton beam design for lung tumors.

PURPOSE: Proton beams can potentially increase the dose delivered to lung tumors without increasing the dose to critical normal tissues because protons can be stopped before encountering the normal tissues. This potential can only be realized if tissue motion and planning uncertainties are correctly included during planning. This study evaluated several planning strategies to determine which method best provides adequate tumor coverage, minimal normal tissue irradiation, and simplicity of use. METHODS AND MATERIALS: Proton beam treatment plans were generated using one or more of three different planning strategies. These strategies included designing apertures and boluses to the PTV, apertures to the PTV and boluses to the CTV, and aperture and bolus to the CTV. RESULTS: The planning target volume as specified in ICRU Report 50 can be used only to design the lateral margins of beams, because the distal and proximal margins resulting from CT number uncertainty, beam range uncertainty, tissue motions, and setup uncertainties, are different than the lateral margins resulting from these same factors. The best strategy for target coverage with the planning tools available overirradiated some normal tissues unnecessarily. The available tools also made the planning of lung tumors difficult. CONCLUSIONS: This study demonstrated that inclusion of target motion and setup uncertainties into a plan should be performed in the beam design step instead of creating new targets. New computerized treatment planning system tools suggested by this study will ease planning, facilitate abandonment of the PTV concept, improve conformance of the dose distribution to the target, and improve conformal avoidance of critical normal tissues.

Algorithms↗

PubMed2001

The use of transgenic mice in pharmacokinetic and pharmacodynamic studies.

Transgenic technology has made it possible to alter the genetic make-up of a laboratory mouse through the removal or insertion of selected genes. The resulting transgenic mouse provides a means for determining the developmental and functional contributions of selected genes and the proteins they encode. The current article reviews examples of the use of transgenic mice in pharmacokinetic and pharmacodynamic studies. In addition to examining current applications of transgenic technology in the areas of pharmacokinetics and pharmacodynamics, the potential for future advancements as well as limitations of the technology are discussed.

Animals↗

PubMed2001

Evaluation of creatine transport using Caco-2 monolayers as an in vitro model for intestinal absorption.

Creatine is a nutraceutical that has gained popularity in both well-trained and casual athletes for its performance-enhancing or ergogenic properties. The major disadvantages of creatine monohydrate formulations are poor solubility and oral bioavailability. In the present study, creatine transport was examined using Caco-2 monolayers as an in vitro model for intestinal absorption. Confluent monolayers of Caco-2 cells (passage 25-35) were used for the permeability studies. Monolayers were placed in side-by-side diffusion chambers. (14)C-Creatine (0.1-0.5 microCi/mL) was added to either the apical or basolateral side, and the transport of the creatine across the Caco-2 monolayer was measured over a 90-min period. The apical to basolateral transport of (14)C-creatine was small, ranging from 0.2-3% of the original amount appearing on the receiver side in a 90-min period. Interestingly, the basolateral to apical permeability of radiolabeled creatine was substantially greater than that observed in the apical to basolateral direction. Studies with drug efflux transport inhibitors indicate that neither the P-glycoprotein nor multidrug resistance-associated protein is involved in the enhanced basolateral to apical transport of creatine.

Biological Transport, Active↗

PubMed2001

Conformal proton radiation treatment for retroperitoneal neuroblastoma: introduction of a novel technique.

BACKGROUND: Postoperative irradiation for locoregionally advanced neuroblastoma requires coverage of the paraspinal retroperitoneum. The proximity of both kidneys and the liver, and a more complex target configuration, can pose a dosimetric challenge for conventional X-ray treatment and intraoperative irradiation. We utilized proton radiation therapy (PRT) to reduce dose to uninvolved kidneys, liver, intestine, and spinal cord. PROCEDURE: A 4-year-old male underwent PRT for neuroblastoma of the right adrenal gland, following chemotherapy and delayed surgical resection. Clinical target volume (CTV), boost volume, and normal structures were outlined on the 3D treatment planning CT scan. The patient received 25.2 CGE (cobalt Gray equivalent) to the CTV and 34.2 CGE to the boost region, using 1.8 CGE per fraction, five treatments per week. Dose-volume histograms (DVHs) were obtained for target and nontarget structures. RESULTS: The 95% isodose volume enclosed CTV and boost volumes. The dose to 50% of the ipsilateral kidney, with tumor involvement of the medial renal surface, was < or = 16 CGE (47% of prescribed total dose). Doses to 50% and 20% of the contralateral kidney in close proximity to deep left-side, paraspinal soft tissue involvement were restricted to 1 CGE and 10 CGE, respectively. Eighty percent of the liver received 27 CGE (80% of prescribed dose). Using a patch technique, unique to charged particle therapy, the spinal cord was almost completely spared during boost volume irradiation. CONCLUSIONS: PRT can achieve excellent dose conformity for advanced retroperitoneal, paraspinal lesions, while respecting normal tissue tolerance levels.

Child, Preschool↗

PubMed2001

Targeting of adenovirus to endothelial cells by a bispecific single-chain diabody directed against the adenovirus fiber knob domain and human endoglin (CD105).

The use of adenoviruses for antivascular cancer gene therapy is limited by their low transduction efficiency for endothelial cells. We have developed a recombinant bispecific antibody as a molecular bridge, linking the adenovirus capsid to the endothelial cell surface protein endoglin, for vascular targeting of adenoviruses. Endoglin (CD105), a component of the transforming growth factor beta receptor complex, represents a promising target for antivascular cancer therapy. Endoglin is expressed predominantly on endothelial cells and is upregulated in angiogenic areas of tumors. We isolated single-chain Fv fragments directed against human endoglin from a human semisynthetic antibody library. One of the isolated scFv fragments (scFv C4) bound specifically to various proliferating primary endothelial cells or cell lines including HUVEC, HDMEC, HMVEC, and HMEC. ScFv C4 was therefore used to construct a bispecific single-chain diabody directed against endoglin and the adenovirus fiber knob domain (scDb EDG-Ad). This bispecific molecule mediated enhanced and selective adenovirus transduction of HUVECs, which was independent from binding to the coxsackievirus and adenovirus receptor (CAR) and alpha(v)-integrins. Thus, adenovirus infection was redirected to a new cellular receptor (CD105) and cell entry pathway. These results demonstrate the utility of bispecific single-chain diabodies, which can be produced in large quantities in bacteria, for the retargeting of adenoviruses in cancer gene therapy.

Adenoviridae↗

PubMed2001

Effect of probenecid on fluorescein transport in the central nervous system using in vitro and in vivo models.

PURPOSE: The purpose of this study was to characterize the function of multidrug resistance-associated proteins (MRPs) (or MRP-like organic anion transport systems) in the blood-brain harrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) using both an in vitro BBB model and an in vivo microdialysis model. METHODS: In vitro functional studies were performed using bovine brain microvessel endothelial cells (BBMEC). The accumulation of fluorescein, an anionic fluorescent dye, in BBMEC was determined with and without the presence of inhibitors of various efflux transport proteins. In vivo microdialysis simultaneously monitored fluorescein concentrations in cortical extracellular fluid and cerebrospinal fluid. The effect of probenecid on the in vivo distribution of fluorescein was studied using a balanced crossover design in the rat. RESULTS: In vitro experiments showed that probenecid, indomethacin, LY-329146, and all MRP inhibitors significantly increased (two- to threefold) the accumulation of fluorescein in BBMEC, whereas LY-335979, a P-gp inhibitor, had no effect on the accumulation of fluorescein. Probenecid significantly increased fluorescein plasma concentration and the plasma free fraction in vivo. The distribution of fluorescein across the BBB and BCSFB was enhanced by 2.2- and 1.9-fold, respectively, when probenecid was coadministered, even after correction for increased fluorescein plasma concentrations and free fraction. CONCLUSIONS: These results demonstrate that MRPs or MRP-like transport system(s) may play an important role in fluorescein distribution across both BBB and BCSFB. This study showed that microdialysis proved to be a powerful in vivo technique for the study of transport systems in the central nervous system, and in vitro/in vivo correlations are possible using these model systems.

Algorithms↗

PubMed2001

Pluronic P85 enhances the delivery of digoxin to the brain: in vitro and in vivo studies.

Drug delivery across the blood-brain barrier is limited by several mechanisms. One important mechanism is drug efflux, mediated by several transport proteins, including P-glycoprotein. The goal of this work was to examine the effect of a novel drug delivery system, Pluronic block copolymer P85, on P-glycoprotein-mediated efflux from the brain using in vitro and in vivo methods. The hypothesis was that specific Pluronic copolymer systems enhance drug delivery to the central nervous system through the inhibition of P-glycoprotein. The effect of P85 on the cellular accumulation and transport of digoxin, a model P-glycoprotein substrate, was examined in porcine kidney epithelial cells (LLC-PK1) transfected with the human MDR1 gene. The effect of P85 on the directional flux across an in vitro BBB was also characterized. In vivo brain distribution studies were accomplished using wild-type and P-glycoprotein knockout mice. Pluronic increased the cellular accumulation of digoxin 3-fold in LLC-PK1 cells and 5-fold in the LLC-PK1-MDR1-transfected cells. Similar effects were observed for a prototypical P-glycoprotein substrate rhodamine-123. P85 treatment decreased the basolateral-to-apical and increased the apical-to-basolateral digoxin flux across LLC-PK1-MDR1 cell monolayers, and analogous results were observed with the in vitro BBB monolayers. The coadministration of 1% P85 with radiolabeled digoxin in wild-type mice increased the brain penetration of digoxin 3-fold and the digoxin level in the P85-treated wild-type mice was similar to that observed in the P-glycoprotein-deficient animals. These data indicate that Pluronic P85 can enhance the delivery of digoxin to the brain through the inhibition of the P-glycoprotein-mediated efflux mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Tumor necrosis factor-alpha induces cyclooxygenase-2 expression and prostaglandin release in brain microvessel endothelial cells.

Primary cultured bovine brain microvessel endothelial cells (BBMECs), were used as an in vitro model of the blood-brain barrier to examine the involvement of eicosanoids in the permeability and cytoskeletal structural changes observed following exposure to tumor necrosis factor-alpha (TNF-alpha). Compared with control monolayers, BBMECs exposed to TNF-alpha formed actin filament tangles and extracellular gaps with a resultant increase in permeability. Both the permeability and cytoskeletal changes observed with TNF-alpha were significantly reduced following pretreatment with NS-398 or indomethacin, inhibitors of cyclooxygenase (COX). Western blot analysis showed that TNF-alpha had no apparent effect on the expression of COX-1, but did induce the expression of COX-2 in the BBMECs. The induction of COX-2 expression occurred within the same time frame (2-4 h following TNF-alpha exposure) as the permeability increases observed with the cytokine. Consistent with the increased expression of COX-2, BBMEC monolayers exposed to TNF-alpha had significantly greater secretion and release of prostaglandin E(2) (PGE(2)) and prostaglandin F(2alpha) (PGF(2alpha)). Furthermore, BBMEC monolayers treated with PGE(2) or PGF(2alpha) showed significant increases in permeability and cytoskeletal structural changes when compared with control monolayers. Together, these results suggest that the TNF-alpha-induced permeability and cytoskeletal structural effects are due, in part, to an induction of the COX-2 system and increased release of prostaglandins in the cerebral microvasculature.

Animals↗

PubMed2001

Economic evaluation of lamivudine compared with interferon-alpha in the treatment of chronic hepatitis B in the United States.

OBJECTIVE: To determine whether lamivudine or interferon-alpha (IFN-alpha) is the more successful treatment for chronic hepatitis B given a fixed drug budget. STUDY DESIGN: A decision-tree model of 1 year. PATIENTS AND METHODS: Average wholesale prices were used to estimate drug costs. A fixed drug budget of $558,910, sufficient to treat 100 patients with IFN-alpha, was assumed. Clinical data were taken from randomized controlled trials. The outcome measures used were hepatitis B "e" antigen (HBeAg) seroconversion rates and rates of progression to cirrhosis. RESULTS: The analysis showed that given the fixed drug budget, 353 patients could be treated with lamivudine, resulting in an expected 62 HBeAg seroconversions, with 6 patients progressing to cirrhosis. Given the same drug budget, 100 patients could be treated with IFN-alpha, leaving 253 patients untreated. This treatment scenario would result in an expected 32 HBeAg seroconversions, with 28 patients progressing to cirrhosis. Compared with no treatment, the costs per additional HBeAg seroconversion obtained were $12,703 for lamivudine and $39,922 for IFN-alpha. In addition, each case of cirrhosis avoided through lamivudine treatment resulted in significant annual cost savings. Lamivudine therapy also provided additional clinical benefits (e.g., normalization of alanine transaminase levels, reduction in hepatitis B virus DNA levels, improvement in liver histology) to patients who do not seroconvert. CONCLUSION: From the perspective of a third-party payer with a fixed drug budget, lamivudine is more cost-effective therapy than IFN-alpha for the treatment of chronic hepatitis B.

Antiviral Agents↗