In Vivo Efficacy of Olorofim against Systemic Scedosporiosis and Lomentosporiosis.

Clinically relevant members of the Scedosporium/Pseudallescheria species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents in vitro, and infection due to these species is difficult to treat. We studied the in vivo efficacy of a new fungicidal agent, olorofim (formerly F901318), against scedosporiosis and lomentosporiosis in neutropenic animals. Cyclophosphamide-immunosuppressed CD-1 mice infected by Scedosporium apiospermum, Pseudallescheria boydii (Scedosporium boydii), and Lomentospora prolificans were treated by intraperitoneal administration of olorofim (15 mg/kg of body weight every 8 h for 9 days). The efficacy of olorofim treatment was assessed by the survival rate at 10 days postinfection, levels of serum (1-3)-ß-d-glucan (BG), histopathology, and fungal burdens of kidneys 3 days postinfection. Olorofim therapy significantly improved survival compared to that of the untreated controls; 80%, 100%, and 100% of treated mice survived infection by Scedosporium apiospermum, Pseudallescheria boydii, and Lomentospora prolificans, respectively, while less than 20% of the control mice (phosphate-buffered saline [PBS] treated) survived at 10 days postinfection. In the olorofim-treated neutropenic CD-1 mice infected with any of the three species, serum BG levels were significantly suppressed and fungal DNA detected in the target organs was significantly lower than in controls. Furthermore, histopathology of kidneys revealed no or only a few lesions with hyphal elements in the olorofim-treated mice, while numerous fungal hyphae were present in control mice. These results indicate olorofim to be a promising therapeutic agent for systemic scedosporiosis/lomentosporiosis, devastating emerging fungal infections that are difficult to treat with currently available antifungals.

Effect of SARS and COVID-19 outbreaks on urology practice and training.

INTRODUCTION: The objective was to investigate the changes in urology practice during coronavirus disease 2019 (COVID-19) pandemic with a perspective from our experience with severe acute respiratory syndrome (SARS) in 2003. METHODS: Institutional data from all urology centres in the Hong Kong public sector during the COVID-19 pandemic (1 Feb 2020-31 Mar 2020) and a non-COVID-19 control period (1 Feb 2019-31 Mar 2019) were acquired. An online anonymous questionnaire was used to gauge the impact of COVID-19 on resident training. The clinical output of tertiary centres was compared with data from the SARS period. RESULTS: The numbers of operating sessions, clinic attendance, cystoscopy sessions, prostate biopsy, and shockwave lithotripsy sessions were reduced by 40.5%, 28.5%, 49.6%, 44.8%, and 38.5%, respectively, across all the centres reviewed. The mean numbers of operating sessions before and during the COVID-19 pandemic were 85.1±30.3 and 50.6±25.7, respectively (P=0.005). All centres gave priority to cancer-related surgeries. Benign prostatic hyperplasia-related surgery (39.1%) and ureteric stone surgery (25.5%) were the most commonly delayed surgeries. The degree of reduction in urology services was less than that during SARS (47.2%, 55.3%, and 70.5% for operating sessions, cystoscopy, and biopsy, respectively). The mean numbers of operations performed by residents before and during the COVID-19 pandemic were 75.4±48.0 and 34.9±17.2, respectively (P=0.002). CONCLUSION: A comprehensive review of urology practice during the COVID-19 pandemic revealed changes in every aspect of practice.

Efficacy of Olorofim (F901318) against Aspergillus fumigatus, A. nidulans, and A. tanneri in Murine Models of Profound Neutropenia and Chronic Granulomatous Disease.

The emergence of azole resistance in Aspergillus fumigatus as well as an increasing frequency of multiresistant cryptic Aspergillus spp. necessitates exploration of new classes of antifungals. Olorofim (formerly F901318) is a new fungicidal agent that prevents the growth of ascomycetous mold species via inhibition of de novo pyrimidine biosynthesis, a mechanism of action distinct from that of currently available antifungal drugs. We studied the in vivo efficacy of olorofim intraperitoneal therapy (15 mg/kg of body weight every 8 h for 9 days) against infection with A. fumigatus, A. nidulans, and A. tanneri in both neutropenic CD-1 mice and mice with chronic granulomatous disease (CGD) (gp91-/-phox mice). In the neutropenic mouse model, 80% to 88% of treated mice survived for 10 days, and in the CGD group, 63% to 88% of treated mice survived for 10 days, depending on the infecting species, while less than 10% of the mice in the control groups survived for 10 days. In the olorofim-treated groups, galactomannan levels were significantly suppressed, with lower organ fungal DNA burdens being seen for all three Aspergillus spp. Histopathological slides revealed a limited number of inflammatory foci with or without detectable fungal elements in the kidneys of neutropenic CD-1 mice and in the lungs of CGD mice. Furthermore, the efficacy of olorofim was unrelated to the triazole MICs of the infecting Aspergillus spp. These results show olorofim to be a promising therapeutic agent for invasive aspergillosis.

Intraoperative dexamethasone alters immune cell populations in patients undergoing elective laparoscopic gynaecological surgery.

BACKGROUND: Anaesthetists use dexamethasone principally for its anti-emetic effect. The purpose of this study was to characterize the effects of a single intraoperative dose of dexamethasone on cellular and metabolic components of the immune system in patients undergoing laparoscopic surgical procedures. METHODS: In this prospective double-blind trial, female patients undergoing elective major laparoscopic surgery were randomized to receive saline (Control group, n =16) or dexamethasone 4 mg (Dexamethasone group, n =16) i.v. after the induction of anaesthesia. Inflammatory markers and immune cell counts were examined at 24 and 48 h and 6 weeks after surgery. The changes from baseline preoperative values were compared between groups using a Mann-Whitney U -test, and linear mixed models were used to validate the findings. RESULTS: No differences in concentrations of serum glucose and interleukin-6 were observed between groups after surgery. The increase in C-reactive protein concentration at 24 h after surgery was greater in the control group [median (interquartile range), 33 (25-65) vs 17 (7-26) mg dl -1 ; P =0.018]. Extensive changes in the counts of white cells, including most lymphocyte subsets, were observed 24 h after surgery, and dexamethasone appeared to attenuate most of these changes. Changes at 48 h and 6 weeks did not differ between groups. CONCLUSIONS: In female patients undergoing elective laparoscopic gynaecological surgery, dexamethasone administration appears to attenuate inflammation and to alter immune cell counts at 24 h, with no effects identified after this time. The importance of these changes for postoperative immune function is unknown. TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry (ACTRN12608000340336).

In vitro activity of the novel antifungal compound F901318 against difficult-to-treat Aspergillus isolates.

Background: F901318 is a new antifungal agent with a novel mechanism of action with activity against Aspergillus species. We investigated the in vitro activity of F901318 against a collection of Aspergillus isolates. Methods: A total of 213 Aspergillus isolates were used in this study. A total of 143 Aspergillus fumigatus sensu stricto isolates were used, of which 133 were azole resistant [25 TR34/L98H; 25 TR46/Y121F/T289A; 33 A. fumigatus with cyp51A-associated point mutations (25 G54, 1 G432 and 7 M220); and 50 azole-resistant A. fumigatus without known resistance mechanisms]. Ten azole-susceptible A. fumigatus isolates were used as WT controls. The in vitro activity was also determined against Aspergillus calidoustus (25 isolates), Aspergillus flavus (10), Aspergillus nidulans (10) and Aspergillus tubingensis (25). F901318 activity was compared with that of itraconazole, voriconazole, posaconazole, isavuconazole, amphotericin B and anidulafungin. Minimum effective concentrations and MICs were determined using the EUCAST broth microdilution method. Results: F901318 was active against all tested isolates: A. fumigatus WT, MIC90 0.125 mg/L (range 0.031-0.125); TR34/L98H,TR46/Y121F/T289A and azole resistant without known resistance mechanisms, MIC90 0.125 mg/L (range 0.031-0.25); A. fumigatus with cyp51A-associated point mutations, MIC90 0.062 mg/L (range 0.015-0.125); and other species, A. calidoustus MIC90 0.5 mg/L (range 0.125-0.5), A. flavus MIC90 0.062 mg/L (range 0.015-0.62), A. nidulans MIC90 0.125 mg/L (range 0.062-0.25) and A. tubingensis MIC90 0.062 mg/L (range 0.015-0.25). Conclusions: F901318 showed potent and consistent in vitro activity against difficult-to-treat Aspergillus spp. with intrinsic and acquired antifungal resistance due to known and unknown resistance mechanisms, suggesting no significant implications of azole resistance mechanisms for the mode of action of F901318.

iPTF16geu: A multiply imaged, gravitationally lensed type Ia supernova.

We report the discovery of a multiply imaged, gravitationally lensed type Ia supernova, iPTF16geu (SN 2016geu), at redshift z = 0.409. This phenomenon was identified because the light from the stellar explosion was magnified more than 50 times by the curvature of space around matter in an intervening galaxy. We used high-spatial-resolution observations to resolve four images of the lensed supernova, approximately 0.3 arc seconds from the center of the foreground galaxy. The observations probe a physical scale of ~1 kiloparsec, smaller than is typical in other studies of extragalactic gravitational lensing. The large magnification and symmetric image configuration imply close alignment between the lines of sight to the supernova and to the lens. The relative magnifications of the four images provide evidence for substructures in the lensing galaxy.

Instrumentation and Measurement Strategy for the NOAA SENEX Aircraft Campaign as Part of the Southeast Atmosphere Study 2013.

Natural emissions of ozone-and-aerosol-precursor gases such as isoprene and monoterpenes are high in the southeast of the US. In addition, anthropogenic emissions are significant in the Southeast US and summertime photochemistry is rapid. The NOAA-led SENEX (Southeast Nexus) aircraft campaign was one of the major components of the Southeast Atmosphere Study (SAS) and was focused on studying the interactions between biogenic and anthropogenic emissions to form secondary pollutants. During SENEX, the NOAA WP-3D aircraft conducted 20 research flights between 27 May and 10 July 2013 based out of Smyrna, TN. Here we describe the experimental approach, the science goals and early results of the NOAA SENEX campaign. The aircraft, its capabilities and standard measurements are described. The instrument payload is summarized including detection limits, accuracy, precision and time resolutions for all gas-and-aerosol phase instruments. The inter-comparisons of compounds measured with multiple instruments on the NOAA WP-3D are presented and were all within the stated uncertainties, except two of the three NO2 measurements. The SENEX flights included day- and nighttime flights in the Southeast as well as flights over areas with intense shale gas extraction (Marcellus, Fayetteville and Haynesville shale). We present one example flight on 16 June 2013, which was a daytime flight over the Atlanta region, where several crosswind transects of plumes from the city and nearby point sources, such as power plants, paper mills and landfills, were flown. The area around Atlanta has large biogenic isoprene emissions, which provided an excellent case for studying the interactions between biogenic and anthropogenic emissions. In this example flight, chemistry in and outside the Atlanta plumes was observed for several hours after emission. The analysis of this flight showcases the strategies implemented to answer some of the main SENEX science questions.

A phase I trial of bortezomib in combination with epirubicin, carboplatin and capecitabine (ECarboX) in advanced oesophagogastric adenocarcinoma.

PURPOSE: The protease inhibitor bortezomib attenuates the action of NF-κB and has shown preclinical activity alone and in combination with chemotherapy. DESIGN: A Phase I dose-escalation study was performed administering bortezomib (0.7, 1.0, 1.3 and 1.6 mg m(-2) on days 1 and 8 from cycle 2 onwards) in combination with Epirubicin 50 mg m(-2) intravenously on day 1, Carboplatin AUC 5 day 1 and Capecitabine 625 mg m(-2) BD days 1-21 every 21 days (VECarboX regimen), in patients with advanced oesophagogastric adenocarcinoma. The primary objective was to define the maximum tolerated dose (MTD) of Bortezomib when combined with ECarboX. RESULTS: 18 patients received bortezomib 0.7 (n = 6), 1.0 (n = 3), 1.3 (n = 6) and 1.6 mg m(-2) (n = 3) and a protocol amendment reducing the capecitabine dose to 500 mg m(-2) BD was enacted due to myelotoxicity. Common treatment-related non-haematological adverse events of any grade were fatigue (83.3 %), anorexia (55.6 %), constipation (55.6 %) and nausea (55.6 %). Common Grade 3/4 haematological toxicities were neutropenia (77.8 %) and thrombocytopenia (44.4 %). Objective responses were achieved in 6 patients (33.3 %) and a further 5 patients (27.8 %) had stable disease for >8 weeks. CONCLUSIONS: The addition of Bortezomib to ECarboX is well tolerated and response rates are comparable with standard chemotherapy.

Assessing graduating dental students' competencies: the impact of classroom, clinic and externships learning experiences.

OBJECTIVES: The present study assessed recent dental graduates' educational experiences with regard to competency development in different learning contexts and preparedness for independent professional performance. METHODS: The present study employed a questionnaire examining University of Manitoba graduating dental students' confidence and perceived importance of 47 competencies expected by the ACFD/CDA by requiring students to rate each competency on a five-point Likert scale. In addition, contribution of each of the three learning environments (classroom, clinic, and externship) towards competency development was assessed. RESULTS: Recent graduates reported most confidence in areas of basic clinical procedures involving radiographic, pharmacologic and caries management, with least confidence in implantology, orofacial pain, trauma and surgical management. Most importance was attributed to interpersonal-communication and basic clinical skills, with least importance in scientific research, implantology and prosthetic laboratory aspects. Overall, graduates felt that clinical setting contributed the most to competency development, followed by classroom and then externship contexts. CONCLUSION: Graduating students' professional preparedness can reflect the quality of dental programme. However, the amount of importance that graduates place on each competency might impact their confidence in the associated competencies and vice versa. In addition, learning settings must be effectively utilised for particular competencies' development.

Stabilization and target delivery of Nattokinase using compression coating.

The aim of the work is to develop a new formulation in order to stabilize a nutraceutical enzyme Nattokinase (NKCP) in powders and to control its release rate when it passes through the gastrointestinal tract of human. NKCP powders were first compacted into a tablet, which was then coated with a mixture of an enteric material Eudragit L100-55 (EL100-55) and Hydroxypropylcellulose (HPC) by direct compression. The activity of the enzyme was determined using amidolytic assay and its release rates in artificial gastric juice and an intestinal fluid were quantified using bicinchoninic acid assay. Results have shown that the activity of NKCP was pressure independent and the coated tablets protected NKCP from being denatured in the gastric juice, and realized its controlled release to the intestine based on in vitro experiments.

Obesity and time to pregnancy.

BACKGROUND: Obesity may reduce fecundity. We examined the obesity-fecundity association in relation to menstrual cycle regularity, parity, smoking habits and age to gain insight into mechanisms and susceptible subgroups. METHODS: Data were provided by 7327 pregnant women enrolled in the Collaborative Perinatal Project at 12 study centres in the United States from 1959 to 1965. Prepregnancy body mass index (BMI) was analysed continuously and categorically [underweight (<18.5 kg/m2), optimal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2) and obese (>or=30.0 kg/m2)]. Adjusted fecundability odds ratios (FORs) were estimated using Cox proportional hazards modelling for discrete time data. RESULTS: Fecundity was reduced for overweight [OR=0.92, 95% confidence interval (95% CI): 0.84, 1.01] and obese (OR=0.82, 95% CI: 0.72, 0.95) women compared with optimal weight women and was more evident for obese primiparous women (OR=0.66, 95% CI: 0.49, 0.89). Fecundity remained reduced for overweight and obese women with normal menstrual cycles. Neither smoking habits nor age modified the association. CONCLUSIONS: Obesity was associated with reduced fecundity for all subgroups of women and persisted for women with regular cycles. Our results suggest that weight loss could increase fecundity for overweight and obese women, regardless of menstrual cycle regularity, parity, smoking habits and age.

A decline in mortality from prostate cancer in the UK Atomic Energy Authority workforce.

Early epidemiological studies of the UKAEA workforce, which followed up the mortality of those who worked to the end of 1979, found a significant excess of prostate cancer deaths in some subsets of the cohort, particularly workers internally monitored for tritium contamination and those employed at the Winfrith laboratories. The excess seemed to be associated with work in heavy-water reactors. We have followed up the mortality in the UKAEA workforce to the end of 1997 and compared the mortality from prostate cancer in the years 1980-97 with the years to 1979. We found a significantly lower mortality from prostate cancer in the later years in many of the subsets of the cohort that were previously identified as high risk. There was no evidence of a continuing raised risk of prostate cancer in any subset. We considered two possible reasons why the observed risk might have declined. There is no evidence that any risk associated with heavy-water reactors would have abated in the later years or that the cohort would be less susceptible to prostate cancer. Our conclusion is that the original observation might have been a chance finding among many significance tests.

Influence of solid phase and formulation processing on stability of Abbott-232 tablet formulations.

Abbott-232 is a chemically stable, highly water soluble non-hygroscopic compound selected for development as a potent uroselective alpha(1A) agonist. An anhydrate, a monohydrate, and an amorphous phase were isolated. The anhydrate was chosen for formulation development based on solid-state characterization. Excipients for immediate release (IR) tablet formulations were selected according to compatibility studies. However, the prototype IR tablets designed for clinical trials were found to be chemically unstable. Thus, process-induced phase transformation was investigated as the likely cause of the observed instability. Since the drug loading in the formulations was low (1%), model granulations containing 30% drug were evaluated to test this hypothesis. Investigation using a variety of analytical techniques indicated that the observed degradation was, indeed, a result of a solution-mediated phase transformation from anhydrate to amorphous Abbott-232 during wet granulation. A new direct compression formulation was, therefore, developed to prevent the solution-mediated process induced phase transition. Since the drug loading was low, a polarized light microscope (PLM) method was used to evaluate the solid phase in the new formulation. PLM confirmed that the original anhydrate form remained unchanged in tablets manufactured by the dry process. Stability studies confirmed that both IR and extended release (ER) tablets of Abbott-232 were successfully developed for clinical trials using direct compression.

Oxygen alert cards and controlled oxygen: preventing emergency admissions at risk of hypercapnic acidosis receiving high inspired oxygen concentrations in ambulances and A&E departments.

BACKGROUND: Appropriate resuscitation of hypoxic patients is fundamental in emergency admissions. To achieve this, it is standard practice of ambulance staff to administer high concentrations of oxygen to patients who may be in respiratory distress. A proportion of patients with chronic respiratory disease will become hypercapnic on this. OBJECTIVES AND METHODS: A scheme was agreed between the authors' hospital and the local ambulance service, whereby patients with a history of previous hypercapnic acidosis with a Pao2 >10.0 kPa--indicating that oxygen may have worsened the hypercapnia--are issued with "O2 Alert" cards and a 24% Venturi mask. The patients are instructed to show these to ambulance and A&E staff who will then use the mask to avoid excessive oxygenation. The scheme was launched in 2001 and this paper present the results of an audit of the scheme in 2004. RESULTS: A total of 18 patients were issued with cards, and 14 were readmitted on 69 occasions. Sufficient documentation for auditing purposes was available for 52 of the 69 episodes. Of these audited admissions, 63% were managed in the ambulance, in line with card-holder protocol. This figure rose to 94% in the accident and emergency department. CONCLUSION: These data support the usability of such a scheme to prevent iatrogenic hypercapnia in emergency admissions.

Spatial analysis and mapping of sexually transmitted diseases to optimise intervention and prevention strategies.

OBJECTIVE: We analysed and mapped the distribution of four reportable sexually transmitted diseases, chlamydial infection/non-gonococcal urethritis (chlamydial infection), gonorrhoea, primary and secondary syphilis (syphilis), and HIV infection, for Wake County, North Carolina, to optimise an intervention. METHODS: We used STD surveillance data reported to Wake County, for the year 2000 to analyse and map STD rates. STD rates were mathematically represented as a spatial random field. We analysed spatial variability by calculating and modelling covariance functions of random field theory. Covariances are useful in assessing spatial patterns of disease locally and at a distance. We combined observed STD rates and appropriate covariance models using a geostatistical method called kriging, to predict STD rates and associated prediction errors for a grid covering Wake County. Final disease estimates were interpolated using a spline with tension and mapped to generate a continuous surface of infection. RESULTS: Lower incidence STDs exhibited larger spatial variability and smaller neighbourhoods of influence than higher incidence STDs. Each reported STD had a clustered spatial distribution with one primary core area of infection. Core areas overlapped for all four STDs. CONCLUSIONS: Spatial heterogeneity within STD suggests that STD specific prevention strategies should not be targeted uniformly across Wake County, but rather to core areas. Overlap of core areas among STDs suggests that intervention and prevention strategies can be combined to target multiple STDs effectively. Geostatistical techniques are objective, population level approaches to spatial analysis and mapping that can be used to visualise disease patterns and identify emerging outbreaks.

Mortality of employees of the United Kingdom Atomic Energy Authority, 1946-97.

BACKGROUND: The workforce of the UK Atomic Energy Authority has been the subject of several previous epidemiological investigations. AIMS: To detect and investigate associations between mortality rates and employment in a substantially increased cohort size and follow up extended to 1997. METHODS AND RESULTS: The new cohort included 51 367 employees, of whom 10 249 were dead. Mortality rates for all workers were low compared to national rates, as were rates in radiation workers and for workers monitored for internal contamination. For radiation workers all cause mortality and all cancer mortality were significantly lower than for non-radiation workers. There was no overall trend of increasing mortality with radiation dose. There was little evidence of raised mortality from leukaemia. The association of prostatic cancer with radiation dose was much less significant than in previous reports. However, the relatively high mortality from uterine cancers among radiation workers remained, though the numbers were very small. The association was with endometrial rather than cervical cancer. Mortality from cancer of the pleura was high among radiation workers, but was not correlated with dose. CONCLUSION: Overall, radiation workers at UKAEA showed no excess mortality. The previously detected association of prostate cancer with high radiation dose may have been a statistical artefact or a risk associated with discontinued activities. Endometrial cancer occurred at higher rates in female radiation workers, but, because there was no correlation with dose, may well be due to something other than their radiation exposure. Cancer of the pleura in radiation workers was almost certainly related to past asbestos exposure.

Hydrogen adsorption on the indium-rich indium phosphide (001) surface: a novel way to produce bridging In-H-In bonds.

The indium phosphide (001) surface provides a unique chemical environment for studying the reactivity of hydrogen toward the electron-deficient group IIIA element, indium. Hydrogen adsorption on the In-rich delta(2 x 4) reconstruction produced a neutral, covalently bound bridging indium hydride. Using vibrational spectroscopy and ab initio cluster calculations, two types of bridging hydrides were identified, a (mu-H)In(2) and a (mu-H)(2)In(3) "butterfly-like" structure. These structures were formed owing to the large thermodynamic driving force for adsorption of H atoms on solid-state indium dimers.

Ultrastructural and biochemical localization of N-RAP at the interface between myofibrils and intercalated disks in the mouse heart.

N-RAP is a recently discovered muscle-specific protein found at cardiac intercalated disks. Double immunogold labeling of mouse cardiac muscle reveals that vinculin is located immediately adjacent to the fascia adherens region of the intercalated disk membrane, while N-RAP extends approximately 100 nm further toward the interior of the cell. We partially purified cardiac intercalated disks using low- and high-salt extractions followed by density gradient centrifugation. Immunoblots show that this preparation is highly enriched in desmin and junctional proteins, including N-RAP, talin, vinculin, beta1-integrin, N-cadherin, and connexin 43. Electron microscopy and immunolabeling demonstrate that N-RAP and vinculin are associated with the large fragments of intercalated disks that are present in this preparation, which also contains numerous membrane vesicles. Detergent treatment of the partially purified intercalated disks removed the membrane vesicles and extracted vinculin and beta1-integrin. Further separation on a sucrose gradient removed residual actin and myosin and yielded a fraction morphologically similar to fasciae adherentes that was highly enriched in N-RAP, N-cadherin, connexin 43, talin, desmin, and alpha-actinin. The finding that N-RAP copurifies with detergent-extracted intercalated disk fragments even though beta-integrin and vinculin have been completely removed suggests that N-RAP association with the adherens junction region is mediated by the cadherin system. Consistent with this hypothesis, we found that recombinant N-RAP fragments bind alpha-actinin in a gel overlay assay. In addition, immunofluorescence shows that N-RAP remains bound at the ends of isolated, detergent-treated cardiac myofibrils. These results demonstrate that N-RAP remains tightly bound to myofibrils and fasciae adherentes during biochemical purification and may be a key constituent in the mechanical link between these two structures.

Physicochemical considerations in the preparation of amorphous ritonavir-poly(ethylene glycol) 8000 solid dispersions.

A systematic study of the properties of ritonavir and the influence of polyethylene glycol 8000 (PEG) on ritonavir revealed that amorphous ritonavir dispersions in PEG would have an improved dissolution profile and could exhibit long-term stability. Ritonavir, a human immunodeficiency virus (HIV) protease inhibitor, is highly lipophilic [distribution coefficient (log D)= 4.3, 25 degrees C, pH 6.8], poorly water soluble (400 microg/mL in 0.1 N HCl, 1 microg/mL at pH 6.8, 37 degrees C), and exhibits an exceedingly slow dissolution rate (0.03 mg/cm(2)-min in 0.1 N HCl at 37 degrees C). These properties indicated that a solid dispersion containing ritonavir might be useful for overcoming problems associated with slow dissolution. In addition, ritonavir is a good glass former [glass-transition temperature (T(g))/melting point (T(m)) > 0.7]. Amorphous ritonavir has an apparent solubility of 4 mg/mL in 0.1 N HCl at 37 degrees C and shows reasonable stability at 25 degrees C. Amorphous ritonavir, therefore, has properties desirable for preparing a solid dispersion containing this phase. Since PEG, a commonly used polymer, improved the aqueous solubility of crystalline ritonavir, it was expected to have a positive influence on the dissolution rate of ritonavir. Moreover, PEG was found to have negligible plasticizing effect on amorphous ritonavir, which was beneficial for the stability of the dispersion. Finally, solid dispersions of amorphous ritonavir in PEG were prepared, and these dispersions had improved in vitro dissolution rate and were physically stable for > 1.5 years at 25 degrees C when protected from moisture. The performance of this solid dispersion has been attributed to the physicochemical properties of amorphous ritonavir.