Front propagation speeds of T7 virus mutants.

We propose a new reaction-diffusion model with an eclipse time to study the spread of viruses on bacterial populations. This new model is both biologically and physically sound, unlike previous ones. We determine important parameter values from experimental data, such as the one-step growth. We verify the proposed model by comparing theoretical and experimental data of the front propagation speed for several T7 virus strains.

Influence of ultrasound determination of fetal head position on mode of delivery: a pragmatic randomized trial.

OBJECTIVE: To evaluate the influence of ultrasound determination of fetal head position on mode of delivery. METHODS: This was a pragmatic open-label randomized controlled trial that included women with a singleton pregnancy in the vertex presentation at ≥ 37 weeks' gestation, cervical dilation ≥ 8 cm and who received epidural anesthesia. Women were assigned randomly to undergo either digital vaginal examination (VE group) or both digital vaginal and ultrasound examinations (VE+US group) to determine fetal head position. When the ultrasound and digital vaginal findings were inconsistent in the VE+US group, the ultrasound result was used for clinical management. The primary outcome assessed was operative delivery (Cesarean or instrumental vaginal delivery), and maternal and fetal morbidity were also assessed. RESULTS: The VE and VE+US groups included 959 and 944 women, respectively. The overall rate of operative delivery was significantly higher in the VE+US group than in the VE group: 33.7% vs 27.1%, respectively (relative risk (RR), 1.24 (95% CI, 1.08-1.43)), as was the rate of Cesarean delivery: 7.8% vs 4.9%, respectively (RR, 1.60 (95% CI, 1.12-2.28)). The rate of instrumental vaginal delivery was also higher, albeit not significantly: 25.8% in the VE+US group vs 22.2% in the VE group (RR, 1.16 (95% CI, 0.99-1.37)). Neonatal outcomes did not differ between the two groups. When analysis was restricted to instrumental vaginal deliveries only, maternal and neonatal morbidity outcomes were similar in both groups. CONCLUSION: Correction of fetal occiput position, determined initially by digital vaginal examination, using systematic ultrasound examination did not improve management of labor and increased the rate of operative delivery without decreasing maternal and neonatal morbidity.

The five myths of MMN: redefining how to use MMN in basic and clinical research.

The goal of this review article is to redefine what the mismatch negativity (MMN) component of event-related potentials reflects in auditory scene analysis, and to provide an overview of how the MMN serves as a valuable tool in Cognitive Neuroscience research. In doing so, some of the old beliefs (five common 'myths') about MMN will be dispelled, such as the notion that MMN is a simple feature discriminator and that attention itself modulates MMN elicitation. A revised description of what MMN truly reflects will be provided, which includes a principal focus onto the highly context-dependent nature of MMN elicitation and new terminology to discuss MMN and attention. This revised framework will help clarify what has been a long line of seemingly contradictory results from studies in which behavioral ability to hear differences between sounds and passive elicitation of MMN have been inconsistent. Understanding what MMN is will also benefit clinical research efforts by providing a new picture of how to design appropriate paradigms suited to various clinical populations.

Use of images in a surgery consultation. Will it improve the communication?

INTRODUCTION: The interviews and interactions with patients are part of everyday health care provider. However, there is sometimes a difficulty in communication, linked to several factors. For this reason, the use of images to illustrate the medical conditions in the outpatient clinic can improve patient communication. We report our initial experience with the use of images to manage the quality of care to surigcal patients. METHODOLOGY: He used a computer to show pictures of the following conditions: surgery for an inguinal hernia, cholelithiasis, cholecystitis and the choledocholithiasis and finally thyroid pathology. Were randomized two groups of patients. Each of the affected patients in any stage of the disease, they explained their problems. In one of the groups also showed the patient was using the current image and continued to give appropriate explanations related to pathology. Thereafter, patients in both groups filled in an anonymous questionnaire in which they responded to what degree it was considered useful this methodology, and degree of satisfaction received outpatient treatment with or without the deployment of images by computer. We have analyzed the average time expected and made a visit. RESULTS: 187 patients will be visited in the consultations over a period of 8 months. In 83 patients have been using images to give the explanations in external consultations. Of these, 24 patients suffering from thyroid, 24 hernias or incisional hernias and 35 patients with biliary tract pathology. Patients in the group were shown images of conditions have responded mostly be very satisfied with the use of images while the explanations are given on the patient's illness. Also, over 80% of patients report being satisfied with this system. The visiting time was not lengthened. DISCUSSION: Despite the existence of different variables that can influence patient satisfaction, use of images to illustrate surgical diseases to patients improves communication and flow of the explanations of the physician. CONCLUSIONS: The relationship doctor-patient communication is the key event in an outpatient setting. It determines a good overall result of the clinical interview. The use of images in an outpatient improves communication between patients and doctors. Moreover, the degree of satisfaction is high and the degree of understanding of the disease. It seems useful to incorporate in our outpatient clinic.

Lipoprotein lipase but not hormone-sensitive lipase activities achieve normality after surgically induced weight loss in morbidly obese patients.

BACKGROUND: Although bariatric surgery is currently the most common practice for inducing weight loss in morbidly obese patients (BMI>40 kg/m2), its effect on the lipid content of adipose tissue and its lipases (lipoprotein lipase [LPL] and hormone-sensitive lipase [HSL]) are controversial. METHODS: We analyzed LPL and HSL activities and lipid content from plasma as well as subcutaneous (SAT) and visceral (VAT) adipose tissue of 34 morbidly obese patients (MO) before and after (6 and 12 months) Roux-en-Y gastric bypass surgery and compare the values with those of normal weight (control) patients. RESULTS: LPL activity was significantly higher in MO (SAT=32.9+/-1.0 vs VAT=36.4+/-3.3 mU/g tissue; p<0.001) than in control subjects (SAT=8.2+/-1.4 vs VAT=6.8+/-1.0 mU/g tissue) in both adipose depots. HSL activity had similar values in both types of tissue (SAT=32.8+/-1.6 and VAT=32.9+/-1.6 mU/g) of MO. In the control group, we found similar results but with lower values (SAT=11.9+/-1.4 vs VAT=12.1+/-1.4 mU/g tissue). Twelve months after surgery, SAT LPL activity diminished (9.8+/-1.4 mU/g tissue, p<0.001 vs morbidly obese), while HSL (46.6+/-3.7 mU/g tissue) remained high. All lipids in tissue and plasma diminished after bariatric surgery except plasma nonesterified fatty acids, which maintained higher levels than controls (16+/-3 vs 9+/-0 mg/dL; p<0.001, respectively). CONCLUSIONS: When obese patients lose weight, they lose not only part of the lipid content of the cells but also the capacity to store triacylglycerides in SAT depots.

Donor leukocyte infusions to treat hematologic malignancy relapse following allo-SCT in a pediatric population.

Donor leukocyte infusions (DLI) can reverse relapse of hematologic malignancy following allogeneic hematopoietic stem cell transplant (HSCT) in some cases. Little is known regarding the effectiveness of DLI in children who relapse after HSCT. We report outcomes of 49 children who received DLI for relapse after allogeneic transplant. Prognosis was particularly poor (0/14 responses) for patients relapsing within 6 months from transplant. DLI rarely induced remission when given as sole therapy for marrow relapse. One-year disease-free survival was 30% (6/20) in patients who received DLI as consolidation following chemotherapy. The development of GVHD grades 1-2 was associated with superior 3-year survival than patients who developed GVHD grades 3-4 (P<0.002). To determine the benefit of DLI, 45 children who received DLI for relapse (four children without matches were excluded) were compared to 1229 children with similar characteristics whose relapse was not treated with DLI. There was no difference in survival (P=0.30) once adjustments were made to account for the time from relapse to DLI. Although a few children achieved durable remissions when DLI was used as part of a post-relapse treatment strategy, DLI was unsuccessful in the majority of cases. Strategies may be better directed at preempting post transplant relapse.

Rosai-Dorfman disease following bone marrow transplantation for pre-B cell acute lymphoblastic leukemia.

A child with acute pre-B cell lymphoblastic leukemia underwent haploidentical bone marrow transplantation (BMT) after first relapse. Approximately 8 months after the BMT, he developed a soft tissue mass overlying a defect in the left frontal bone. He was found to have several additional osteolytic lesions but no evidence of lymphadenopathy or organomegaly. A biopsy of the presenting lesion demonstrated a polymorphous infiltrate composed predominantly of S-100 protein and CD68 immunoreactive histiocytic cells. Together with the presence of emperipolesis, the process was interpreted as Rosai-Dorfman (R-D) disease. He received chemotherapy with vinblastine, prednisone, 6-mercaptopurine and methotrexate and has been in remission for over 4 years. Only one previous example of acute lymphoblastic leukemia in childhood has been reported with R-D disease.

Energyscapes and prey fields shape a North Atlantic seabird wintering hotspot under climate change.

There is an urgent need for a better understanding of animal migratory ecology under the influence of climate change. Most current analyses require long-term monitoring of populations on the move, and shorter-term approaches are needed. Here, we analysed the ecological drivers of seabird migration within the framework of the energyscape concept, which we defined as the variations in the energy requirements of an organism across geographical space as a function of environmental conditions. We compared the winter location of seabirds with their modelled energy requirements and prey fields throughout the North Atlantic. Across six winters, we tracked the migration of 94 little auks (Alle alle), a key sentinel Arctic species, between their East Greenland breeding site and wintering areas off Newfoundland. Winter energyscapes were modelled with Niche Mapper™, a mechanistic tool which takes into account local climate and bird ecophysiology. Subsequently, we used a resource selection function to explain seabird distributions through modelled energyscapes and winter surface distribution of one of their main prey, Calanus finmarchicus. Finally, future energyscapes were calculated according to IPCC climate change scenarios. We found that little auks targeted areas with high prey densities and moderately elevated energyscapes. Predicted energyscapes for 2050 and 2095 showed a decrease in winter energy requirements under the high emission scenario, which may be beneficial if prey availability is maintained. Overall, our study demonstrates the great potential of the energyscape concept for the study of animal spatial ecology, in particular in the context of global change.

SOM's mathematics.

Since the discovery of the SOM's by T. Kohonen, many results that provide a better description of their behaviour have been found. Most of them are very convincing, but from a mathematical point of view, only a few are actually proved. In this paper, we make a review of some results that are still to be proved and give some framework to formulate various questions.

Fronts with continuous waiting-time distributions: theory and application to virus infections.

We generalize to arbitrary waiting-time distributions some results which were previously derived for discrete distributions. We show that for any two waiting-time distributions with the same mean delay time, that with higher dispersion will lead to a faster front. Experimental data on the speed of virus infections in a plaque are correctly explained by the theoretical predictions using a Gaussian delay-time distribution, which is more realistic for this system than the Dirac delta distribution considered previously [J. Fort and V. Méndez, Phys. Rev. Lett. 89, 178101 (2002)].

[Compliance with the 2002 consensus document of the Spanish Society of Nephrology for the control of diabetic nephropathy in Catalonia (ECCODIAB)]. / Estudio sobre el grado de cumplimiento ambulatorio del documento de consenso 2002 para el control de la nefropatía diabética en Cataluña (ECCODIAB).

OBJECTIVE: To evaluate the level of compliance with the 2002 consensus document (Spanish Society of Nephrology) on guidelines for the detection, prevention and treatment of diabetic nephropathy in Catalonia. SUBJECTS AND METHODS: Multicenter (23 hospitals), observational, cross-sectional, descriptive study conducted in 413 diabetic patients (61.7% men, 38.3% women) with a median age of 66.2 +/-11.5 years (26-93 years). The ANOVA test (post-hoc analysis; p value< 0.05) was used to study the relationships between the stages of diabetic nephropathyand different variables. RESULTS: 90.3% of the patients had type 2 DM. The following anthropometric parameters were observed: BMI 29.8 +/- 5 kg/m2 (BMI > 30 kg/m2: 48.7%) and waist circumference 104.1 +/- 14 cm (48.6% men > 102 cm and 78.9% women > 88 cm). Serum creatinine 1.9 +/- 1.3 mg/dl and simplified MDRD equation 45.3 +/- 25.0 ml/min/1.73 m2 [65.8%with CKD stages 3 and 4]. 80% of patients had ophthalmologic examination and 52.8% antiplatelet treatment. Hb A1c was 7.3 +/- 1.3%, but the percentage of patients with glycated hemoglobin > 7% and 8% was 54.9 and 28.6% [only 50.2% had been seen by an endocrinologist in the last 6 months]. 52.8% of patients were treated with insulin and 44.1% with anti-diabetic drugs, although only 19.6% used the new anti-diabetic drugs. 61% of patients had an LDLc > 100 mg/dl (61% treated) and 44% had triglycerides (TG) > 150 mg/dl (72% treated). 95% of patients presented with hypertension (BP > or = 130/80 mmHg),91% were undergoing antihypertensive treatment (79.7% with angiotensin-converting enzyme inhibitors and / or angiotensin receptor blockers). 81% with microalbuminuria and 78%with established proteinuria were receiving anti-proteinuric treatment. Of the patients considered to be refractory to BP (>3 drugs), only 28.9% underwent ambulatory BP monitoring. Significant differences were observed between stages of diabetic nephropathy and glycated hemoglobin (HBA1c; p = 0.048), systolic blood pressure (SBP; p = 0.024), lipidic control (HDLc; p = 0.015 and TG; p = 0.034), anemia (Hb; p = 0.010) and CKD (creatinine and sMDRD; p = 0.000). The levels of compliance with the therapeutic objectives regarding lipid control (LDL < or = 100 mg/dl and TG< or = 150 mg/dl), BP < or = 130/80 mmHg and HbA1c < or =7% were 1 objective: 68%, 2 objectives: 21.8% and 3 objectives: only 4% of patients. CONCLUSIONS: According to the results of our study, only a reduced proportion of patients fulfilled the different therapeutic end-points indicated. Future measures will be directed at improving physician-patient relationships with the main aim of intensifying the therapeutic measures to attain better metabolic and blood pressure control, nephroprotection and prevention in the appearance of cardiovascular events.

Microplastic pollution in the Greenland Sea: Background levels and selective contamination of planktivorous diving seabirds.

Microplastics have been reported everywhere around the globe. With very limited human activities, the Arctic is distant from major sources of microplastics. However, microplastic ingestions have been found in several Arctic marine predators, confirming their presence in this region. Nonetheless, existing information for this area remains scarce, thus there is an urgent need to quantify the contamination of Arctic marine waters. In this context, we studied microplastic abundance and composition within the zooplankton community off East Greenland. For the same area, we concurrently evaluated microplastic contamination of little auks (Alle alle), an Arctic seabird feeding on zooplankton while diving between 0 and 50 m. The study took place off East Greenland in July 2005 and 2014, under strongly contrasted sea-ice conditions. Among all samples, 97.2% of the debris found were filaments. Despite the remoteness of our study area, microplastic abundances were comparable to those of other oceans, with 0.99 ± 0.62 m-3 in the presence of sea-ice (2005), and 2.38 ± 1.11 m-3 in the nearby absence of sea-ice (2014). Microplastic rise between 2005 and 2014 might be linked to an increase in plastic production worldwide or to lower sea-ice extents in 2014, as sea-ice can represent a sink for microplastic particles, which are subsequently released to the water column upon melting. Crucially, all birds had eaten plastic filaments, and they collected high levels of microplastics compared to background levels with 9.99 and 8.99 pieces per chick meal in 2005 and 2014, respectively. Importantly, we also demonstrated that little auks took more often light colored microplastics, rather than darker ones, strongly suggesting an active contamination with birds mistaking microplastics for their natural prey. Overall, our study stresses the great vulnerability of Arctic marine species to microplastic pollution in a warming Arctic, where sea-ice melting is expected to release vast volumes of trapped debris.

Microsurgical cannulation of the thoracic duct in cats. Technical note.

The authors describe a new technique for the microsurgical cannulation of the thoracic duct. A small silastic tube is utilized which can be joined to a subcutaneously implanted one-way flow, CSF, Ommaya-type reservoir. Extended drainage is avoided. No deletion or alteration of major venous channels occurs. Lymph collection is accomplished by tapping the subcutaneous reservoir with a small-bore needle.

High-risk Ewing's sarcoma: end-intensification using autologous bone marrow transplantation.

Because of retrospective analysis showing survival to be related to primary tumor size, in February 1982 a study to test this hypothesis prospectively was begun at the University of Florida. Patients with primary tumors 8 cm or less in maximum diameter and no metastases received adjuvant chemotherapy consisting of vincristine, cyclophosphamide, doxorubicin, and dactinomycin plus radiotherapy or surgery (standard-risk protocol). All others received a similar regimen followed by end-intensification with high-dose melphalan and autologous bone marrow transplantation (Protocol HR-2). Because of poor results of HR-2, another high-risk protocol (HR-3) was initiated in January 1985. Patients on HR-3 received 2 cycles of chemotherapy containing vincristine, cyclophosphamide, and doxorubicin followed by local radiation therapy and maintenance chemotherapy. At the end of this therapy, autologous bone marrow transplantation (ABMT) was performed, using a preparatory regimen of total body irradiation and intensive chemotherapy. The 2-year disease-free survival rate was 70% for the standard-risk protocol, 20% for HR-2, and 80% for HR-3. The follow-up on HR-3 is still short, but the results are promising enough to warrant further clinical trials.

Liver transplantation for factor VII deficiency.

Factor VII deficiency is a serious, potentially lethal disorder of blood coagulation caused by a defect in hepatic factor VII synthesis. We report two children, sisters, both with severe, recurrent hemorrhagic complications from factor VII deficiency, successfully treated with orthotopic liver transplantation. Postoperatively, they remain symptom free with normal coagulation profiles.

Can tests for IgA, IgG, or IgM antibodies to cardiolipin or phosphatidylserine substitute for lupus anticoagulant assays in screening for antiphospholipid antibodies?

Antiphospholipid antibodies (APL) are detected by both ELISA and tests for lupus anticoagulants (LA). We evaluated ELISA tests for IgG, IgM, and IgA isotopes of antibodies binding cardiolipin (CL) and phosphatidylserine (PS) in samples from LA patients presenting with recurrent miscarriages. All values were expressed in multiples of the normal median (MOM). In 32% (11/34) of cases, not only were all ELISA values at or below 2.5 MOM, but the distribution of these ELISA MOM values within the normal range was similar to distribution of values from LA negative controls with the same history. Neither the use of PS as the antigen nor the addition of IgA assays improved the correlation of ELISA results with the presence of LA. ELISAs are inadequate as the sole screening test for these separate, but often associated, families of APL.

Health-related quality-of-life effects of oxaprozin and nabumetone in patients with osteoarthritis of the knee.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for the treatment of signs and symptoms of osteoarthritis (OA). Nabumetone and oxaprozin are 2 of the newer NSAIDs and have been shown to have similar safety and efficacy profiles. Nabumetone 1000 mg to 1500 mg once a day (QD) and oxaprozin 1200 mg QD are commonly recommended doses. This study compared the health-related quality of life (HRQOL) of patients receiving oxaprozin 1200 mg QD with that of patients receiving nabumetone 1000 mg QD or nabumetone 1500 mg QD for the treatment of signs and symptoms of OA of the knee. Two similarly designed, independent, randomized, double-masked, placebo-controlled clinical trials were conducted. In trial 1, patients were randomized to receive oxaprozin 1200 mg QD (n = 109), nabumetone 1000 mg QD (n = 110), or placebo (n = 109); in trial 2, patients received oxaprozin 1200 mg QD (n = 116), nabumetone 1500 mg QD (n = 115), or placebo (n = 116). HRQOL was measured by the Medical Outcomes Study Short-Form-36 Health Survey (1-week recall period) at baseline and weeks 2 and 6. Data from the 2 trials were combined to assess differences across the 4 groups in 8 domains and 2 summary scores at baseline, and changes in HRQOL scores at weeks 2 and 6. At week 2, the oxaprozin group showed significantly greater improvement than the placebo group in role physical, vitality, and mental component summary (MCS) scores (P < 0.05), and in physical functioning, bodily pain, social functioning, and physical component summary (PCS) scores (P < 0.01). The nabumetone 1500-mg group showed significantly greater improvement than the placebo group in bodily pain and social functioning (P < 0.05), and in vitality and MCS score (P < 0.01). No significant differences were observed between the nabumetone 1000-mg and placebo groups. At week 2, the oxaprozin group showed a greater change than the nabumetone 1000-mg group in PCS score (P < 0.05). At week 6, oxaprozin treatment resulted in significantly greater improvement than placebo in physical functioning, role physical, and bodily pain (P < 0.05); social functioning, role emotional, and mental health (P < 0.01); and vitality and MCS score (P < 0.001). The nabumetone 1500-mg group showed significantly greater responses than the placebo group in vitality (P < 0.05), mental health (P < 0.01), and MCS score (P < 0.001). The oxaprozin group had significantly better scores than the nabumetone 1500-mg group in the PCS (P < 0.05), and it showed significantly greater improvement than the nabumetone 1000 mg group in role physical and PCS score (P < 0.01) and in role emotional (P < 0.05). No statistically significant differences were found between placebo and nabumetone 1000 mg at week 6. Results of this study suggest that oxaprozin 1200 mg QD has a significant positive impact on the HRQOL of patients with OA of the knee compared with nabumetone 1000 mg QD and placebo.

Economic and gastrointestinal safety comparisons of etodolac, nabumetone, and oxaprozin from insurance claims data from patients with arthritis.

This study was conducted to compare the effect of etodolac, nabumetone, and oxaprozin use on gastrointestinal (GI) safety and associated costs based on insurance claims information from practice settings. Data were obtained from a national claims database (MarketScan) for the years 1992 to 1994. The claims data of interest were for patients with arthritis who had used etodolac, nabumetone, or oxaprozin exclusively during a 9-month follow-up period (ONLY groups), or these drugs plus (PLUS groups) the other nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, naproxen, diclofenac, sulindac, piroxicam, ketoprofen, or indomethacin. For each group, we obtained information on the use of inpatient and outpatient services for GI-related events and the associated costs. All GI admissions were classified as NSAID-induced or possibly NSAID-induced events based on International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9 CM) codes. All outpatient upper GI ulcers or bleeding episodes were also identified by specific ICD-9 CM code. There were no significant between-group demographic differences. The proportions of patients with NSAID-induced and possibly NSAID-induced GI admissions were 0.1% and 0.4% for the etodolac-ONLY, 0.3% and 1.0% for the nabumetone-ONLY, and 0.1% and 0.5% for the oxaprozin-ONLY groups, respectively (P > 0.05), and a similar pattern was observed among the PLUS groups. In outpatient settings, 3.9%, 4.2%, and 4.9% of the etodolac-, nabumetone-, and oxaprozin-ONLY patients, respectively (P > 0.05), and 6.0%, 5.3%, and 4.7% of the etodolac-, nabumetone-, and oxaprozin-PLUS patients, respectively, had at least one upper GI ulcer/bleeding claim (P > 0.05). The total health care costs for 9 months were approximately $3000 each for the etodolac-, nabumetone-, and oxaprozin-ONLY groups. Oxaprozin, nabumetone, and etodolac had similar GI-safety and associated-costs profiles based on information from practice settings. Also, in patients who used multiple NSAIDs, the groups did not differ in their GI-safety and cost profiles.

Polymorphism and crystallization behavior of Abbott-79175, a second-generation 5-lipoxygenase inhibitor.

The crystal polymorphism of Abbott-79175, a potent second-generation 5-lipoxygenase inhibitor, has been studied. Crystallization from an ethyl acetate/heptane system in which moisture content was not controlled and from an ethanol/water system produced a crystal form I, which by differential scanning calorimetry, thermogravimetric analysis, and Karl Fischer analysis was likely a hemihydrate. This hemihydrate form of the compound was demonstrated to reversibly dehydrate/hydrate with the use of low heat and vacuum followed by exposure to water vapor (100% relative humidity). The dehydrated version of I was designated IA. However, it was shown that a relative humidity approaching 100% was required for the water to re-enter the crystal structure. X-ray powder diffraction and solid state 13C NMR data on polycrystalline samples crystallized from seven single organic solvents suggested two nonsolvated forms of the compound, II and III. The heptane addition rate to a dry ethyl acetate solution of the drug was shown to greatly affect the crystal habit, the crystallite size, and specific surface area upon its precipitation. Solution calorimetry of forms I, IA, and II showed that I had the most endothermic heat of solution, with IA and II having lower values. Initial dissolution rates of compressed disks of these forms in water showed rates of IA > II approximately I. Considering all data, including evidence of conversion of II to I in aqueous suspension, it is suggested that the relative thermodynamic stability (at least when water was present) in decreasing order is I > II > IA, although I and II are similar energetically. The lower terminal dissolution rate for form IA was due to, in part, conversion to the less soluble Form I.

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.