Preparation of controlled release anticancer agents. I: 5-Fluorouracil-ethyl cellulose microspheres

Microspheres of 5-fluorouracil have been prepared, using three grades of ethyl cellulose as wall forming materials, and utilizing a solvent evaporation technique under ambient conditions. An alcoholic solution of 5-fluorouracil and polymer was dispersed in liquid paraffin containing 33.3 per cent n-heptane. The effect of stirring rate, time of stirring, drug loading, and polymer grade on drug release in two different media were evaluated. The drug loaded particles were spherical in shape and had a diameter range of 25-200 mm and were suitable for incorporating into a gel base. Drug release studies in aqueous media, showed that acidic media provide a faster release rate than neutral media. The drug release study from an aqueous gel base preparation at pH 7.0 through a synthetic membrane was found to be promising for formulation of a gel-microsphere product for the treatment of skin lesions.     

Endocervical reactive atypia: a histologic-cytologic study

Of 1,500 cervical tissue specimens, 27 cases showed histologic changes of reactive glandular atypia which we defined as endocervical cells with large hyperchromatic, often irregular nuclei, which did not fulfill the criteria for endocervical adenocarcinoma. Eighteen of these 27 cases had preceding or concurrent cervico-vaginal smears. Six of these showed cells which were similar to those seen in histologic sections. The cytologic characteristics of these cells are defined. To determine if atypia is related to inflammatory-regenerative changes, 29 cases of endocervical polyps were examined, of which 11 showed histologic changes of endocervical reactive atypia; 4 showed these changes cytologically as well. Twenty-eight cases of routine hysterectomy specimens were examined, of which 2 cases showed endocervical reactive atypia, which indicated that the atypical changes were indeed reactive. Nine out of 27 cases were associated with hormonal usage. Fourteen cases were associated with squamous intraepithelial lesions or evidence of human papilloma virus. Follow-up of our 27 index cases revealed no progression to adenocarcinoma. These findings indicate that atypia, as we define it, of the endocervix can be due to inflammatory-reparative changes or possibly related to hormonal usage, and permit its separation from precursor lesions of endocervical adenocarcinoma.     

Effects of cobalt and chromium ions on glycolytic flux and the stabilization of hypoxia‐inducible factor‐1α in macrophages in vitro

Implant wear and corrosion have been associated with adverse tissue reactions that can lead to implant failure. Wear and corrosion products are therefore of great clinical concern. For example, Co²⁺ and Cr³⁺ originating from CoCrMo‐based implants have been shown to induce a proinflammatory response in macrophages in vitro. Previous studies have also shown that the polarization of macrophages by some proinflammatory stimuli is associated with a hypoxia‐inducible factor‐1α (HIF‐1α)‐dependent metabolic shift from oxidative phosphorylation (OXPHOS) towards glycolysis. However, the potential of Co²⁺ and Cr³⁺ to induce this metabolic shift, which plays a determining role in the proinflammatory response of macrophages, remains largely unexplored. We recently demonstrated that Co²⁺, but not Cr³⁺, increased oxidative stress and decreased OXPHOS in RAW 264.7 murine macrophages. In the present study, we analyzed the effects of Co²⁺ and Cr³⁺ on glycolytic flux and HIF‐1α stabilization in the same experimental model. Cells were exposed to 6 to 24 ppm Co²⁺ or 50 to 250 ppm Cr³⁺. Glycolytic flux was determined by analyzing extracellular flux and lactate production, while HIF‐1α stabilization was analyzed by immunoblotting. Results showed that Co²⁺, and to a lesser extent Cr³⁺, increased glycolytic flux; however, only Co²⁺ acted through HIF‐1α stabilization. Overall, these results, together with our previous results showing that Co²⁺ increases oxidative stress and decreases OXPHOS, suggest that Co²⁺ (but not Cr³⁺) can induce a HIF‐1α‐dependent metabolic shift from OXPHOS towards glycolysis in macrophages. This metabolic shift may play an early and pivotal role in the inflammatory response induced by Co²⁺ in the periprosthetic environment.     

Inclusion complexation of furosemide in cyclodextrins. Part 2: Implication on bioavailability

The effect of inclusion complexation of furosemide in cyclodextrins (CyD) on the bioavailability of the drug was studied on normal human volunteers. The excretion rate of the drug was determined by HPLC for a period of 24 h. post dosing. Several pharmacokinetic parameters were calculated and statistically analyzed. viz., peak excretion rate, peak excretion time, half peak time, elimination rate constant, area under the excretion rate time-curve as well as the total amount of drug excreted. The obtained results show that on administration of furosemide in the form of an inclusion complex in CyDs particularly beta-CyD or its dimethyl derivative may improve its biological performance, taking into consideration that furosemide is characterized by a rapid onset and a short duration of action. Inclusion complexation of furosemide in CyDs leads to a more or less delay in its onset of action, a significant increase in its duration of action as well as significant augmentation in its overall biological availability.     

Establishment of a formal program for retinoblastoma: Feasibility of clinical coordination across borders and impact on outcome

Retinoblastoma is an ocular tumor that occurs in young children, in either heritable or sporadic manner. The relative rarity of retinoblastoma, and the need for expensive equipment, anesthesia, and pediatric ophthalmologic expertise, are barriers for effective treatment in developing countries. Also, with an average age‐adjusted incidence of two to five cases per million children, patient number limits development of local expertise in countries with small populations. Lebanon is a small country with a population of approximately 4.5 million. In 2012, a comprehensive retinoblastoma program was formalized at the Children's Cancer Institute (CCI) at the American University of Beirut Medical Center, and resources were allocated for efficient interdisciplinary coordination to attract patients from neighboring countries such as Syria and Iraq, where such specialized therapy is also lacking. Through this program, care was coordinated across hospitals and borders such that patients would receive scheduled chemotherapy at their institution, and monthly retinal examinations and focal laser therapy at the CCI in Lebanon. Our results show the feasibility of successful collaboration across borders, with excellent patient and physician adherence to treatment plans. This was accompanied by an increase in patient referrals, which enables continued expertise development. However, the majority of patients presented with advanced intraocular disease, necessitating enucleation in 90% of eyes in unilateral cases, and more than 50% of eyes in bilateral cases. Future efforts need to focus on expanding the program that reaches to additional hospitals in both countries, and promoting early diagnosis, for further improvement of globe salvage rates.     

Prevalence of phonatory symptoms in patients with type 2 diabetes mellitus

To look at the prevalence of phonatory symptoms in patients with type 2 diabetes mellitus. The correlation between these symptoms with duration of the disease, glycemic control, and neuropathy will be described. A total of 105 consecutive patients diagnosed with type 2 diabetes mellitus by their primary endocrinologist were evaluated. A control group consisting of 33 healthy subjects was recruited for this study. Demographic data included: age, gender, allergy, smoking, duration of the disease, glycemic control, and presence or absence of neuropathy. Subjects were also asked about the presence or absence of the following symptoms: hoarseness, vocal tiring or fatigue, vocal straining, and aphonia or complete loss of voice. Patients were also asked to fill out the Voice Handicap Index 10. The mean age of patients with diabetes was 53.21 + 9.68 years with male-to-female ratio of 2/3. The most common phonatory symptoms were vocal tiring or fatigue and hoarseness (34.3 and 33.3 %). There was a significant difference in the prevalence of hoarseness and vocal straining (p value 0.045 and 0.015, respectively) compared to controls. There was a significant correlation between glycemic control, neuropathy, and hoarseness (p value 0.030 and 0.001, respectively). Vocal straining and aphonia also correlated significantly with the presence of neuropathy. Close to 16 % of diabetic patients had a VHI-10 above or equal to 7. Diabetic patients are more likely to have phonatory symptoms compared to controls, namely straining and hoarseness. One out of seven patients with diabetes has reported that phonatory symptoms had a significant impact on their quality of life. The presence of neuropathy and poor glycemic control should alert the treating physician to these vocal complaints.