Ahmet Araman

Evaluation of PSMA PET/CT imaging using a 68Ga-HBED-CC ligand in patients with prostate cancer and the value of early pelvic imaging.

PurposeThe aim of the study was to evaluate the diagnostic value of the prostate-specific membrane antigen (PSMA) ligand 68Ga-HBED-CC (PSMA PET/CT) in patients with prostate cancer and evaluate the value of early imaging of the pelvis. Materials and methodsThe files of 28 patients were retrospectively evaluated. All patients had a histopatological confirmation of prostate cancer. PSMA PET/CT images were obtained at 5 and 60 min after injection from all patients. ResultsIntense pathologic radiotracer uptake was observed in 23 patients (77%) at the site of primary tumour. Lymph node metastases were detected in 10 patients (36%) and bone metastases were detected in seven patients (25%). Bone scan (n=25) results revealed metastatic bone lesions in four patients, equivocal results in nine patients and normal results in 12 patients. PSMA PET/CT confirmed bone metastases in all four patients. Pathologic radiotracer uptake in PSMA PET/CT scans was observed only in one patient among those who had equivocal bone scans. PSMA PET/CT showed additional bone lesions in two patients who had a normal bone scan. When we compared early and late pelvic images we found no difference in the number of lesions detected. The maximum standardized uptake value (SUVmax) for primary tumour, lymph nodes and bone metastases was significantly higher in late images. ConclusionPSMA PET/CT imaging seems to be a valuable imaging modality for evaluation of primary prostate cancer and it seems to have potential for the detection of lymph node and bone metastases. Early images 5 min p.i. can help to better distinguish between urinary bladder (before tracer accumulation occurs) and tumour lesions.

Evaluation of Mechanical and Mucoadhesive Properties of Clomiphene Citrate Gel Formulations Containing Carbomers and Their Thiolated Derivatives

The aim of our study was to prepare clomiphene citrate gel formulations that possess appropriate mechanical properties, stay on the vaginal mucosa for a long period of time, and provide sustained drug release for the local treatment of human papilloma virus infections. In this respect, 1% CLM gels including polyacrylic acid (PAA) polymers such as Carbopol® 934P (C934P), Carbopol® 971P (C971P), Carbopol® 974P (C974P) in various concentrations, and their conjugates containing thiol groups were prepared. Polyacrylic acid-cysteine (PAA-Cys) conjugates were synthesized in laboratory conditions. Mechanical properties of the gels such as hardness, compressibility, elasticity, adhesiveness, and cohesiveness were measured by TA-XTPlus texture analyzer and the vaginal mucoadhesion of formulations was investigated by mucoadhesion test. Based on obtained data, gel formulations containing C934P and its conjugate had appropriate hardness and compressibility to be applied to the vaginal mucosa and highest elasticity to show good spreadability and highest cohesion to prevent the disintegration of gel in the vagina. The mucoadhesion of the gels changed significantly depending on the polymer type and concentration (p < 0.05). The addition of conjugates containing thiol groups caused an increase in mucoadhesion (p < 0.05). The gels containing C934P-Cys showed highest adhesiveness and mucoadhesion due to the highest amount of thiol groups. A significant decrease was observed in the drug release of gel formulations as the polymer concentration increased (p < 0.05). The increase in the drug release related to the conjugate addition was not statistically significant (p > 0.05). A change in the amount of CLM was not observed in all formulations at the end of the stability test.

Comparison of 25 and 50 μg Vaginally Administered Misoprostol for Preinduction of Cervical Ripening and Labor Induction

Our purpose was to compare the efficacy of 25 µg and 50 µg intravaginally administered misoprostol tablets for cervical ripening and labor induction. Either 25-µg (n: 58) or 50-µg (n: 56) misoprostol tablets were randomly administered intravaginally to 114 subjects with an unripe cervix for labor induction. The physician was blinded to the medication. Intravaginal misoprostol was given every 4 h until the onset of labor. The mean Bishop score before misoprostol administration was 2.1 ± 1.6 in the 25-µg group and 2.0 ± 1.4 in the 50-µg group (p > 0.05). With the 25-µg dose the time until delivery was significantly longer (991.2 ± 514.4 min vs. 703.12 ± 432.6 min in the 50-µg group). The use of oxytocin augmentation was significantly higher in the 25-µg group (63.8%) than the 50-µg group (32.1%; p < 0.05). The proportions of patients with tachysystoles and hypersystoles were not significantly different between the two groups (19 and 6.9%, respectively, in the 25-µg group and 25 and 17.8%, respectively, in 50-µg group; p > 0.05). Overall, in the 25-µg group more women achieved vaginal delivery (79.3 vs. 60.7%; p < 0.05). The rate of cesarean sections due to nonreassuring fetal status was higher in the 50-µg misoprostol group (28.6 vs. 10.3%; p < 0.05). The number of neonates with a low 1-min Apgar score (<7) was significantly higher in the 50-µg misoprostol group (26.8 vs. 8.6%; p < 0.05), but 5-min Apgar scores and umbilical artery blood gas values at the time of delivery were not significantly different between the groups (p > 0.05). One patient in the 25-µg group suffered a ruptured uterus. Intravaginal administration of 25 µg of misoprostol is a clinically effective labor induction regimen and has the least adverse effects and complications.

Investigations on mefenamic acid sustained release tablets with water-insoluble gel

Mefenamic acid (MA) has analgesic, anti-inflammatory and antipyretic properties. Available conventional dosage forms are capsules and film-coated tablets. No commercial sustained release preparation of MA exists in the market. The usual oral dose is 250 or 500 mg and reported half-life is 2 h. Sodium alginate (NaAL) is the sodium salt of alginic acid, a natural polysaccharide extracted from marine brown algae. It has the ability to form a water-insoluble gel with a bivalent metal ions as calcium. Therefore, NaAL has been studied for preparing sustained release formulations in pharmaceutical technology. In this study, tablet formulations containing different ratios of NaAL and calcium gluconate (CaGL) were prepared by direct compression method. In vitro release studies were carried out using USP 23 basket method and release data were kinetically evaluated. According to release studies, it can be emphasized that NaAL and CaGL can be used for design of sustained release preparation of MA.

Evaluation and comparison of Ga-68 DOTA-TATE and Ga-68 DOTA-NOC PET/CT imaging in well-differentiated thyroid cancer.

BackgroundSomatostatin receptor (Sstr) scintigraphy with radiolabelled somatostatin analogues has been used extensively for the diagnosis and therapy of Sstr-expressing tumours. It has been shown that well-differentiated thyroid cancer (WDTC) cells have a high expression of Sstr2, Sstr3 and Sstr5. Hence, WDTC cells could be an ideal target for the evaluation of lesion uptake of Ga-68 DOTA-1-NaI3-octreotide (DOTA-NOC), which has a high affinity not only to Sstr2 but also to Sstr3 and Sstr5. The aim of the present study was to evaluate the value of Ga-68 DOTA-NOC as a target for Sstr2-expressing, Sstr3-expressing and Sstr5-expressing tumours in WDTC patients and to compare the results with those of Ga-68 DOTA-TATE in the same patient population. MethodThirteen patients with WDTC were included in our study: nine with papillary thyroid cancer, three with Hurthle cell carcinoma and one with follicular thyroid carcinoma. All patients had elevated serum thyroglobulin levels and negative post-therapeutic I-131 whole-body scans, which were obtained after the last radioiodine treatment. All patients had undergone two consecutive PET imaging studies with Ga-68 DOTA-D-Phe1-Tyr3-octreotate (DOTA-TATE) and Ga-68 DOTA-NOC, respectively. All images were evaluated visually, and maximum standardized uptake values were calculated. ResultsBoth Ga-68 DOTA-TATE and Ga-68 DOTA-NOC PET images gave comparable results. Among the 13 patients, imaging with both Ga-68 DOTA-TATE and Ga-68 DOTA-NOC gave negative results in five (38%) patients and positive results in eight (62%) patients. A total of 45 lesions were identified on Ga-68 DOTA-TATE images and 42 on Ga-68 DOTA-NOC images; three lesions were missed. Lesion uptake was significantly higher on Ga-68 DOTA-TATE images. Maximum standardized uptake values of Ga-68 DOTA-TATE and Ga-68 DOTA-NOC were 12.9±9.1 and 6.3±4.1 (n=54, P<0.001), respectively. ConclusionOur study suggested that Ga-68 DOTA-TATE has a higher lesion uptake even in WDTC patients and may have potential advantage over Ga-68 DOTA-NOC.

Matrix-Type Transdermal Patches of Verapamil Hydrochloride : In Vitro Permeation Studies Through Excised Rat Skin and Pharmacodynamic Evaluation in Rats

The objectives of this study were to develop matrix-type transdermal patches of verapamil hydrochloride (VRP) with pectin as a matrix polymer to investigate the influence of several terpenes on in vitro permeation of VRP through rat skin and to evaluate pharmacodynamic activity of transdermal formulations in rats. Matrix-type transdermal patches containing VRP were prepared using pectin as a matrix agent and propylene glycol as a plasticizer agent. Terpenes such as nerolidol, d-limonene, eucalpytol, menthone, and menthol were also used as a chemical enhancer to improve the skin penetration of VRP. The permeation studies were perfomed using Franz-type diffusion cells and full-thickness excised abdominal rat skin. Effects of terpenes on the permeation parameters of VRP were evaluated. In vitro skin permeation studies showed that nerolidol was the most promising enhancer among the enhancers examined in the present study, followed by d-limonene. Pharmacodynamic activity of the transdermal patches containing nerolidol or d-limonene was evaluated in rats by the measurement of systolic blood pressure for 360 min with the use of the tail cuff method. VRP transdermal patches significantly decreased the systolic blood pressure after 30 min and transdermal patches containing nerolidol and d-limonene maintained the decrease in blood pressure during the observation of 360 min.

Impacts of chemical enhancers on skin permeation and deposition of terbinafine

Abstract Context/Objective: The addition of chemical enhancers into formulations is the most commonly employed approach to overcome the skin barrier. The objective of this work was to evaluate the effect of vehicle and chemical enhancers on the skin permeation and accumulation of terbinafine, an allylamine antifungal drug. Methods: Terbinafine (1% w/w) was formulated as a Carbopol 934 P gel formulation in presence and absence of three chemical enhancers, nerolidol, dl-limonene and urea. Terbinafine distribution and deposition in stratum corneum (SC) and skin following 8-h ex vivo permeation study was determined using a sequential tape stripping procedure. The conformational order of SC lipids was investigated by ATR-FTIR spectroscopy. Results and discussion: Nerolidol containing gel formulation produced significantly higher enhancement in terbinafine permeation through skin and its skin accumulation was increased. ATR-FTIR results showed enhancer induced lipid bilayer disruption in SC. Urea resulted in enhanced permeation of terbinafine across the skin and a balanced distribution to the SC was achieved. But, dl-limonene could not minimize the accumulation of terbinafine in the upper SC. Conclusion: Nerolidol dramatically improved the skin permeation and deposition of terbinafine in the skin that might help to optimize targeting of the drug to the epidermal sites as required for both of superficial and deep cutaneous fungal infections.

A poly(vinyl alcohol) nanoparticle platform for kinetic studies of inhaled particles

The lack of a well defined nanosystem that retains its physicochemical properties and can be tracked in complex biological environments is one reason why the study of NP transport across biological barriers is currently so difficult. As a result, surprisingly little is known about the fate of sub-micron particles once they deposit in the airways of the lung. The aim of this study was to design and manufacture a novel nanoparticle (NP) core that would be physically stable, i.e., not aggregate in biological fluids, and act as a tracking system to investigate NP distribution in the lung. Accordingly, covalent fluorescent labeling (to allow particle tracking) of 40% hydrolyzed poly(vinyl alcohol) was undertaken by inducing dissociation of the carboxylic acid group (ArCOO−) of 5(6)-carboxyfluorescein (CF) which then reacted with the hydroxyl group of poly(vinyl alcohol) (PVA) to produce a covalently linked PVA-CF ester. Polymer purification was followed by NP manufacture and characterization in biological media. In contrast to commercial latex particles which aggregated in both cell culture medium and Hank’s balanced salt solution (HBSS), the PVA nanoparticles retained their original size (ca. 220 nm), maintained a neutral surface charge in cell culture medium for 24 h and were not acutely toxic to respiratory cells in vitro.

Comparison of Ga-68 DOTA-TATE and Ga-68 DOTA-LAN PET/CT imaging in the same patient group with neuroendocrine tumours: preliminary results.

Introduction Recent studies have suggested that PET imaging with Ga-68-labelled DOTA-somatostatin analogues such as octreotide and octreotate is useful in diagnosing neuroendocrine tumours (NETs) and has superior value over both computed tomography and planar and SPECT somatostatin receptor scintigraphy. Purpose The aim of the present study was to evaluate the role of Ga-68 DOTA-lanreotide (Ga-68-DOTA-LAN) in patients with somatostatin receptor (sst)-expressing tumours and to compare the results of Ga-68 DOTA-D-Phe1-Tyr3-octreotate (Ga-68-DOTA-TATE) in the same patient population. Materials and methods Twelve patients with NETs who were referred to our department for somatostatin receptor scintigraphy were included in the study. There were four patients with well-differentiated neuroendocrine tumour (WDNET) grade 1, two patients with WDNET grade 2, and three patients with poorly differentiated neuroendocrine carcinoma (PDNEC) grade 3. There was also one patient with medullary thyroid cancer, one patient with meningioma and one patient with MEN-1. All patients underwent two consecutive PET imaging studies with Ga-68-DOTA-TATE and Ga-68 DOTA-LAN. All images were evaluated visually, and maximum standardized uptake value was calculated for quantitative evaluation. Results On visual examination of maximum intensity projection images, GA-68 DOTA-LAN was seen to have high background activity and high bone marrow uptake. Both tracers defined 67 lesions. Ga-68 DOTA-TATE images revealed 63 (94%) clearly defined lesions, missing four lesions. In contrast, Ga-68 DOTA-LAN images defined only 23 (44%) lesions, missing 44 (56%) lesions. Thirty-two bone lesions were detected on Ga-68-DOTA-TATE images. Among them, only 11 (34%) were positive on Ga-68 DOTA-LAN images, whereas 21 (66%) were negative. When we evaluated liver, mediastinum and gastrointestinal tract lesions, Ga-68 DOTA-LAN was seen to be positive for 12 (34%) lesions and negative for 23 (66%) lesions. Conclusion Although the results are preliminary, the image quality obtained by Ga-68-DOTA-TATE seems to be superior to that obtained by Ga-68 DOTA-LAN. With its significantly higher lesion uptake and higher ability to detect lesions, Ga-68-DOTA-TATE seems to be a better radioligand compared with Ga-68-DOTA-LAN for the diagnosis of NETs.

Inhaled extended-release microparticles of heparin elicit improved pulmonary pharmacodynamics against antigen-mediated airway hyper-reactivity and inflammation

Inhaled heparin appears to provide benefit in the management of airway hyper-reactivity and inflammation. The pharmacodynamics of inhaled heparin are however transient. Providing sustained heparin concentrations in the respiratory tract should provide for an extended duration of action. We examined the in-vivo efficacy of a nebulised controlled-release microparticle formulation of heparin in modifying antigen-induced airway hyper-reactivity (AHR) and lung inflammation. Heparin-loaded biodegradable poly (D,L-lactide-co-glycolide) microparticles were prepared by spray-drying. Aerosol properties for both nebulised heparin solution and heparin microparticles displayed characteristics consistent with heparin delivery to the respiratory tract. In vitro release assays showed heparin to be released from the microparticles over 8-12 h and for the heparin to remain functional. Temporal pharmacodynamic responses were studied in an ovalbumin-sensitised in vivo model exhibiting AHR and airway inflammation. Despite a reduced total dose of heparin deposited in the airways following nebulisation with heparin microparticles, this treatment led to a more sustained inhibitory effect upon AHR and airway inflammation than equivalent doses of nebulised heparin solution. The work supports extended-release heparin as an inhalation dosing strategy in experimental therapeutic applications aimed at improving the pharmacodynamics of heparin in the treatment of AHR and lung inflammation.