Exploring the feasibility of the use of biopolymers as a carrier in the formulation of amorphous solid dispersions – Part I: Gelatin

Biopolymers have rarely been used so far as carriers in the formulation of amorphous solid dispersions (ASD) to overcome poor solubility of active pharmaceutical ingredients (APIs). In an attempt to enlarge our knowledge on this topic, gelatin, type 50PS was selected. A screening study was initiated in which twelve structurally different poorly soluble biopharmaceutical classification system (BCS) Class II drugs (carbamazepine, cinnarizine, diazepam, itraconazole, nifedipine, indomethacin, darunavir (ethanolate), ritonavir, fenofibrate, griseofulvin, ketoconazole and naproxen) were selected for evaluation. Solid dispersions of five different drug loadings of these twelve compounds were prepared by lyophilization and evaluated for their solid state properties by mDSC and XR(P)D, and in vitro dissolution performance. Even without any process optimization it was possible to form either fully amorphous or partially amorphous systems, depending on the API and API to carrier ratio. Hence in this respect, gelatin 50PS behaves as any other carrier. Dissolution of the API from the solid dispersions significantly exceeded that of their crystalline counterparts. This study shows the potential of gelatin as a carrier to formulate amorphous solid dispersions.     

Improving Confidence in the Determination of Free Fraction for Highly Bound Drugs Using Bidirectional Equilibrium Dialysis

Equilibrium dialysis has been widely used for the measurement of the fraction of unbound drug (f_u) in plasma, but it suffers from the accuracy and reliability for low f_u values. To address this concern, an orthogonal approach, called the bidirectional equilibrium dialysis, is described to simultaneously measure a pair of f_u values for each drug based on equilibration in 2 opposite dialysis directions: from plasma to buffer (f_u,p/b) and from buffer to plasma (f_u,b/p). Hypothetically, if true equilibrium is attained in both dialysis directions, the measured f_u,b/p and f_u,p/b values for a given drug should converge, and thus, the ratio of f_u,b/p to f_u,p/b becomes unity (1.0). Thus, the ratio can be used as a tangible readout for data reliability. This methodology has been extensively tested in the present study using various drugs with distinct plasma binding characteristics. Our results clearly showed that low f_u values (<0.01) could be reliably determined and verified using either the standard or dilution bidirectional equilibrium dialysis method for some known highly bound drugs; for extensively bound drugs with high logD_7.4, such as montelukast, bedaquiline, and venetoclax, only a range of f_u can be reported with confidence because of uncertainty in the true equilibrium.     

Antioxidant properties of ursodeoxycholic acid

We have investigated potential antioxidant properties of the clinically relevant bile acid UDCA, which reaches therapeutic concentrations up to 0.09 and 29 mM, respectively, in human plasma and bile. UDCA was an excellent scavenger of OHz.rad; generated by FeCl(3)-EDTA, H(2)O(2) and ascorbate in the deoxyribose oxidation test, showing IC(min) and IC(50) values of 0.02 and 0.2 mM, respectively, and a second-order rate constant for reaction with OHz.rad; of 2+/-0.1 x 10(10)M(-1)s(-1). Notably, the drug could enhance at 1.5 mM concentration the antioxidant capacity of human bile against OHz.rad;-induced deoxyribose oxidation. UDCA also showed antioxidant effects in the deoxyribose test performed with nonchelated iron ions, such as Fe(2+) plus H(2)O(2) (IC(min): 7 mM, IC(50): 20 mM) or Fe(3+) plus H(2)O(2) and ascorbate (IC(min): 0.3 mM, IC(50): 5 mM), and inhibited ferrozine-Fe(2+) and desferrioxamine-Fe(3+) complexes formation with IC(50) values of, respectively, 12 and 0.3 mM, indicating that the drug interacts more with iron(III) than with iron(II). Moreover, UDCA significantly inhibited phospholipid liposome peroxidation induced by the OHz.rad;-generating system FeCl(3)-EDTA, H(2)O(2) and ascorbate (IC(min): 0.75 mM, IC(50): 3 mM), and by peroxyl radicals generated in the aqueous phase by AAPH (IC(min): 8 mM, IC(50): 14 mM). UDCA, even at 25 mM concentration, was ineffective on the lipoperoxidation mediated by Fe(2+) alone, but at the same concentration counteracted significantly that by Fe(3+) plus ascorbate, further pointing to its preferential antioxidant interaction with iron(III).In conclusion, UDCA has direct antioxidant properties, which are especially relevant against Fe(3+)- and OHz.rad;-dependent biomolecular oxidative damage; such properties are evident at therapeutically relevant drug concentrations, suggesting that UDCA could act as an antioxidant in vivo.     

USCAP Specialty Conference: Case 1-Type I Pleuropulmonary Blastoma

Pleuropulmonary blastoma (PPB) was defined in 1988 by Manivel et al. in a series describing 11 intrathoracic pulmonary neoplasms in young children [1]. The PPB is a unique peripheral pulmonary or pleural-based tumor of childhood that is characterized in its earliest form as a bland-appearing multiloculated cyst with small foci of tumor cells and in later forms as mixed and predominantly primitive, overtly malignant neoplasms [2,3]. Prior to the introduction of the PPB as a distinct entity, this tumor had been reported in the literature as pulmonary blastoma, sarcoma arising in mesenchymal cystic hamartoma, embryonal sarcoma, malignant mesenchymoma, primary pulmonary rhabdomyosarcoma and rhabdomyosarcoma arising in congenital adenomatoid malformation or bronchogenic cyst. Over the past 15 years, PPB has come to be recognized in centers around the world. With the establishment of the Pleuropulmonary Blastoma Registry by Jack Priest, MD, and colleagues, there has been improved understanding of this rare pediatric neoplasm. The registry Web site serves as an important resource for physicians and families ().     

Screening of a polar extract of Paeonia rockii: composition and antioxidant and antifungal activities

Ethnopharmacological relevance

The genus Paeonia (Paeoniaceae), is one of the most important source of crude drugs in traditional Chinese medicine and investigation on many species is large. Up to now studies on Paeonia rockii, one of the eight species recognized in the section Moutan, are very limited.

Aim of the study

This research aimed to investigate the composition of Paeonia rockii roots and to evaluate the in vitro free-radical scavenging and antifungal activities of a polar extract (PPR) and its major constituents.

Materials and methods

PPR was obtained from defatted dried roots of Paeonia rockii using MeOH as extraction solvent. Its n-BuOH soluble portion (PPR-B) was purified by Sephadex LH-20 followed by RP-HPLC to give nineteen compounds belonging to the classes polyphenols, monoterpenes and triterpenes. Their structure were spectrally characterized (UV, 1D and 2D NMR, MS). The polyphenols content of PPR and PPR-B was examined by the Folin-Ciocalteau colorimetric assay and HPLC method. Both extracts (PPR and PPR-B) and their major constituents were tested for the free-radical scavenging activity by DPPH-test, and for the antifungal activity by three methods (micro-broth dilution method, XTT assay and Candida albicans morphological analysis).

Results

5-Butylhydroxy-γ-lactone (1), and ethyl-arabinopyranoside (2) have been isolated for the first time as naturally occurring compounds and taxifolin (3) was reported for the first time in Paeonia spp. Nine polyphenols, four monoterpenes and three triterpenes were also identified. Both the extracts PPR and PPR-B had high polyphenol content, and high concentration of gallic acid derivatives and paeoniflorin, chemotaxonomic characteristic markers of the genus. PPR, gallic acid and methyl-gallate displayed high potency in scavenging free-radicals (DPPH test, EC₅₀ 13.3, 1.2, 1.9 μg/ml, respectively). Both the extracts and gallic acid individually showed an interesting antifungal property (MIC₅₀ at 24 h 25, 0.9 and 30 μg/ml, respectively) and notably, a combination of paeoniflorin/gallic acid (MIC₅₀ = 0.5 + 20 μg/ml, respectively) was more active than the single compound in inhibiting Candida growth.

Conclusion

The polar methanolic extract (PPR), its n-BuOH soluble fraction and constituents of Paeonia rockii were extensively investigated. Both extracts and some of their compounds have the ability to scavenge free-radicals and to inhibit Candida albicans growth.     

Pleuropulmonary blastoma: A report of three cases and review of literature

Pleuropulmonary blastoma is a rare and highly aggressive pulmonary malignancy in children. Clinically, the malignancy is often mistaken for symptoms of respiratory tract infection or pneumothorax. The neoplasm is histologically characterized by primitive blastema and a malignant mesenchymal stroma that demonstrates multidirectional differentiation. The patients with PPB are managed by multimodal therapy. We present a report of 3 cases of histopathologically diagnosed pleuropulmonary blastoma. The patients presented with chief complaints of difficulty in breathing, cough, fever and chest pain. Radiographs of the patients showed partial to complete opacification of hemithorax. Contrast enhanced computed tomography scans revealed large well defined heterogenously enhancing solid mass lesions in the hemithorax. Knowledge of types, imaging findings, staging and association with other tumors is crucial for correct diagnosis of pleuropulmonary blastoma and subsequent adequate management.     

18例结肠息肉切除术后并发出血的内镜治疗

目的：探讨结肠息肉切除术后并发出血的内镜治疗.方法：回顾性分析在2010年1月～2013年6月,于我院行结肠息肉切除治疗并发出血18例,通过急诊结肠镜检查并进行内镜下止血处理.结果：18例均通过急诊结肠肠镜检查并成功进行内镜下止血并均止血成功.结论：对结肠息肉切除术后并发出血,急诊结肠镜检查并进行止血是有效可行的方法.     

Pancreatic metastasis of a pleuropulmonary blastoma in an adult

Pleuropulmonary blastoma (PPB) is a rare dysontogenetic tumor that usuallydevelops in the first decade of life and has been recognized as a distinctclinico-pathological entity different from the ordinary pulmonary blastoma ofadulthood. Since the tumor grows aggressively and tends to metastasize early,physicians have to be aware of late onset of symptoms and uncommonmanifestations. We report a case of PPB in a young adult and its recurrencein the pancreas after primary surgical treatment and adjuvant chemotherapy.Keeping in mind the moderate prognosis of PPB in children, accurate assessmentand treatment of PPB require a team approach of oncology, radiology andsurgery to establish new therapeutic guidelines in the future.     

Familial association of pleuropulmonary blastoma with cystic nephroma and other renal tumors: a report from the International Pleuropulmonary Blastoma Registry

OBJECTIVE: To characterize the association of pleuropulmonary blastoma (PPB) with cystic nephroma (CN) and other renal tumors. STUDY DESIGN: Complete clinicopathologic review of cases from the International PPB Registry and literature. RESULTS: We identified 18 patients with PPB associated with 20 renal tumors (15 CN), either in themselves or family members. All patients with PPB were <5 years of age. All but one of the renal diagnoses were made before 4 years of age. Eleven children had both PPB and renal tumor, one of whom also had a sibling with CN. Six children with PPB alone had one or more family members with CN. The mother of one child with PPB had Wilms' tumor. Pulmonary disease was bilateral in four patients. Renal disease was bilateral in three patients. Two children with PPB and bilateral renal cystic tumors also had intussusceptions because of small bowel juvenile polyps. In six families, dysplasia/neoplasia affected organs other than lung and kidney. CONCLUSIONS: CN or related tumors were found in 9.2% of 152 Registry-reviewed PPB cases. The occurrence of rare pulmonary and renal tumors together in patients and/or family members, the early age of onset, and the multiplicity of tumors is compatible with a constitutional genetic predisposition.