Analysis on kidney injury-related clinical risk factors and evaluation on the therapeutic effects of hemoperfusion in children with Henoch-Schonlein purpura.

OBJECTIVE: To investigate risk factors related to kidney injury in children with Henoch-Schonlein purpura (HSP) and to study the therapeutic effects of hemoperfusion (HP) on kidney injury in HSP children, providing clinical evidence for early prevention and treatment of HSP. PATIENTS AND METHODS: Children who suffered from HSP for the first time were selected as study objects and they were followed up for 12 months. Single factor analysis and multi-factor Logistic regression analysis were performed for children's demographic characteristics (age, gender), clinical manifestations (rash duration time, rash recurrence times, digestive tract hemorrhage, abdominal pain, arthralgia, HSP recurrence) and laboratory indexes (peripheral blood WBC, PLT, ESR, CRP, serum IgG, serum IgA, IgM, serum C3, serum C4, TC, TG, HDL, LDL). Meanwhile, participants were divided into treatment group (HP treatment) and control group, and the protective effects of HP on renal function of HSP children were discussed. RESULTS: Single factor analysis indicated age ≥ 6 years, rash recurrence ≥ 3 times, rash duration time ≥ 1 month, digestive tract hemorrhage, peripheral blood PLT, WBC, serum TC and serum LDL levels had statistically significant differences between the two groups. Multi-factor Logistic regression analysis indicated rash recurrence ≥ 3 times, digestive tract hemorrhage, decline of peripheral blood PLT count, and increases of serum TC and LDL were closely related to kidney injury of HSP children. After discharge, kidney injury comparison between treatment group and control group in follow-up had a statistical difference. CONCLUSIONS: Rash recurrence ≥ 3 times, digestive tract hemorrhage, decline in peripheral blood PLT count, increases of serum TC and LDL, are risk factors of kidney injury in HSP children. HP can protect renal function of HSP children.

Comparison of the efficacy of different treatment modalities for Kimura's disease.

The objective of this study was to investigate the clinical features of Kimura's disease in the head and neck region and to compare the local recurrence rate between three therapies used for the treatment of this disease. The clinicopathological information of 46 hospitalized patients suffering from Kimura's disease in the head and neck region over a 10-year period was reviewed retrospectively. All lesions were clinically observed in the head and neck region. These 46 patients underwent a total of 58 treatments; nine patients underwent multiple treatments due to local recurrence. Of the 58 treatments, 32 involved surgical excision alone, 24 involved surgical excision and postoperative low-dose radiotherapy (20-40Gy), one was a combination of ultrasound-guided core needle biopsy and radiotherapy, and one was a combination of incisional biopsy and subsequent radiotherapy. During the follow-up period, nine patients suffered 16 local recurrences. The recurrence rate of surgical excision combined with low-dose radiotherapy was much lower than that of surgical excision alone or radiotherapy alone (both P<0.05). It is concluded that Kimura's disease is a benign condition with a good prognosis, and surgical excision combined with postoperative low-dose radiotherapy is associated with the lowest local recurrence rate in the treatment of this disease.

Salivary gland tumours in a northern Chinese population: a 50-year retrospective study of 7190 cases.

The aims of this study were to investigate the epidemiological and clinical characteristics of epithelial salivary gland tumours in a northern Chinese population and to evaluate the current TNM classification system. A demographic and descriptive analysis of 7190 epithelial salivary gland tumours was performed. There were 4654 benign tumours and 2536 malignant tumours. The percentage of tumours located in the parotid, submandibular, sublingual, and minor salivary glands was 62.66%, 9.92%, 2.57%, and 24.85%, respectively; 22.26%, 35.76%, 92.97%, and 61.89% of the tumours, respectively, were malignant. Over 90% in the tongue and maxillary sinus were malignant. Warthin tumour, salivary duct carcinoma, and squamous cell carcinoma were predominant in males, while basal cell adenoma, myoepithelioma, and pleomorphic adenoma were predominant in females. Further, 2.55% of the tumours were in children and adolescents: 44.81% of the tumours were malignant, as opposed to 35.02% in adults. According to the 7th TNM classification, the percentages of T3 and stage III tumours were approximately 10%. Salivary gland tumours show distribution patterns according to histological type, location, and patient age and sex. The limitations of the current TNM classification of salivary gland carcinoma should be considered and revisions made.

Combined application of ultrasound and SPECT/CT has incremental value in detecting parathyroid tissue in SHPT patients.

PURPOSE: The goal of this study is to investigate whether combined application of ultrasound and 99mTc-sestamibi SPECT/CT had the incremental value in accurately detecting parathyroid tissue in patients with SHPT over either method alone. PATIENTS AND METHODS: Sixty patients with SHPT on hemodialysis were evaluated preoperatively with parathyroid 99mTc-sestamibi SPECT/CT scintigraphy and ultrasound prior to parathyroidectomy. The sensitivity, specificity and accuracy of 99mTc-sestamibi SPECT/CT scintigraphy, ultrasound and combined application were determined respectively. RESULTS: The sensitivity, specificity and accuracy of ultrasound were 81% (155/192), 47% (17/36) and 82% (172/228), respectively. The sensitivity, specificity and accuracy of 99mTc-sestamibi SPECT/CT were 85% (163/192), 58% (21/36) and 89% (184/228) respectively. The accuracy of 99mTc-sestamibi SPECT/CT in the diagnosis of parathyroid tissue in patients with SHPT is significantly higher than that of ultrasound. The sensitivity, specificity and accuracy of combined application of ultrasound and 99mTc-sestamibi SPECT/CT were 93% (178/192), 61% (22/36) and 97% (200/228). The sensitivity, specificity and accuracy of combined application of ultrasound and 99mTc-sestamibi SPECT/CT were higher than those of either ultrasound or 99mTc-sestamibi SPECT/CT. CONCLUSIONS: The combined application of ultrasound and 99mTc-sestamibi SPECT/CT had incremental value in accurately detecting parathyroid tissue in patients with SHPT over either method alone.

Clinicopathological study of distant metastases of salivary adenoid cystic carcinoma.

Most studies of the clinicopathological characteristics and prognosis of patients with distant metastasis of salivary adenoid cystic carcinoma (SACC) have used small patient samples. To further explore this issue, a descriptive and prognostic study of 467 patients with SACC who were treated from 1963 to 2009 was conducted at a single institution. One hundred and forty-five patients (31.0%) had distant metastases. At least 20% of patients who presented with the early-stage disease and no recurrence developed distant metastasis. The overall 5-, 10-, and 20-year survival rates were 85.6%, 67.4%, and 50.4%, respectively, for patients without distant metastasis, and 69.1%, 45.7%, and 14.3%, respectively, for patients with distant metastasis. The median survival time after distant metastasis was 36 months (range 1-112 months). The prognosis was similar between patients who received treatment for metastasis and those who did not. Patients who were diagnosed with early-stage disease and without local recurrence of the primary tumours could also develop distant metastases. The biological characteristics of adenoid cystic carcinoma were different from those of squamous cell carcinoma. At present, the effectiveness of treatment for distant metastases is not ideal and further research is needed.

Conservation of salivary secretion and facial nerve function in partial superficial parotidectomy.

Conventional total superficial parotidectomy (TP) has commonly been used, but partial superficial parotidectomy (PP) offers the possibility of better preserving glandular function and avoiding palsy of the facial nerves. In this study, the extent to which saliva secretion and facial nerve function were conserved in patients who received TP vs. PP was compared. Data were collected from patients who received a PP (n=163) or a TP (n=105) for benign primary tumours in the superficial lobe of the parotid glands between 1995 and 2009 at a single hospital. The incidence of transient facial paralysis was significantly lower in patients who received PP than in those who received TP. Secretory function was preserved for patients with a conserved Stensen's duct, whereas patients in whom the duct had been ligated lost secretory function. Partial superficial parotidectomy reduces the incidence of postoperative facial nerve dysfunction and is conducive to preserving Stensen's duct and saliva secretion.

Transcutaneous electrical nerve stimulation on acupoints reduces fentanyl requirement for postoperative pain relief after total hip arthroplasty in elderly patients.

BACKGROUND: Transcutaneous electrical nerve stimulation (TENS) is regarded as an effective treatment for various types of pain. However, no randomized controlled trial has investigated TENS on acupoints for postoperative analgesia in elderly patients. This study aim to investigate whether TENS on acupoints has any favorable effect on complementary analgesia after total hip arthroplasty (THA) for elderly patients compared with a sham control treatment. METHODS: Sixty-eight elderly patients requiring THA surgery were enrolled and randomly allocated to one of two groups. Group Acu received true TENS on acupoints (bilateral P6, L14; ST36, GB31 ipsilateral to the surgery site) and Group Sham received sham treatment. All patients received patient-controlled analgesia for two days postoperatively. Analgesia was assessed by postoperative fentanyl requirement and pain intensity using a visual analogue scale (VAS-10 cm). The incidence of analgesia-related side effects, optional medication use and effects of patients' blinding were recorded. RESULTS: Fentanyl consumption in Group Acu was lower than that in Group Sham at 24 h (mean ± SD; 360±117 vs. 572±132 µg; P<0.001) and 48 h (712±184 vs. 1022±197 µg; P<0.001) after surgery. Postoperative pain intensity measured by VAS was similar in both groups. The incidence of opioid-related side effects and rescue medication for postoperative analgesia was significantly higher in Group Sham than in Group Acu. Differences between the groups regarding the effects of patients' blinding were not significant. CONCLUSION: TENS on specific acupoints is an effective and complementary approach to reduce postoperative analgesic requirement in elderly patients after THA.

The value of multislice spiral CT features of cavitary walls in differentiating between peripheral lung cancer cavities and single pulmonary tuberculous thick-walled cavities.

OBJECTIVES: Form discordance of cavity walls (FDCW) and form concordance of cavity walls (FCCW) in multislice spiral CT (MSCT) were investigated to determine their value in differentiating between peripheral lung cancer cavities and single pulmonary tuberculous thick-walled cavities. An assessment of the role of multiplanar reconstruction (MPR) in detecting FDCW and FCCW was also performed. METHODS: MSCT cross-sectional images of 116 consecutive cases (including 60 cases with available MPR images) with peripheral lung cancer cavities and 118 consecutive cases (including 62 cases with available MPR images) with single pulmonary tuberculous thick-walled cavities (wall thickness >3 mm) were retrospectively analysed. According to the characteristics of cavitary internal and external walls on MSCT, these cavities were divided into two types (FDCW and FCCW). FDCW was further divided into three subtypes (FDCW-I, FDCW-II and FDCW-III); FCCW was further divided into two subtypes (FCCW-I and FCCW-II). RESULTS: On the cross-sectional and MPR images, the total detection rate of FDCW-I and FDCW-III in peripheral lung cancer cavities was 76.7% (89/116) and 93.3% (56/60), respectively, whereas the total detection rate of FCCW-I and FCCW-II in single pulmonary tuberculous thick-walled cavities was 75.4% (89/118) and 91.9% (57/62), respectively. CONCLUSIONS: FDCW-I, FDCW-III, FCCW-I and FCCW-II were valuable in differentiating between peripheral lung cancer cavities and single pulmonary tuberculous thick-walled cavities. MPR could improve the detection of FDCW-I and FDCW-III in peripheral lung cancer cavities and FCCW-I and FCCW-II in single pulmonary tuberculous thick-walled cavities.

Variants in several genomic regions associated with asperger disorder.

Asperger disorder (ASP) is one of the autism spectrum disorders (ASD) and is differentiated from autism largely on the absence of clinically significant cognitive and language delays. Analysis of a homogenous subset of families with ASP may help to address the corresponding effect of genetic heterogeneity on identifying ASD genetic risk factors. To examine the hypothesis that common variation is important in ASD, we performed a genome-wide association study (GWAS) in 124 ASP families in a discovery data set and 110 ASP families in a validation data set. We prioritized the top 100 association results from both cohorts by employing a ranking strategy. Novel regions on 5q21.1 (P = 9.7 × 10(-7) ) and 15q22.1-q22.2 (P = 7.3 × 10(-6) ) were our most significant findings in the combined data set. Three chromosomal regions showing association, 3p14.2 (P = 3.6 × 10(-6) ), 3q25-26 (P = 6.0 × 10(-5) ) and 3p23 (P = 3.3 × 10(-4) ) overlapped linkage regions reported in Finnish ASP families, and eight association regions overlapped ASD linkage areas. Our findings suggest that ASP shares both ASD-related genetic risk factors, as well as has genetic risk factors unique to the ASP phenotype.

Association and gene-gene interaction of SLC6A4 and ITGB3 in autism.

Autism is a heritable neurodevelopmental disorder with substantial genetic heterogeneity. Studies point to possible links between autism and two serotonin related genes: SLC6A4 and ITGB3 with a sex-specific genetic effect and interaction between the genes. Despite positive findings, inconsistent results have complicated interpretation. This study seeks to validate and clarify previous findings in an independent dataset taking into account sex, family-history (FH) and gene-gene effects. Family-based association analysis was performed within each gene. Gene-gene interactions were tested using extended multifactor dimensionality reduction (EMDR) and MDR-phenomics (MDR-P) using sex of affecteds and FH as covariates. No significant associations with individual SNPs were found in the datasets stratified by sex, but associations did emerge when we stratified by family history. While not significant in the overall dataset, nominally significant association was identified at RS2066713 (P = 0.006) within SLC6A4 in family-history negative (FH-) families, at RS2066713 (P = 0.038) in family-history positive (FH+) families but with the opposite risk allele as in the FH- families. For ITGB3, nominally significant association was identified at RS3809865 overall (P = 0.040) and within FH+ families (P = 0.031). However, none of the associations survived the multiple testing correction. MDR-P confirmed gene-gene effects using sex of affecteds (P = 0.023) and family history (P = 0.014, survived the multiple testing corrections) as covariates. Our results indicate the extensive heterogeneity within these two genes among families. The potential interaction between SLC6A4 and ITGB3 may be clarified using family history as an indicator of genetic architecture, illustrating the importance of covariates as markers of heterogeneity in genetic analyses.

Dissecting the locus heterogeneity of autism: significant linkage to chromosome 12q14.

Autism is a common neurodevelopmental disorder with a significant genetic component and locus heterogeneity. To date, 12 microsatellite genome screens have been performed using various data sets of sib-pair families (parents and affected children) resulting in numerous regions of potential linkage across the genome. However, no universal region or consistent candidate gene from these regions has emerged. The use of large, extended pedigrees is a recognized powerful approach to identify significant linkage results, as these families potentially contain more potential linkage information than sib-pair families. A genome-wide linkage analysis was performed on 26 extended autism families (65 affected, 184 total individuals). Each family had two to four affected individuals comprised of either avuncular or cousin pairs. For analysis, we used a high-density single-nucleotide polymorphism genotyping assay, the Affymetrix GeneChip Human Mapping 10K array. Two-point analysis gave peak heterogeneity limit of detection (HLOD) of 2.82 at rs2877739 on chromosome 14q. Suggestive linkage evidence (HLOD>2) from a two-point analysis was also found on chromosomes 1q, 2q, 5q, 6p,11q and 12q. Chromosome 12q was the only region showing significant linkage evidence by multipoint analysis with a peak HLOD=3.02 at rs1445442. In addition, this linkage evidence was enhanced significantly in the families with only male affected (multipoint HLOD=4.51), suggesting a significant gender-specific effect in the etiology of autism. Chromosome-wide haplotype analyses on chromosome 12 localized the potential autism gene to a 4 cM region shared among the affected individuals across linked families. This novel linkage peak on chromosome 12q further supports the hypothesis of substantial locus heterogeneity in autism.

An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder.

Gene-gene interactions are likely involved in many complex genetic disorders and new statistical approaches for detecting such interactions are needed. We propose a multi-analytic paradigm, relying on convergence of evidence across multiple analysis tools. Our paradigm tests for main and interactive effects, through allele, genotype and haplotype association. We applied our paradigm to genotype data from three GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) on chromosome 15 in 470 Caucasian autism families. Previously implicated in autism, we hypothesized these genes interact to contribute to risk. We detected no evidence of main effects by allelic (PDT, FBAT) or genotypic (genotype-PDT) association at individual markers. However, three two-marker haplotypes in GABRG3 were significant (HBAT). We detected no significant multi-locus associations using genotype-PDT analysis or the EMDR data reduction program. However, consistent with the haplotype findings, the best single locus EMDR model selected a GABRG3 marker. Further, the best pairwise genotype-PDT result involved GABRB3 and GABRG3, and all multi-locus EMDR models also selected GABRB3 and GABRG3 markers. GABA receptor subunit genes do not significantly interact to contribute to autism risk in our overall data set. However, the consistency of results across analyses suggests that we have defined a useful framework for evaluating gene-gene interactions.

Identification of significant association and gene-gene interaction of GABA receptor subunit genes in autism.

Autism is a common neurodevelopmental disorder with a significant genetic component. Existing research suggests that multiple genes contribute to autism and that epigenetic effects or gene-gene interactions are likely contributors to autism risk. However, these effects have not yet been identified. Gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the adult brain, has been implicated in autism etiology. Fourteen known autosomal GABA receptor subunit genes were studied to look for the genes associated with autism and their possible interactions. Single-nucleotide polymorphisms (SNPs) were screened in the following genes: GABRG1, GABRA2, GABRA4, and GABRB1 on chromosome 4p12; GABRB2, GABRA6, GABRA1, GABRG2, and GABRP on 5q34-q35.1; GABRR1 and GABRR2 on 6q15; and GABRA5, GABRB3, and GABRG3 on 15q12. Intronic and/or silent mutation SNPs within each gene were analyzed in 470 white families with autism. Initially, SNPs were used in a family-based study for allelic association analysis--with the pedigree disequilibrium test and the family-based association test--and for genotypic and haplotypic association analysis--with the genotype-pedigree disequilibrium test (geno-PDT), the association in the presence of linkage (APL) test, and the haplotype family-based association test. Next, with the use of five refined independent marker sets, extended multifactor-dimensionality reduction (EMDR) analysis was employed to identify the models with locus joint effects, and interaction was further verified by conditional logistic regression. Significant allelic association was found for markers RS1912960 (in GABRA4; P = .01) and HCV9866022 (in GABRR2; P = .04). The geno-PDT found significant genotypic association for HCV8262334 (in GABRA2), RS1912960 and RS2280073 (in GABRA4), and RS2617503 and RS12187676 (in GABRB2). Consistent with the allelic and genotypic association results, EMDR confirmed the main effect at RS1912960 (in GABRA4). EMDR also identified a significant two-locus gene-gene effect model involving RS1912960 in GABRA4 and RS2351299 in GABRB1. Further support for this two-locus model came from both the multilocus geno-PDT and the APL test, which indicated a common genotype and haplotype combination positively associated with disease. Finally, these results were also consistent with the results from the conditional logistic regression, which confirmed the interaction between GABRA4 and GABRB1 (odds ratio = 2.9 for interaction term; P = .002). Through the convergence of all analyses, we conclude that GABRA4 is involved in the etiology of autism and potentially increases autism risk through interaction with GABRB1. These results support the hypothesis that GABA receptor subunit genes are involved in autism, most likely via complex gene-gene interactions.

Ordered-subset analysis of savant skills in autism for 15q11-q13.

Autism is a complex disorder characterized by genetic and phenotypic heterogeneity. Analysis of phenotypically homogeneous subtypes has been used to both confirm and narrow potential autism linkage regions such as the chromosomal region 15q11-q13. Increased evidence for linkage in this region had been found in a subgroup of 21 autism families (total families = 94) stratified based on a savant skill factor (SSF) from the Autism Diagnostic Interview, Revised (ADI-R). We examined the savant phenotypic finding in our sample of 91 multiplex autism families. Using two-point parametric analysis in stratification with a cutoff point of a savant skill score of 0.16, our families failed to demonstrate linkage to 15q11-q13. In addition, ordered subset analysis (OSA) using SSF as a covariate also failed to show evidence for linkage. Our findings do not support savant skills as an informative phenotypic subset for linkage in our sample.

Multiple primary tumours of the parotid gland.

The authors reviewed the clinical and histopathological records of 69 cases of multiple primary tumours (MPT) of the parotid gland treated at Peking University School of Stomatology. It accounted for 3.4% of all parotid tumours (2055 patients). Fifty-nine patients were male and 10 were female. The median age was 58 (range 24-80) years. The average time interval between the diagnosis of bilateral parotid tumours was 5 years (range 5 months-15 years). Three clinical types were classified as bilateral parotid tumours (31 cases), unilateral multifocal parotid tumours (29 cases), and the combination of bilateral parotid tumours with unilateral multifocal parotid tumours (9 cases). Histologically, Warthin's tumour was the most common type (60 patients), followed by pleomorphic adenoma (8 cases). Three cases were malignant including adenoid cystic carcinoma, squamous cell carcinoma and mucoepidermoid carcinoma. The histopathologies of tumours were of the same type in 63 patients, and distinctly different in six patients. The tumours were found and diagnosed synchronously in 48 patients, and metachronously in 21 patients. Since some parotid tumours are MPTs, careful preoperative diagnosis is necessary. B-mode ultrasound is the technique of choice for the screening of MPT. Meticulous intraoperative inspection and palpation of the glandular tissues and periglandular lymph nodes are necessary.

Analysis of genetic diversity of hordein in wild close relatives of barley from Tibet.

We analyzed genetic diversity in the storage protein hordein encoded at Hor-1, Hor-2 and Hor-3 loci in seeds from 211 accessions of wild close relatives of barley, Hordeum vulgare ssp. agriocrithon and H. vulgare ssp. spontaneum. Altogether 32, 27 and 13 different phenotypes were found for Hor-1, Hor-2 and Hor-3, respectively. A comparison of our results with those of previous studies indicates that Tibetan samples reflect the highest diverse level of hordein phenotypes when compared to samples from Israel and Jordan. This high degree of polymorphism supports the hypothesis that Tibet is one of the original centers of H. vulgare L.

Clinical risk factors but not bone density are associated with prevalent fractures in prepubertal children.

OBJECTIVE: The aim of this study was to investigate the association of clinical risk factors and bone density with prevalent fractures in prepubertal children. METHODS: Bone mineral density (BMD) in lumbar spine, femoral neck and total body bone was assessed by dual-energy X-ray absorptiometry. Clinical data on risk factors were collected by measurement and questionnaires. RESULTS: Of 324 children, 32 (10%) had a prevalent fracture (upper limb 69%). Most fractures were due to low-energy falls at home (69%). Children with fractures were older (P = 0.04), had higher levels of sports participation (P = 0.03), lower levels of breastfeeding (P = 0.05) and tended towards higher usage of inhaled corticosteroids in the previous year (P = 0.05). However, both BMD and apparent BMD did not differ between those with and without prevalent fracture. No differences were observed in the proportion of maternal fractures, maternal smoking during pregnancy, asthma history and oral prednisolone in last year (all P > 0.05). A final model incorporating age, weight, height, breastfeeding history, sports participation and inhaled corticosteroid usage accounted for 10% of the variability in the odds of fracture (P = 0.03). CONCLUSION: These results suggest that BMD may be less important than clinical risk factors for total fracture risk in prepubertal children. However, sample size limitations mean that further investigation in larger populations with less heterogeneity in fracture types is warranted.

Diagnosis and treatment of epithelial salivary gland tumours in children and adolescents.

In a series of 2,871 epithelial salivary gland neoplasms managed in the Peking University School of Stomatology between 1974 and 1999, 86 arose in children <16 years of age (52 parotid, 12 submandibular gland, 2 sublingual gland, and 20 minor salivary gland). Considerable delay was encountered in diagnosis (benign 24 months and malignant 16 months). In this group of children, 46 tumours (53%) proved to be malignant, with an incidence in the parotid, submandibular, sublingual, and minor salivary glands of 31/52 (60%), 2/12, 0/2, and 13/20 (65%), respectively. Sixty-six of 86 neoplasms (77%) occurred in children between 10 and 16 years of age. Only six neoplasms were encountered in children of 5 years or younger, four of which were high-grade malignant tumours. Benign tumours were successfully treated by local excision with only one recurrence. Of 46 malignant neoplasms, 8 were treated palliatively; of the remainder 8 were lost to follow-up and 2 patients died of their disease.

Comparative effects of (SBE)7m-beta-CD and HP-beta-CD on the stability of two anti-neoplastic agents, melphalan and carmustine.

The purpose of this study was to evaluate and compare the potential use of two parenterally safe beta-cyclodextrins derivatives, (SBE)7m-beta-CD and HP-beta-CD, as solubilizers and stabilizers for melphalan and carmustine, two very unstable antineoplastic agents. Phase solubility and chemical stability of the compounds in the presence of the cyclodextrins were studied. UV, fluorescence, and several NMR techniques were used to probe the potential causes for the differences observed. The phase solubility method was found to provide only qualitative data on the binding of melphalan to the cyclodextrins since rapid degradation and the presence of products of degradation complicated the interpretation of the results. Qualitatively, however, the solubilizing potential was similar for the two cyclodextrins. The chemical stability studies indicate that both of the drugs had similar binding constants for both cyclodextrins; however, the intrinsic reactivities in the complexes were significantly lower with (SBE)7m-beta-CD than for HP-beta-CD. The main cause for this distinct difference appeared to correlate with differences in the site of binding and the polarity of the binding site.

New injectable melphalan formulations utilizing (SBE)(7m)-beta-CD or HP-beta-CD.

The objective of this work was to evaluate the potential of using (SBE)(7m)-beta-CD and HP-beta-CD as enabling excipients to improve on the current melphalan injectable formulation. Melphalan is an anti-neoplastic agent formulated for parenteral use as a sterile, non-pyrogenic, freeze-dried powder. It is marketed by Glaxo-Wellcome as ALKERAN((R)) for Injection (Alkeran). A major concern with melphalan therapy, other than its intrinsic cytotoxicity and biocompatibility, arises from its marginal aqueous solubility and chemical stability; thus, co-solvents are used in the current two-vial formulation. Because of the two-vial system, the product is also inconvenient to use. Two approaches to improve melphalan's formulation utilizing cyclodextrins, including the use of aqueous (SBE)(7m)-beta-CD or HP-beta-CD solutions as the reconstitution diluents, and/or the use of (SBE)(7m)-beta-CD as a freeze-drying excipient in a melphalan formulation, are presented. Results showed that, when the cyclodextrins were used as diluents, the use of organic co-solvents can be eliminated and the shelf-life of the reconstituted melphalan greatly enhanced. When the freeze-dried melphalan/(SBE)(7m)-beta-CD formulation was prepared, the formulation was found to be stable; and a simplified one-vial delivery system was achieved. In conclusion, the parenterally safe beta-cyclodextrins derivatives can provide promising alternatives and improved formulations for melphalan injectable and perhaps similar problematic drugs.