Phase IB study of doxorubicin in combination with the multidrug resistance reversing agent S9788 in advanced colorectal and renal cell cancer.

S9788 is a new triazineaminopiperidine derivate capable of reversing multidrug resistance (MDR) in cells resistant to chemotherapeutic agents such as doxorubicin. It does not belong to a known class of MDR revertants, but its action involves the binding of P-glycoprotein. Thirty-eight evaluable patients with advanced colorectal or renal cell cancer were treated with doxorubicin alone (16 patients) followed after disease progression with combination treatment of doxorubicin plus S9788 (12 patients) or upfront with the combination of doxorubicin plus S9788 (22 patients). S9788 was given i.v. as a loading dose of 56 mg m-2 over 30 min followed by doxorubicin given at 50 mg m-2 as a bolus infusion. Thereafter, a 2-h infusion of S9788 was administered at escalating doses ranging from 24 to 120 mg m-2 in subsequent cohorts of 4-10 patients. Pharmacokinetic analysis demonstrated that concentrations of S9788 that are known to reverse MDR in vitro were achieved in patients at non-toxic doses. Compared with treatment with doxorubicin alone, treatment with the combination of doxorubicin and S9788 produced a significant increase in the occurrence of WHO grade 3-4 granulocytopenia. Treatment with S9788 was cardiotoxic as it caused a dose-dependent and reversible increase in corrected QT intervals as well as clinically non-significant arrhythmias on 24- or 48-h Holter recordings. Although clinically relevant cardiac toxicities did not occur, the study was terminated as higher doses of S9788 may increase the risk of severe cardiac arrhythmias. Twenty-nine patients treated with S9788 plus doxorubicin were evaluable for response, and one patient, who progressed after treatment with doxorubicin alone, achieved a partial response. We conclude that S9788 administered at the doses and schedule used in this study results in relevant plasma concentrations in humans and can safely be administered in combination with doxorubicin.     

Psychological aspects of female urinary incontinence in general practice.

The aim of this study was to determine whether urge incontinence was associated with a higher prevalence of psychological symptoms than other types of incontinence. The psychological aspects of 110 women presenting with urinary incontinence in general practice were assessed by means of standardised questionnaires and medical history-taking. The results showed no difference in psychological characteristics between patients with urge incontinence and those with other types of incontinence. These findings were contrary to the conclusions of almost all other studies based on populations selected for specialist care. It was concluded that in general practice the psychological approach to urinary incontinence depends more on the individual needs of the patient than specifically on the type of incontinence.     

Role of arthrography in imaging of the temporomandibular joint in 1992]

In this text we briefly want to discuss the role of the arthrographic examination of the temporomandibular joint for detection of disc pathology. We will mention the normal anatomy and function of the temporomandibular joint, the technique for performing arthrograms and the classification of the most frequent disc pathology. This will be illustrated by some arthrographic examples of anterior disc displacement without reduction, disc perforation, and medial disc displacement. Finally the advantages of arthrography in comparison with other investigation techniques will be discussed.     

Recurrent pregnancy loss due to familial and non-familial habitual molar pregnancy.

OBJECTIVES: To present a series of women with recurrent molar pregnancies, including rare familial cases, and discuss etiology and treatment options. METHODS: We performed a detailed clinical evaluation and pedigree analysis of five Egyptian women with recurrent pregnancy loss due to molar pregnancy. RESULTS: The women had a history of four to nine consecutive hydatidiform moles but of no viable pregnancies. Two of the women had molar pregnancies with different husbands who themselves had viable offspring from previous wives; and three of them, who belonged to a family with extensive intermarriage, had a pedigree consistent with an autosomal recessive maternal-effect mutation. CONCLUSIONS: Recurrent pregnancy loss due to habitual molar pregnancy is uncommon and familial cases are extremely rare. The etiology of this disorder is not well understood but likely results from a maternal-effect mutation. Management options are limited, especially for couples who desire to have their own genetic offspring.     

Assessment of autonomic dysfunction in Parkinson's disease: the SCOPA-AUT.

We developed a questionnaire to assess autonomic symptoms in patients with Parkinson's disease (PD) and evaluated its reliability and validity. Based on the results of a postal survey in 46 PD patients, 21 multiple system atrophy patients, and 8 movement disorders specialists, items were included according to their frequency, burden, and clinical relevance. The questionnaire was evaluated in 140 PD patients and 100 controls, and test-retest reliability was established in a sample of 55 PD patients. The SCOPA-AUT consists of 25 items assessing the following regions: gastrointestinal (7), urinary (6), cardiovascular (3), thermoregulatory (4), pupillomotor (1), and sexual (2 items for men and 2 items for women) dysfunction. Test-retest reliability was good. Autonomic problems increased significantly with increasing disease severity for all autonomic regions, except sexual dysfunction. We conclude that SCOPA-AUT is a reliable and valid questionnaire that evaluates autonomic dysfunction in PD.     

Application of an immunosensor for the detection of the β-lactam antibiotic, cephalexin

Public concern surrounding antibiotic contamination in food and food products has made it imperative to develop analytical methods for their detection. Polyclonal antibodies were used in the development of a surface plasmon resonance (SPR)-based inhibition immunoassay for cephalexin. A conjugate consisting of cephalexin-bovine serum albumin (BSA) was immobilized on the dextran gel surface of the sensor chip. Binding/regeneration studies of antibody to immobilized cephalexin were studied and dissociation of the antibody from the immobilized cephalexin was easily achieved with 10 mmol l^-1 NaOH. Forty surface regeneration cycles were carried out and found to be reproducible with only a 7.4% decrease in binding over this number of regenerations. Model inhibition immunoassays for cephalexin were developed in PBS and spiked milk samples with detection ranges of 4.88 to 2,500 ng ml^-1 and 244 to 3,906 pg ml^-1, respectively.     

Effects of preoperative chemoradiotherapy on postsurgical morbidity and mortality in cT3-4 +/- cM1lymph cancer of the oesophagus and gastro-oesophageal junction.

OBJECTIVE: Very few studies have examined post-operative morbidity after resection of oesophageal carcinoma, especially in patients treated with induction chemo- and radiotherapy for locally advanced stages. This study assessed the effects of induction chemoradiotherapy on post-operative course after resection of locally advanced oesophageal carcinoma (cT3-4 + cM1lymph). METHODS: Induction therapy consisted of 5-fluorouracil days 1-5 and days 21-25, cisplatin day 1 + day 21 and concomitant radiotherapy 18-20 fractions of 2Gy (total dose 36-40Gy). Induction chemoradiotherapy was completed in 109 patients. Surgery was performed in 90 patients (operability: 90/109 = 83%): 85 patients underwent resection with curative intent (resectability: 85/109 = 78%), bypass operation was performed in five patients. Nineteen patients could not be operated on. Results were compared to a matched group of pT3M1LYM/pT4 patients (n = 86) who underwent primary surgery in the same period. RESULTS: Resection was complete (R0) in 68 patients (68/90 = 76%). Mean duration of surgery was 428 min (range: 240-690). Peroperative complications were haemorrhage in three patients (3/90 = 3.3%), tracheobronchial perforation in three patients (3/90 = 3.3%). Median total hospital stay was 20.5 days (range: 8-355). Mean duration of intubation was 7 days (range: 1-190); 67 patients (67/90 = 74.4%) were intubated for less than 24 h. Non-tumour related hospital mortality after resection was 8.3% (7/84 patients). Mortality after two-field lymphadenectomy was 5.2 versus 11.7% after three-field lymphadenectomy. After primary surgery (n = 86) overall mortality was 2.3% (P = 0.015) and nil after two- and three-field lymphadenectomy (P = 0.011). Medical morbidity consisted of pneumonia in 43 patients (43/90 = 48%), atelectasis in ten patients (10/90 = 11%), dysrhythmia in 21 patients (21/90 = 23%), sepsis in 11 patients (11/90 = 12%) and adult respiratory distress syndrome in ten patients (10/90 = 11%). Surgical morbidity included pleural effusion in 16 patients (16/90 = 18%), tracheal fistula in two patients (2/90 = 2%), chylothorax in two patients (2/90 = 2%) and acute pancreatitis in one patient (1/90 = 1%). Ten patients (10/90 = 11%) had a radiologically confirmed anastomotic leak; however only in four out of them with clinical manifestation; treatment was conservative in all four patients. Major morbidity occurred in 27 patients (27/90 = 30%). Overall rate of morbidity was significantly higher after three-field lymphadenectomy (85%) as compared to two-field lymphadenectomy (68.7%; P = 0.023). CONCLUSIONS: Chemoradiotherapy followed by resection of cT3-4 +/- cM1lymph oesophageal carcinoma is feasible with acceptable mortality. Mortality, however, seems to be significantly higher when compared to a group of pT3M1LYM/pT4 patients who underwent primary surgery (8.3 versus 2.3%; P = 0.015) in the same period in our department.     

Expression of ciliary neurotrophic factor (CNTF) in charcot‐marie‐tooth type 1A (CMT1A) disease

CMT1A patients bear the same genetic defect but often present with a wide range of clinical disability. Knowing the relationship between the phenotypic variability and other parameters, such as electrophysiological findings, age, gender, disease duration and environmental factors may be important for understanding the pathogenetic mechanisms underlying CMT1A. We studied 15 families and 7 sporadic cases affected by CMT1A (27 adults and 9 children) from the clinical, neurophysiological and genetic standpoint. A detailed patient history included: disease onset and progression, distribution of weakness, additional symptoms, life habits, genealogical tree, exposure to toxic substances, geographic provenance, instruction grade, job, use of drugs, and concurrent diseases. A questionnaire about diet was administered. The disability was evaluated by modified Rankin scale, deambulation index, functional independence measure and Barthel index. As previously reported, disease onset was in the first decade in 50% of cases and before the age of 20 years in 70% of cases. Severe disability was rarely observed, only 2 patients walking with a cane. No clear influence of gender over clinical severity was observed. Interestingly, genetic anticipation was observed in all the families. Data on the influence of environmental factors will also be presented.     

Immunoproliferative small-intestinal disease with lymphoma--diagnostic difficulties and pitfalls. Case reports

Immunoproliferative small-intestinal disease and related diffuse intestinal lymphoma is a debilitating illness prevalent in South Africa. Case reports are presented to illustrate that the early course may be deceptively prolonged and 'benign'; diarrhoea is not invariable, and an initial clinical response to antibiotics may occur. The combination of villous atrophy and a predominantly plasma cell infiltration of the lamina propria in jejunal biopsy specimens may indicate lymphoma in adjacent bowel or regional lymph nodes.     

Synthesis of 14C‐labeled piperidines and application to synthesis of [14C]SCH 351125, a CCR5 receptor antagonist

1‐Benzyl‐4‐hydroxy[2‐¹⁴C]piperidine, a useful intermediate in labeled compound synthesis, was prepared from [¹⁴C]formaldehyde in high yield. The distribution pattern of ¹⁴C in the product is consistent with a mechanism involving reversible iminium ion formation and rapid equilibration of the iminium ion through a cationic aza‐Cope rearrangement. These steps precede the rate‐determining intramolecular cyclization step. SCH 351125 is a potent, selective CCR5 receptor antagonist with potential as a treatment for HIV infection. [¹⁴C]SCH 351125, required for metabolism studies, was prepared from 1‐benzyl‐4‐hydroxy[2‐¹⁴C]piperidine in six steps. [¹⁴C]SCH 351125 is a mixture of four atropisomers. Preparation of [¹⁴C]SCH 351125 besylate salt of the desired atropisomer pair is also described. Copyright © 2007 John Wiley & Sons, Ltd.