Intravenous digital subtraction renal angiography: use in screening for renovascular hypertension

Intravenous digital subtraction renal angiography (DSRA) has been compared with conventional angiography only in small, selected series of hypertensive patients. The authors prospectively examined with intravenous DSRA 94 patients at increased risk for renovascular hypertension and compared these studies with conventional angiography. A stenosis of at least one main renal artery was identified with intravenous DSRA in 22 patients and confirmed in 20 patients. No significant stenoses were seen with conventional angiography in any of the 64 patients in whom lesions were not seen with intravenous DSRA. Since inadequate DSRA studies were considered positive for renal artery stenosis, the sensitivity of intravenous DSRA was 100% (25 of 25); specificity, 93% (64 of 69); positive predictive value, 83% (25 of 30); and negative predictive value, 100% (64 of 64). The authors conclude that intravenous DSRA is a sensitive test for identifying stenosis of the main renal arteries and is appropriate to use as a screening test among patients at increased risk for renovascular hypertension.     

Causes of jaundice during hepatic artery infusion chemotherapy

Jaundice develops in many patients with liver metastases from colorectal adenocarcinoma during hepatic arterial infusion chemotherapy (HAIC). The usual cause is thought to be hepatotoxicity from the chemotherapeutic agent or biliary obstruction from progressive neoplastic disease. The authors evaluated the abdominal computed tomography and ultrasound examinations performed on 49 patients who were jaundiced during long-term HAIC. In only one patient was diffuse intrahepatic biliary dilatation caused by an obstructing mass in the porta. Two patients had metastatic hepatic lesions causing focal biliary obstruction. Intrahepatic dilatation without an obstructing mass occurred in 20 patients. Percutaneous or endoscopic cholangiograms were commonly interpreted prospectively as showing extrinsic compression by metastases, but no mass was confirmed on imaging studies. Seven patients had focal intrahepatic ductal dilatation from stricture without an associated mass. The remaining 19 patients had normal-caliber ducts; their jaundice was caused by chemical hepatitis. This series suggests that the most common causes of jaundice in these patients are chemical hepatitis and common bile duct stricture, complications of intraarterial chemotherapy, rather than neoplastic obstruction. Stricture formation may be confused with extrinsic compression on direct cholangiograms.     

Translational development of splice-modifying antisense oligomers

Introduction: Antisense nucleic acid analogues can interact with pre-mRNA motifs and influence exon or splice site selection and thereby alter gene expression. Design of antisense molecules to target specific motifs can result in either exon exclusion or exon inclusion during splicing. Novel drugs exploiting the antisense concept are targeting rare, life-limiting diseases; however, the potential exists to treat a wide range of conditions by antisense-mediated splice intervention.

Areas covered: In this review, the authors discuss the clinical translation of novel molecular therapeutics to address the fatal neuromuscular disorders Duchenne muscular dystrophy and spinal muscular atrophy. The review also highlights difficulties posed by issues pertaining to restricted participant numbers, variable phenotype and disease progression, and the identification and validation of study endpoints.

Expert opinion: Translation of novel therapeutics for Duchenne muscular dystrophy and spinal muscular atrophy has been greatly advanced by multidisciplinary research, academic-industry partnerships and in particular, the engagement and support of the patient community. Sponsors, supporters and regulators are cooperating to deliver new drugs and identify and define meaningful outcome measures. Non-conventional and adaptive trial design could be particularly suited to clinical evaluation of novel therapeutics and strategies to treat serious, rare diseases that may be problematic to study using more conventional clinical trial structures.     

Alloimmunization to platelet-specific antigens on glycoproteins IIb- IIIa and Ib/IX in multiply transfused thrombocytopenic patients

The rate of alloimmunization to platelet-specific antigens associated with platelet glycoproteins (GPs) IIb-IIIa and Ib/IX was studied in 293 multiply transfused thrombocytopenic patients. Antibodies to platelet-specific antigens were measured with a solid-phase assay using platelet GP IIb-IIIa or Ib/IX as the antigenic targets. Nine patients were found to have antibodies to platelet GP IIb-IIIa, and no patients had antibodies to platelet GP Ib/IX. In six of these nine patients, the specificity of the antibody was shown by using GP IIb-IIIa from donors with different platelet-specific antigen phenotypes. In the remaining three patients with antibodies to platelet GP IIb-IIIa, no specificity could be identified. These patients had autoimmune thrombocytopenia in association with lymphoma. The alloimmunization rate to platelet-specific antigens associated with GP IIb-IIIa was 2 percent, whereas the rate of alloimmunization to HLA antigens was 23 percent. Of the patients alloimmunized to HLA antigens, 9 percent also had antibodies to platelet-specific antigens. A poor response to HLA-identical platelet transfusions was observed only in those patients with positive assays in the solid-phase test. These results suggest that the incidence of antibodies to platelet-specific antigens carried on GP IIb-IIIa is low. Platelet-specific antibodies may be found more frequently in patients alloimmunized to HLA antigens than in those not so alloimmunized.     

Clinical features and molecular modelling of novel MPZ mutations in demyelinating and axonal neuropathies

Mutations in the myelin protein zero (MPZ) gene have been associated with different Charcot–Marie–Tooth disease (CMT) phenotypes, including classical demyelinating CMT1B and the axonal form of the disease (CMT2). The MPZ role in the pathogenesis of both demyelinating and axonal inherited neuropathies was evaluated in the Italian population by screening a cohort of 214 patients with CMT1 or CMT2. A MPZ mutation frequency of 7.9% in demyelinating cases and of 4.8% in axonal cases was observed. In the total cohort (264 patients), including those with mutations in other genes, a mutation frequency of 5.8% (7/121) in demyelinating cases and 4.2% (6/143) in axonal cases was found. Three novel MPZ mutations, two missense (p.Ser111Cys, p.Thr124Ala) and one frameshift (p.Tyr145fs) were found, and a molecular modelling approach was used to test the effects of these mutations on the protein structure. Electrostatic distribution changes within the protein, caused by the amino acid substitution, fit in with phenotypes presented by patients herein described. Our findings suggest that the clinical features associated with MPZ mutations depend partly on the nature of amino acid change and that molecular modelling may provide useful support, based on effects on secondary and tertiary protein structure, to predict the phenotype associated with MPZ mutations.     

Intraoperative radiotherapy during radical prostatectomy for intermediate‐risk to locally advanced prostate cancer: treatment technique and evaluation of perioperative and functional outcome vs standard radical prostatectomy,in a matched‐pair analysis

OBJECTIVE

To evaluate a novel approach with intraoperative radiotherapy (IORT) administered in the surgical field, after pelvic lymphadenectomy (PL) and before radical retropubic prostatectomy (RRP), evaluating acute and late toxicity, complications and biochemical progression‐free survival (bPFS), as the adequate treatment of locally advanced prostate cancer is still a controversial issue.

PATIENTS AND METHODS

Between June 2005 and October 2007, 33 consecutive patients with intermediate‐risk or locally advanced prostate cancer were selected for PL + IORT + RRP. IORT was delivered by a mobile linear accelerator in the operating room (electron beam, 12 Gy at 90% isodose). According to the pathological findings further adjuvant radio‐ or hormone therapy could be administered. The median follow‐up was 16 months. This group was compared retrospectively with a historical group of 100 patients who had undergone RRP and further adjuvant therapy, selected with equivalent criteria. The comparison was conducted as a matched‐pair analysis. The perioperative outcomes (surgical time, estimated blood loss, blood transfusions, days of catheterization, days of drainage, days of hospitalization), continence as the functional outcome, acute and late toxicity, rate of complications and bPFS were evaluated and compared.

RESULTS

The baseline characteristics of the two groups were equivalent but the node count and the number of positive lymph nodes was higher in the IORT group. The IORT group had longer surgery, and a shorter hospital stay and catheterization. There were no differences in continence rate, and no major complications in either group. The acute and late toxicity and bPFS were equivalent. A retrospective comparison and the short follow‐up were the major limitations.

CONCLUSIONS

IORT administered before RRP seems a feasible approach, with little effect on the variables evaluated.     

Antihypertensive efficacy of metoprolol XL/Low dose chlorthalidone (6.25 mg) combination: a randomized,comparative study in Indian patients with mild-to-moderate essential hypertension

Objective

High blood pressure is one of the most important risk factors, directly responsible for increasing the cardiovascular morbidity and mortality. The primary objective was to evaluate the efficacy of metoprolol XL/chlorthalidone against metoprolol XL/hydrochlorothiazide with respect to mean fall in systolic and diastolic blood pressure. The secondary objective was to compare the response rates and to evaluate the tolerability of study medications in patients with mild-tomoderate essential hypertension.

Methods

Total 130 eligible patients (65: metoprolol XL 25 mg/chlorthalidone 6.25 mg; 65: metoprolol XL 25 mg/HCTZ 12.5 mg) were enrolled in this randomized, comparative, multicentric, 12-weeks study. Sixty-two patients from each group completed the study. After 4-weeks of treatment, non-responders from chlorthalidone 6.25 mg combination group were shifted to metoprolol XL 50 mg/chlorthalidone 12.5 mg and non-responders from HCTZ 12.5 mg combination group were escalated to metoprolol XL 50 mg/HCTZ 12.5 mg.

Results

The study treatment groups were comparable with respect to demography and baseline disease characteristics. Both the starting therapies were comparable with respect to mean fall in SBP (p = 0.788) and DBP (p = 0.939), and response rates (p = 1.0) after 4-weeks of therapy. Also both the step-up therapies showed similar mean fall in SBP (p = 0.277) and DBP (p = 0.507) at the end of 12-weeks. However, significantly more number of patients from chlorthalidone 12.5 mg/metoprolol XL 50 mg group responded to therapy as compared to that from HCTZ 12.5 mg/metoprolol XL 50 mg group (p = 0.045). All the reported adverse events were of mild-to-moderate intensity. There were no clinically significant trends in electrolytes (Na⁺, K⁺, Cl^-)and fasting blood sugar, evident across the treatment groups.

Conclusion

Chlorthalidone in combination with metoprolol XL is as effective and well tolerated as widely used combination of metoprolol XL/HCTZ, thus providing an alternative therapeutic option.     

Prediction of the effect of erythromycin, diltiazem, and their metabolites, alone and in combination, on CYP3A4 inhibition

Predictive models of complex drug-drug interactions between multiple inhibitors and their metabolites have not been evaluated. The purpose of this study was to evaluate an interaction model for cytochrome P450 3A4 (CYP3A4) that incorporated the simultaneous reversible and irreversible inhibition by multiple inhibitors. Erythromycin (ERY) and diltiazem (DTZ), and their major metabolites, N-desmethylerythromycin (nd-ERY) and N-desmethyldiltiazem (nd-DTZ), were chosen to evaluate the model. k(inact) (rate constant for maximal inactivation), K(I) (inhibitor concentration at 50% maximal inactivation), and K(i) (reversible inhibition constant) were estimated for ERY, DTZ, nd-ERY, and nd-DTZ, respectively, using cDNA-expressed CYP3A4 and human liver microsomes under optimal experimental conditions. To evaluate the interaction model, combinations of inhibitors and metabolites were incubated at concentrations equal to K(I), (1/2)K(I), and 2K(I) of each inhibitor for specified durations in both enzyme systems. The models were further evaluated by the incubation of combinations of inhibitors with the substrate testosterone for 10 min. CYP3A4 inhibition in the presence of drug mixtures was predicted from the inhibition parameters determined for each drug or metabolite alone. The CYP3A4 activity in the presence of multiple inhibitors was well predicted by the model incorporating additive irreversible inhibition as modified by mutual competitive inhibition (percent mean error and percent mean absolute error ranged from -0.06 to 0.04 and from 0.03 to 0.09, respectively). In conclusion, the additive model predicted the combined effect of multiple inhibitors on CYP3A inhibition in vitro. However, simultaneous reversible and irreversible inhibition effects should be taken into account in a reaction mixture of substrate and multiple inhibitors of CYP3A4.