Variability in the presentation of complicated jejunal diverticulosis.

Jejunal diverticulosis is a rare disease which normally presents for the first time with acute complications, often requiring surgical intervention. The diverticulae are acquired, occurring more commonly after middle age, but their aetiology is unclear. We discuss this condition in the context of four cases which presented to our hospital as emergencies over a five year period: small bowel obstruction, gastrointestinal haemorrhage, small bowel volvulus, and visceral perforation. Our aim is to encourage clinicians to include jejunal diverticular disease as a differential diagnosis in patients with abdominal symptoms.

Accuracy of radiological staging in identifying high-risk colon cancer patients suitable for neoadjuvant chemotherapy: a multicentre experience.

AIM: A pilot study was undertaken to determine the accuracy of computed tomography (CT) staging in identifying patients with high-risk colon cancers who would be considered as candidates for a neoadjuvant therapy trial (FOxTROT) and those at low risk (T1/T2) who would be excluded. METHOD: Participating radiologists from 19 centres attended workshops for standardization of image interpretation according to previously defined prognostic criteria: good prognosis tumours, including, T1/T2; intermediate prognosis, T3 < 5 mm tumour invasion beyond the muscularis propria (MP); and poor prognosis tumours, including T3 with tumour extension ≥ 5 mm beyond the MP or T4. The CT findings were compared with histopathology as the reference standard. RESULTS: Of 94 patients with radiological and pathological data, 71% were categorized by CT as having a poor prognosis. The sensitivity and specificity of CT in identifying these tumours were 87% (95% CI, 74-94) and 49% (95% CI, 33-65). Sensitivity and specificity for tumour infiltration beyond the MP (T3/T4 vs T1/T2) were 95% (95% CI, 87-98) and 50% (95% CI, 22-77), respectively. Including all CT-staged T3 and T4 patients in the trial would have increased the proportion eligible for entry to 89% (n = 84) without affecting the false-positive rate of 7%. Some 20% of T3/T4 patients would have been ineligible for FOxTROT because of synchronous metastases. CONCLUSION: In a multicentre setting, CT scanning identified high-risk (T3/4) colon cancers with minimal overstaging of T1/T2 tumours, thus establishing the feasibility of radiologically guided neoadjuvant chemotherapy.

Accuracy of multidetector computed tomography in identifying poor prognostic factors in colonic cancer.

BACKGROUND: Recent neoadjuvant strategies for high-risk colonic tumours have renewed interest in accurate preoperative staging. The aim of this study was to validate prospectively the accuracy of multidetector computed tomography (MDCT) in stratifying patients into good and poor prognostic groups in a multicentre setting. METHODS: Staging MDCT scans of 84 patients with colonic cancer were reviewed by two independent radiologists and stratified into low-risk (T1/T2 and T3 with extramural tumour depth (EMD) of less than 5 mm) and high-risk (T3 with EMD of at least 5 mm and T4) tumours. Nodal status and extramural venous invasion (EMVI) were also assessed. RESULTS: The accuracy, sensitivity, specificity and positive predictive value of stratification by CT compared with histological examination was 74 (95 per cent confidence interval 64 to 82), 78 (65 to 87), 67 (49 to 81) and 81 (68 to 89) per cent respectively. Accuracy for detecting malignant lymph nodes and EMVI was 58 and 70 per cent respectively. The agreement for predicting prognostic stratification was moderate (kappa = 0.54). CONCLUSION: As the ability of CT to identify node status is poor, the depth of tumour invasion beyond the muscularis propria is the most accurate way to identify patients with a poor prognosis who may be suitable for neoadjuvant treatment.

Diagnostic precision of CT in local staging of colon cancers: a meta-analysis.

AIM: To determine the accuracy of computed tomography (CT) in detecting disease with invasion beyond the muscularis propria (MP) and malignant lymph nodes. MATERIALS AND METHODS: A literature search of Ovid, Embase, the Cochrane database, and Medline using Pubmed, Google Scholar and Vivisimo search engines was performed to identify studies reporting on the accuracy of CT to predict the staging of colonic tumours. Publication bias was demonstrated by Funnel plots. The sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated using a bivariate random effects model and hierarchical summary operating curves (HSROC) were generated. RESULTS: Nineteen studies fulfilled all the necessary inclusion criteria. The pooled sensitivity, specificity, DOR for detection of tumour invasion were 86% (95% CI: 78-92%); 78% (95% CI: 71-84%); 22.4 (95% CI: 11.9-42.4). Similarly, the values for nodal detection were 70% (95% CI: 63-73%); 78% (95% CI: 73-82%); 8.1(95% CI: 4.7-14.1). In the subgroup analysis, the best results were obtained in studies utilizing multidetector CT (MDCT). CONCLUSION: Preoperative staging CT accurately distinguishes between tumours confined to the bowel wall and those invading beyond the MP; however, it is significantly poorer at identifying nodal status. MDCT provides the best results.

CT staging of colon cancer.

Computer tomography (CT) has been the principal investigation in the staging of colon cancers. The information obtained with routine CT has been limited to identifying the site of the tumour, size of the tumour, infiltration into surrounding structures and metastatic spread. The Foxtrot trial National Cancer Research Institute (NCRI) has been specifically designed to evaluate the efficacy of neoadjuvant treatment in colon cancers by using preoperative chemotherapy with or without an anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibody to improve outcome in high-risk operable colon cancer. Patients are selected based on their staging CT examination. The criteria for poor prognosis are T4 and T3 tumours with more than 5mm extramural depth. Thus the success of the trial would depend upon the confidence of the radiologist to identify the patients that would receive the neoadjuvant treatment. The aim of this review is to explain the process of identifying high-risk features seen on the staging CT images. This will help to identify a cohort of patients that could truly benefit from neoadjuvant strategies.

The effect of keto-analogues of essential amino acids in severe chronic uremia.

Alpha keto-analogues of valine, leucine, isoleucine, methionine, phenylalanine, and (in one instance) tryptophan and histidine, along with the remaining essential amino acids, were administered orally to 10 patients with severe chronic uremia fed a diet low in protein but adequate in calories. Ketoacid dosage varied from 6 to 14 g daily, as sodium or calcium salts. Net nitrogen intake, calculated as intake minus urinary protein nitrogen, averaged 1.8 g/day. The urea space was either estimated or measured with [(14)C]urea and daily changes in the body urea pool were calculated. Urea appearance was measured as the sum of urea excretion and the change in urea pool. If these ketoacids were converted to amino acids and utilized for protein synthesis, a fall in urea nitrogen appearance should occur. In five subjects, ketoacids were given for 15-18 days and then withdrawn. Urea nitrogen appearance increased 1.55 g/day on withdrawing ketoacids, and corrected nitrogen balance decreased by 1.73 g/day. In two other subjects ketoacid administration was followed, on two occasions each, by a period of administration of nine essential amino acids. In three of these four instances, urea appearance rose significantly with amino acids. In four patients studied at high blood urea levels, ketoacid treatment was relatively ineffective; two of these patients responded more favorably when studied again after peritoneal dialysis. One of these improved enough clinically to be managed as an out-patient for short intervals, despite virtual anuria. No accumulation of ketoacids in plasma or urine could be detected, and no toxicity was identified.

Bioequivalence of racemic drugs.

Although pharmacokinetic and pharmacodynamic differences between the enantiomers of a chiral drug have been known or suspected for many years, racemate drugs have frequently been developed and approved without clinical pharmacologic consideration of their chiral components. In the late 1970s, the technology to isolate, manufacture, and detect pure enantiomers of racemate drugs became generally available. This availability has created new demands on both pharmaceutical firms and regulatory agencies. To prepare for this new technology, the Center for Drug Evaluation and Research at the Food and Drug Administration is formulating a policy statement to guide evaluation of new chiral drugs. At this time, it appears that whatever new policies are developed will not necessarily be applied retroactively to previously approved racemate drugs. Additional policies to guide the development and approval of generic and OTC chiral drugs may be required. In the Office of Generic Drugs in the Center, abbreviated new drug or antibiotic applications are approved on the basis of adequate chemistry, manufacturing, and control procedures and comparative pharmacokinetics (bioequivalence). The generic drug must be a racemate or single enantiomer if the corresponding innovator drug is a racemate or single enantiomer respectively. Whether a generic firm will be required to provide bioequivalence information on enantiomers of a racemate is determined on a case-by-case basis. Although it might be claimed that a generic drug product should be required only to undergo the same general kind of pharmaceutical evaluation as did the innovator, there may be instances when the approval of a generic drug or antibiotic will require measurement of specific enantiomers of a chiral drug.

Influence of higher rates of agitation on release patterns of immediate-release drug products.

The dissolution procedure serves as a quality control test to assure batch-to-batch uniformity and bioequivalence of a product once the bioavailability of the product has been established. It can also be used to detect manufacturing and/or process variations that could reduce product bioavailability. Dissolution testing must be conducted at an appropriate agitation rate. Tests conducted at high agitation rates may lose the ability to differentiate between good and bad products. Although the effect of high agitation rates has been known for some time, several immediate-release drug products still have United States Pharmacopeia (USP) monograph dissolution procedures that require very high agitation rates. A systematic survey was conducted on marketed tablets of chloroquine phosphate, griseofulvin, hydroxychloroquine sulfate, isocarboxazide, primaquine phosphate, and sulfadiazine. Each of these products has a USP monograph requiring a dissolution test at a paddle speed of 100 rpm. To study the influence of agitation rate on the dissolution rate of these products, dissolution studies were conducted at paddle speeds of 50, 75, and 100 rpm with the USP apparatus 2 (paddle method). The dissolution rate increased with an increase in the agitation rate from 50 to 75 rpm. However, no significant increase in the dissolution rate was noted with an increase in the agitation rate from 75 to 100 rpm. The data support the position that the higher agitation rate of 100 rpm is not necessary for a quality control procedure or a compendial standard for the products tested.

Correlation of in vivo bioavailability of erythromycin stearate tablets with in vitro tests.

Correlations between the bioavailability parameters for erythromycin stearate tablets from five manufacturers and in vitro tests of these tablets were examined using forward (stepwise), multiple linear regression analysis. Bioavailability parameters were determined in clinical studies employing a balanced, incomplete block design. In vitro tests used disintegration, dissolution, and dissolution/dialysis as the independent variables in regression equations. Significant correlations were found between linear combinations of these parameters and the time of peak and the peak serum levels. The inclusion of an in vitro disintegration test to describe peak serum levels of erythromycin is noteworthy since it has been suggested that disintegration tests are of less value than dissolution techniques employed in the present investigation may be useful for selection of appropriate physicochemical tests for continued monitoring of the bioavailability of erythromycin stearate tablets.

Bioavailability of regular and controlled-release chlorpheniramine products.

The bioavailability of chlorpheniramine regular-release versus controlled-release products was compared using 15 human subjects. The dosage forms evaluated were an 8-mg barrier coated-bead capsule, an 8-mg repeat action tablet, two 4-mg tablets, and 4- and 8-mg syrups. Single doses of each product were administered orally in a 5-way crossover study, plasma samples were collected at specific time intervals, and chlorpheniramine levels assayed by HPLC. Pharmacokinetic analysis was based on a two-compartment open model. The average plasma elimination half-life of chlorpheniramine was calculated to be approximately 18.3 hr. The controlled-release products gave a higher Cmax than the 4-mg syrup, but less than two 4-mg tablets. The controlled-release products also extended the time necessary to attain peak drug levels compared to the 4- and 8-mg syrups. The area under the curve (AUC) data for the controlled-release products was not equivalent to equal amounts of the regular-release products. The study indicated that while the controlled-release chlorpheniramine products were successful in prolonging the time course of absorption, this was at the expense of incomplete bioavailability of the drug.

A review of the safety of generic drugs.

Generic drugs have been around for many years. The Drug Price Competition and Patent Term Restoration Act 1984 makes the abbreviated new drug application process available to drugs approved after 1962. It does not lower any standards for generic drugs. FDA's comprehensive drug approval process evaluates information concerning (1) chemistry, manufacturing, and controls, (2) in vivo bioequivalence, (3) labeling, (4) in vitro dissolution data where applicable, and (5) inspection and auditing of all facilities. This stringent and comprehensive approval process ensures the quality of generic drug products marketed in the US and assures the health professionals and patients of the safety and efficacy of generic drug products.

Analytical methods validation: bioavailability, bioequivalence and pharmacokinetic studies. Conference report.

This is a summary report of the conference on Analytical Methods Validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies. The conference was held from December 3 to 5, 1990 in the Washington, DC area and was sponsored by the American Association of Pharmaceutical Scientists, US Food and Drug Administration, Federation International Pharmaceutique, Health Protection Branch (Canada) and Association of Official Analytical Chemists. The purpose of the report is to represent our assessment of the major agreements and issues discussed at the conference. The report is also intended to provide guiding principles for validation of analytical methods employed in bioavailability, bioequivalence and pharmacokinetic studies in man and animals. The objectives of the conference were: 1. To reach a consensus on what should be required in analytical methods validation and the procedures to establish validation; 2. To determine processes of application of the validation procedures in the bioavailability, bioequivalence and pharmacokinetic studies; 3. To develop a report on analytical methods validation (which may be referred to in developing future formal guidelines). Acceptable standards for documenting and validating analytical methods with regard to processes, parameters or data treatments were discussed because of their importance in assessment of pharmacokinetic, bioavailability and bioequivalence studies. Other topics which were considered essential in the conduct of pharmacokinetic studies or in establishing bioequivalency criteria, including measurement of drug metabolites and stereoselective determinations, were also deliberated.

Role of liver and brain lysosomal and mitochondrial enzymes in development of delayed neuropathy in hens by 0,0-diisopropyl phosphorofluoridate.

Subacute dose of 0,0-diisopropyl phosphorofluoridate (DFP), a potent organophosphorus ester capable of producing delayed neurotoxicity (OPIDN), did not produce any significant change in the levels of lysosomal and mitochondrial marker enzymes of brain, liver and serum at any time after treatment in hens protected with atropine. The results suggest the absence of any involvement of mitochondrial and lysosomal enzymes at any stage in the development of OPIDN in susceptible species by treating with DFP.

The role of imipramine hydrochloride on plasma transaminase and glucose level on rats under altitude stress.

The effect of exposure of albino rats to simulated high altitude stress of 5000 metres for 3 and 6 hrs on plasma transaminases, non-protein nitrogen (NPN), total protein percentages and blood sugar levels have been studied both with and without the administration of an anti-stress drug Imipramine HCl at 2.0 mg/kg body weight. The drug appears to have a slight hepatotoxic effect.

Anti-C1q antibodies and their association with complement components in Indian systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease, characterized by immune complex formation and systemic inflammation. Complement components such as C1q and mannose-binding lectin (MBL) play an important role in the clearance of immune complexes. Anti-C1q antibodies are associated with lupus nephritis and reduced levels of the complement components. The objective of this study was to detect anti-C1q antibodies in SLE patients and to evaluate their association with the complement components. Sixty SLE patients were included, of whom 75% had lupus nephritis (LN) and 25% were without renal manifestations (non-LN). The disease activity was assessed at the time of evaluation by the systemic lupus erythematosus disease activity index (SLEDAI). Anti-C1q antibodies, circulating immune complexes, and serum MBL levels were detected by enzyme-linked immunosorbent assay. The anti-C1q antibody prevalence was 58.3%. The LN patients showed 60% anti-C1q positivity with a higher percentage in membranoproliferative glomerulonephritis patients (51.9%). Anti-dsDNA positivity was slightly higher among the anti-C1q positives than in the anti-C1q negatives (65.7% vs. 60%). A higher percentage of reduced C3 and C4 levels was noted among the anti-C1q positives. The LN patients showed a higher percentage of low MBL levels among anti-C1q negatives than in the anti-C1q positives (61.1% vs. 55.6%). Non-LN patients showed a higher percentage of low MBL levels among anti-C1q positives than among anti-C1q negatives (87.5% vs. 57.1%). Anti-C1q antibodies were found in both LN and non-LN patients, but there was no correlation with the clinical severity of the disease.

Perfusion CT to assess angiogenesis in colon cancer: technical limitations and practical challenges.

OBJECTIVE: Perfusion CT may have the potential to quantify the degree of angiogenesis of solid tumours in vivo. This study aims to identify the practical and technical challenges inherent to the technique, and evaluate its feasibility in colorectal tumours. METHODS: 51 patients from 2 institutions prospectively underwent a single perfusion CT on 2 different multidetector scanners. The patients were advised to breath-hold as long as possible, followed by shallow breathing, and were given intravenous buscopan to reduce movement. Numerous steps were explored to identify the challenges. RESULTS: 43 patients successfully completed the perfusion CT as per protocol. Inability to detect the tumour (n=3), misplacement of dynamic sequence co-ordinates (n=2), failure of contrast injection (n=2) and displacement of tumour (n=1) were the reasons for failure. In 14 cases excessive respiratory motion displaced the tumour out of the scanning field along the temporal sequence, leading to erroneous data capture. In nine patients, minor displacements of the tumour were corrected by repositioning the region of interest (ROI) to its original position after reviewing each dynamic sequence slice. In 20 patients the tumour was stable, and data captured from the ROI were representative, and could have been analysed by commercially available Body Tumor Perfusion 3.0® software (GE Healthcare, Waukesha, WI). Hence all data were manually analysed by MATLAB® processing software (MathWorks, Cambridge, UK). CONCLUSION: Perfusion CT in tumours susceptible to motion during acquisition makes accurate data capture challenging and requires meticulous attention to detail. Motion correction software is essential if perfusion CT is to be used routinely in colorectal cancer.

Protective effect of the hydro-alcoholic extract of Rubia cordifolia roots against ethylene glycol induced urolithiasis in rats.

UNLABELLED: This study investigated the protective effect of the hydro-alcoholic extract of roots of Rubia cordifolia Linn. (HARC) against ethylene glycol induced urolithiasis and its possible underlying mechanisms using male Wistar albino rats. Ethylene glycol feeding resulted in hyperoxaluria, hypocalciuria as well as increased renal excretion of phosphate. Supplementation with HARC significantly prevented change in urinary calcium, oxalate and phosphate excretion dose-dependently. The increased calcium and oxalate levels and number of calcium oxalate crystals deposits in the kidney tissue of calculogenic rats were significantly reverted by HARC treatment. The HARC supplementation also prevents the impairment of renal functions. RESULTS: Indicate that the HARC can protect against ethylene glycol induced urolithiasis as it reduced and prevented the growth of urinary stones. Therefore, HARC is helpful to prevent the recurrence of the disease as it showed its effect on early stages of stone development. The mechanism underlying this effect is mediated possibly through an antioxidant, nephroprotection and its effect on the urinary concentration of stone-forming constituents and risk factors.