Clinical trial: alvimopan for the management of post-operative ileus after abdominal surgery: results of an international randomized, double-blind, multicentre, placebo-controlled clinical study.

BACKGROUND: Post-operative ileus (POI) affects most patients undergoing abdominal surgery. AIM: To evaluate the effect of alvimopan, a peripherally acting mu-opioid receptor antagonist, on POI by negating the impact of opioids on gastrointestinal (GI) motility without affecting analgesia in patients outside North America. METHODS: Adult subjects undergoing open abdominal surgery (n = 911) randomly received oral alvimopan 6 or 12 mg, or placebo, 2 h before, and twice daily following surgery. Opioids were administered as intravenous patient-controlled analgesia (PCA) or bolus injection. Time to recovery of GI function was assessed principally using composite endpoints in subjects undergoing bowel resection (n = 738). RESULTS: A nonsignificant reduction in mean time to tolerate solid food and either first flatus or bowel movement (primary endpoint) was observed for both alvimopan 6 and 12 mg; 8.5 h (95% CI: 0.9, 16.0) and 4.8 h (95% CI: -3.2, 12.8), respectively. However, an exploratory post hoc analysis showed that alvimopan was more effective in the PCA (n = 317) group than in the non-PCA (n = 318) group. Alvimopan was well tolerated and did not reverse analgesia. CONCLUSION: Although the significant clinical effect of alvimopan on reducing POI observed in previous trials was not reproduced, this trial suggests potential benefit in bowel resection patients who received PCA.

Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease.

Mild-to-moderate AD patients were randomized to placebo or rosiglitazone (RSG) 2, 4 or 8 mg. Primary end points at Week 24 were mean change from baseline in AD Assessment Scale-Cognitive (ADAS-Cog) and Clinician's Interview-Based Impression of Change Plus Caregiver Input global scores in the intention-to-treat population (N=511), and results were also stratified by apolipoprotein E (APOE) genotype (n=323). No statistically significant differences on primary end points were detected between placebo and any RSG dose. There was a significant interaction between APOE epsilon4 allele status and ADAS-Cog (P=0.014). Exploratory analyses demonstrated significant improvement in ADAS-Cog in APOE epsilon4-negative patients on 8 mg RSG (P=0.024; not corrected for multiplicity). APOE epsilon4-positive patients did not show improvement and showed a decline at the lowest RSG dose (P=0.012; not corrected for multiplicity). Exploratory analyses suggested that APOE epsilon4 non-carriers exhibited cognitive and functional improvement in response to RSG, whereas APOE epsilon4 allele carriers showed no improvement and some decline was noted. These preliminary findings require confirmation in appropriate clinical studies.

Treatment of primary miliary osteoma cutis with incision, curettage, and primary closure.

BACKGROUND: Primary miliary osteoma cutis is characterized by de novo bone formation in skin without a known associated or pre-existing cutaneous disorder. These lesions often develop on the face and cause cosmetic concern. OBJECTIVE: Multiple treatments have been attempted, including topical and systemic agents and surgical techniques. The ideal treatment modality should be simple and effective with minimal side effects. METHODS: The technique of scalpel incision over visible lesions, curette extraction of bony fragments, and primary suture repair was used to remove multiple lesions of primary miliary osteoma cutis on the cheeks of an affected patient. RESULTS: This surgical technique resulted in a significant reduction of visible and palpable lesions and a smoother surface contour with minimal scarring. CONCLUSION: This surgical technique offers a simple but effective method for removal of multiple bony fragments in primary miliary osteoma cutis with minimal side effects.

A survey of skin cancer screening in the primary care setting: a comparison with other cancer screenings.

OBJECTIVE: To determine primary care physicians' perceived importance and frequency of performance of skin cancer screening in comparison with other cancer screening examinations. DESIGN: Descriptive survey study. PARTICIPANTS: Five thousand US family physicians and internal medicine specialists randomly selected from the Official American Board of Medical Specialists Directory of Board-Certified Medical Specialists. MAIN OUTCOME MEASURES: Self-reported importance and performance of cancer screening examinations. RESULTS: Eligible physicians (1363 total: 814 family physicians and 549 internists) completed the survey with a response rate of 30%. Overall, 52% of respondents rated skin cancer screening as "extremely" important, compared with 79% for digital rectal examination, 88% for clinical breast examination, and 87% for Papanicolaou testing. Thirty-seven percent of physicians reported performing complete body skin examinations on 81% to 100% of patients, compared with digital rectal examination, for which 78% of physicians reported performing the examination on 81% to 100% of patients, or the clinical breast examination, for which 82% of physicians reported performing the examination on 81% to 100% of patients. A higher percentage of physicians in practice for more than 30 years ranked skin cancer screening as extremely important and reported a higher frequency of screening examinations. Physicians in a suburban practice setting reported performing skin examinations more often than those in urban or rural settings. Overall, the self-reported frequency of skin examination was strongly correlated with the physician's importance rating of skin cancer screening. CONCLUSIONS: A majority of primary care physicians rate skin cancer screening as extremely important. The reported importance of skin cancer screening and frequency of skin cancer examination among primary care physicians is significantly less than for other cancer examinations. This likely represents a multitude of factors, including logistic constraints and lack of consensus on the efficacy of skin cancer screening. Arch Fam Med. 2000;9:1022-1027

Genetic predisposition to skin cancer.

Here we review recent insights in the genetics of skin cancer susceptibility as gleaned from studies of three hereditary syndromes: basal cell nevus syndrome, familial melanoma/dysplastic nevus syndrome, and xeroderma pigmentosum. We provide a brief synopsis of the recent findings related to these syndromes in an attempt to illustrate several emerging themes in the genetics of skin cancer. These themes include 1) the recent identification of multiple cancer susceptibility genes that occur in a myriad of cellular regulatory pathways; 2) the relative specificity of certain regulatory pathways to the development of specific types of cancer; and 3) the important role of DNA damage caused by ultraviolet radiation and defective DNA repair mechanisms in the development of skin cancer. We also review the implications of this knowledge to clinical practice relative to risk assessment, primary prevention, and therapy.

A relative cost-effectiveness analysis of different methods of screening for diabetic retinopathy.

The relative cost and cost-effectiveness of different methods of screening diabetic patients for sight-threatening retinopathy are assessed. The resource costs per screening visit, both to the health service and to patients, of ophthalmoscopic examination by primary screeners including general practitioners, hospital physicians, and ophthalmic opticians are estimated together with those of a similar screening test by ophthalmological clinical assistants. The total resource cost per screen of screening using non-mydriatic photography is also estimated. Using estimates of sensitivity, specificity, and prevalence generated in the screening of 3318 diabetic patients in three UK centres, the relative cost-effectiveness of screening methods is estimated in terms of their cost per true positive case detected. On the assumption that a patient makes a special trip for eye screening, the cost per true positive case detected for primary screeners ranges from 633 pounds for a GP-screened group in one centre to 1079 pounds for another GP-screened group in a second centre; the cost per true positive case detected of photography ranges from 497 pounds for a camera that is taken to general practices in one centre to 1546 pounds for a hospital-based camera. Relative cost-effectiveness changes if, in some contexts, the screening can take place without requiring an additional patient visit, and is strongly related to the relative sensitivity of the screening methods and to the prior probability (prevalence or incidence) of retinopathy in the diabetic population.

Screening for treatable diabetic retinopathy: a comparison of different methods.

The results of the screening of 3318 diabetic patients for sight-threatening diabetic retinopathy in three UK centres are reported. The aims of the study were to determine the extent of diabetic retinopathy in the screened population and to assess the relative effectiveness of different screening methods in appropriately referring cases from a diabetic population, in a context very close to a routine clinical service. Patients were assessed by ophthalmoscopic examination by an ophthalmological clinical assistant. The clinical assistants' referral grades formed the reference standard against which to assess the effectiveness of other screening methods including ophthalmoscopy by primary screeners who were general practitioners (GPs), ophthalmic opticians and hospital physicians, and the assessment by consultant ophthalmologists of non-mydriatic Polaroid fundus photography. The performance of primary screeners based on ophthalmoscopy ranged from a sensitivity of 0.41, with a specificity of 0.89, for one of the GP groups, to a sensitivity of 0.67, with a specificity of 0.96, for the hospital physician group. The performance of the non-mydriatic camera ranged from a sensitivity of 0.35, with a specificity of 0.95, to a sensitivity of 0.67, with a specificity of 0.98.

The effect of midazolam administration on the pharmacokinetics of antipyrine in the rat.

1. The clearance and elimination half-lives for i.v. doses of antipyrine were determined in 6 groups of 6 male CD rats with no prior treatment, then again following 7 days treatment with graded oral doses of midazolam, and finally after 3 i.p. doses of phenobarbitone. 2. Substantial increases in clearance and decreases in half-lives were observed following phenobarbitone treatment, demonstrating that antipyrine provides a reliable index of enzyme induction. 3. After treatment with midazolam, maximal induction was seen in animals dosed at 27 or 80 mg/kg per day; an intermediate effect was found with 9 mg/kg per day and no effect at 0.2 and 1.0 mg/kg per day. 4. The results indicate that there is a substantial margin of safety between the proposed human therapeutic doses (7.5 to 15 mg/day) and the minimum effective dose that leads to enzyme induction in laboratory animals.

Local myotoxicity of ketamine hydrochloride in the marmoset.

An investigation of raised plasma aspartate aminotransferase (AST) in marmosets after intramuscular ketamine injection suggested a local myotoxicity. This was confirmed by a range of histopathological findings from myofibrillar striation loss to necrosis. In addition to the elevations in AST levels, creatine kinase and the lactate dehydrogenase-5 isoenzyme levels were elevated. It was further demonstrated that, although the physical properties of the injectable solution (pH, osmolality) and to a lesser extent the injection procedure itself caused slight changes in plasma enzyme levels, the ketamine was predominantly responsible for the lesion. No hepatic interactions were seen. This effect should be taken into consideration when this anaesthetic is used in the marmoset if the primary objectives of the experiment entail routine blood analyses.

Effect of anthelmintic treatment on the milk yield of dairy cows in England, Scotland and Wales.

One hundred and twenty dairy herds collaborated in a trial to determine the effect on milk yield of anthelmintic treatment given at calving. Cows and heifers were divided into five groups. Three were each given a different anthelmintic: thiabendazole, fenbendazole or levamisole. One group was given a placebo and the fifth was untreated. Analysis of data from 9000 lactations showed a treatment effect just significant at the 5 per cent level, of 42 kg milk, 1.8 kg fat and 1.4 kg protein. There was no evidence that the three anthelmintics differed in their effect on yield. The effect of treatment was not greater in heifers than in cows, nor was there a difference between spring and autumn calvers. There was no indication that the effect of treatment was markedly greater in some herds than others and it was not related to periparturient faecal egg count.

Effect of progesterone treatment on the calving-to-conception interval of Friesian dairy cows.

A total of 615 autumn calving Friesian dairy cows in seven herds were allocated to treatment or control groups according to date of previous calving, parity and milk yield. All cows were scored for body condition at the start of the breeding season. A silastic coil impregnated with progesterone with a capsule containing oestradiol benzoate attached was inserted into the vaginas of the 310 treated cows. The coils were removed after 12 days and cows inseminated 48 and 72 hours later. Cows more than 47 days post partum were inseminated on the first day of the breeding season. Thereafter, cows were inseminated on a weekly basis when between 47 to 54 days post partum. The 305 control cows were observed from 42 days post partum and inseminated when observed to be in oestrus. In both groups, cows returning to service were reinseminated at observed oestrus. Pregnancy was diagnosed by milk progesterone assay and by rectal palpation. The mean intervals to first service were 74.8 days for the treated and 90.4 days for control cows. No significant differences were found in the pregnancy rates to first service, services per conception or barren percentage for treated and control groups respectively. The mean calving-to-conception intervals differed significantly, 93.1 days for treated and 107.3 days for control cows. There was no significant association between condition scores and either pregnancy rates to first service, barren percentage or calving-to-conception intervals.