Metabolism of homoharringtonine,a cytotoxic component of the evergreen plant Cephalotaxus harringtonia

Homoharringtonine (HHT), first isolated from the Chinese evergreen Cephalotaxus harringtonia, has been demonstrated to have a broad antitumor activity in rodents and antileukemic effects in humans. We found that HHT was metabolized to an acid product [HHT-acid; 2'-hydroxy-2'-(alpha-acetic acid)-6'-hydroxy-6'-methylheptanoyl cephalotaxine] when incubated with either human plasma or mouse plasma in vitro. The conversion was faster, however, in mouse plasma, and was both time- and temperature-dependent. Boiled plasma prevented the conversion of HHT to HHT-acid, suggesting that the conversion was enzymatically mediated. When mice were given an intravenous (i.v.) injection of HHT (4 mg/kg), the HHT-acid metabolite was found in both plasma and urine. In mice, HHT-acid was detected in the plasma within 5 min of the i.v. injection of HHT and declined rapidly thereafter. The initial half-lives (t 1/2 alpha) of HHT and HHT-acid were 9 and 17 min, respectively. Twenty-four hours after HHT dosing in mice, approximately 29% of the dose was excreted in the urine as HHT and 20% as HHT-acid. High-pressure liquid chromatography and mass spectrometry were used to confirm the identity and quantify HHT and its metabolite, HHT-acid. The HHT concentration inhibiting 50% of the growth of human leukemic HL-60 cells was 20 ng/ml, while for HHT-acid it was 14,500 ng/ml, indicating that the acid form was more than 700 times less cytotoxic than HHT. The lethal dose of HHT affecting 50% (LD50) of mice was 6.7 mg/kg, but HHT-acid produced no apparent toxic effects at doses up to 280 mg/kg.     

Asthma in children: Management practices among paediatricians and family physicians

OBJECTIVE:

To ascertain the variation in asthma management practices among paediatricians and family physicians to determine how to improve care.

DESIGN:

Questionnaire study of paediatricians and family physicians that focused on the use of beta₂-agonists, inhaled corticosteroids, patient asthma education, quantitative measurements of airflow and diagnostic investigations for asthma. Case scenarios were used in the questionnaire.

RESULTS:

The response rate was 66% (415 of 632) among paediatricians and 42% (1156 of 2750) among family physicians. In general, both groups followed consensus guidelines. There were some differences in management practices among paediatricians and family physicians. Paediatricians were more likely to develop an action plan and less likely to use xanthines or inhaled anticholinergic agents. However, family physicians were more likely to use spirometry or home peak expiratory flow rates to make a diagnosis of asthma.

CONCLUSION:

Family physicians and paediatricians require a different focus on educational interventions to improve the care of children with asthma.     

Imprint cytology versus frozen section: intraoperative analysis of sentinel lymph nodes in breast cancer

Background: Intraoperative analysis of the sentinel node status in breast cancer adds the benefit of proceeding to axillary dissection at the same time as the primary breast operation, without the need for a second trip to theatre. However, the method of intra­operative analysis must be both rapid and accurate for use in this setting. Methods: A prospective series of 20 consecutive patients in one hospital who underwent sentinel node biopsy was performed. Intraoperative evaluation by imprint cytology and frozen section was compared with the final histopathological results. The time taken for both procedures was recorded. Results: A total of 21 sentinel node procedures was performed. The sentinel node was found in 20 procedures (95%). The average time to perform intraoperative pathological analysis was 17 min (range: 5?35 min). Of the eight positive sentinel nodes, five were positive on imprint cytology alone and five were positive on frozen section alone (62.5% accuracy). The statistical false negative rate was 18.8% and the ‘false reassurance rate’ (patients with an initially negative node that was subsequently positive on formal histology who required a second trip to theatre for axillary dissection) was 37.5%. All patients with a negative sentinel node had a negative axilla. Conclusions: Intraoperative analysis of sentinel lymph nodes in breast cancer can be performed quickly. Imprint cytology and frozen section show comparable accuracy in predicting sentinel node status.     

Acyloxymethyl acidic drug derivatives: in vitro hydrolytic reactivity

A series of acyloxymethyl drug derivatives of the NH-acidic drugs, phenytoin and theophylline and of the carboxylic acid drugs, thioctic acid and indomethacin, were prepared in order to determine the effect of varying the nature of the drug on the in vitro rate of hydrolysis catalyzed by porcine liver esterase and human plasma. The acyl portion was comprised of either valeric acid (val) or γ-linolenic acid (GLA). With the exception of some GLA prodrugs, the derivatives displayed first-order kinetics in both enzyme systems. The NH-acidic drug derivatives were hydrolyzed faster than the carboxylic drug derivatives by porcine liver esterase and human plasma. It was found that the short chain valeric acid derivatives were hydrolyzed faster than the GLA derivatives. The rates of hydrolysis for the relatively smaller prodrugs of theophylline and thioctic acid were greater than the rates of hydrolysis for the bulkier phenytoin and indomethacin prodrugs indicating steric hindrance was important. The lipophilicity index, log K, of the valeric acid drug derivatives was plotted against the logarithm of the hydrolysis rate constant, k, and it was observed that log k decreased with an increase in log K. A comparison of these results with those of previous studies where the alkyl and acyl moieties were varied of acyloxyalkyl theophylline derivatives has provided a rationale, based on lipophilicity, for the structure of a prodrug to be designed based on an in vitro desired rate of hydrolysis.     

CT evaluation of appendicitis and diverticulitis. Part II: Diverticulitis

CT has become the primary imaging modality for evaluation of possible diverticulitis. In studies of patients taken to surgery for suspected diverticulitis without first undergoing CT, 25–33 % of resected specimens show no inflammation. The overall accuracy of CT in establishing or excluding the diagnosis is between 84 and 99 %. In patients without diverticulitis, an alternative diagnosis is seen in 50–58 % of cases. The appearance of carcinoma with perforation and diverticulitis may be the same, and, as a result, the degree of certainty in the diagnosis should be stated. Techniques include use of either oral and intravenous contrast or rectally administered contrast. No case of colonic perforation due to rectally administered water-soluble contrast for CT has been reported, although there have been cases of perforation using barium and fluoroscopy. All techniques scan the entire abdomen and pelvis since there are frequent alternative diagnoses seen beyond the area of initial pain.     

Children's over‐the‐counter medicines pharmacoepidemiological (COPE) study

Objective To quantify the extent and types of minor ailments in children that were presented at community pharmacies and the types of over‐the‐counter (OTC) medicines purchased in response to these ailments. Method Data on all requests and sales of OTC medicines for children (aged 16 years and under) and consultations for minor ailments in children were recorded in eight community pharmacies for one week every month over a 12‐month period. Participants were members of the public who consulted the pharmacists or other pharmacy staff in the community pharmacies. Key findings A total of 976 consultations was recorded with 61.5% requesting an OTC medicine by name and 38.5% by symptom presentation. An average of 10.2 consultations was made per pharmacy per week. Requests for treatment were usually made within five days of symptom occurrence (86%). Most of the consultations were made by mothers (75%), although 17% were by fathers. The most commonly purchased OTC medicine was paracetamol. There were five requests for aspirin and one was for a 2‐year old child. A total of 62 cases (6%) was referred back to the child's primary care physician (general practitioner). Conclusions Symptoms related to cough and cold were the most common problems in children presenting to community pharmacies for treatment. Paracetamol was the most widely used OTC medicine in children. Pharmacy staff do question the request for OTC medicines such as aspirin, to ensure its safe use. Community pharmacies play an important role as the first port of call for advice on minor ailments in children and have an opportunity to provide health promotion to carers of children.     

CT evaluation of appendicitis and diverticulitis. Part I: Appendicitis

CT has become the primary imaging modality for evaluation of possible appendicitis. About 20 % of patients taken to surgery for appendicitis without CT have had a normal appendix removed. CT has demonstrated overall accuracy of between 93 % and 98 %. Alternative diagnoses are seen in 34–80 % of patients without appendicitis but who were suspected of having appendicitis. For evaluation of appendicitis different techniques have been successful, including the use of no contrast, use of oral and intravenous contrast, and use of rectally administered contrast. Scanning of the entire abdomen and pelvis and scanning of an area limited to the right lower quadrant are also options. Ultrasonography has been shown to have a role in pediatric patients. If ultrasonography is positive, CT is not necessary. If ultrasonography is negative, CT should follow.     

Cisapride in the treatment of post-operative ileus

The effect of cisapride on duration of post-operative ileus after surgery was investigated in a randomized, double-blind, placebo-controlled study. Patients undergoing elective upper gastrointestinal (n = 47) or colonic (n = 22) surgery were pre-operatively randomly allocated to treatment with either cisapride 30 mg t.d.s., by rectal administration, or placebo. Treatment started exactly 48 h after surgery if the patient at this time had not passed stool. Time to passage of first stool after surgery was estimated. Mean time to passage of stool was 85 (32) h (s.d.) for cisapride-treated and 91 (43) h for placebo-treated patients. No difference between the treatment groups was noted. Treatment with cisapride did not shorten the duration of postoperative ileus after either upper gastrointestinal or colonic surgery.     

Eating disorder behaviors of ethnically diverse urban female adolescent athletes and non-athletes.

This study compared Caucasian, Hispanic, and African-American urban adolescent athlete and non-athlete females for relative frequency of behavioral and psychological indices of eating disorders, while controlling for physical size. High school female athletes (n=571) and non-athletes (n=463) completed the Eating Disorder Inventory (EDI) composed of eight subscales that measure behavioral and psychological indices common in anorexia nervosa and bulimia nervosa. The MANCOVA for the main effect of ethnicity showed Caucasians and Hispanics scored significantly higher than African-Americans on six of the eight behavioral and psychological subscales of the EDI (p<0. 05). A MANCOVA for the main effect of athletic status showed no significant differences between athletes and non-athletes on the behavioral subscales of the EDI (p>0.05). This study suggests that Hispanic and Caucasian urban adolescent females are comparably more at-risk for eating disorders than African-American urban adolescent females. In addition, athletes were no more at-risk than non-athletes for eating disordered behaviors.