Modulation of P450-dependent ifosfamide pharmacokinetics: a better understanding of drug activation in vivo.

The anti-cancer prodrug ifosfamide (IF) is metabolized by liver P450 enzymes by two alternative pathways. IF is activated to 4-hydroxy IF (4-OH-IF), which ultimately yields the alkylating mustard isophosphoramide, whereas IF N-dechlororethylation inactivates the drug and produces the neurotoxic metabolite chloroacetaldehyde (CA). Both reactions are catalysed by multiple liver P450 enzymes in vitro in isolated rat liver microsomes. The present pharmacokinetic study investigates the potential for modulation of these alternative pathways of IF metabolism in vivo using the adult male Fischer 344 rat model. Rats were treated with IF alone or in conjunction with various P450 inducers and inhibitors in an effort to improve the balance between drug activation and drug inactivation. Plasma concentrations, areas under the curve (AUC) and half-lives were calculated for 4-OH-IF and CA, allowing estimations of the extent of IF activation and deactivation/toxification. Induction of liver P450 2B enzymes by 4-day high-dose phenobarbital (PB) pretreatment significantly decreased the fraction of IF undergoing 4-hydroxylation (AUC(4-OH-IF)/AUC(4-OH-IF)+AUC(CA)), from 37% to 22% of total metabolism (P < 0.05), consistent with in vitro findings that the PB-inducible P450 enzyme 2B1 plays a major role in IF N-dechloroethylation. Pretreatment with the P450 3A inducer dexamethasone proportionally decreased the AUC for both IF metabolites, without any net impact on the fraction of IF undergoing metabolic activation. By contrast, the P450 2B1 inhibitor metyrapone preferentially increased the AUC for the 4-hydroxylation pathway in 3-day low-dose PB-induced rats, thereby increasing the total fraction of IF metabolized via the activation pathway from 36% to 54% (P < 0.05), whereas the P450 inhibitors orphenadrine and troleandomycin had no significant affect on AUC values. These findings demonstrate specific roles for P450 2B and 3A enzymes in catalysing these pathways of IF metabolism in vivo, and demonstrate the potential for modulation of IF''s alternative metabolic pathways in a therapeutically useful manner. These studies also highlight several clinically relevant drug interactions that may occur during concomitant administration of IF with drugs and other compounds that modulate hepatic P450 enzyme levels.     

Metformin-associated lactic acidosis: a rare or very rare clinical entity?

AIMS: Lactic acidosis is a well recognized complication of biguanide therapy which is potentially serious. Although the prevalence of metformin-associated lactic acidosis (MALA) is much lower than that associated with phenformin, it is still being reported sporadically which raises concerns for the practising clinicians. We review the currently available world-wide data of the prevalence of MALA, the risk factors for its development and the current practical guidelines on the use of metformin to minimize the risk of this potential hazard. METHODS: An extensive literature search was conducted from both Medline and Ovid (1965-98) using the following keywords: 'Type 2 diabetes mellitus', 'oral hypoglycaemic drugs', 'biguanides', 'metformin-associated lactic acidosis' and 'renal impairment'. RESULTS: MALA was found to be a very rare clinical entity, being 20 times less common than phenformin-associated lactic acidosis. Amongst all the risk factors, renal impairment appears to be the major precipitating factor for the development of MALA in metformin-treated patients. We also found cases of MALA where no precipitating factors were identified and the underlying mechanism in these cases remains unclear. Practical recommendations of metformin use to minimize the risk of MALA have been listed based on previous reports. CONCLUSIONS: The low prevalence of MALA is comparable to the prevalence of sulphonylurea-induced hypoglycaemia. Metformin has many beneficial metabolic effects in the management of Type 2 diabetes mellitus. Provided that the recommended guidelines for metformin use are strictly adhered to, its widespread use would be safe and the incidence of MALA will be further reduced.     

Clinical use of sodium bicarbonate during cardiopulmonary resuscitation--is it used sensibly?

This study retrospectively analyzed the pattern of sodium bicarbonate (SB) use during cardiopulmonary resuscitation (CPR) in the Brain Resuscitation Clinical Trial III (BRCT III). BRCT III was a prospective clinical trial, which compared high-dose to standard-dose epinephrine during CPR. SB use was left optional in the study protocol. Records of 2915 patients were reviewed. Percentage, timing and dosage of SB administration were correlated with demographic and cardiac arrest variables and with times from collapse to Basic Life Support, to Advanced Cardiac Life Support (ACLS) and to the major interventions performed during CPR. SB was administered in 54.5% of the resuscitations. The rate of SB use decreased with increasing patient age-primarily reflecting shorter CPR attempts. Mean time intervals from arrest, from start of ACLS and from first epinephrine to administration of the first SB were 29+/-16, 19+/-13, and 10.8+/-11.1 min, respectively. No correlation was found between the rate of SB use and the pre-ACLS hypoxia times. On the other hand, a direct linear correlation was found between the rate of SB use and the duration of ACLS. We conclude that when SB was used, the time from initiation of ACLS to administration of its first dose was long and severe metabolic acidosis probably already existed at this point. Therefore, if SB is used, earlier administration may be considered. Contrary to physiological rationale, clinical decisions regarding SB use did not seem to take into consideration the duration of pre-ACLS hypoxia times. We suggest that guidelines for SB use during CPR should emphasize the importance of pre-ACLS hypoxia time in contributing to metabolic acidosis and should be more specific in defining the duration of "protracted CPR or long resuscitative efforts", the most frequent indication for SB administration.     

Management Strategies for Pain in Breast Carcinoma Patients: Current Opinions and Future Perspectives

Breast cancer is the most frequently encountered carcinoma in women worldwide. Pain is the most distressing symptom in patients with breast carcinoma and can occur at all stages of the disease due to the cancer per se as well as due to various diagnostic and treatment modalities. A proper pain assessment helps in identification of pain syndromes and guides in formulating analgesic strategies. Primary therapies of breast carcinoma like surgery, chemotherapy, and radiotherapy for bony metastases can cause substantial pain relief. However, multimodal analgesic approaches incorporating pharmacological, interventional as well as non-conventional techniques should be employed prior to, in conjunction with, and after primary therapies of breast cancer. The prevalence of chronic neuropathic pain following breast cancer surgery may exceed 50% by current estimates, and with the increase in life expectancy of these patients, providing adequate pain relief is of paramount importance to improve their quality of life. In this review, we discuss prevailing methods of evaluation and management of pain in patients of breast carcinoma and the new techniques that may become the mainstay of pain management protocols in future.     

Patterns of Insulin Dependence in an African Diabetic Clinic

SUMMARY Analysis of the age of onset of diabetes amongst insulin-treatedpatients in a large African diabetic clinic revealed a bimodaltype of distribution, 23 per cent having an age of onset before30 years and 77 per cent with onset at 30 years of age. All66 of the young insulin-treated group (21.7±4.8 years(mean±1 SD)), and a random selection of 50 older insulin-treatedpatients (49.7±10 years), were studied. The older groupwere better controlled (HbA₁ 8.4±1.7 per cent vs. 10.8±2.6per cent, p<0.001), on lower doses of insulin (49±23vs. 71±23 u/day, p<0.001) and had higher body massindex (26.0±5.6 vs. 21.8±3.5, p<0.001). SerumC-peptide (0.24±0.15 vs. 0.07±0.10 nmol/l, p<0.0001),and C-peptide/glucose ratio (2.57±2.65 vs. 0.56+0.98nmol/mmolx 10², p<0.001) were very significantly higher inolder patients. Patients with later onset disease thus had betterpreservation of pancreatic function, higher body mass indexand better glycaemic control on lower doses of insulin. Thesefeatures suggest that older insulin-treated patients could infact be ‘Type 2’ or non-insulin dependent patients,and the condition may be controllable with diet and/or oralhypoglycaemic agents, at least in some.     

氯胺酮在吗啡急性耐受大鼠的外周镇痛作用

我们产证明氯胺酮引起的外周镇痛作用与阿片受体的激活有关。本实验旨在建立吗啡外周镇痛耐受的大鼠模型，进一步观察氯胺酮的外周镇痛作用与阿片受体的关系。外周感受野局部皮下注射５μｌ吗啡（１０μｇ／μｌ）明显的抑制伤害性肌电反应。随吗啡注射次数的增加，伤害性反应的抑制逐渐减弱，一般于第五次注射，吗啡不再产生抑制，出现外周镇痛的急性耐受。但是，在耐受动物的同一部位注射０μｌ氯胺酮（５０μｇ／μｌ），仍产生很