Abnormal liver function tests associated with severe rhabdomyolysis

Rhabdomyolysis is a syndrome of skeletal muscle injury with release of cellular constituents such as potassium,phosphate,urate and intracellular proteins such as myoglobin into the circulation,which may cause complications including acute kidney injury,electrolyte disturbance and cardiac instability.Abnormal liver function tests are frequently observed in cases of severe rhabdomyolysis.Typically,there is an increase in serum aminotransferases,namely aspartate aminotransferase and alanine aminotransferase.This raises the question of liver injury and often triggers a pathway of investigation which may lead to a liver biopsy.However,muscle can also be a source of the increased aminotransferase activity.This review discusses the dilemma of finding abnormal liver function tests in the setting of muscle injury and the potential implications of such an association.It delves into some of the clinical and experimental evidence for correlating muscle injury to raised aminotransferases,and discusses pathophysiological mechanisms such as oxidative stress which may cause actual liver injury.Serum aminotransferases lack tissue specificity to allow clinicians to distinguish primary liver injury from muscle injury.This review also explores potential approaches to improve the accuracy of our diagnostic tools,so that excessive or unnecessary liver investigations can be avoided.     

Responses of CDKs and p53 in Delayed Ischemic Neuronal Death

Stroke is a debilitating disease that affects millions each year.While in many cases cerebral ischemic in jury can be limited by effectivw resuscitation or thrombolytic treatment,the injured neurons wither in a process known as delayed neuronal death(DND).Mounting evidence indicates that DND is not simply necrosis played out in slow motion but apoptosis is triggered.Of particular interest are two groups of signal proteins that participate in apoptosis-cyclin dependent kinases(CDKs) and p53-among a myriad of signaling events after an ischemic insult.Recent investigations have shown that CDKs,a family of enzymes initially known for their role in cell cycle regulation,are activated in injured neurons in DND.As for p53,new reports suggest that its up-regulation may represent a failed attempt to rescue in jured neurons,although its up-regulation was previously considered an indication of apoptosis.These observations thus rekindle an old quest to identify new neuroprotective targets to minimize the stroke damage.In this review,the author will examine the evidence that indicates the participation of CDKs and p53 in DND and then introduce pre-clinical data to explore CDK inhibition as a potential neuroprotective target.Finally,using CDK inhibition as an example,this paper will discuss the pertinent criteria for a viable neuroprotective strategy for ischemic in jury.     

Catabolic effects and the influence on hormonal variables under treatment with gynodian-depot® or dehydroepiandrosterone (DHEA) oenanthate

53 patients from a mainly climacteric population were treated monthly with 200 mg dehydro-epiandrosterone (DHEA) oenanthate or with 1 ampoule Gynodian-Depot®. Pronounced adiposity was present in 15 of these cases. Hormonal variables were determined before the treatment and during the depot effect of the preparations in order to study the principle which supports the oestrogenic influence and any weight-reducing influence under administration of DHEA. The elimination of lowpolar oestrogens increased considerably in 4 out of 13 post-menopausal cases treated with DHEA. This effect is probably indirect and presupposes intact ovaries. The incorporation of exogenous DHEA into the excretion of 17-ketosteroids and of 17-ketogenic steroids, such as those of androsterone + aethiocholanolone, depends on the size of the initial pool inasmuch as it is higher in small initial pools than in saturated pools - the size of the pool being age-dependent.

An average weight loss of >1 kg/mth was observed under DHEA treatment in 7 out 15 adipose cases. In comparison to the other 8 adipose cases, these 7 were younger and therefore also displayed higher values for 17-ketosteroids and their individual fractions. These circumstances appeared to explain why the administration of DHEA resulted in higher levels of free plasma DHEA which, in contrast to the cases without loss of weight, also resulted in an increase of renal DHEA-sulphate clearance. It was concluded from the findings that this is the explanation for the catabolic effect of exogenous DHEA.

Post-menopausally increased FSH and LH fractions were markedly suppressed in about half of the determinations after Gynodian-Depot administration, the findings indicating that DHEA is probably involved in suppression of the LH fraction.     

Bioequivalence, pharmacokinetic and pharmacodynamic response to combined extended release formulations of felodipine and metoprolol in healthy volunteers

Objective: The primary aim of this study was to investigate whether bioequivalence is achieved for a new fixed combination of extended-release (ER) felodipine and controlled-release (CR/ZOK) metoprolol␣compared with the free combination of felodipine ER metoprolol CR/ZOK. The second aim was to study whether there was an interaction in pharmacokinetics and pharmacodynamics between felodipine and metoprolol when administered as ER formulation. Methods: Two four-way cross-over studies were performed in 36 young subjects and 24 elderly subjects with frequent measurement of drug plasma concentrations, blood pressures and heart rate. The pharmacokinetic analysis included enantioselective analysis in six subjects. Results: Bioequivalence between the fixed combination and the free combination was observed for the two drugs (mean difference 27%) except for a minor deviation regarding C_max of metoprolol in the elderly. No significant interaction was shown except for a small increase (6%) of metoprolol AUC in the younger subjects. Mean plasma S-/R-enantiomer ratios were almost identical for the different treatments. Blood pressure and heart rate was significantly reduced for the fixed combination compared with felodipine ER in the younger and the elderly subjects. No significant difference regarding pharmacodynamics was detected between the fixed combination and the corresponding free combination. Conclusion: The fixed combination consistently provides fairly constant and effective felodipine and metoprolol concentrations after once-daily administration of one tablet. It is clinically interchangeable with the free combination of metoprolol CR/ZOK tablets and felodipine ER tablets. Finally, felodipine and metoprolol do not interact on a pharmacokinetic level when administered as the fixed combination. Received: 29 October 1996 / Accepted in revised form: 21 March 1997     

Prostate Cancer: To Treat or Not to Treat?

ContextTo treat or not to treat is one of the most difficult dilemmas facing prostate cancer patients, especially elderly men with early prostate cancer or small cancer that is contained within the prostate.ObjectiveThe primary objective of this review is to analyse the treatment options for patients with localised prostate cancer. This information can be considered alongside other important factors like natural history of disease and diagnostic tests.Evidence acquisitionSeveral randomised and nonrandomised clinical trials published in the literature investigating the natural history of the disease, diagnostic tests, and treatment options for localised prostate cancer have been reviewed for this paper.Evidence synthesisAnalysis of prostate-specific antigen (PSA) kinetics should play a major role in the management of localised prostate cancer. Trials investigating long-term outcomes of active surveillance are under way.ConclusionTaking all these factors into consideration, the data support active surveillance as an appropriate choice for patients with well-differentiated or moderately differentiated, low-volume prostate cancer who have a life expectancy of <10 yr. Men with higher grade tumours and longer life expectancy may be at excess risk of death from prostate cancer if managed with active surveillance.     

Contrast sensitivity and acuity relationship in strabismic and anisometropic amblyopia.

The contrast sensitivity function (CSF) and visual acuity were determined in children and adults with unilateral amblyopia due to strabismus or anisometropia with central fixation. The preschool children were examined repeatedly during occlusion treatment. All amblyopes had CSF deficits. The CSF was characterised by its peak value (the maximal sensitivity, Smax, and the spatial frequency at which Smax occurs, Frmax) calculated by a single peak least-square regression method. The two amblyopic groups showed discrepancies in relationship of both Smax and Frmax versus visual acuity both initially and during treatment. The strabismic cases had a more marked visual acuity deficit in relation to the contrast sensitivity losses, whereas these parameters are affected similarly in anisometropic amblyopes. The relationship between recovery of visual acuity and CSF during the initial month of occlusion treatment was of prognostic significance for the outcome of visual acuity improvement.     

Repair of osteochondral defects in the rabbit knee with Gore-Tex (expanded polytetrafluoroethylene). An experimental study

In 28 knee joints in 14 rabbits 4 mm circular osteochondral defects were created in each medial femoral condyle. In 24 of the knee joints 4 mm Gore-Tex (E-PTFE) patches were glued into the defects with fibrin glue. Four joints were left without implants and served as controls. In 16 joints the membrane showed good macroscopic incorporation into the joint surface. In four joints the E-PTFE patches were lying loose. In the controls the defects were covered by thin irregular layers of reparative tissue. On histological examination at 12 weeks, cells were seen proliferating through the membrane and overlying its joint facing surface with the morphological appearance of the outer layers of the normal articular surface. We conclude that Gore-Tex might be of potential value in restoring the architecture of a damaged articular surface.