Recently published papers: Out with the old and in with the new ... then something new for the old!

New therapies are challenging older, established practices. One recently published report shows us that we may be able to avoid endotracheal intubation in patients with a reduced level of consciousness. Recombinant activated factor VII is proving to be useful in many coagulation disorders, and intracerebral haemorrhage can be added to this list. Homeopathy, in the form of potassium dichromate, shows promise as a new treatment for excessive tracheal secretions. Rotation protocols for antibiotics have been evaluated with respect to their ability to prevent the development of new resistant micro-organisms in our hospitals and units. Finally, glucocorticoids may be of benefit to septic patients outside the intensive care unit (ICU) and may prevent their deterioration and admission to the ICU.     

Out with the old,in with the new: an updated risk stratification equation for pulmonary arterial hypertension

The Symplicity studies suggest that intravascular renal sympathetic nervous denervation improves blood pressure in patients with resistant hypertension, thus potentially opening a market for devices to be used when conventional drug therapy fails to restore blood pressure control. However, the size and durability of the antihypertensive, renal and sympatholytic effects of renal denervation, the long-term safety, improvement of quality of life, the possibility to relax antihypertensive drug treatment, the cost-effectiveness, and long-term hard cardiovascular-renal outcomes still remain to be firmly established. Most ongoing studies are small, industry-driven and purely observational with objectives to test new catheters and source of energy for renal nerve ablation or to search for ancillary benefits and new indications of the technique. The most urgent need, that is adequately powered randomized clinical trials testing renal denervation versus usual medical therapy delivered according to the state-of-the-art are under-represented and seldom funded by industry. The authors make a plea for a coordinated research effort in Europe. With this objective, they established collaboration with leading European experts and started the European Network for Coordinating Research on Renal Denervation. In the meantime, renal denervation should remain the ultima ratio in adherent and truly resistant patients with severe hypertension, confirmed by ambulatory monitoring, in whom secondary hypertension has been excluded and in whom all other efforts to reduce blood pressure have failed.     

Chronic lymphocytic leukemia--the old and the new

Chronic Lymphocytic Leukemia (CLL) is the most frequent lymphoproliferative disease and leukaemia in western countries. CLL occurs more frequently in men than women, the median age at diagnosis is 65 years. CLL is defined as a persisting chronic lymphocytosis > 5 G/l with classical morphological features (small lymphocytic cells with round nuclei, dense chromatin and small cytoplasmic rim) and a classical immunophenotype (CD5+, CD19+, CD20+, CD23+); however, deviations from classical morphology are frequent. In cases with classical diagnostic features in the peripheral blood, a bone marrow biopsy is not necessary for diagnosis. Prognostic features comprise the stage of the disease according to the Rai or Binet systems, laboratory markers such as LDH, beta-2-microglobulin, lymphocyte doubling time and CD38 expression by flow cytometry (and ZAP-70 expression if available) as well as the status on IgV(H) hypermutations and cytogenetic analysis. Up to 2/3 of patients do not need treatment at the time of diagnosis and can initially be followed using a watch and wait strategy. If therapy becomes necessary, initial standard treatment still is chlorambucil. Later, purine analogues and Alemtuzumab are treatment options for refractory or relapsing disease. Therapies with antibodies such as Alemtuzumab and Rituximab in combination with purine analogues are currently under clinical investigation. With recurrent or atypical infections, hypogammaglobulinemia should be searched for and immunoglobulins should be substituted if necessary. However, their prophylactic use is not recommended.     

Antiepileptic drugs: the old and the new

During the past decade several new antiepileptic drugs (AEDs) have become available, including new formulations of some of the older medications. Understanding the pharmacokinetics of the new AEDs is important because they are primarily used for adjunctive therapy and interactions with other medications can result in significant toxicities. The new-generation AEDs do not cause serious morbidity in overdose, and treatment is primarily supportive. Specific medications should be chosen based on the patient's history and presentation.     

Breast cancer: The new biology in conflict with the old dogma

Let us summarize the pathophysiology of breast cancer according to the new biology. One or more unknown factors, (eg, hormonal, hereditary) lead to the development of proliferative changes in the glandular tissue of the breast. These changes are premalignant and render the patient at higher risk for breast cancer. Among those who show proliferative change, a smaller group (less than 4% of women who have breast biopsies and about 12% of those with proliferative change) develop atypical changes and are at particularly high risk.The explanation for these histologic events may be as follows: the etiologic agents of breast cancer produce a series of mutations that may activate oncogenes necessary for malignant transformation. Activation of these genes may produce in sequence proliferative growth, proliferative growth with atypia, in situ carcinoma, low grade invasive intraductal carcinoma, and subsequently overt clinical breast cancer. At some point this sequence becomes autonomous, ie, no longer dependent on the original etiologic factors. The cancer enters a progression phase in which its cells develop the capacity to invade blood vessels, survive in metastatic sites, lose their estrogen receptors, accelerate their growth rate, and develop resistance to chemotherapeutic agents. Not all precancerous lesions or in situ cancers evolve into clinical disease. Autopsy studies on women with no evidence of breast cancer show that 20% have invasive or in situ cancer of the breast.²⁸By the time we interrupt this chain with detection of a palpable or mammographically visible breast mass, it may be too late to completely reverse the process. Early detection may help some. Adjuvant chemotherapy may contribute a bit more. In view of the recent histologic data, it might be desirable to investigate the possibility of identifying women at special high risk by means of biopsy. Such women could then be given either special diagnostic attention or considered for prophylactic mastectomy. One might speculate that women at special high risk of breast cancer might be protected by prophylactic radiation of both breasts. Such a procedure might be far less cosmetically unsatisfactory than prophylactic mastectomy.With our better understanding of cancer biology, we may be able to develop therapy that will substantially improve cure rates. We need new clinical trials designed to test various aspects of the new biology of cancer. Dupont and Page have identified a very high risk group: can we devise acceptable and effective prophylaxis for this group? Adjuvant chemotherapy seems to modestly improve survival: can we confirm this and increase the salvage with better regimens? According to the new biology, certain steps in cancer progression can be predicted: can we develop therapeutic strategies that take advantage of this theoretic possibility? These and other questions demand attention in future studies.     

Acetaminophen in children: An old drug with new warnings

Question I frequently suggest to parents to use acetaminophen to treat their children’s fever and pain. Recently, I had a child in my office who presented with a target-lesion skin rash a day after receiving acetaminophen. The rash resolved after 3 days and after stopping administration of acetaminophen. Does acetaminophen carry a risk of adverse events such as this?Answer Like any other medication or active substance, acetaminophen preparations might carry a risk of adverse events. In recent years a potential association between acetaminophen and asthma was investigated, and the US Food and Drug Administration recently published a warning about potential severe but rare skin reactions associated with acetaminophen. Although acetaminophen is mostly a safe medication, health care providers should be alert and advise parents about the possibility of rare but severe adverse events.Acetaminophen is the over-the-counter (OTC) antipyretic¹ and analgesic² medication most commonly used in children. While a large number of parents underdose the medication for fever³ and are also unaware of the availability of the medication in a form for rectal administration (eg, for children who are vomiting),⁴ acetaminophen is being used commonly worldwide.^5–7Despite its frequent use and years of research, the exact mechanism of action of acetaminophen is unknown. Reduction of pain through suppression of inflammatory-related prostaglandins has been offered as a possible mechanism, and reduction of fever via a central effect on the temperature centre in the brain has also been shown. It is metabolized by the liver.Since the approval of acetaminophen by the US Food and Drug Administration (FDA) in 1951, a tremendous amount of research has been conducted on the drug, and thousands of reports have been published documenting its potential adverse effects.     

Methadone: A new old drug with promises and pitfalls

Although methadone is not a new medication, its use in pain management has increased rapidly over the past decade. This article reviews the unique pharmacologic properties of methadone, including its long-acting nature, highly variable clearance rate, and its antagonism of the N-methyl-d-aspartate receptor. We discuss potential benefits and risks of methadone over other opioid medications. Preclinical studies suggest methadone may reduce abuse potential, tolerance development, and sensitization of nociceptive pathways. Pharmacologic properties of methadone suggest potential greater risk of dangerous or fatal side effects from overdose, QT interval prolongation, and drug interactions. However, clinical studies have yet to confirm that methadone produces either better clinical outcomes or higher rates of adverse events than other opioid analgesics. Clinicians who understand the special properties of methadone and follow recommended precautionary prescribing and monitoring practices can safely and effectively use methadone for pain treatment.