Causes and treatment of bone pain of malignant origin

Pain relief has been one of the oldest and most important duties of the physician. There has been little change with regard to this obligation of all caregivers. One-third of patients with advanced cancer will develop clinically relevant skeletal metastases and chronic pain during the course of their disease. All physicians involved in the treatment of cancer patients should know the basic principles of pain treatment. These are described in the following article with special regard to bone pain of malignant origin. Correct assessment of pain intensity and frequency, as well as of the probable causes of pain, and the administration of adequate analgesic treatment should achieve satisfactory results in the vast majority of patients. Every physician should obtain detailed knowledge of the indications and adequate administration of pain-killing therapy as well as possible adverse effects and their successful treatment. It is important in particular to concentrate on a few nonsteroidal anti-inflammatory drugs (NSAIDs) as well as opiates. Knowledge of adequate doses, maximal recommended daily doses, pharmacological properties, important adverse effects and interactions is essential for success in the daily routine. Only by selecting 2 or 3 drugs from each step in the analgesic ladder (WHO) will the nonspecialised physician obtain sufficient experience for optimal analgesia. Physicians should also not hesitate to contact other specialists (medical oncologists, radiotherapists, neurosurgeons, anaesthesiologists and others) in order to maximise benefit for an individual patient.     

Increased airway osmolarity inhibits the action of nitric oxide in the rabbit

Retractile mesenteritis is a rare inflammatory mesenteric disorder that involves the intestine secondarily. The natural history of this process is diverse, but most patients require some empiric therapeutic measures. Up to now, pharmacological therapy has included corticosteroids, colchicine, and immunosuppressive drugs. Although these drugs are successful in most patients, some have been refractory to these therapies and, in others, the beneficial effects were counterbalanced by adverse reactions. Many patients require surgery, but most have poor results. This report describes a 42-year-old man with histologically proven retractile mesenteritis refractory to surgical intervention who had a good response to oral progesterone (10 mg/day for 6 months) with complete disappearance of tumor mass and clinical symptoms. No adverse effects were detected. Current knowledge about the mechanism by which progesterone affects fibrogenesis is scanty. It seems likely that progesterone down-regulates proliferation and metabolism of fibroblasts and fibrogenesis.     

Indications for, and use of, cytotoxic agents in SLE

Over the past decade, cytotoxic drugs have come to assume an increasingly important role in the management of systemic lupus erythematosus. Intravenous cyclophosphamide has become the standard treatment for lupus affecting major organs, in particular lupus nephritis. Cytotoxics with less potential for adverse side effects such as azathioprine and methotrexate are widely used in the management of non-major organ lupus and as an adjunct to reduce corticosteroid requirements. Recent clinical experience in lupus with newer cytotoxic drugs such as cyclosporin A, adenosine analogues, and mycophenolate mofetil appear promising and may offer improvements in lupus management in the future.     

Adverse effects of fertility drugs

Ovulation-induction agents are commonly used in the treatment of infertility in patients with or without ovulatory disturbances. These agents include clomifene, bromocriptine, gonadotrophin preparations and gonadotrophin-releasing hormone (GnRH) and its analogues. Each agent is associated with its own specific adverse effects. Although many of these adverse effects are benign and self-limited, some, in particular those effects associated with gonadotrophins, may be life-threatening. Commonly noted adverse effects encountered with the use of pharmacological agents to treat infertility include the following. Clomifene has been associated with hot flushes, multiple gestation, visual disturbances, cervical mucus abnormalities and luteal phase deficiency. Similarly, most of the adverse symptoms associated with bromocriptine are short-lived, such as nausea and postural hypotension. On the other hand, gonadotrophin therapy, even when used appropriately, may lead to the ovarian hyperstimulation syndrome (which is occasionally life-threatening) and a high incidence of multiple gestation. Pulsatile GnRH therapy maybe accompanied by similar adverse effects to those of gonadotrophins, but with a far lower incidence. With regards to the long term safety of these medications, the relationship between fertility drugs and epithelial ovarian cancer is controversial, and causality has yet to be proven. Indeed, a working knowledge of the many adverse effects associated with these medications is essential to any physician prescribing ovulation induction agents, in order to ensure maximum patient safety, compliance and understanding.     

How often and what type of control tests should be done during long- term anti-epileptic treatment?

During long-term epileptic treatment, it is essential to monitor the efficacy of the drugs used. Any adverse effects of this treatment must be detected early or preferably avoided. However, the type of control and the frequency with which this should be carried out are controversial. All anti-epileptic drugs are potentially liable to provoke adverse reactions of different types and degrees. Determinations of the blood-levels of anti-epileptic drugs are useful to attain optimus drug levels, and to identify any relationship there might be between these drugs and possible adverse effects. However, this usefulness varies, depending on the particular anti-epileptic drug concerned. Therefore measurement as a routine is not justified, but should be undertaken to obtain the answer to specific questions. Laboratory analysis of blood to determine liver function, blood cell counts, coagulation, etc. is necessary in some cases. This may imply problems of interpretation and of cost. Is most cases it is of little help in the early detection or prevention of the most serious adverse reactions, which cause the greatest mortality. Therefore although such measures are necessary, attention should be paid to clinical methods for the early detection of symptoms and signs which may indicate the presence of adverse effects. Similarly, EEG should not be done as a routine for the assessment of the effect of treatment, but should be used when indicated for the follow-up of specific epileptic syndromes. An EEG may be useful for prognosis before suspending long-term epileptic treatment.     

Dose-related adverse effects of anticonvulsants

The serum concentration at which a given drug has full efficacy in delivering seizure control bears no predictable relationship to the concentration at which adverse effects will appear. In theory, the threshold for adverse effects should be considerably higher than that for efficacy. For each agent this obviously happens most of the time, or the anticonvulsant would not be on the market, but there are also patients in whom this relationship is reversed. The adverse effects of this class of drugs are discussed from three points of view: the adverse effect type, the kinetic factors that so frequently determine the presence of adverse effects, and the specific characteristics of each drug. Some less well recognized adverse effects syndromes that are not strictly dose related are considered. The importance of adverse effects in therapeutic monitoring is then addressed, and some strategies for maximising efficacy without the burden of long term functional impairment or distress are discussed. The usefulness of monotherapy is stressed with due attention to rational choice of second drugs, when necessary, based on mechanisms of antiepileptic action and adverse effects profiles. While most of these symptoms evolve gradually, there are times when acute, drastic, and even life threatening clinical overdose situations present themselves. Special attention is given to these scenarios, drawing on the drug profiles and clinical pharmacokinetics that define these events to propose methods of coping with the problems efficiently and effectively.     

Ergot alkaloids. Current status and review of clinical pharmacology and therapeutic use compared with other oxytocics in obstetrics and gynaecology

Ergot alkaloids are well known preparations. Ergot alkaloids used in obstetrics and gynaecology are ergometrine (ergonovine; EM), methylergometrine (methergine; ME) and bromocriptine. The pharmaceutical properties of ME EM) are critical. To guarantee stability, ME and EM ampoules should be stored in a cool, dark place. ME and EM tablets are unstable in all conditions and they show an unpredictable bioavailability, which prevents oral use of the drugs for any purpose. ME and EM are known for their strong uterotonic effect and, compared with other ergot alkaloids, for their relatively slight vasoconstrictive abilities. ME and EM do have a place in the management of the third stage of labour as they are strong uterotonics. They act differently from oxytocin and prostaglandins, and have different adverse effects. Oxytocin should be used as prophylaxis or a the drug of first choice; next, ME or EM should be used, and if none of these drugs produce the desired effects, prostaglandins should be used to control bleeding. Ergot alkaloid use in gynaecology has been limited and today is discouraged even in essential menorrhagia. It is suggested that EM and ME be used (parenterally) only in first trimester abortion curettage, to reduce blood loss. Bromocriptine has been used for lactation suppression. However, alternatives such as cabergoline, which possess fewer adverse effects, are now available and therefore preferred for this indication. In sum, there is no place for the prophylactic use of ME and EM in obstetrics or gynaecology. They can be used for therapeutic purposes in the third stage of labour. During use, the practitioner must be alert for adverse effects.     

Practical treatment guide for dose individualisation in cancer chemotherapy

Dosages of anticancer drugs are usually calculated on the basis of a uniform standard, the body surface area (BSA). Although many physiological functions are proportionate to BSA, overall drug clearance is only partially related to this parameter. Consequently, following administration of equivalent drug dosages based on BSA, a wide variability in plasma drug concentrations can be found between patients, as a result of which some patients experience little toxicity while others may show severe toxic symptoms. A clear pharmacokinetic/pharmacodynamic correlation has been demonstrated for some anticancer drugs, and this relationship provides a background against which rational dose optimisation can be implemented for individual patients. The 3 strategies that can be employed for optimising dosage regimens, none based on BSA, are described and criticised. A priori adaptive dosage determination is based on the relative contribution of identifiable characteristics of patient, drug therapy and disease state that influence plasma drug concentrations; the dosage regimen is based on each patient's profile with regard to these characteristics. Although this approach is most successful with drugs whose clearance is closely tied to renal function, patient characteristics such age, obesity, serum albumin or hepatic function may be useful. The anticancer drug most closely identified with this approach is carboplatin, although dosage reduction strategies for etoposide, taxanes, anthracyclines, topotecan, oxazaphosphorines, vinca alkaloids or melphalan are advocated for patients with renal or hepatic dysfunction. The importance of pharmacogenetics for fluorouracil and mercaptopurine is also briefly discussed. The second approach consists of adaptive dosage adjustments during repetitive or continuous administration of a drug. It has been used for several years to administer methotrexate therapy and, more recently, it has been developed more fully and applied to continuous infusion of fluorouracil or etoposide. It was based, after determination of a target plasma concentration or area under the plasma drug concentration-time curve (AUC), on modification of the drug dosage during the cycle of chemotherapy or for the next cycle. Finally, the third approach of adaptive dosage adjustment with feedback control, based on population pharmacokinetics, with limited sampling strategy, may allow a feedback revision of the dosage following measurement of plasma drug concentration and comparison with the population previously studied. This approach is a theoretical strategy which has not, until now, been used prospectively in clinical oncology. For drugs such as anticancer agents with a very narrow therapeutic index, every effort should be made to minimise interpatient variability in drug exposure in order to maximise the benefit while keeping the risk of serious adverse effects at an acceptable level. This is particularly important when treatment is being given with curative intent.     

Drug management of hypertensive disorders of pregnancy

Drugs used in the acute and long-term management of hypertension in pregnancy and the preeclampsia-eclampsia syndrome have been reviewed and their therapeutic effects and maternal and fetal adverse effects have been considered. The review also focuses on recent developments in the areas of prevention and management of pre-eclampsia-eclampsia syndrome. Although a number of new drugs have emerged, as potentially useful in the management of hypertension in pregnancy and pre-eclampsia-eclampsia syndrome, some remain at the cornerstone of therapy; for example, methyldopa for long-term treatment of chronic hypertension, hydralazine or nifedipine for rapid reduction of severely elevated blood pressure, and magnesium sulphate for eclampsia. Some of these agents, especially the calcium antagonists, show promise in that their use is associated with fewer side effects. Safety for the fetus, however, has not been adequately evaluated yet. Neither aspirin nor calcium supplements appear to improve the outcome in pregnancy. Currently, the dilemma whether to treat hypertension in pregnancy and pre-eclampsia-eclampsia syndrome with old, established, cost-effective drugs or the promising newer drugs provides an interesting academic challenge.     

Pathophysiology and treatment of painful diabetic neuropathy of the lower extremity

BACKGROUND: Symptomatic peripheral neuropathy is the most common complication of diabetes mellitus, affecting up to 62% of Americans with diabetes. METHODS: We reviewed the literature using the National Library of Medicine's MEDLINE search service. In total, we reviewed 54 articles. RESULTS: Hyperglycemia leads to increased activity in the polyol pathway in nerve cells; this ultimately results in abnormal nerve function. Numerous pharmacologic agents have been used to treat symptomatic peripheral neuropathy, but all of these drugs can be associated with adverse side effects. Recent work has indicated that subsensory electrical stimulation may be preferred to pharmacotherapy, since it is equally effective and has a more favorable safety profile. CONCLUSION: Although the pathophysiology of diabetic neuropathy is well understood, treatment of the symptoms associated with this condition can be challenging. Additional research is needed to reveal a safe and effective treatment for this debilitating sequela of diabetes mellitus.     

The risks and costs of upper gastrointestinal disease attributable to NSAIDs

NSAIDs, including both aspirin and nonaspirin NSAIDs, are among the most frequently used drugs, and their use may result in serious adverse gastrointestinal outcomes and significant medical costs. The increased risks for adverse upper GI hemorrhage and peptic ulcer disease associated with NSAID use have been demonstrated in observational studies and clinical trials; an overview of these results is presented in this article. The magnitude of these risks should play an important role in clinical decision making and should influence decisions regarding the use of this class of drugs.     

Adverse effects of direct-acting vasodilators

Direct-acting vasodilating agents enter the vascular smooth muscle cell to cause vasodilatation. For long term treatment of hypertension, the use of these drugs as monotherapy is accompanied by activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system. These counteracting mechanisms limit the antihypertensive efficacy of these drugs, and cause adverse effects such as tachycardia and fluid retention. These adverse effects require treatment with beta-blockers and diuretics. However, there is still an important role for intravenous vasodilator therapy in hypertensive emergencies. In the treatment of chronic heart failure, vasodilator therapy has been an important advance. Combination therapy with hydralazine and nitrates is efficacious in improving survival, but ACE inhibitors have an incremental benefit on survival over this combination.     

Use of carprofen for the treatment of pain and inflammation in dogs

Most studies of nonsteroidal anti-inflammatory drugs (NSAID) do not demonstrate appreciable differences in efficacy. As awareness of the adverse effects associated with NSAID use increases, safety is becoming the primary concern among physicians when selecting NSAID for use by their human patients. However, veterinarians may be less aware of the safety concerns associated with NSAID use. A wide range of NSAID is used to treat human beings with osteoarthrits; however, it is imperative to remember that dogs are especially sensitive to these drugs, and reports of serious, and occasionally fatal, complications are numerous. Carprofen is a propionic acid-derived NSAID that has anti-inflammatory, analgesic, and antipyretic activity. In animals, carprofen is as potent as indomethacina and more potent than aspirin or phenlbutazone, but carprofen appears to be safer than most other NSAID.     

Update on prevention of malaria for travelers

Individuals from industrialized nations frequently travel to countries with malaria, so health care providers need to be familiar with current recommendations for prevention of malaria. Changes in drug susceptibility of malaria parasites and evolving knowledge of how well drugs are tolerated necessitate periodic review of guidelines for prophylaxis of malaria, especially of chloroquine-resistant Plasmodium falciparum malaria. Mefloquine is the drug of choice for chemoprophylaxis for most travelers, with doxycycline and chloroquine being less effective alternatives. Mefloquine is well tolerated at prophylactic dosages, but anecdotal reports have raised concerns about its adverse effects. Resistance to this drug has emerged in parts of Southeast Asia and may spread to other regions of the world. The major disadvantages of doxycycline are the need for daily dosing, its contraindication for young children and pregnant women, and its adverse effects. Chloroquine is effective for prophylaxis only in Central America, the Caribbean, and parts of the Middle East. Few new drugs will be available in the near future because of reduced funding for antimalarial drug research and development; therefore, the usefulness of currently available drugs needs to be prolonged by rational use. Increased efforts should be made to ensure that alternative drugs will be available for prevention of malaria.     

Adverse effects of local use of beta-blockaders in glaucoma. A literature review and a survey of reports to the adverse drug reaction authority 1986-95

The review is based on a survey of studies on adverse reactions related to topical administration of beta-blockers for glaucoma. Locally applied beta-blocking agents are partially resorbed from the nasal mucosa. Concentrations which give rise to systemic effects occur invariably. Several reports exist of congestive heart failure, arrhythmias, severe respiratory symptoms, depression, hallucinations and confusion provoked by topical use of beta-blockers, especially timolol. It is impossible to estimate from the literature how often the various adverse effects occur. One has the impression, however, that adverse effects in the pulmonary and central nervous systems have not been fully considered. Between 1986 and 1995 the Norwegian Medicines Control Authority received reports on adverse reactions related to topical use of beta-blockers in 17 patients. Six of these patients had cardiovascular and four of them severe respiratory symptoms. The latter group also included three fatal cases. The adverse effects seem to occur most frequently in the elderly, and it has been suggested that timolol should not be used in elderly people. Adverse effects related to treatment with topical beta-blockers are probably underreported in Norway.     

Epidemiology and treatment of post-stroke depression

Depression is a common and serious complication after stroke. According to epidemiological studies, at least 30% of stroke patients experience depression, both early and late after stroke. However, in clinical practice only a minority of the patients are diagnosed and even fewer are treated. There are several studies confirming the magnitude of the problem but the main conclusion which can be drawn from the few treatment studies published is that tricyclic antidepressants cannot be recommended for the treatment of post-stroke depression, mainly because of the high frequency of contraindications and adverse effects. Until now there has only been 1 double-blind, placebo-controlled treatment study from which some general conclusions can be drawn. The study evaluated a selective serotonin reuptake inhibitor (citalopram) and concluded that the drug was well tolerated and effective for the treatment of post-stroke depression. However, when treatment was initiated very early, both the treatment group and the placebo group improved equally during the first 7 weeks after stroke. This finding could indicate diagnosis difficulties during the first few weeks after stroke. A recent study, although small, comparing the combination of drugs with either noradrenergic (desipramine plus mianserin) or noradrenergic and serotonergic effects (imipramine plus mianserin) for post-stroke depression, indicated that drugs with the dual effect may be more effective. Many more double-blind placebo-controlled treatment studies and studies comparing the efficacy and adverse effects of various antidepressants in patients with post-stroke depression need to be conducted. According to 3 small studies, electroconvulsive therapy (ECT) seems to be quite well tolerated and therefore ECT may also be considered in the treatment of post-stroke depression. Future studies should also address the long term efficacy of treatment for post-stroke depression.     

New non-steroidal anti-rheumatic drugs: selective inhibitors of inducible cyclooxygenase

MODE OF ACTION OF NON-STEROIDAL ANTI-INFLAMMATORY DRUGS: Non-steroidal anti-inflammatory drugs (NSAID) exert their major therapeutic and adverse effects by inhibition of prostanoid synthesis. Also the interactions with antihypertensive drugs and lithium are caused by this mechanism of action. Cyclooxygenation is a key enzymatic step in the synthesis of prostanoids. 1990 2 isoforms of the enzyme cyclooxygenase have been identified: Prostanoids synthesized by the constitutive cyclooxygenase (COX-1) are involved in physiological homeostasis. In contrast, the inducible cyclooxygenase (COX-2) produces large amounts of prostanoids, mainly contributing to the pathophysiological process of inflammation. COX-2 SELECTIVE NSAID: The discovery of the cyclooxgenase-isoenzymes ushered in a new generation of NSAID: A drug with selectivity for COX-2 would inhibit proinflammatory prostanoid synthesis while sparing physiologic prostanoid synthesis. Thus, a selective COX-2 inhibitor should be anti-inflammatory with less or no gastrointestinal or other NSAID-typical adverse effects. The experiences with currently used NSAID, which show an increasing incidence of side effects as COX-1 inhibition increases, and studies with the COX-2 selective NSAID salsalate and meloxicam, which have less adverse effects than nonselective COX inhibitors in equivalent antiphlogistic dosage, prove the concept of selective COX-2 inhibition to avoid the NSAID typical side effects. Newly developed drugs with a very high selectivity for COX-2 are now tested in clinical trials. CONCLUSION: So far the results suggest, that selective and highly selective COX-2 inhibitors have significantly fewer gastrointestinal and renal adverse effects and do not inhibit platelet aggregation.     

Is there a future for antiarrhythmic drug therapy?

Drug therapy has traditionally been the mainstay of treatment for both ventricular and supraventricular arrhythmias. However, increasing knowledge about the potentially significant adverse effects of these medications, together with the emergence of new, nonpharmacological approaches to the treatment of arrhythmias, has led some to question the future of antiarrhythmic drug therapy. Antiarrhythmic drugs are quite effective in terminating a variety of arrhythmias, including atrioventricular (AV) node re-entrant and AV tachycardias (particularly calcium antagonists and adenosine), atrial flutter (class III agents) and atrial fibrillation (class IA and IC drugs. The chronic use of antiarrhythmic drugs has been increasingly limited by a fear of adverse effects (especially proarrhythmia) and the availability of highly effective nonpharmacological alternatives (particularly ablation for re-entrant tachycardias involving the AV node and bypass tracts and cardiovertor/defibrillators for malignant ventricular arrhythmias. Atrial fibrillation (AF) continues to be a therapeutic challenge for which there is no safe and curative nonpharmacological therapy. Antiarrhythmic drugs of classes IA, IC and III show efficacy in preventing recurrence of AF but there are concerns about possible pro-arrhythmic complications. In the future, antiarrhythmic agents will continue to be used acutely to terminate a broad range of sustained arrhythmias. Chronic use is likely to depend on the development of safer and/or more effective compounds, as well as on improved ways of predicting which patients are likely to develop pro-arrhythmic reactions. The development of molecular electrophysiology will allow for the identification of agents with selected ion channel blocking profiles which may prove efficacious with a lower risk of complications. Finally, an improved understanding of arrhythmia substrates may permit the identification of therapy that prevents arrhythmias by acting on the underlying substrate, rather than simply trying to modify the electrical end product.     

Treatment of inflammatory rheumatic disorders in pregnancy: what are the safest treatment options?

The interaction of pregnancy and the rheumatic diseases varies, ranging from life-threatening conditions such as thromboembolic events and progressive renal disease in some autoimmune disorders, to minor flares of peripheral arthritis in inflammatory rheumatic disease. As a consequence, treatment strategy will vary according to the maternal or fetal compromise expected. All nonsteroidal anti-inflammatory drugs (NSAIDs), including high dose aspirin (acetylsalicylic acid), can cause adverse effects during pregnancy related to the inhibition of prostaglandin synthesis. Prolongation of gestation and labour, constriction of the ductus arteriosus, persistent fetal circulation, impairment of renal function and bleeding are risks of third trimester exposure of pregnant women to all inhibitors of cyclo-oxygenase. Most of these adverse effects can be prevented by discontinuing NSAIDs 8 weeks prior to delivery. Low dose aspirin has not been associated with fetal or neonatal toxicity. Some corticosteroids such as prednisone and prednisolone do not readily cross the placenta and can be safely used during pregnancy as immunosuppressive drugs. Maternal complications related to corticosteroids may occur and close monitoring is therefore mandatory. There is limited information on the safety of disease-modifying antirheumatic drugs including gold, antimalarials, penicillamine (D-penicillamine), sulfasalazine and cyclosporin. Of these agents, sulfasalazine has the best record for tolerability and can be used by pregnant patients. Gold compounds and penicillamine should be discontinued when pregnancy is recognised. Hydroxychloroquine has not been associated with congenital malformations and seems preferable to chloroquine in patients requiring treatment with antimalarials. Use of cyclosporin may be an alternative to other therapy in pregnant patients with severe rheumatic disease. Indications for treatment with colchicine during pregnancy are few, except for familial Mediterranean fever. Azathioprine can be used when the maternal condition requires a cytotoxic drug during the first trimester. Cyclophosphamide, chlorambucil and methotrexate are contraindicated during pregnancy because of their teratogenic potential. Their use may be considered in late pregnancy if the mother has a life-threatening condition.