By Y. Umul. University of La Vernee.

In vitro tests show imipenem to act synergistically with aminoglycoside antibiotics against some isolates of Pseudomonas aeruginosa order urispas 200mg line muscle relaxant and tylenol 3. Imipenem has been shown to be active against most strains of the following microorganisms discount urispas 200 mg amex spasms 1983 trailer, both in vitro and in clinical infections. Escherichia coli Gardnerella vaginalis Haemophilus influenzae Haemophilus parainfluenzae Klebsiella spp. Therefore, it is important to consider this diagnosis in patients who present with diarrhoea subsequent to the administration of antibacterial agents. These drugs should not be used concomitantly unless the potential benefits outweigh the risks. Gastrointestinal: Pseudomembranous colitis, diarrhoea, nausea, vomiting, haemorrhagic colitis, hepatitis (including fulminant hepatitis), jaundice, gastroenteritis, abdominal pain, glossitis, tongue papillar hypertrophy, staining of the teeth and/or tongue, heartburn, pharyngeal pain, increased salivation. Haematologic: Pancytopaenia, bone marrow depression, thrombocytopaenia, neutropaenia, leukopaenia, haemolytic anaemia. Skin: Stevens-Johnson syndrome, toxic epidermal necrolysis, erythema multiforme, angioneurotic edema, flushing, cyanosis, hyperhidrosis, skin texture changes, candidiasis, pruritus vulvae. In a severe attack administer every 20 minutes for 3 doses then administer 4 to 6 hourly after that. Inhaled medicines, including ipratropium bromide, may cause paradoxical bronchospasm. Bradycardia Note: current international guidelines do not recommend isoprenaline as the first line agent to treat any condition. Contains sulfite Contains sodium metabisulfite, a sulfite that may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. This may be gradually increased if necessary while carefully monitoring the patient. Doses sufficient to increase the heart rate to more than 130 beats per minute may increase the likelihood of inducing ventricular arrhythmias. Such increases in heart rate will also tend to increase cardiac work and oxygen requirements which may adversely affect the failing heart or the heart with a significant degree of arteriosclerosis. Particular caution is necessary in administering isoprenaline to patients with coronary artery disease, coronary insufficiency, diabetes, hyperthyroidism, and sensitivity to sympathomimetic amines. Cardiovascular: Tachycardia, palpitations, angina, Adams-Stokes attacks, pulmonary oedema, hypertension, hypotension, ventricular arrhythmias, tachyarrhythmias. Other: Flushing of the skin, sweating, mild tremors, weakness Isoprenaline Hydrochloride! Cardiovascular: Blood pressure and pulse rate are frequently elevated following administration of ketamine. Respiratory: Although respiration is frequently stimulated, severe depression of respiration or apnea may occur following rapid intravenous administration of high doses of ketamine. Laryngospasms and other forms of airway obstruction have occurred during ketamine anaesthesia. Neurological: In some patients, enhanced skeletal muscle tone may be manifested by tonic and clonic movements sometimes resembling seizures Gastrointestinal: Anorexia, nausea and vomiting have been observed; however this is not usually severe Ketamine! Labetalol is completely absorbed from the gastrointestinal tract with peak plasma levels occurring 1-2 hours after oral administration. Despite "first-pass" metabolism there is a linear relationship between oral doses of 100-3000 mg and peak plasma levels. The absolute bioavailability of labetalol is increased when administered with food. The hepatic injury is usually reversible, but hepatic necrosis and death have been reported. Cardiac Failure Sympathetic stimulation is necessary in supporting circulatory function in congestive heart failure, and beta blockade carries the potential hazard of further depressing myocardial contractility and precipitating more severe failure. Discontinuation of therapy Discontinuation of therapy in a patient with coronary artery disease may lead to rebound angina, arrhythmia or myocardial infarction. Diabetes and Hypoglycaemia Beta blockers may mask tachycardia occurring with hypoglycaemia.

Biological activity and characteristics of triamcinolone-acetonide for- mulated with the self-regulating drug carriers buy discount urispas 200mg spasms and cramps, Transfersomes (R) discount urispas 200mg with visa muscle relaxant generic. Ultraflexible vesicles, Transfersomes, have an extremely low pore penetration resistance and transport therapeutic amounts of insulin across the intact mammalian skin. Transdermal immunization with large proteins by means of ultradeformable drug carriers. Transdermal immunisation with an integral membrane component, gap junction protein, by means of ultradeformable drug carriers, Transfer- somes. Formulation of interleukin-2 and interferon-alpha con- taining ultradeformable carriers for potential transdermal application. The effect of cholate on solubilisation and permeability of simple and protein-loaded phosphatidylcholine/sodium cholate mixed aggregates designed to mediate transdermal delivery of macromolecules. Permeabilisation and solubilisation of soybean phosphatidylcholine bilayer vesicles, as membrane models, by polysorbate, Tween 80. Anti-inflammatory effects of locally applied enzyme-loaded ultradeformable vesicles on an acute cutaneous model. Ethosomes – Novel vesicular carriers for enhanced delivery: Characterization and skin penetration properties. A clinical evaluation of a novel liposomal carrier for acyclovir in the topical treatment of recurrent herpes labialis. Interactions of elastic and rigid vesicles with human skin in vitro: Electron microscopy and two-photon excitation microscopy. The in vivo and in vitro interactions of elastic and rigid Vesicles with human skin. Liposomal recombinant human superoxide dismutase for the treatment of Peyronie’s disease: A randomized placebo-controlled double-blind prospective clinical study. Genes are introduced into cells or tissues either to inhibit undesirable gene expression or to express therapeutic proteins (3). Target disease states for gene delivery can be broadly categorized into two major classes: inherited and acquired. The two standard procedures used in gene delivery are addition/replacement and ablation (4). While performing the former, a normal gene is introduced into the cell type to replace activity of the defective gene (4). Whether one performs ex vivo or in vivo gene therapy, important focal points are duration of expression of the gene or therapeutic protein and specificity in deliv- ering the gene to the site of action with minimal adverse effects (1–3). Currently, genes packaged in viral vectors, such as retrovirus, adenovirus, adeno-associated virus, and herpes simplex virus, remain the leading therapeutic candidates for gene therapy, as they have produced functional improvements in several animal models of previously mentioned genetic diseased states. However, because of the risk fac- tors (pathogenicity, immunogenicity) associated with viral vectors, a major empha- sis has been placed on the formulation of nanoparticulate drug delivery vehicles for gene delivery (3). The term “nanometer” in the metric scale of linear measurement refers to one- billionth of a meter. According to National Nanotechnology Initiative, nanotechnol- ogy is defined as research and technology resulting in “the controlled creation and usage” of unique small particles, varying from 1 to 100 nm in length. Looking at the biological systems, it is evident that they are composed of inherent “nanoblocks. This chapter focuses on the formulation of nanoparticulate drug delivery systems for gene delivery. The gene-loaded gold nanoparticles target the cells at a critical velocity that can puncture the cell membrane, and ultimately release the genes into the cell nucleus (9). This method, which involves physical transfer of genes, has the potential to replace the traditional transfection techniques characterized by dismal efficiency rates and immunotoxicity (9). It is to be noted, however, that original gene gun suffers from lack of precision and can crush the cells due to “sticking of gold par- ticles (pit damage)”. To overcome these pitfalls, Pui and Chen’s laboratory, at Uni- versity of Minnesota, devised a similar gene gun by using the patented technique called “continuous gene transfection” (9). As reported by Pui and Chen, the gold particle–coated gene composite is loaded into a capillary with the help of a syringe. The applied electric field forces the gene suspension or spray out of the capillary at a constant velocity. The suspension is a complex mixture of “highly charged and dispersed gene-coated particles” (9).

Clinically important drug interactions • Drugs that increase effects/toxicity of valproic acid: aspirin order 200 mg urispas spasms in back, alcohol discount 200 mg urispas visa muscle relaxant otc cvs, felbamate, rifampin, diazepam. Perform platelet counts and coagulation tests before initiating therapy and periodically thereafter. Food: Advise patients to limit foods containing potassium: salt substitutes, orange juice, bananas. Contraindications: Hypersensitivity to valsartan, anuria, hyper- sensitivity to sulfonamides (thiazide diuretics, oral hypo- glycemic drugs). Adjustment of dosage • Kidney disease: Creatinine clearance 40–90 mL/min: admin- ister q24h; creatinine clearance 10–20 mL/min: administer q96h; creatinine clearance <10 mL/min: administer 5–7 days. Warnings/precautions • Use with caution in patients with: hearing impairment, intes- tinal obstruction, and in patients receiving other potentially nephrotoxic or ototoxic drugs, kidney disease, elderly. Adverse reactions • Common: nausea, vomiting, taste disturbances, rash on face and upper body (parenteral administration). Clinically important drug interactions: Vancomycin increases effects/toxicity of aspirin, aminoglycosides, cyclosporine, loop diuretics, nondepolarizing neuromuscular blockers, general anesthetics. If extrava- sation is suspected, remove catheter and discontinue adminis- tration. It is used to treat entero- coccal infections resistant to ampicillin, preferable in combination with an aminoglycoside. Contraindications: Chronic nephritis (until controlled), hyper- sensitivity to beef/pork proteins, hypersensitivity to vasopressin, coronary artery disease, angina pectoris. Warnings/precautions • Use with caution in patients with seizures, asthma, migraine, heart failure, goiter, atherosclerosis. Adverse reactions • Common: hypertension, headache, fever, skin pallor, tremor, abdominal cramps, nausea, diaphoresis. Clinically important drug interactions • Drugs that increase effects/toxicity of vasopressin: carbamaze- pine, clofibrate, chloropropamide, ganglionic blockers, fludro- cortisone, phenformin, urea. Parameters to monitor • Intake of fluids and urinary and other fluid output to minimize renal toxicity. Editorial comments • Physician should be advised that dosage for treating diabetes insipidus is highly variable. Adjustment of dosage • Kidney disease: Mild to moderate: reduce dose by 25%; severe: reduce dose by 50%. Increase to 240 mg in morning and 120 mg in evening and then 240 mg q12h if needed. Sit at the edge of the bed for several minutes before standing, and lie down if feeling faint or dizzy. Clinically important drug interactions • Drugs that increase effects/toxicity of calcium blockers: cimet- idine, β blockers, cyclosporine. Impaired renal function prolongs duration of action and increases tendency for toxicity. If anginal pain is not reduced at rest or during effort, reassess patient as to medication. If reepithelialization has not occurred in 21 days, other therapy should be considered. Adverse reactions • Common: lacrimation, irritation, infection of the conjunctiva. Editorial comments • May be administered together with topical gentamicin, eryth- romycin, and chloramphenicol. Mechanism of action: Disrupts cell division in metaphase by inhibition of microtubule formation. Warnings/precautions • Use with caution in patients with decreased bone marrow reserve, liver disease. Decrease doses in patients receiving other chemotherapy or with recent radiation therapy. Advice to patient • Use two forms of birth control including hormonal and barrier methods. Clinically important drug interaction • Drugs that increase effects/toxicity of vinblastine: antineo- plastic agents (cause bone marrow suppression), mitomycin (bronchospasm), erythromycin, ritonavir. If a medication-induced neuropathy is suspected, discontinue treatment immediately.

They emphasized psychoanalytic concepts discount urispas 200mg with amex spasms gums, such as resistance to regression and modes of handling primary process material order urispas 200mg with visa muscle relaxant 1. Fourteen subjects were rated for the maturity with which they handled primary process as manifested in Rorschach test responses. Their verbal behavior during eight hours of isolation and -70- postisolation interview was then assessed by a scheme of content analysis which stressed modes of dealing with primary process material. In the first of these, subjects engaged in a variety of behaviors within the limits set by the situation and instructions. They talked freely, experienced pleasurable affect, little unpleasant affect, thought rationally, and engaged in daydreams, fantasy, and playful thinking without being threatened by the situation. In the second reaction pattern, there was unpleasant affect, anxiety-laden intrusions of the primary process, preoccupation with terminating the experiment, and impaired efficiency in rational or secondary process thinking. They found these two reaction patterns to be significantly correlated in the expected direction with the Rorschach measure of maturity of handling primary process materials. Those who on the Rorschach handled primary process in a mature and effective way were those who reacted in an adaptive way to isolation. Conversely, those who on the Rorschach handled primary process with poor control or avoided it reacted negatively to isolation. This finding is consistent with several others which point to the exaggeration of usual personality defenses under the stress of isolation (18, 56, 65). An overview of these data emphasizes the truism of marked individuality of response. Whether differences observed among various studies is a systematic function of varying experimental conditions is as yet unclear. The findings on suggestibility as a personality attribute and those on the relationship to satiation and pain thresholds remain conceptually unrelated to the other work. The Goldberger and Holt demonstration of relationships between preisolation personality attributes and the content of response to isolation is a carefully executed study which has a clear theoretical orientation and makes complex but reliable assessments of verbal and other behavior. Other studies have tended toward utilization of too simplified an index of response such as length of stay which fails to take into account complex behavior during the isolation situation. It may well be that personality variables and their interrelationships are insufficiently reflected in such a simple measure of tolerance for isolation. Thus specification of terms such as "schizoid" and "withdrawn" may have more meaning, permit replication of procedures, and evaluation of results. Although some of this difficulty in the present studies stems from their preliminary nature, there appears to be some insensitivity to the need for both conceptual and operational specification of measurement and assessment techniques. Progress with the problem of personnel selection and utilization for a variety of tasks, as well as theoretical clarification, awaits such refinement in research programs. Feeling States Changes in subjective feeling in response to reduced environmental input has been a common observation in these studies. These observations range over many different experimental conditions, from the uniform visual stimulation presented by W. Cohen (19) in which the pattern of input to one modality is reduced, to sensory deprivation in the water tank suspension procedure used by Lilly (50) and Cambareri (16), where the effort is made at a total reduction of sensory input. They also noted the presence of headaches, fatigue, and mild nausea, persisting in some cases for twenty-four hours after confinement. Lilly (50) whose subjects both had a number of trial exposures to the situation in order to get used to it found in the actual situation early feelings of relaxation and enjoyment, followed by tension, restlessness, and an extremely heightened awareness of residual stimulation. This course continued into fantasy and reverie, and finally into the projection of visual imagery. Following the isolation experience, subjects reported a sense of refreshment as though having just awakened from sleep. Camberari (16), on the other hand, utilizing a similar procedure without preliminary exposures, found no such progressive stages, and subjects came out of the immersion feeling fatigued rather than rested. Suggestible subjects felt secure during most of their stay in the tank, although there were some reports of apprehension, fear, and panic. The nonsuggestible subjects generally tended to deny any affective or emotional involvement. Cohen (19) found that his subjects had feelings of drowsiness, excessive yawning, and their voices took on a hesitant, drawling quality. In a study of perceptual deprivation, Hebb, Heath, and Stuart (38) reported that subjects who wore earplugs for three consecutive days while going about their normal activities showed slight to marked irritability, seclusiveness, and personality disturbances not due to discomfort. One subject manifested poor speech coordination while in the experimental conditions.

Improvement in sexual dys- function is seen in the majority of patients with long-term use generic urispas 200 mg mastercard muscle relaxant vs painkiller. Adjustment of dosage • Kidney disease: Creatinine clearance <10 mL/min: decrease dose by 25–50% urispas 200 mg sale muscle relaxant football commercial. Adjustment of dosage in hepatic disease has not been fully evaluated; it is recommended to monitor flecainide plasma levels because of significantly increased half-life. Onset of Action Duration 1–6 h 12–30 h Food: Foods that increase urinary pH may cause increased levels of flecainide in patients on a strict vegetarian diet. Foods or bev- erages such as acidic juices that lower urinary pH may decrease effectiveness of flecainide. Advice to patient • Notify dentist or treating physician prior to surgery if taking this medication. Clinically important drug interactions • Drugs that increase effects/toxicity of flecainide: β blockers, amiodarone, disopyramide, verapamil, cimetidine, high-dose antacids, carbonic anhydrase inhibitors. Parameters to monitor • Determine serum levels of flecainide, particularly in patients with kidney or liver impairment. Trough levels are particularly important; the probability of adverse reactions increases greatly if this level is >1 µg/mL. Editorial comments • Flecainide is suited for patients with symptomatic and persist- ent atrial fibrillation and atrial tachycardias that are refractory to radiofrequency ablation. Patients must have a structually normal heart and be monitored closely for side effects and effi- cacy. Warnings/precautions • Use with caution in patients with the following conditions: kidney, liver disease, high dose pelvic radiation, akylating anti- neoplastic drugs. Advice to patients • Use good mouth care to avoid adverse reactions in the oral cavity. Editorial comments • Use latex gloves and safety glasses when handling cytotoxic drugs. Mechanism of action: Inhibits fungal cytochrome P450 synthe- sis of ergosterol, resulting in decreased cell wall integrity and leakage of essential cellular components. Start fluconazole several days before the anticipated onset of neutropenia and continue for 7 days after the neutrophil count rises about 1000 cells/ mm3. Adjustment of dosage • Kidney disease: Creatinine clearance 10–50 mL/min: admin- ister 50% of usual dose. Warnings/precautions • Use with caution in patients with hypersensitivity to other azoles, kidney disease. Advice to patient • Report symptoms of possible liver dysfunction: jaundice, anorexia, dark urine, pale stools, nausea, vomiting. Clinically important drug interactions • Fluconazole increases effects/toxicity of following drugs: cyclosporine, glipizide, glyburide, phenytoin, theophylline, tolbutamide, warfarin, zidovudine, cisapride. Adjustment of dosage • Kidney disease: Creatinine clearance 20–40 mL/min: adminis- ter q12h; creatinine clearance 10–20 mL/min: increase dosage interval to q24h; creatinine clearance <10 mL/min: increase dosage interval to q24–48h. Warnings/precautions: Use with caution in patients with kidney disease, bone marrow depression (extreme caution). Clinically important drug interactions: Flucytosine increases effects/toxicity of amphotericin B. Therapeutic concentrations are 25–100 µg/mL with peak plasma concentrations between 40 and 60 µg/mL. Editorial comments • Flucytosine is generally administered with amphotericin B to improve its efficacy. Adjustment of dosage • Kidney disease: Guidelines are not available for adjustment of dosage in patients with kidney disease; monitor closely for pos- sible increased toxicity. Warnings/precautions: Use with caution in patients with the fol- lowing conditions: renal insufficiency, fever, infection, bone marrow depression, epilepsy, spasicity, peripheral neuropathy. Advice to patient • Use two forms of birth control including hormonal and barrier methods.

It is not absorbed by the body and does not interfere with stomach or bowel secreton or produce misleading radiographic artefacts 200 mg urispas with mastercard spasms right side of stomach. Barium sulphate may be used in either single- or double-contrast techniques or computer-assisted axial tomography order 200 mg urispas fast delivery muscle relaxant menstrual cramps. For double contrast examinaton gas can be introduced into the gastrointestnal tract by using suspensions of barium sulphate containing carbon dioxide or by using separate gas-producing prepara- tons based on Sodium bicarbonate. Air administered through a gastrointestnal tube can be used as an alternatve to carbon dioxide to achieve a double-contrast efect. Amidotrizoates (meglumine amidotrizoate and Sodium amidot- rizoate) are iodinated ionic monomeric organic compounds. Both salts have been used alone in diagnostc radiography including computer-assisted axial tomography but a mixture of both is ofen preferred to minimize adverse efects and to improve the quality of the examinaton. Amidotrizoates are used in a wide range of procedures including urography and examinaton of the gallbladder, biliary ducts and spleen. Owing to their high osmolality and the resultng hypertonic solutons, they are associated with a high incidence of adverse efects. Radiodensity depends on iodine concentraton, and osmolality depends on number of partcles in a given weight of solvent. The osmolality for a given radiodensity can be reduced by using an ionic dimeric medium such as meglumine iotroxate which contains twice the number of iodine atoms in a molecule or by using a non-ionic medium such as iohexol. Low osmolality media such as iohexol are associated with a reducton in some adverse efects (see below), but they are generally more expen- sive. Iohexol is used for a wide range of diagnostc procedures including urography, angiography and arthrography and also in computer-assisted axial tomography. It is absorbed from the gastrointestnal tract, excreted into the bile and concentrated in the gallbladder thus making it ideal for chole- cystography. Propyliodone is an iodinated organic compound which is used for the examinaton of the bronchial tract. Hypersensitvity: Anaphylactoid reactons to iodinated radiocontrast media are more common with ionic, high osmolality compounds. Patents with a history of asthma or allergy, drug hypersensi- tvity, adrenal suppression, heart disease, previous reacton to contrast media, and those receiving beta-adrenoceptor antag- onists (beta-blockers) are at increased risk. Non-ionic media are preferred for these patents and beta-blockers should be discontnued if possible. Dose Adult and Child- Radiographic examinaton of gastrointestnal tract: route and dosage depend on procedure and preparaton used (consult literature). Contraindicatons Intestnal obstructon; conditons such as pyloric stenosis or lesions which predispose to obstructon; intestnal perforaton or conditons with risk of perforaton; such as acute ulceratve colits; divertculits; or afer rectal or colonic biopsy; sigmoidoscopy or radiotherapy; hypersensitvity; gastrointestnal haemorrhage; infammaton. Adverse Efects Constpaton or diarrhoea; abdominal cramps and bleeding; perforaton of bowel resultng in peritonits; adhesions; granulomas and high mortality rate; electrocardiographical changes-may occur with rectal administraton; pneumonits or granuloma formaton-following accidental aspiraton into lungs; bloatng; constpaton; stomach pain; ringing in ears; nausea; vomitng; pale skin; weakness. Contraindicatons Severe renal disease and hepatc disease; jaundice caused by biliary-tract obstructon; impaired absorpton due to acute gastrointestnal disorders. Precautons Hypersensitvity to iodine-containing compounds or other contrast media; severe hyperthyroidism; hyperuricaemia or cholangits; may interfere with thyroid- functon tests; adequate resuscitaton facilites must be immediately available when radiographic procedures are carried out; interactons (Appendix 6c). Adverse Efects Nausea and vomitng; abdominal pain and diarrhoea; mild stnging on micturiton; rashes and fushing; acute renal failure; thrombocytopenia and hypersensitvity reactons reported; also uricosuric and antcholinesterase efects. Meglumine Iotroxate* Pregnancy Category-D Indicatons Examinaton of the gallbladder and biliary tract. Dose Intravenous injecton Adult- Examinaton of gallbladder and biliary tract: 100 ml of meglumine iotroxate 10. Adverse Efects Nausea, vomitng, metallic taste; fushing; sensatons of heat; weakness; dizziness; headache; cough; rhinits; sweatng; sneezing; lacrimaton; visual disturbances; pruritus; salivary gland enlargement; pallor; cardiac disorders, haemodynamic disturbances and hypotension or hypertension; convulsions; paralysis; coma; rigors; arrhythmias; pulmonary oedema; circulatory failure and cardiac arrest; occasionally anaphylactoid or hypersensitvity reactons; hyperthyroidism; pain on injecton; extravasaton may result in tssue damage; thrombophlebits; thrombosis; venospasm and embolism. Dose Instllaton into the lungs Adult-Examinaton of bronchial tract: consult literature. Contraindicatons Hypersensitvity to iodine-containing compounds; severe heart disease.

One child with acute myeloid leukaemia had received teniposide instead of etoposide cheap urispas 200 mg free shipping spasms thoracic spine. The Working Group also noted that it was not completely clear in these two studies whether the diagnosis of acute lympho- blastic leukaemia excluded primary mixed leukaemia and thus allowed differentiation of lymphoblastic from myeloid disease 200 mg urispas sale spasms back muscles. A total of 465 children [ages not given] with primary rhabdomyosarcoma (diagnosis around 1984) took part in this trial. The analysis was restricted to 207 children who had survived more than 36 weeks from entry into the protocol. They had received etoposide daily in combination with two courses of dactinomycin (cumulative dose of etoposide, 600 mg/m2) or three courses of cisplatin (cumulative dose of etoposide, 900 mg/m2), after they had been treated with induction regimens that included cyclophosphamide and doxorubicin. Interim analyses of the risks for acute myeloid leukaemia and myelodysplastic syndrome were carried out when four cases had been observed. Two of the four cases had received etoposide (600 mg/m2) and dactino- mycin, and two had received etoposide (900 mg/m2) and cisplatin. The three cases of acute myeloid leukaemia were of the myelomonocytic and monoblastic types and myelodysplastic syndrome progressing to acute myeloid leukaemia; the other case was myelodysplastic syndrome. The calculated cumulative six- year rate of development of acute myeloid leukaemia or myelodysplastic syndrome was 3. Twelve trials were selected from a pool of approximately 100 in which etoposide or teniposide had been used. Selection was made without knowledge of the number of secondary leukaemias that had occurred to date in the trials. The 12 trials (11 for patients with solid tumours and one for patients with acute lymphoblastic leukaemia) were divided into three strata according to the cumulative dose of eto- poside: low (< 1500 mg/m2), moderate (1500–3000 mg/m2) and high (> 3000 mg/m2). For trials in which teniposide was used, a 1:2 ratio was used to convert the dose of teniposide to that of etoposide. Patients treated with the low dose had primary rhabdo- myosarcoma (n = 222) or medulloblastoma (advanced stage) (n = 229). The patients with rhabdomyosarcoma had also received cyclophosphamide or equivalent doses of ifosfamide (25 000–35 000 mg/m2). Patients treated with the moderate dose had primary neuroblastoma (n = 319), germ-cell tumour (adult and paediatric) (n = 700) or acute lymphoblastic leukaemia (high risk) (n = 251). Patients given the higher dose had primary rhabdomyosarcoma (n = 313) or Ewing sarcoma (n = 257). They also received cyclophosphamide or equivalent doses of ifosfamide (25 000– 35 000 mg/m2). The six-year actuarial risks for acute myeloid leukaemia or myelo- dysplastic syndrome were 3. The p values for homogeneity of the risks for secondary leukaemia across the cumulative dose strata were 0. Thus, the data provide no support for an effect of the cumulative dose of epipodo- phyllotoxins on leukaemogenic activity, at least not within the cumulative dose range encompassed by the monitoring plan. It is also not clear which patients received teniposide and which received etoposide. Of these, 223 patients received etoposide in combination with cyclophosphamide, vincristine, dactinomycin, doxorubicin and cisplatin, with a total dose of etoposide of 600–900 mg/m2. Four cases of acute myeloid leukaemia, one of myelodysplastic syndrome and one of osteogenic sarcoma were reported. The median time from the initiation of primary treatment to the diagnosis of leukaemia was 39 months. Three of four leukaemia patients had received etoposide in combination with doxorubicin, cyclophosphamide (13 000–21 900 mg/m2), cisplatin and other agents and radiotherapy during their treatment. The incidence of acute myeloid leukaemia among patients who had received etoposide in combination with doxorubicin, cyclophos- phamide, cisplatin and other agents and radiotherapy during their treatment was 52 per 10 000 person–years. When cyclophosphamide alone or cyclophosphamide plus doxo- rubicin but no etoposide was part of the regimen, the incidence was 7. The relative risk for acute myeloid leukaemia in a comparison of the etoposide-containing regimen and that without etoposide was thus 7. The patient who developed myelodysplastic syndrome after five years and seven months had received etoposide (840 mg/m2) in combination with doxorubicin, cyclophosphamide (18 500 mg/m2), cisplatin and other agents and radiotherapy during his treatment.