- Email: [email protected]
Miscellaneous drugs, materials, medical devices, and techniques
N.H. Choulis
49
Alcohol
Miscellaneous drugs, materials, medical devices, and techniques
(SEDA-31, 757)
Cardiovascular It has been suggested that there are individual differences in subjective responses to alcohol, and an exaggerated cardiac response to alcohol has been suggested to be a marker of increased sensitivity to its stimulant properties. The relation between cardiac reactivity to alcohol measured on the ascending limb of the Blood Alcohol Concentration (BAC) curve and its subjective stimulant and sedative effects throughout the BAC curve has been examined in 39 male social drinkers (1A). Cardiac responses to ethanol correlated positively with stimulant effects at numerous times during the ascending and descending limbs of the BAC curve. There were no associations between the cardiac changes and alcohol-related sedative effects at any time. The effects of potentially lethal serum concentrations of ethanol on features of the electrocardiogram that may be asso ciated with cardiac dysrhythmias have been studied in 84 patients with assumed acute ethanol intoxication and 27 hospitalized controls (2C). In subjects with moderately increased to high serum osmolality, the PR and QTc intervals were prolonged
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32049-6 2010 Elsevier B.V. All rights reserved.
compared with sober subjects. The authors suggested that ethanol at high to very high concentrations in the blood causes several electrocardiographic changes that might be associated with an increased risk of dysrhythmias.
Nervous system Cerebellar degeneration has been attributed to alcoholism (3C). Alcoholic cerebellar degeneration (ACD) is one of the most common neurological complications in alcoholics. As far as it is known, however, only four Japanese autopsy cases have been reported, and only limited pathological data are now available in Japan. ACD has been studied in six Japanese autopsy cases, including three asymptomatic cases, in order to elucidate the pattern of progression of the cerebellar lesions. The findings suggested that in ACD, severe lesions develop successively in the anterior superior vermis, the anterior superior hemisphere, the anterior inferior hemisphere and the anterior inferior vermis. In addition, cerebellar symptoms can often occur if the anterior superior and anterior inferior hemispheres are involved, in addition to the anterior superior vermis. Liver The possible role of alcohol in hepatotoxicity associated with therapeutic doses of paracetamol has been studied in a report of two patients who were regular consumers of alcohol and who developed
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liver failure within 3–5 days after hospitalization and stopping alcohol consumption while being treated with paracetamol 4 g/day (4A). The serum paracetamol concentration in one of these patients was not in the toxic range. Possible susceptibility factors for hepatotoxicity in patients taking therapeutic doses of paracetamol were investigated. In patients with susceptibility factors, such as regular consumption of alcohol, liver failure is possi ble when therapeutic doses of paracetamol are taken. The authors therefore proposed that the dose of paracetamol should not exceed 2 g/day in such patients and that liver function should be monitored closely while they are taking paracetamol. Death Ethanol-related deaths occur at all ages, including children, as in the case of a 5-year-old boy who died after drinking ethanol at the party held by his parents (5A). Urine and blood concentrations were 4 and 5 g/l respectively, which might explain sudden death. In addition, analysis of his hair showed the presence of ethyl glucuronide, a marker of alcohol consumption, suggesting that he had probably drunk alcohol before death. There were pathological lesions in the liver consistent with this. Tumorigenicity Moderate alcohol intake has been associated with a modest (30–50%) increase in the risk of breast cancer, but it is unclear whether certain individuals have greater susceptibility to the harmful effects of alcohol (6r). Individuals differ in their ability to metabolize alcohol through genetic differences in alcohol dehydrogenase, the enzyme that catalyses the oxidation of about 80% of ethanol to acetaldehyde, a known carcinogen. Women with breast cancer have been studied to see whether they differ with respect to alcohol consumption and alcohol metabolism from their sisters without breast cancer, using data from the Breast Cancer Family Registry (n = 811 sister sets). Neither alcohol drinking nor alcohol metabolizing ADH1B and ADH1C genotypes were
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associated with breast cancer. However, only 19 and 42% of sisters were discordant for ADH1B and ADH1C respectively, and even fewer were discordant for both genotype and alcohol intake, making it difficult to detect differences if they existed.
Teratogenicity Alcohol consumption during pregnancy is another hazard, particularly for boys, as has been reported in a study of prenatal exposure to alcohol. The association between maternal alcohol consumption during pregnancy and cryptorchidism (undescended testis) among 2496 boys was examined in a prospective Danish–Finnish birth cohort study. There were 128 cases of cryptorchidism in 2368 boys and at 3 months of age 33 cases out of 2215 (7C). The odds for cryptorchidism increased with increasing weekly alcohol consumption. After adjustment for con founders (country, smoking, caffeine intake, binge episodes, social class, maternal age, parity, maturity, and birth weight), the odds remained significant for women who had a weekly consumption of five or more alcoholic drinks. The authors therefore concluded that regular alcohol intake during pregnancy increases the risk of congenital cryptorchidism. However, the mechanism for this association is unknown. Pregnant women should be advised to avoid alcohol.
Artificial sweeteners (SED-15, 348) Tumorigenicity Attempts have been made to determine the role of habitual use of the most common artificial sweeteners in the development of urinary tract tumors in 197 patients with histologically confirmed transitional tumors and 397 controls with acute, non-neoplastic, and non-urinary tract disease admitted to a hospital between 1999 and 2006 (8c). All were interviewed about their use of artificial sweeteners and exposure to other known or suspected risk factors for urinary tract tumors. Artificial sweeteners had been used by 51 patients with urinary tract tumors (26%) and 87
Miscellaneous drugs, materials, medical devices, and techniques
controls (22%). The risk of urinary tract tumors was significantly increased in those who had used artificial sweeteners for more than 10 years compared with non-users. The OR (95% CI) for long-term consumers was 2.18 (1.22, 3.89) and for short-term users 1.10 (0.61, 2.00) after adjustment for age, sex, BMI, social status, and years of tobacco use.
Bisphosphonates (SED-15, 523; SEDA-28, 590; SEDA-29, 602; SEDA-30, 561) Musculoskeletal Osteonecrosis of the jaw The range of adverse reactions to bisphos phonates has been reviewed, with particular emphasis on the association between longterm treatment and osteonecrosis of the jaw, a potentially serious adverse effect that occurs mostly in patients with multiple myeloma or breast cancer (9R). While the etiology is uncertain, there is a strong association with dental pathology and interventions, highlighting the need for close attention to dental health. The clinical features, predisposing factors, and treatment outcomes in patients with oral bisphosphonate-related osteonecrosis of the jaw have been studied retrospectively (10A). Of 98 patients with osteonecrosis of the jaw, 13 had used oral bisphosphonates and two were excluded because of previous adminis tration of intravenous bisphosphonates. In the other 11 patients the mean duration of alendronate use before osteonecrosis of the jaw was 4.1 years. It was triggered by dental surgery in nine patients and by ill-fitted den tures in two. Heavy smokers were particu larly at risk. Among the nine patients with at least 6 months of follow-up, the osteonecro sis healed completely in three, partially in four, and not at all in two. The authors con cluded that osteonecrosis of the jaw is a rare devastating adverse effect of oral bispho sphonates associated with a high financial burden. Osteonecrosis of the jaw associated with bisphosphonate therapy has been studied in 12 patients with multiple myeloma or bone
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metastases from solid tumors (11c). With drawal of the bisphosphonate was not asso ciated with resolution of the osteonecrosis, and surgical manipulation of the involved site worsened the underline bone pathology. Hyperbaric oxygen, which has proven effica cious in other forms of osteonecrosis by establishing an oxygen gradient, is of no defi nitive benefit to patients with bisphospho nate-induced exposed bone. Antibiotic therapy is useful in controlling pain and swel ling, but ineffective in preventing progression of the exposed bone. To date, prevention is the only possible therapeutic approach to the management of this complication. The frequency, clinical presentation, radiology, pathology, and treatment of osteonecrosis of the jaw due to bisphospho nates have been investigated in a prospec tive study of 80 patients, of whom 22 developed osteonecrosis (11 men and 11 women, median age 25 years) (12C). Ten of them had multiple myeloma, 5 had breast cancer and 7 had other malignancies; 14 had used zoledronate, 3 pamidronate, 4 pami dronate followed by zoledronate and 1 ibandronate followed by zoledronate. The median time of exposure was 32 months compared with 27 months in patients with out osteonecrosis. The mean induction time until bone exposure was 26 months for those who used zoledronate, 54 months for pamidronate, and 48 months for pamidro nate followed by zoledronate. There was exposure of the mandible in 13 cases, the maxilla in 6, and both jaws in 3. In 5 patients osteonecrosis occurred sponta neously and in 17 it occurred after tooth extraction. Nine had had previous extrac tions of molars, six of premolars, and two of front teeth. The cumulative hazard was 3.5 times higher in those using zoledronate than in the other groups. There was no association of osteonecrosis with age, sex, the use of high doses of conventional chemotherapy, or the use of glucocorticoids, thalidomide, or borte zomib. Patients with multiple myeloma and breast cancer were at higher risk. The prevalence of bisphosphonate associated osteonecrosis of the jaw has been studied in the catchment area of a university hospital maxillofacial unit in a
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retrospective study of all patients with osteonecrosis, osteomyelitis, and osteora dionecrosis treated for 5 years (13c). There was odontogenic or surgically induced osteomyelitis in 40%, osteoradio necrosis in 28%, osteonecrosis after treatment with bisphosphonates in 10%, osteomyelitis or sequestrum due to trauma in 8%, and osteomyelitis of unknown origin in 14%. All the patients with bisphosphonate-asso ciated osteonecrosis had had metastatic dis eases of the bone (plasmacytoma, breast carcinoma, and prostate cancer) for up to 5 years. All had been given a nitrogencontaining bisphosphonate (either pamidro nate or zoledronate). There had been a possible trigger, such as previous tooth extraction, pressure denture sore or period ontal disease in 13 of the 17 patients with bisphosphonate-associated osteonecrosis and in 14 of the 45 with osteoradionecrosis.
suggesting that fractures may indeed have an effect on mortality.
Osteoporosis On the other hand, osteoporosis is a silent disease, because skeletal deterioration proceeds with no outward symptoms until a symptomatic fracture occurs; the condition is therefore under-recognized and affected individuals are under-treated (14R, 15R). Vertebral fractures may not cause recognizable symptoms or the patient may present with an acute self-limiting episode of back pain. However, subclinical fractures are important predictors of future risks. People with vertebral fractures have an increased mortality rate, which extends beyond the first year. Reduced survival is difficult to attribute to direct effects of the fracture, and enhanced mortality appears to be a consequence of co-morbidities. All types of osteoporotic fractures are asso ciated with increased age-specific mortality; this effect lasts for at least 5 years after the fracture event and the impact is worse in men than in women (16R). In a randomized controlled trial of intravenous bisphospho nate in men and women with prior hip frac tures, there were reductions in subsequent fractures and mortality (17R). This study and others have shown increased mortality soon after a fracture and a subsequent return to the expected mortality rates,
Dimethylsulfoxide (DMSO)
Cyanoacrylates (SED-15, 1022) Tumorigenicity Cyanoacrylates are liquids that are used in the manufacture of polymers and adhesives. They have long been thought to be linked to malignancies. A 36-year-old man with pre-B cell acute lymphoblastic leukemia had used industrial strength glue to reattach a chipped tooth for about 1 year, and such use was associated with chronic exposure of his oral mucosa to the glue (18A). This case raises the possibility that chronic exposure to cyanoacrylates may be associated with acute lymphoblastic leukemia.
(SED-15, 1131) Nervous system Toxicity related to the infusion of dimethylsulfoxide (DMSO) cryopreserved peripheral blood stem cells mainly comprises cardiovascular events. Autologous stem cell transplantation complicated by cerebral infarction and myocardial damage has been reported (19A), and it has been postulated that DMSO may have been responsible. Of 51 patients who received DMSOpreserved peripheral blood stem cells, only one had neurotoxicity in the form of a gen eralized tonic seizure after the infusion (20A). However, there was no neurotoxicity in eight patients with pre-existing neurological dis ease, nor in patients who received particu larly large volumes of DMSO. In all patients, there were mild non-neurological adverse effects. • A 49-year-old man who received two infusions of DMSO-cryopreserved autologous peripheral blood progenitor cells after myeloablative chemotherapy for a relapsing lymphoma had a tonic–clonic seizure over a few minutes after the start of each infusion and developed a profound and sustained but reversible encephalopathy with coma after the second infusion (21A).
Miscellaneous drugs, materials, medical devices, and techniques His neurological condition correlated with the electrophysiological findings (electroencephalo graphy and multimodality evoked potentials) and to a lesser extent with MRI abnormalities. • A 50-year-old woman with nodular-sclerosing Hodgkin’s disease received stem cells cryo preserved in 10% DMSO, which were infused after high-dose conditioning with carmustine, etoposide, cytarabine, and melphalan, and pre medication with diphenhydramine 50 mg and hydrocortisone 200 mg (22A). After infusion of the second bag, she became pale, lost conscious ness, and developed mydriasis, trismus, and respiratory arrest. The stem cell infusion was immediately stopped. She was given phenytoin 15 mg/kg and assisted ventilation, and she recov ered consciousness in less than an hour. She was given intravenous phenytoin 4.5 mg/kg for 5 days and then switched to oral therapy. Later the remaining cryopreserved stem cells were reinfused and there were no adverse effects. A brain CT scan was normal but an electro encephalogram showed diffuse abnormalities in electrical activity with irregular slow-wave paroxysms. A brain MRI scan showed a small punctate area of hyperintensity in the right middle frontal lobe of unclear significance.
Disulfiram
(SED-15, 1148; SEDA-31, 760)
Cardiovascular A 27-year-old man took disulfiram and ethanol and developed significant hypotension and ischemic electrocardiographic changes (23A). He was treated with intravenous fluids and noradrenaline (norepinephrine), which has been advocated as the pressor agent of choice. Drug–drug interactions Dexamfetamine Disulfiram has also shown promise in several clinical trials for cocaine addiction, but its potential usefulness in the treatment of amphetamine addiction has not been examined. The effects of disulfiram, 250 mg/day for 4 days, on acute physiological and subjective responses to dexamfetamine have been studied in 10 healthy volunteers, 5 men and 5 women, in an outpatient crossover, double-blind, placebo-controlled study (24c). Disulfiram did not affect dexamfetamine-induced increases in heart rate, blood pressure, cortisol concentration, or prolactin, but it
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did enhance some of the subjective effects of dexamfetamine, including ratings of ‘high’, ‘anxious’, ‘bad drug effects’, ‘want more drug’, and ‘drug liking’, and was also associated with a reduced performance in the Sustained Attention to Response Test.
DYESTUFFS Fluorescein
(SEDA-29, 607)
Nervous system It is important to identify intraoperative leakage of cerebrospinal fluid (CSF) in successful closure after endoscopic cranial base surgery, for which intrathecal injection of fluorescein is useful. However, complications have been reported with various doses and the technique has fallen out of favor. Low-dose intrathecal fluorescein has been studied in a retrospective chart review and postoperative patient survey in 54 patients undergoing endoscopic cranial base surgery (25c). Intraoperative CSF leak was identified with fluorescein in 25 patients and helped determine the reconstruction technique. There was postoperative leakage of CSF in five patients and it resolved with lumbar drainage. There were no seizures. Most of the adverse events were non-specific, transient and probably not caused by fluorescein, including malaise (n = 31), headache (n = 30), dizziness (n = 17), or nausea and vomiting (n = 13). Three patients had persistent postoperative subjective leg weakness (n = 2) and numbness (n = 2); however, two of them had undergone lumbar drainage. The authors concluded that low-dose intrathecal fluorescein after premedication with a glucocorticoid and an antihistamine is generally safe. However, fluorescein should be administered with caution, because it can occasionally cause weakness and numbness in the legs. Immunologic The Netherlands Pharmaco vigilance Center has received reports of two anaphylactic reactions associated
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with fluorescein in a 49-year-old man and a 56-year-old woman; the woman subsequently died (26S).
Indocyanine green
(SED-15, 2595;
SEDA-31, 760) Sensory systems Visual field defects have been reported after macular hole surgery with indocyanine green-assisted internal limiting membrane peeling in a retrospective review of 140 eyes, in 96 of which indocyanine green 0.25% was used (27c). There were nasal visual field defects in 11 eyes, temporal visual field defects in 7 and concentric visual field defects in 1. In the group in whom indocyanine green was used, the visual field defects were far higher in the left eye than in the right. The authors speculated that the postoperative nasal visual field defects were caused by enhanced toxicity of indocyanine green, resulting from exposure to illumination. Changes in macular function and potential retinal toxicity have been studied using multifocal electroretinography after epiret inal membrane surgery in 13 eyes of 13 patients; internal limiting membrane peel ing was facilitated by staining with indocya nine green 0.5 or 1.25 mg/ml (28c). The median best corrected visual acuity improved from 20/70 at baseline to 20/30 at 6 months postoperatively. At 3 months those in whom indocyanine green 0.5 mg/ml had been used had no significant changes in multifocal electroretinographic N1 and P1 response amplitudes and peak latencies, whereas those in whom indocyanine green 1.25 mg/ml had been used had significant reductions in N1 and P1 response amplitudes compared with baseline. There were no sig nificant changes in either group at 6 months after surgery. These findings suggest that the use of a higher concentration of indocyanine green to stain the internal limiting membrane can result in transient retinal functional impairment postoperatively. The lowest pos sible concentration of indocyanine green should be used intraoperatively to minimize potential retinal toxicity.
N.H. Choulis
Tartrazine Tartrazine is a synthetic lemon yellow azo dye used as a food coloring; it can be com bined with Brilliant Blue FCF or Green S to produce various shades of green. Many foods contain tartrazine in varying propor tions, although nowadays the trend is to avoid it or to substitute a non-synthetic dyestuff, such as annatto, malt color, or b-carotene. Pharmaceutical products contain ing tartrazine include vitamins, antacids, med icinal capsules, and certain prescription drugs. In animals the acceptable daily intake was 7.5 mg/kg (29R). Extrapolating from these data, the estimated maximum theore tical intake of tartrazine in children is 37% of the acceptable daily intake at the 97.5th percentile. One can therefore conclude that toxic effects of tartrazine should not be expected in humans.
Immunologic Of all the azo dyes, tartrazine is the most allergenic and particularly causes reactions among asthmatics and those with aspirin intolerance. Symptoms from tartrazine hypersensitivity can occur from either ingestion or cutaneous exposure, and the effects can include anxiety, migraine, depression, blurred vision, itching, general weakness, hot sensations, a feeling of suffocation, purple skin patches, and sleep disturbances. It has been suggested that children with hyperactivity can develop increased irritability, restlessness, and sleep disturbances after taking tartrazine (30C).
Methylthioninium chloride (methylene blue) (SED-15, 2314; SEDA-28, 595; SEDA-29, 610; SEDA-30, 569) Drug–drug interactions Serotonergic drugs The UK MHRA has received two reports of nervous system toxicity when intravenous methylthioninium was used as a visualizing agent for thyroid or parathyroid surgery (31Sr). This has previously been attributed to an interaction with selective serotonin
Miscellaneous drugs, materials, medical devices, and techniques
reuptake inhibitors (SSRIs) (SEDA-30, 569). The MHRA has advised health-care professionals to • assess carefully the need for intravenous methylthioninium chloride for visualization in surgical procedures; • avoid methylthioninium chloride in patients who have recently used serotonergic drugs; • use the smallest possible dose of intravenous methylthioninium chloride if it cannot be avoided; • observe patients closely for nervous system effects for up to 4 hours after administration.
Nicotine
(SED-15, 2508; SEDA-29, 610; SEDA-30, 571; SEDA-31, 571)
Death In 90 smokers who were admitted to an intensive care unit and were given nicotine replacement therapy to prevent withdrawal, and who were matched, based on the severity of illness and age, with one control smoker who did not receive nicotine replacement therapy, the mean mortality rate predicted by the Acute Physiology and Chronic Health Evaluation III was 9.2% in the cases and 10.3% in the controls (32c). However, the observed hospital mortality rate was 20% in the cases and 7% in the control group. When adjusted for the severity of illness and invasive mechanical ventilation, nicotine replacement therapy was independently associated with increased mortality. Fetotoxicity Maternal smoking during pregnancy causes significant fetal morbidity and is a public health problem, as 36% of women in the UK and 11% of those in the USA smoke during pregnancy (33R). Behavioral support for smoking cessation, provided outside of routine antenatal care, is effective in promoting smoking cessation by pregnant women, but relatively few pregnant women have access to such support. Effective pharmacological aids to smoking cessation, which have been studied in non-pregnant populations, include nicotine replacement therapy, bupropion (amfebutamone), and
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varenicline. However, there is very little evidence to justify the use of these drugs in pregnancy, and it is doubtful that definitive trials of the effectiveness of either bupropion or varenicline for smoking cessation will be conducted in pregnant women in the foreseeable future. In the short-to-medium term, research information relating to the use of these drugs in pregnancy is therefore likely to be derived from observational studies, which are more difficult to interpret than clinical trials. There is therefore not enough evidence that nicotine replacement therapy is effective for smoking cessation in pregnancy and bupropion and varenicline cannot be recommended.
Sevelamer The FDA approved the use of sevelamer in 1998. It is a phosphate binder that is used to reduce the amount of phosphorus in the blood of patients with chronic kidney dis ease who are on dialysis. Its common adverse effects include diarrhea, infection, pain, vomiting, indigestion, low blood pres sure, headache, blood clot formation, reduced absorption of vitamins D, E, and K and folic acid, and bowel obstruction. Ser ious adverse effects that require medical attention include severe abdominal pain, new or worsening constipation, and other severe intestinal symptoms.
Comparative studies Raised serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Unlike calcium-based binders, sevelamer attenuates arterial calcification, but it is not known whether it affects mortality or morbidity. In a multicenter, randomized, open study of all-cause and cause-specific mortality, sevelamer was compared with calcium-based binders in 2103 patients on hemodialysis of whom 1068 completed the study (34c). All-cause mortality rates and cause-specific mortality rates were not significantly different. However, there was a significant effect of
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age: the effect of sevelamer in reducing mortality was limited to patients over 65 years of age. There was a suggestion that sevelamer was associated with lower overall, but not cardiac, mortality in older patients.
Acid–base balance Sevelamer hydrochlor ide contains multiple amines, which may cause a significant dietary acid load. To evaluate the effect of sevelamer on arterial blood gases, two groups of patients on stable hemodialysis were followed for 24 months (35c). Those who were given sevelamer (n = 7) did not achieve the goals of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) for phosphorus and Ca � P product; those who were given calcium salts (n = 7) achieved those goals. Sevelamer was associated with worsening of chronic metabolic acidosis, which lasted throughout the study, and there were no significant changes in acid–base balance in the controls. The authors concluded that sevelamer caused small but persistent acid–base disturbances, which did not outweigh its beneficial effects on mineral and lipid metabolism. In a retrospective study the effect of seve lamer on metabolic acidosis was studied in 36 patients on hemodialysis and 36 matched for sex, diabetes mellitus, age and duration of dialysis who were not taking sevelamer (36c). Sevelamer significantly reduced the mean concentrations of bicarbo nate, base excess, and pH, but mean chloride concentrations and the anion gap did not change; there were no changes in the control group. The concentrations of bicarbonate, base excess, and pH correlated significantly with the daily dose and cumulative dose of sevelamer.
Talc
(SED-15, 3592; SEDA-29, 612)
Talc powder is widely used as an inert excipient in the manufacture of tablets and as a drying ingredient in baby powders.
N.H. Choulis
However, inappropriate use can cause severe unwanted effects. Respiratory Pulmonary embolism has been reported after the intravenous administration of talc and zinc oxide (37A). • A 74-year-old woman recovering from colonic surgery died immediately after receiving an intravenous infusion of about 1.5 ml of a white emulsion that was believed to contain 1% propofol. However, it was suspected that a zinc oxide shake lotion (containing 20% zinc oxide, 20% talc, 25% glycerol, and 35% water), intended for external treatment, had been mistaken for propofol. At autopsy, an anatomical cause of death could not be found. Propofol and other drugs that she had received were found in therapeutic or subtherapeutic concentrations. However, the concentration of zinc in the lungs was about 200 times higher than that found in a control case, 10 times higher in cardiac blood, and 3–4 times higher in kidney and liver tissues. There was no increase in venous blood. Histology showed a large pulmonary embolism containing birefringent sharp-edged crystals, which were identified as talc, and an amorphous component (zinc oxide). There were similar smaller emboli in the brain, heart, liver, pancreas and kidneys.
Sensory systems Talc from surgical gloves can cause granulomas in the conjunctivae, with chronic inflammation (38A). Respiratory Chronic exposure to talc during carpet installation resulted in silicopneumoconiosis in a 30-year-old man who had worked as a carpet installer for 15 years (39Ar).
Tumorigenicity A 68-year-old woman with stage III ovarian papillary serous carcinoma had used talc daily for 30 years to powder her genital area. Examination of her pelvic lymph nodes under polarized light microscopy showed diffuse areas of birefringence compatible with talc, confirmed by scanning electron microscopy and X-ray spectroscopy (40A).
Miscellaneous drugs, materials, medical devices, and techniques
Toluene The effects of toxic chemicals are usually studied in experimental animals for the pur pose of understanding and predicting their effects in humans. For this purpose, it is often assumed, as proposed by Lehman and Fitzhugh, that rats are less sensitive to the adverse effects than humans (41H). However, there is little direct evidence that this is so, because sufficient data for making this cross-species comparison are not available for most chemicals (42R). Cross-species comparisons are possible for the effects of toluene, a neurotoxic chemi cal, whose acute effects have been well documented in many studies (43c, 44c, 45E). These studies have provided a data base sufficient for a quantitative compari son of the sensitivities of rats and humans to the acute effects of toluene. Meta-analyses of these data have been previously pre sented (46ME). For regulatory purposes, it is necessary to quantify effects as a function of the magni tude of a subject’s external exposure to a toxic chemical, e.g. the concentration of toluene in the inhaled air. Many acute effects depend on the duration of exposure because of increasing uptake of the chemi cal with time. In risk assessment, the potency of a toxic chemical is often quanti fied by measuring the exposure or internal dose needed to produce an effect that lies on some threshold of statistical detectabil ity, e.g. a lowest observable adverse effect level (LOAEL) or a benchmark dose. Alternatively, potency can be expressed as the dose or exposure needed to obtain a certain degree of effect, such as the dose that produces 50% of the maximum effect (ED50). It is difficult to convert information on the acute neurotoxicity of organic solvents into predictive relations between exposure and effects in humans, because (1) the data are usually derived from experimental ani mals, whose sensitivity to the chemical rela tive to humans is unknown; (2) the specific end-points measured in laboratory animals seldom translate into effects of concern in humans and (3) the mode of action of the
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chemical is rarely understood. Ways of esti mating the hazard and cost of exposure to organic solvents have therefore been sought, focusing on the acute behavioral effects of toluene in rats and humans (47H). Available published data include studies of shock avoidance behavior in rats and choice reaction time in humans. A meta-analysis of these data has suggested that there is a 10% change in rat avoidance behavior at a blood concentration of toluene that is 25 times higher than the concentration at which a 10% change in human choice reaction time occurs. By con trast, in vitro studies have suggested that nicotinic acetylcholine receptors in humans and rats do not differ in sensitivity to toluene. Analysis of other dose–response relations for visual and cognitive functions in rats suggests that the apparent difference between rats and humans may be driven by the specific end-points measured in the two species rather than by inherent differences in sensitivity to toluene. It has also been suggested that doseequivalent relations can be used to compare the societal costs of two chemicals. For example, ethanol-induced changes in choice reaction time, for which societal costs can be estimated, can be used as a benchmark for estimating the monetary benefits of con trolling exposure to organic solvents. This dose-equivalence method is applicable to solvents, because the data fulfil three important assumptions about an equiva lence relationship based on a single effect: (1) a common dose metric (the concentra tion of the chemical in the brain); (2) a common effect to provide a linking variable (the choice reaction time); and (3) a com mon mode of action (interference with neu ronal ion channel function).
TECHNIQUES Arterial embolization The role of hepatic arterial embolization and chemoembolization has been assessed
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in 60 patients with large-volume metastatic neuroendocrine tumors, melanomas, or gastrointestinal stromal tumors (GISTs) with over 75% liver involvement (48C). Radiological responses, progression-free survival, overall survival, and postprocedure complications were assessed. Of the 48 patients for whom follow-up imaging was available, there were partial responses in 12, minimal responses in 6, stable disease in 22 and progressive disease in 8. Median overall survival and progression-free survi val were 9.3 and 4.9 months respectively. Treatment resulted in radiological responses or disease stabilization in 82% and symptomatic responses in 65% of patients with neuroendocrine tumors. Patients with neuroendocrine tumors had higher response rates and longer survival than patients with melanoma and GISTs. There were major complications in 21
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N.H. Choulis
Table 1. Major complications after hepatic arterial embolization (48C) Complication (n)
Deaths
Tumor lysis syndrome (4) Anasarca (4) Hepatic failure (3) Myocardial infarction (2) Sepsis (2) Hepatic and renal failure (2) Renal failure (2) Hypertension (1) Pancreatitis (1)
1 1 2 2 2 2 1 1 0
patients after 23 of 123 sessions (Table 1). Nine of the 12 who died after major compli cations had additional susceptibility factors, including carcinoid heart disease, sepsis, and rapidly worsening performance status.
References 1. Brunelle C, Barrett SP, Pihl RO. Relation ship between the cardiac response to acute intoxication and alcohol-induced subjective effects throughout the blood alcohol concen tration curve. Hum Psychopharmacol 2007;22(7):437–43. 2. Aasebø W, Erikssen J, Jonsbu J, Stavem K. ECG changes in patients with acute ethanol intoxication. Scand Cardiovasc J 2007; 41(2):79–84. 3. Yokota O, Tsuchiya K, Terada S, Oshima K, Ishizu H, Matsushita M, Kuroda S, Akiyama H. Alcoholic cerebellar degeneration: a clin icopathological study of six Japanese autopsy cases and proposed potential progression pattern in the cerebellar lesion. Neuro pathology 2007;27(2):99–113. 4. Krahenbuhl S, Brauchli Y, Kummer O, Bodmer M, Trendelenburg M, Drewe J, Haschke M. Acute liver failure in two patients with regular alcohol consumption ingesting paracetamol at therapeutic dosages. Digestion 2007;75(4):232–7. 5. Klys M, Wozniac K, Rojek S, RzepeckaWozniak E, Kowalski P. Ethanol-related
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death of a child: an unusual case report. Forens Sci Int 2008;179(1):e1–4. Terry MB, Knight JA, Zablotska L, Wang Q, John EM, Andrulis IL, Senie RT, Daly M, Ozcelik H, Briollais L, Santella RM. Alcohol metabolism, alcohol intake, and breast can cer risk: a sister-set analysis using the Breast Cancer Family Registry. Breast Cancer Res Treat 2007;106(2):281–8. Damgaard IN, Jensen TK, Nordic Cryp torchidism Study Group, Petersen JH, Skak kebaek NE, Toppari J, Main KM. Risk factors for congenital cryptorchidism in a prospective birth cohort study. PLoS One 2008;3(8):e3051. Andreatta MM, Munoz SE, Lantieri MJ, Eynard AR, Navarro A. Artificial sweetener consumption and urinary tract tumors in Cordova, Argentina. Prev Med 2008;47(1): 136–9. Dunstan CR, Felsenberg D, Seibel MJ. Ther apy insight: the risks and benefits of bisphos phonates for the treatment of tumor-induced bone disease. Nat Clin Pract Oncol 2007; 4(1):42–55.
Miscellaneous drugs, materials, medical devices, and techniques 10. Yarom N, Yahalom R, Shoshani Y, Hamed W, Regev E, Elad S. Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical fea tures, predisposing factors and treatment outcome. Osteoporos Int 2007;18(10): 1363–70. 11. Nastro E, Musolino C, Allegra A, Oteri G, Cicciu M, Alonci A, Quartarone E, Alati C, De Ponte FS. Bisphosphonate-associated osteonecrosis of the jaw in patients with mul tiple myeloma and breast cancer. Acta Hematol 2007;117(3):181–7. 12. Boonyapakorn T, Schirmer I, Reichart PA, Sturm I, Massenkeil G. Bisphosphonate induced osteonecrosis of the jaws: prospec tive study of 80 patients with multiple myeloma and other malignancies. Oral Oncol 2008;44(9):857–69. 13. Walter C, Grotz KA, Kunkel ML, Al- Nawas B. Prevalence of bisphosphonate associated osteonecrosis of the jaw within the field of osteonecrosis. Supp Care Cancer 2007;15(2): 197–202. 14. Brecher L, Pomerantz SC, Snyder BA, Janora DM, Klotzbach-Shimonura KM, Cavaliery T. Osteoporosis prevention pro ject: a model of multi disciplinary educa tional intervention. J Am Osteopath Assoc 2002;102(6):327–35. 15. Diamond T, Lindenberg M. Osteoporosis detection in the community. Are patients adequately managed? Aust Family Physician 2002;31:751–2. 16. Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet 1999;353(9156):878–82. 17. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z. HORIZON Pivotal Frac ture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809–22. 18. Layden BT, Joseph M, Tallman MS, Platanias LC. Acute lymphoblastic leukemia in a patient with chronic cyanoacrylate expo sure. Acta Haematol 2007;118(4):242–3. 19. Chen-Plotkin AS, Vossel KA, Samuels MA, Chen MH. Encephalopathy, stroke and myo cardial infarction with DMSO use in stem
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cell transplantation. Neurology 2007;68(11): 859–61. 20. Mueller LP, Theurich S, Christopeit M, Grothe W, Muetherig A, Weber T, Guenther S, Behre G. Neurotoxicity upon infusion of dimethylsulfoxide-cryopreserved peripheral blood stem cells in patients with and without pre-existing cerebral disease. Eur J Hematol 2007;78(6):527–31. 21. Bauwens D, Hantson P, Laterre PF, Michaux L, Latinne D, De Tourtchaninoff M, Cosnard G, Hernalsteen D. Recurrent seizure and sus tained encephalopathy associated with dimethylsulfoxide-preserved stem cell infu sion. Leuk Lymphoma 2005;46(11):1671–4. 22. Júnior AM, Arrais CA, Saboya R, Velasques RD, Junqueira PL, Dulley FL. Neurotoxicity associated with dimethylsulfoxide-preserved hematopoietic progenitor cell infusion. Bone Marrow Transplant 2008;41(1):95–6. 23. Milne HJ, Parke TRJ. Hypotension and ST depression as a result of disulfiram ethanol reaction. Eur J Emerg Med 2007;14(4):228–9. 24. Sofuoglu M, Poling J, Waters A, Sewell A, Hill K, Kosten T. Disulfiram enhances sub jective effects of dextroamphetamine in humans. Pharmacol Biochem Behav 2008; 90(3):394–8. 25. Placantonakis DG, Tabaee A, Anand VK, Hiltzik D, Schwartz TH. Safety of low-dose intrathecal fluorescein in endoscopic cranial base surgery. Neurosurgery 2007;61(3 Suppl): 161–5. 26. Anonymous. Fluorescein. Reports of ana phylactic reactions. WHO Newslett 2008;3:6. 27. Tsuiki E, Fujikawa A, Miyamura N, Yamada K, Mishina K, Kitaoka T. Visual field defects after macular hole surgery with indocyanine green-assisted internal limiting membrane peeling. J Ophthalmol 2007;143(4):704–5. 28. Lai TYY, Kwok AKH, Au AWH, Lam DSC. Assessment of macular function by multifo cal electroretinopathy following epiretinal membrane surgery with indocyanine greenassisted internal limiting membrane peeling. Graefes Arch Clin Exp Ophthalmol 2007; 245(1):148–54. 29. Elhkim MO, Heraud F, Bemrah N, Gauchard F, Lorino T, Lambre C, Fremy JM, Poul JM. New considerations regarding the risk assessment on tartrazine. An update tox icological assessment, intolerance reactions
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and maximum theoretical daily intake in France. Regul Toxicol Pharmacol 2007;47(3): 308–16. Rowe KS, Rowe KJ. Synthetic food coloring and behavior: a dose response effect in a double- blind, placebo-controlled, repeatedmeasures study. J Pediatr 1994;125:691–8. Anonymous. Methylthioninium chloride (methylene blue). CNS toxicity with sero tonergic drugs. WHO Newslett 2007;5:9. Lee AH, Afessa B. The association of nico tine replacement therapy with mortality in a medical intensive care unit. Crit Care Med 2007;35(6):1517–21. Coleman T. Recommendations for the use of pharmacological smoking cessation strate gies in pregnant women. CNS Drugs 2007; 21(12):983–93. Suki WN, Zabaneh R, Cangiano JL, Reed J, Fischer D, Garrett L, Ling BN, ChasanTaber S, Dillon MA, Blair AT, Burke SK. Effects of sevelamer and calcium-based phosphate binders on mortality in hemodia lysis patients. Kidney Int 2007;72(9):1130–7. Vlahakos DV, Retsa K, Kalogeropoulos S, Katsoudas S, Bacharaki D, Agroyannis B. Chronic acid-base perturbations in hemodia lysis patients treated with sevelamer hydro chloride: a two-year follow-up study. Artif Organs 2007;31(12):892–5. Oka Y, Miyazaki M, Takatsu S, Kunitomo K, Uno F, Maruyama M, Matsuda H. Sevela mer hydrochloride exacerbates metabolic acidosis in hemodialysis patients, depending on the dosage. Ther Apher Dial 2007;11(2): 107–13. Pragst F, Correns A, Priem F, Herre S, Mar tin H. A sudden death with lung embolism after inadvertent infusion of zinc oxide shave lotion. Forensic Sci Int 2007;170(2):207–12 Layon F, Taylor RH. Conjuctival granuloma caused by surgical talc. J AAPOS 2007;11(4): 402–3.
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39. Szeinuk J, Wilk-Rivard EJ. Case report: sili catosis in a carpet installer. Environ Health Perspect 2007;115(6):932–5. 40. Cramer DW, Welch WR, Berkowitz RS, Godleski JJ. Presence of talc in pelvic lymph nodes of a woman with ovarian cancer and long-term genital exposure to cosmetic talc. Obstet Gynecol 2007;110(2):498–501. 41. Lehman AJ, Fitzhugh OG. 100-fold margin of safety. Assoc Food Drug Off US Quart Bull 1954;18:33–5. 42. Benignus VA, Boyer WK, Kenyon EM, Bushnen PJ. Quantitative comparisons of the acute neurotoxicity of toluene in rats and humans. Toxicol Sci 2007;100(1):146–55. 43. Echeverria D, Fine L, Langolf G, Schork A, Sampaio C. Acute neurobehavioral effects of toluene. Br J Indust Med 1989;46:483–95. 44. Rahill AA, Weiss B, Morrow PE, Frampton MW, Cox C, Gibb R, Gelein R, Speers D, Utell MJ. Human performance during expo sure to toluene. Aviat Space Environ Med 1996;67:640–7. 45. Shafer TJ, Bushnell PJ, Benignus VA, Woodward JJ. Perturbation of voltage-sensi tive Ca2+ channel function by volatile organic solvents. J Pharmacol Exp Ther 2005; 315:1109–8. 46. Benignus VA, Boyes WK, Bushnell PJ. A dosimetric analysis of behavioral effects of acute toluene exposure in rats and humans. Toxicol Sci 1998;43:186–95. 47. Bushnell PJ, Boyes WK, Shafer TJ, Bale AS, Benignus VA. Approches to extrapolating animal toxicity data on organic solvents to public health. Neurotoxicology 2007; 28(2):221–6. 48. Kamat PP, Gupta S, Ensor JE, Murthy R, Ahrar K, Madoff DC, Wallace MJ, Hicks ME. Hepatic arterial embolization and chemoem bolization in the management of patients with large-volume liver metastases. Cardiovasc Intervent Radiol 2008;31(2):299–307.
49
Alcohol
Miscellaneous drugs, materials, medical devices, and techniques
(SEDA-31, 757)
Cardiovascular It has been suggested that there are individual differences in subjective responses to alcohol, and an exaggerated cardiac response to alcohol has been suggested to be a marker of increased sensitivity to its stimulant properties. The relation between cardiac reactivity to alcohol measured on the ascending limb of the Blood Alcohol Concentration (BAC) curve and its subjective stimulant and sedative effects throughout the BAC curve has been examined in 39 male social drinkers (1A). Cardiac responses to ethanol correlated positively with stimulant effects at numerous times during the ascending and descending limbs of the BAC curve. There were no associations between the cardiac changes and alcohol-related sedative effects at any time. The effects of potentially lethal serum concentrations of ethanol on features of the electrocardiogram that may be asso ciated with cardiac dysrhythmias have been studied in 84 patients with assumed acute ethanol intoxication and 27 hospitalized controls (2C). In subjects with moderately increased to high serum osmolality, the PR and QTc intervals were prolonged
Side Effects of Drugs, Annual 32 J.K. Aronson (Editor) ISSN: 0378-6080 DOI: 10.1016/S0378-6080(10)32049-6 2010 Elsevier B.V. All rights reserved.
compared with sober subjects. The authors suggested that ethanol at high to very high concentrations in the blood causes several electrocardiographic changes that might be associated with an increased risk of dysrhythmias.
Nervous system Cerebellar degeneration has been attributed to alcoholism (3C). Alcoholic cerebellar degeneration (ACD) is one of the most common neurological complications in alcoholics. As far as it is known, however, only four Japanese autopsy cases have been reported, and only limited pathological data are now available in Japan. ACD has been studied in six Japanese autopsy cases, including three asymptomatic cases, in order to elucidate the pattern of progression of the cerebellar lesions. The findings suggested that in ACD, severe lesions develop successively in the anterior superior vermis, the anterior superior hemisphere, the anterior inferior hemisphere and the anterior inferior vermis. In addition, cerebellar symptoms can often occur if the anterior superior and anterior inferior hemispheres are involved, in addition to the anterior superior vermis. Liver The possible role of alcohol in hepatotoxicity associated with therapeutic doses of paracetamol has been studied in a report of two patients who were regular consumers of alcohol and who developed
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liver failure within 3–5 days after hospitalization and stopping alcohol consumption while being treated with paracetamol 4 g/day (4A). The serum paracetamol concentration in one of these patients was not in the toxic range. Possible susceptibility factors for hepatotoxicity in patients taking therapeutic doses of paracetamol were investigated. In patients with susceptibility factors, such as regular consumption of alcohol, liver failure is possi ble when therapeutic doses of paracetamol are taken. The authors therefore proposed that the dose of paracetamol should not exceed 2 g/day in such patients and that liver function should be monitored closely while they are taking paracetamol. Death Ethanol-related deaths occur at all ages, including children, as in the case of a 5-year-old boy who died after drinking ethanol at the party held by his parents (5A). Urine and blood concentrations were 4 and 5 g/l respectively, which might explain sudden death. In addition, analysis of his hair showed the presence of ethyl glucuronide, a marker of alcohol consumption, suggesting that he had probably drunk alcohol before death. There were pathological lesions in the liver consistent with this. Tumorigenicity Moderate alcohol intake has been associated with a modest (30–50%) increase in the risk of breast cancer, but it is unclear whether certain individuals have greater susceptibility to the harmful effects of alcohol (6r). Individuals differ in their ability to metabolize alcohol through genetic differences in alcohol dehydrogenase, the enzyme that catalyses the oxidation of about 80% of ethanol to acetaldehyde, a known carcinogen. Women with breast cancer have been studied to see whether they differ with respect to alcohol consumption and alcohol metabolism from their sisters without breast cancer, using data from the Breast Cancer Family Registry (n = 811 sister sets). Neither alcohol drinking nor alcohol metabolizing ADH1B and ADH1C genotypes were
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associated with breast cancer. However, only 19 and 42% of sisters were discordant for ADH1B and ADH1C respectively, and even fewer were discordant for both genotype and alcohol intake, making it difficult to detect differences if they existed.
Teratogenicity Alcohol consumption during pregnancy is another hazard, particularly for boys, as has been reported in a study of prenatal exposure to alcohol. The association between maternal alcohol consumption during pregnancy and cryptorchidism (undescended testis) among 2496 boys was examined in a prospective Danish–Finnish birth cohort study. There were 128 cases of cryptorchidism in 2368 boys and at 3 months of age 33 cases out of 2215 (7C). The odds for cryptorchidism increased with increasing weekly alcohol consumption. After adjustment for con founders (country, smoking, caffeine intake, binge episodes, social class, maternal age, parity, maturity, and birth weight), the odds remained significant for women who had a weekly consumption of five or more alcoholic drinks. The authors therefore concluded that regular alcohol intake during pregnancy increases the risk of congenital cryptorchidism. However, the mechanism for this association is unknown. Pregnant women should be advised to avoid alcohol.
Artificial sweeteners (SED-15, 348) Tumorigenicity Attempts have been made to determine the role of habitual use of the most common artificial sweeteners in the development of urinary tract tumors in 197 patients with histologically confirmed transitional tumors and 397 controls with acute, non-neoplastic, and non-urinary tract disease admitted to a hospital between 1999 and 2006 (8c). All were interviewed about their use of artificial sweeteners and exposure to other known or suspected risk factors for urinary tract tumors. Artificial sweeteners had been used by 51 patients with urinary tract tumors (26%) and 87
Miscellaneous drugs, materials, medical devices, and techniques
controls (22%). The risk of urinary tract tumors was significantly increased in those who had used artificial sweeteners for more than 10 years compared with non-users. The OR (95% CI) for long-term consumers was 2.18 (1.22, 3.89) and for short-term users 1.10 (0.61, 2.00) after adjustment for age, sex, BMI, social status, and years of tobacco use.
Bisphosphonates (SED-15, 523; SEDA-28, 590; SEDA-29, 602; SEDA-30, 561) Musculoskeletal Osteonecrosis of the jaw The range of adverse reactions to bisphos phonates has been reviewed, with particular emphasis on the association between longterm treatment and osteonecrosis of the jaw, a potentially serious adverse effect that occurs mostly in patients with multiple myeloma or breast cancer (9R). While the etiology is uncertain, there is a strong association with dental pathology and interventions, highlighting the need for close attention to dental health. The clinical features, predisposing factors, and treatment outcomes in patients with oral bisphosphonate-related osteonecrosis of the jaw have been studied retrospectively (10A). Of 98 patients with osteonecrosis of the jaw, 13 had used oral bisphosphonates and two were excluded because of previous adminis tration of intravenous bisphosphonates. In the other 11 patients the mean duration of alendronate use before osteonecrosis of the jaw was 4.1 years. It was triggered by dental surgery in nine patients and by ill-fitted den tures in two. Heavy smokers were particu larly at risk. Among the nine patients with at least 6 months of follow-up, the osteonecro sis healed completely in three, partially in four, and not at all in two. The authors con cluded that osteonecrosis of the jaw is a rare devastating adverse effect of oral bispho sphonates associated with a high financial burden. Osteonecrosis of the jaw associated with bisphosphonate therapy has been studied in 12 patients with multiple myeloma or bone
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metastases from solid tumors (11c). With drawal of the bisphosphonate was not asso ciated with resolution of the osteonecrosis, and surgical manipulation of the involved site worsened the underline bone pathology. Hyperbaric oxygen, which has proven effica cious in other forms of osteonecrosis by establishing an oxygen gradient, is of no defi nitive benefit to patients with bisphospho nate-induced exposed bone. Antibiotic therapy is useful in controlling pain and swel ling, but ineffective in preventing progression of the exposed bone. To date, prevention is the only possible therapeutic approach to the management of this complication. The frequency, clinical presentation, radiology, pathology, and treatment of osteonecrosis of the jaw due to bisphospho nates have been investigated in a prospec tive study of 80 patients, of whom 22 developed osteonecrosis (11 men and 11 women, median age 25 years) (12C). Ten of them had multiple myeloma, 5 had breast cancer and 7 had other malignancies; 14 had used zoledronate, 3 pamidronate, 4 pami dronate followed by zoledronate and 1 ibandronate followed by zoledronate. The median time of exposure was 32 months compared with 27 months in patients with out osteonecrosis. The mean induction time until bone exposure was 26 months for those who used zoledronate, 54 months for pamidronate, and 48 months for pamidro nate followed by zoledronate. There was exposure of the mandible in 13 cases, the maxilla in 6, and both jaws in 3. In 5 patients osteonecrosis occurred sponta neously and in 17 it occurred after tooth extraction. Nine had had previous extrac tions of molars, six of premolars, and two of front teeth. The cumulative hazard was 3.5 times higher in those using zoledronate than in the other groups. There was no association of osteonecrosis with age, sex, the use of high doses of conventional chemotherapy, or the use of glucocorticoids, thalidomide, or borte zomib. Patients with multiple myeloma and breast cancer were at higher risk. The prevalence of bisphosphonate associated osteonecrosis of the jaw has been studied in the catchment area of a university hospital maxillofacial unit in a
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retrospective study of all patients with osteonecrosis, osteomyelitis, and osteora dionecrosis treated for 5 years (13c). There was odontogenic or surgically induced osteomyelitis in 40%, osteoradio necrosis in 28%, osteonecrosis after treatment with bisphosphonates in 10%, osteomyelitis or sequestrum due to trauma in 8%, and osteomyelitis of unknown origin in 14%. All the patients with bisphosphonate-asso ciated osteonecrosis had had metastatic dis eases of the bone (plasmacytoma, breast carcinoma, and prostate cancer) for up to 5 years. All had been given a nitrogencontaining bisphosphonate (either pamidro nate or zoledronate). There had been a possible trigger, such as previous tooth extraction, pressure denture sore or period ontal disease in 13 of the 17 patients with bisphosphonate-associated osteonecrosis and in 14 of the 45 with osteoradionecrosis.
suggesting that fractures may indeed have an effect on mortality.
Osteoporosis On the other hand, osteoporosis is a silent disease, because skeletal deterioration proceeds with no outward symptoms until a symptomatic fracture occurs; the condition is therefore under-recognized and affected individuals are under-treated (14R, 15R). Vertebral fractures may not cause recognizable symptoms or the patient may present with an acute self-limiting episode of back pain. However, subclinical fractures are important predictors of future risks. People with vertebral fractures have an increased mortality rate, which extends beyond the first year. Reduced survival is difficult to attribute to direct effects of the fracture, and enhanced mortality appears to be a consequence of co-morbidities. All types of osteoporotic fractures are asso ciated with increased age-specific mortality; this effect lasts for at least 5 years after the fracture event and the impact is worse in men than in women (16R). In a randomized controlled trial of intravenous bisphospho nate in men and women with prior hip frac tures, there were reductions in subsequent fractures and mortality (17R). This study and others have shown increased mortality soon after a fracture and a subsequent return to the expected mortality rates,
Dimethylsulfoxide (DMSO)
Cyanoacrylates (SED-15, 1022) Tumorigenicity Cyanoacrylates are liquids that are used in the manufacture of polymers and adhesives. They have long been thought to be linked to malignancies. A 36-year-old man with pre-B cell acute lymphoblastic leukemia had used industrial strength glue to reattach a chipped tooth for about 1 year, and such use was associated with chronic exposure of his oral mucosa to the glue (18A). This case raises the possibility that chronic exposure to cyanoacrylates may be associated with acute lymphoblastic leukemia.
(SED-15, 1131) Nervous system Toxicity related to the infusion of dimethylsulfoxide (DMSO) cryopreserved peripheral blood stem cells mainly comprises cardiovascular events. Autologous stem cell transplantation complicated by cerebral infarction and myocardial damage has been reported (19A), and it has been postulated that DMSO may have been responsible. Of 51 patients who received DMSOpreserved peripheral blood stem cells, only one had neurotoxicity in the form of a gen eralized tonic seizure after the infusion (20A). However, there was no neurotoxicity in eight patients with pre-existing neurological dis ease, nor in patients who received particu larly large volumes of DMSO. In all patients, there were mild non-neurological adverse effects. • A 49-year-old man who received two infusions of DMSO-cryopreserved autologous peripheral blood progenitor cells after myeloablative chemotherapy for a relapsing lymphoma had a tonic–clonic seizure over a few minutes after the start of each infusion and developed a profound and sustained but reversible encephalopathy with coma after the second infusion (21A).
Miscellaneous drugs, materials, medical devices, and techniques His neurological condition correlated with the electrophysiological findings (electroencephalo graphy and multimodality evoked potentials) and to a lesser extent with MRI abnormalities. • A 50-year-old woman with nodular-sclerosing Hodgkin’s disease received stem cells cryo preserved in 10% DMSO, which were infused after high-dose conditioning with carmustine, etoposide, cytarabine, and melphalan, and pre medication with diphenhydramine 50 mg and hydrocortisone 200 mg (22A). After infusion of the second bag, she became pale, lost conscious ness, and developed mydriasis, trismus, and respiratory arrest. The stem cell infusion was immediately stopped. She was given phenytoin 15 mg/kg and assisted ventilation, and she recov ered consciousness in less than an hour. She was given intravenous phenytoin 4.5 mg/kg for 5 days and then switched to oral therapy. Later the remaining cryopreserved stem cells were reinfused and there were no adverse effects. A brain CT scan was normal but an electro encephalogram showed diffuse abnormalities in electrical activity with irregular slow-wave paroxysms. A brain MRI scan showed a small punctate area of hyperintensity in the right middle frontal lobe of unclear significance.
Disulfiram
(SED-15, 1148; SEDA-31, 760)
Cardiovascular A 27-year-old man took disulfiram and ethanol and developed significant hypotension and ischemic electrocardiographic changes (23A). He was treated with intravenous fluids and noradrenaline (norepinephrine), which has been advocated as the pressor agent of choice. Drug–drug interactions Dexamfetamine Disulfiram has also shown promise in several clinical trials for cocaine addiction, but its potential usefulness in the treatment of amphetamine addiction has not been examined. The effects of disulfiram, 250 mg/day for 4 days, on acute physiological and subjective responses to dexamfetamine have been studied in 10 healthy volunteers, 5 men and 5 women, in an outpatient crossover, double-blind, placebo-controlled study (24c). Disulfiram did not affect dexamfetamine-induced increases in heart rate, blood pressure, cortisol concentration, or prolactin, but it
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did enhance some of the subjective effects of dexamfetamine, including ratings of ‘high’, ‘anxious’, ‘bad drug effects’, ‘want more drug’, and ‘drug liking’, and was also associated with a reduced performance in the Sustained Attention to Response Test.
DYESTUFFS Fluorescein
(SEDA-29, 607)
Nervous system It is important to identify intraoperative leakage of cerebrospinal fluid (CSF) in successful closure after endoscopic cranial base surgery, for which intrathecal injection of fluorescein is useful. However, complications have been reported with various doses and the technique has fallen out of favor. Low-dose intrathecal fluorescein has been studied in a retrospective chart review and postoperative patient survey in 54 patients undergoing endoscopic cranial base surgery (25c). Intraoperative CSF leak was identified with fluorescein in 25 patients and helped determine the reconstruction technique. There was postoperative leakage of CSF in five patients and it resolved with lumbar drainage. There were no seizures. Most of the adverse events were non-specific, transient and probably not caused by fluorescein, including malaise (n = 31), headache (n = 30), dizziness (n = 17), or nausea and vomiting (n = 13). Three patients had persistent postoperative subjective leg weakness (n = 2) and numbness (n = 2); however, two of them had undergone lumbar drainage. The authors concluded that low-dose intrathecal fluorescein after premedication with a glucocorticoid and an antihistamine is generally safe. However, fluorescein should be administered with caution, because it can occasionally cause weakness and numbness in the legs. Immunologic The Netherlands Pharmaco vigilance Center has received reports of two anaphylactic reactions associated
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with fluorescein in a 49-year-old man and a 56-year-old woman; the woman subsequently died (26S).
Indocyanine green
(SED-15, 2595;
SEDA-31, 760) Sensory systems Visual field defects have been reported after macular hole surgery with indocyanine green-assisted internal limiting membrane peeling in a retrospective review of 140 eyes, in 96 of which indocyanine green 0.25% was used (27c). There were nasal visual field defects in 11 eyes, temporal visual field defects in 7 and concentric visual field defects in 1. In the group in whom indocyanine green was used, the visual field defects were far higher in the left eye than in the right. The authors speculated that the postoperative nasal visual field defects were caused by enhanced toxicity of indocyanine green, resulting from exposure to illumination. Changes in macular function and potential retinal toxicity have been studied using multifocal electroretinography after epiret inal membrane surgery in 13 eyes of 13 patients; internal limiting membrane peel ing was facilitated by staining with indocya nine green 0.5 or 1.25 mg/ml (28c). The median best corrected visual acuity improved from 20/70 at baseline to 20/30 at 6 months postoperatively. At 3 months those in whom indocyanine green 0.5 mg/ml had been used had no significant changes in multifocal electroretinographic N1 and P1 response amplitudes and peak latencies, whereas those in whom indocyanine green 1.25 mg/ml had been used had significant reductions in N1 and P1 response amplitudes compared with baseline. There were no sig nificant changes in either group at 6 months after surgery. These findings suggest that the use of a higher concentration of indocyanine green to stain the internal limiting membrane can result in transient retinal functional impairment postoperatively. The lowest pos sible concentration of indocyanine green should be used intraoperatively to minimize potential retinal toxicity.
N.H. Choulis
Tartrazine Tartrazine is a synthetic lemon yellow azo dye used as a food coloring; it can be com bined with Brilliant Blue FCF or Green S to produce various shades of green. Many foods contain tartrazine in varying propor tions, although nowadays the trend is to avoid it or to substitute a non-synthetic dyestuff, such as annatto, malt color, or b-carotene. Pharmaceutical products contain ing tartrazine include vitamins, antacids, med icinal capsules, and certain prescription drugs. In animals the acceptable daily intake was 7.5 mg/kg (29R). Extrapolating from these data, the estimated maximum theore tical intake of tartrazine in children is 37% of the acceptable daily intake at the 97.5th percentile. One can therefore conclude that toxic effects of tartrazine should not be expected in humans.
Immunologic Of all the azo dyes, tartrazine is the most allergenic and particularly causes reactions among asthmatics and those with aspirin intolerance. Symptoms from tartrazine hypersensitivity can occur from either ingestion or cutaneous exposure, and the effects can include anxiety, migraine, depression, blurred vision, itching, general weakness, hot sensations, a feeling of suffocation, purple skin patches, and sleep disturbances. It has been suggested that children with hyperactivity can develop increased irritability, restlessness, and sleep disturbances after taking tartrazine (30C).
Methylthioninium chloride (methylene blue) (SED-15, 2314; SEDA-28, 595; SEDA-29, 610; SEDA-30, 569) Drug–drug interactions Serotonergic drugs The UK MHRA has received two reports of nervous system toxicity when intravenous methylthioninium was used as a visualizing agent for thyroid or parathyroid surgery (31Sr). This has previously been attributed to an interaction with selective serotonin
Miscellaneous drugs, materials, medical devices, and techniques
reuptake inhibitors (SSRIs) (SEDA-30, 569). The MHRA has advised health-care professionals to • assess carefully the need for intravenous methylthioninium chloride for visualization in surgical procedures; • avoid methylthioninium chloride in patients who have recently used serotonergic drugs; • use the smallest possible dose of intravenous methylthioninium chloride if it cannot be avoided; • observe patients closely for nervous system effects for up to 4 hours after administration.
Nicotine
(SED-15, 2508; SEDA-29, 610; SEDA-30, 571; SEDA-31, 571)
Death In 90 smokers who were admitted to an intensive care unit and were given nicotine replacement therapy to prevent withdrawal, and who were matched, based on the severity of illness and age, with one control smoker who did not receive nicotine replacement therapy, the mean mortality rate predicted by the Acute Physiology and Chronic Health Evaluation III was 9.2% in the cases and 10.3% in the controls (32c). However, the observed hospital mortality rate was 20% in the cases and 7% in the control group. When adjusted for the severity of illness and invasive mechanical ventilation, nicotine replacement therapy was independently associated with increased mortality. Fetotoxicity Maternal smoking during pregnancy causes significant fetal morbidity and is a public health problem, as 36% of women in the UK and 11% of those in the USA smoke during pregnancy (33R). Behavioral support for smoking cessation, provided outside of routine antenatal care, is effective in promoting smoking cessation by pregnant women, but relatively few pregnant women have access to such support. Effective pharmacological aids to smoking cessation, which have been studied in non-pregnant populations, include nicotine replacement therapy, bupropion (amfebutamone), and
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varenicline. However, there is very little evidence to justify the use of these drugs in pregnancy, and it is doubtful that definitive trials of the effectiveness of either bupropion or varenicline for smoking cessation will be conducted in pregnant women in the foreseeable future. In the short-to-medium term, research information relating to the use of these drugs in pregnancy is therefore likely to be derived from observational studies, which are more difficult to interpret than clinical trials. There is therefore not enough evidence that nicotine replacement therapy is effective for smoking cessation in pregnancy and bupropion and varenicline cannot be recommended.
Sevelamer The FDA approved the use of sevelamer in 1998. It is a phosphate binder that is used to reduce the amount of phosphorus in the blood of patients with chronic kidney dis ease who are on dialysis. Its common adverse effects include diarrhea, infection, pain, vomiting, indigestion, low blood pres sure, headache, blood clot formation, reduced absorption of vitamins D, E, and K and folic acid, and bowel obstruction. Ser ious adverse effects that require medical attention include severe abdominal pain, new or worsening constipation, and other severe intestinal symptoms.
Comparative studies Raised serum phosphorus and calcium are associated with arterial calcification and mortality in dialysis patients. Unlike calcium-based binders, sevelamer attenuates arterial calcification, but it is not known whether it affects mortality or morbidity. In a multicenter, randomized, open study of all-cause and cause-specific mortality, sevelamer was compared with calcium-based binders in 2103 patients on hemodialysis of whom 1068 completed the study (34c). All-cause mortality rates and cause-specific mortality rates were not significantly different. However, there was a significant effect of
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age: the effect of sevelamer in reducing mortality was limited to patients over 65 years of age. There was a suggestion that sevelamer was associated with lower overall, but not cardiac, mortality in older patients.
Acid–base balance Sevelamer hydrochlor ide contains multiple amines, which may cause a significant dietary acid load. To evaluate the effect of sevelamer on arterial blood gases, two groups of patients on stable hemodialysis were followed for 24 months (35c). Those who were given sevelamer (n = 7) did not achieve the goals of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative (K/DOQI) for phosphorus and Ca � P product; those who were given calcium salts (n = 7) achieved those goals. Sevelamer was associated with worsening of chronic metabolic acidosis, which lasted throughout the study, and there were no significant changes in acid–base balance in the controls. The authors concluded that sevelamer caused small but persistent acid–base disturbances, which did not outweigh its beneficial effects on mineral and lipid metabolism. In a retrospective study the effect of seve lamer on metabolic acidosis was studied in 36 patients on hemodialysis and 36 matched for sex, diabetes mellitus, age and duration of dialysis who were not taking sevelamer (36c). Sevelamer significantly reduced the mean concentrations of bicarbo nate, base excess, and pH, but mean chloride concentrations and the anion gap did not change; there were no changes in the control group. The concentrations of bicarbonate, base excess, and pH correlated significantly with the daily dose and cumulative dose of sevelamer.
Talc
(SED-15, 3592; SEDA-29, 612)
Talc powder is widely used as an inert excipient in the manufacture of tablets and as a drying ingredient in baby powders.
N.H. Choulis
However, inappropriate use can cause severe unwanted effects. Respiratory Pulmonary embolism has been reported after the intravenous administration of talc and zinc oxide (37A). • A 74-year-old woman recovering from colonic surgery died immediately after receiving an intravenous infusion of about 1.5 ml of a white emulsion that was believed to contain 1% propofol. However, it was suspected that a zinc oxide shake lotion (containing 20% zinc oxide, 20% talc, 25% glycerol, and 35% water), intended for external treatment, had been mistaken for propofol. At autopsy, an anatomical cause of death could not be found. Propofol and other drugs that she had received were found in therapeutic or subtherapeutic concentrations. However, the concentration of zinc in the lungs was about 200 times higher than that found in a control case, 10 times higher in cardiac blood, and 3–4 times higher in kidney and liver tissues. There was no increase in venous blood. Histology showed a large pulmonary embolism containing birefringent sharp-edged crystals, which were identified as talc, and an amorphous component (zinc oxide). There were similar smaller emboli in the brain, heart, liver, pancreas and kidneys.
Sensory systems Talc from surgical gloves can cause granulomas in the conjunctivae, with chronic inflammation (38A). Respiratory Chronic exposure to talc during carpet installation resulted in silicopneumoconiosis in a 30-year-old man who had worked as a carpet installer for 15 years (39Ar).
Tumorigenicity A 68-year-old woman with stage III ovarian papillary serous carcinoma had used talc daily for 30 years to powder her genital area. Examination of her pelvic lymph nodes under polarized light microscopy showed diffuse areas of birefringence compatible with talc, confirmed by scanning electron microscopy and X-ray spectroscopy (40A).
Miscellaneous drugs, materials, medical devices, and techniques
Toluene The effects of toxic chemicals are usually studied in experimental animals for the pur pose of understanding and predicting their effects in humans. For this purpose, it is often assumed, as proposed by Lehman and Fitzhugh, that rats are less sensitive to the adverse effects than humans (41H). However, there is little direct evidence that this is so, because sufficient data for making this cross-species comparison are not available for most chemicals (42R). Cross-species comparisons are possible for the effects of toluene, a neurotoxic chemi cal, whose acute effects have been well documented in many studies (43c, 44c, 45E). These studies have provided a data base sufficient for a quantitative compari son of the sensitivities of rats and humans to the acute effects of toluene. Meta-analyses of these data have been previously pre sented (46ME). For regulatory purposes, it is necessary to quantify effects as a function of the magni tude of a subject’s external exposure to a toxic chemical, e.g. the concentration of toluene in the inhaled air. Many acute effects depend on the duration of exposure because of increasing uptake of the chemi cal with time. In risk assessment, the potency of a toxic chemical is often quanti fied by measuring the exposure or internal dose needed to produce an effect that lies on some threshold of statistical detectabil ity, e.g. a lowest observable adverse effect level (LOAEL) or a benchmark dose. Alternatively, potency can be expressed as the dose or exposure needed to obtain a certain degree of effect, such as the dose that produces 50% of the maximum effect (ED50). It is difficult to convert information on the acute neurotoxicity of organic solvents into predictive relations between exposure and effects in humans, because (1) the data are usually derived from experimental ani mals, whose sensitivity to the chemical rela tive to humans is unknown; (2) the specific end-points measured in laboratory animals seldom translate into effects of concern in humans and (3) the mode of action of the
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chemical is rarely understood. Ways of esti mating the hazard and cost of exposure to organic solvents have therefore been sought, focusing on the acute behavioral effects of toluene in rats and humans (47H). Available published data include studies of shock avoidance behavior in rats and choice reaction time in humans. A meta-analysis of these data has suggested that there is a 10% change in rat avoidance behavior at a blood concentration of toluene that is 25 times higher than the concentration at which a 10% change in human choice reaction time occurs. By con trast, in vitro studies have suggested that nicotinic acetylcholine receptors in humans and rats do not differ in sensitivity to toluene. Analysis of other dose–response relations for visual and cognitive functions in rats suggests that the apparent difference between rats and humans may be driven by the specific end-points measured in the two species rather than by inherent differences in sensitivity to toluene. It has also been suggested that doseequivalent relations can be used to compare the societal costs of two chemicals. For example, ethanol-induced changes in choice reaction time, for which societal costs can be estimated, can be used as a benchmark for estimating the monetary benefits of con trolling exposure to organic solvents. This dose-equivalence method is applicable to solvents, because the data fulfil three important assumptions about an equiva lence relationship based on a single effect: (1) a common dose metric (the concentra tion of the chemical in the brain); (2) a common effect to provide a linking variable (the choice reaction time); and (3) a com mon mode of action (interference with neu ronal ion channel function).
TECHNIQUES Arterial embolization The role of hepatic arterial embolization and chemoembolization has been assessed
900
in 60 patients with large-volume metastatic neuroendocrine tumors, melanomas, or gastrointestinal stromal tumors (GISTs) with over 75% liver involvement (48C). Radiological responses, progression-free survival, overall survival, and postprocedure complications were assessed. Of the 48 patients for whom follow-up imaging was available, there were partial responses in 12, minimal responses in 6, stable disease in 22 and progressive disease in 8. Median overall survival and progression-free survi val were 9.3 and 4.9 months respectively. Treatment resulted in radiological responses or disease stabilization in 82% and symptomatic responses in 65% of patients with neuroendocrine tumors. Patients with neuroendocrine tumors had higher response rates and longer survival than patients with melanoma and GISTs. There were major complications in 21
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N.H. Choulis
Table 1. Major complications after hepatic arterial embolization (48C) Complication (n)
Deaths
Tumor lysis syndrome (4) Anasarca (4) Hepatic failure (3) Myocardial infarction (2) Sepsis (2) Hepatic and renal failure (2) Renal failure (2) Hypertension (1) Pancreatitis (1)
1 1 2 2 2 2 1 1 0
patients after 23 of 123 sessions (Table 1). Nine of the 12 who died after major compli cations had additional susceptibility factors, including carcinoid heart disease, sepsis, and rapidly worsening performance status.
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