Sequence requirements for plasmid nuclear import.

The nuclear envelope is a major barrier for nuclear uptake of plasmids and represents one of the most significant unsolved problems of nonviral gene delivery. We have previously shown that the nuclear entry of plasmid DNA is sequence-specific, requiring a 366-bp fragment containing the SV40 origin of replication and early promoter. In this report, we show that, although fragments throughout this region can support varying degrees of nuclear import, the 72-bp repeats of the SV40 enhancer facilitate maximal transport. The functions of the promoter and the origin of replication are not needed for nuclear localization of plasmid DNA. In contrast to the import activity of the SV40 enhancer, two other strong promoter and enhancer sequences, the human cytomegalovirus (CMV) immediate-early promoter and the Rous sarcoma virus LTR, were unable to direct nuclear localization of plasmids. The inability of the CMV promoter to mediate plasmid nuclear import was confirmed by measurement of the CMV promoter-driven expression of green fluorescent protein (GFP) in microinjected cells. At times before cell division, as few as 3 to 10 copies per cell of cytoplasmically injected plasmids containing the SV40 enhancer gave significant GFP expression, while no expression was obtained with more than 1000 copies per cell of plasmids lacking the SV40 sequence. However, the levels of expression were the same for both plasmids after cell division in cytoplasmically injected cells and at all times in nuclear injected cells. Thus, the inclusion this SV40 sequence in nonviral vectors may greatly increase their ability to be transported into the nucleus, especially in nondividing cells.

Cell-specific nuclear import of plasmid DNA.

One factor limiting the success of non-viral gene therapy vectors is the relative inability to target genes specifically to a desired cell type. To address this limitation, we have begun to develop cell-specific vectors whose specificity is at the level of the nuclear import of the plasmid DNA. We have recently shown that nuclear import of plasmid DNA is a sequence-specific event, requiring the SV40 enhancer, a region known to bind to a number of general transcription factors (Dean DA, Exp Cell Res 1997; 230: 293). From these studies we developed a model whereby transcription factor(s) bind to the DNA in the cytoplasm to create a protein-DNA complex that can enter the nucleus using the protein import machinery. Our model predicts that by using DNA elements containing binding sites for transcription factors expressed in unique cell types, we should be able to create plasmids that target to the nucleus in a cell-specific manner. Using the promoter from the smooth muscle gamma actin (SMGA) gene whose expression is limited to smooth muscle cells, we have created a series of reporter plasmids that are expressed selectively in smooth muscle cells. Moreover, when injected into the cytoplasm, plasmids containing portions of the SMGA promoter localize to the nucleus of smooth muscle cells, but remain cytoplasmic in fibroblasts and CV1 cells. In contrast, a similar plasmid carrying the SV40 enhancer is transported into the nuclei of all cell types tested. Nuclear import of the SMGA promoter-containing plasmids could be achieved when the smooth muscle specific transcription factor SRF was expressed in stably transfected CV1 cells, supporting our model for the nuclear import of plasmids. Finally, these nuclear targeting sequences were also able to promote increased gene expression in liposome- and polycation-transfected non-dividing cells in a cell-specific manner, similar to their nuclear import activity. These results provide proof of principle for the development of cell-specific non-viral vectors for any desired cell type.

Nuclear targeting of plasmid DNA in human corneal cells.

PURPOSE: To characterize the mechanisms of plasmid DNA nuclear localization in primary cultures of human corneal epithelial cells and keratocytes. METHODS: Purified, supercoiled plasmid DNA was microinjected into the cytoplasm of human corneal epithelial cells and keratocytes that had been established from donor corneas two to three passages previously, and localized 8 hours later by in situ hybridization. To confirm the sequence-specificity of nuclear import observed in microinjected cells, liposome-mediated transient transfection experiments also were performed on human corneal epithelial cell and keratocyte cultures. RESULTS: Primary cultures of human corneal epithelial cells and keratocytes have the capacity to transport plasmid DNA from the cytoplasm to the nucleus in the absence of cell division. This transport activity is sequence-dependent requiring portions of the simian virus 40 (SV40) early promoter and enhancer. The majority of this nuclear transport activity resides within the enhancer domain of the SV40 DNA, a region rich in transcription factor binding sites. This DNA nuclear import sequence also manifested itself in liposome-mediated transfection experiments, causing a greater than 2-fold increase in reporter gene expression in human corneal cells in a beta-galactosidase-expressing vector and up to a 1000-fold increase in a luciferase-expressing vector when compared to similar expression plasmids lacking the sequence. CONCLUSION: These results demonstrate that primary, non-transformed human corneal epithelial cells and keratocytes display sequence-specific nuclear import of plasmid DNA in the absence of mitosis. The small sequence that mediates nuclear localization of plasmids is active both in microinjected and cationic liposome transfected cells, and leads to increased gene expression. Thus, inclusion of this DNA sequence into non-viral vectors should improve the efficiency of ocular gene transfer in vivo.

Nuclear import of plasmid DNA in digitonin-permeabilized cells requires both cytoplasmic factors and specific DNA sequences.

Although much is known about the mechanisms of signal-mediated protein and RNA nuclear import and export, little is understood concerning the nuclear import of plasmid DNA. Plasmids between 4.2 and 14.4 kilobases were specifically labeled using a fluorescein-conjugated peptide nucleic acid clamp. The resulting substrates were capable of gene expression and nuclear localization in microinjected cells in the absence of cell division. To elucidate the requirements for plasmid nuclear import, a digitonin-permeabilized cell system was adapted to follow the nuclear localization of plasmids. Nuclear import of labeled plasmid was time- and energy-dependent, was inhibited by the lectin wheat germ agglutinin, and showed an absolute requirement for cytoplasmic extract. Addition of nuclear extract alone did not support plasmid nuclear import but in combination with cytoplasm stimulated plasmid nuclear localization. Whereas addition of purified importin alpha, importin beta, and RAN was sufficient to support protein nuclear import, plasmid nuclear import also required the addition of nuclear extract. Finally, nuclear import of plasmid DNA was sequence-specific, requiring a region of the SV40 early promoter and enhancer. Taken together, these results confirm and extend our findings in microinjected cells and support a protein-mediated mechanism for plasmid nuclear import.

A validated, reliable method of scoring the severity of medication errors.

A method of scoring the severity of medication errors that does not require knowledge of patient outcomes was developed and tested. Thirty health care professionals from four U.K. hospitals scored 50 medication errors in terms of potential patient outcomes on a scale of 0 to 10, where 0 represented a case with no potential effect and 10 a case that would result in death. Sixteen error cases reported in the literature with actual patient outcomes were included among the cases to assess the validity of the scores. Ten of the errors were scored twice. The severity of the error cases, the occasion on which they were scored, the judge, each judge's profession, and the interactions between these were considered as potential sources of variability in scoring. The data were analyzed by applying generalizability theory to two models: one based on the 10 cases that were scored twice and ignoring the effect of differences in profession and one based on all 50 cases and ignoring the effect of the occasion of scoring. Generalizability coefficients for different numbers of judges and scoring occasions were calculated. A generalizability coefficient of 0.8 or more was considered to represent acceptable reliability. Most of the variance was attributable to differences in the cases. The analysis showed that, to achieve a generalizability coefficient of more than 0.8, at least four judges would have to score each case, each on one occasion, with the mean score used as a severity indicator. A reliable, valid method of scoring the severity of medication errors that did not require knowledge of patient outcomes was developed; at least four judges were required in order to achieve reliable scores, and reliability was not affected by the professions of the judges or the number of occasions on which the errors were scored.

Mathematical modeling of pharmacy systems.

Mathematical modeling and its potential applications in pharmacy are discussed. A model is a simplified representation of the real world. As an experimental approach, modeling minimizes expense, risk, and disruption, but its validity can be hard to ascertain. Mathematical models describe numerically the relationships among elements of a system and are a powerful tool in making decisions affecting that system. There are two types of mathematical models: analytical models, which directly describe the relationships between system inputs and outputs using mathematical equations (such as pharmacokinetic models), and simulation models, which involve the replication, usually with a computer, of events as they occur in the real world. Analytical models are easier to develop but are not appropriate for describing highly complex systems. In continuous-time simulation, the system is represented as an uninterrupted flow of material; in discrete-event simulation, it is assumed that events occur only at distinct times. Various simulation programs are commercially available. The stages of a mathematical modeling study are (1) formulate the problem, (2) determine the model's structure, (3) collect and analyze initial data, (4) develop the model further, (5) validate the model, (6) experiment using the model, and (7) use the results. There have been many applications of modeling in health care, but relatively few have involved the study of pharmacy systems. Mathematical modeling offers pharmacists a low-risk, low-cost tool for aiding decisions about pharmacy systems by predicting alternative futures.

Assessment of learning by emergency medicine residents and pharmacy students participating in a poison center clerkship.

An AAPCC-designated poison center developed and validated an objective testing instrument to evaluate learning during a poison center clinical rotation for 2nd-year emergency medicine residents and 5th-year pharmacy students. The examination contained multiple-choice, true-false, and fill-in questions pertaining to basic clinical toxicology. A pretest was administered prior to the rotation and a post-test was administered upon completion of the rotation. Overall pre-test mean was 56.2%; physician pre-test mean was 73.8%, and student pre-test mean was 43.9%. Overall post-test mean was 78.7%; physician post-test mean was 85.7%, and student post-test mean was 81%. Pre-test scores ranged from 21 to 86% for the group, and post-test scores ranged from 68 to 96%. The mean difference in pre-test to post-test score was 26.9%. These data suggest that a poison center rotation can result in significant increases in post-test scores in comparison to pre-test scores.

Outpatient N-acetylcysteine treatment for acetaminophen poisoning: an ethical dilemma or a new financial mandate?

The mainstay of treatment for acetaminophen-induced hepatotoxicity, produced by the accumulation of the toxic metabolite N-acetylbenzoquinoneimine, is an enteral 18-dose course of N-acetylcysteine (NAC). However, absence of characteristic symptomatology is a frequent reason for premature cessation of NAC and early discharge of the toxic acetaminophen poisoned patient. We report a series of confirmed acetaminophen poisonings who were discharged early with NAC and instructions to self-administer. All cases of acute acetaminophen poisoning without concomitant drugs, reported to a certified Regional Poison Information Center for a 3-mo period of time, were reviewed. Inclusion criteria included patients who were discharged with orders to complete the course of NAC outside of a hospital, despite toxic serum acetaminophen concentrations. Data parameters evaluated included age, amount taken, symptoms, laboratory results, treatment, and medical outcome. 131 cases of confirmed toxic acetaminophen poisoning yielded 6 patients who received 4 to 6 doses of NAC during hospitalization, but were discharged to home with the remaining 11-13 doses. Patients' ages ranged from 16-28 y (mean 20.0 y). Serum acetaminophen concentrations measured at 4 h post-ingestion ranged from 171-198 mcg/ml (mean 182 mcg/ml). Follow-up by the certified Regional Poison Information Center at 1-3 w post-discharge determined dosing compliance to be 83%. All 6 patients remained asymptomatic with normal liver function testing. Since health care reform encourages practitioners to reconsider established approaches to the delivery of health care, perhaps home delivery of NAC would not only be clinically preferred to premature cessation of the antidote, but also offer cost savings. Self-administration of NAC in the home setting may be representative of a new era in America's health care delivery system.

Iron complexation with oral deferoxamine in a swine model.

A controversial therapy in the management of acute iron poisoning is the oral administration of deferoxamine which purportedly complexes unabsorbed iron, exerts protection at the cellular level, and/or enhances the renal elimination of ingested iron. To study the effects of oral deferoxamine on iron absorption, fasted male pigs weighing an average of 10 kg simulated potentially toxic iron overdoses in 12 to 24-mo-old children. A control group of 13 pigs received 60 mg elemental iron/kg via oral gavage followed by 50 ml of distilled water. Serum iron (SI) levels were obtained at 0, 1 2, 4, 6 and 8 h post-iron dosing. The study group of 10 pigs received 60 mg elemental iron/kg po followed by 10 g deferoxamine (1 g/kg). SI levels were obtained at the same intervals. There was no mortality in either group. Statistical differences in SI were noted at 6 and 8 h. Characteristic urine discoloration secondary to deferoxamine was noted at 4 h in the study group. Deferoxamine reduced some peak 51 levels but did not diminish the total absorption of iron.

Comparison of medication errors in an American and a British hospital.

Medication errors in a hospital in the United States and a hospital in the United Kingdom were compared. The study was conducted in wards with a high oral-drug-related workload in two large university hospitals. The U.S. hospital was studied in August 1993 and the U.K. hospital in May and June 1993. The U.S. hospital had a typical unit dose drug distribution system, and the U.K. hospital had the ward-based system commonly used in that country, in which a pharmacist visits each ward several times daily and reviews each patient's medication chart. The medication chart is used by the physician to order drugs and obviates the need for transcription of orders. A disguised-observation technique was used to determine frequencies and types of medication errors. Medication errors were identified retrospectively in the U.S. hospital by comparing the observer's notes with the original drug orders made in the patient's chart by the physician. In the U.K. hospital, identification of errors took place concurrently; as doses were administered, they were compared with the orders on the medication chart. In the U.S. and U.K. hospitals, 919 and 2756 opportunities for error were observed, respectively. The medication error rate in the U.S. hospital was 6.9% (95% confidence interval [CI], 5.2% to 8.5%), significantly higher than the 3.0% rate observed in the U.K. hospital (95% CI, 2.4% to 3.7%) (95% CI for the difference, 2.1% to 5.7%). Omitted doses and incorrect doses were the most common types of errors in the U.K. hospital; incorrect doses and unordered doses were the most common types in the U.S. hospital. An American hospital with a unit dose distribution system had a significantly higher medication error rate than a British hospital with a ward-based supply system.

A demographic profile of the Specialist in Poison Information.

In 1983 the first certification examination was administered to Specialists in Poison Information (SPI). This marked the first attempt to validate the status of professionals working in poison centers as a separate entity in the field of medicine and toxicology. Not all specialists are certified, therefore the process characterizes only a portion of those currently practicing. To establish a demographic profile of all SPI's currently practicing in poison centers, a questionnaire was developed and sent to all SPI utilizing the American Association of Poison Control Center's (AAPCC) mailing list. A 57-response survey encompassing a variety of topics affecting SPI's was developed and mailed to 607 currently practicing SPI's (288 Certified SPI's and 319 SPI's). Among the requested information were demographics such as age, educational degrees, years worked at the poison center, and percent of time spent answering poison calls. SPI's were also asked to identify whether their center was certified. Responses were then tabulated and analyzed. One-hundred eighty-three surveys were completed and returned. One-hundred twenty-nine (70%) were Certified SPI's and 54 (30%) were not, although 11 had taken the examination unsuccessfully. Fifty and three-tenths percent of the respondents had worked 1-5 y at a poison center, 35% 5-10 y and 14.7% had greater than 10 y experience. Fifty-six and three-tenths were nurses, 36.1% pharmacists, and 7.6% were classified as "other". This category included MD's, EMT's and those having educational degrees other than the aforementioned.(ABSTRACT TRUNCATED AT 250 WORDS)

The cost of employee turnover to a regional poison information center.

The quality and effectiveness of a regional poison information center (RPIC) are directly related to the skills and experience of the professional staff of specialists in poison information and to having the appropriate number of individuals in order to accurately and concisely respond to the thousands of telephone calls concerning acute/chronic poisoning emergencies. Since RPICs are traditionally small departments, the loss of even 1 key staff member can cause devastating results. A realistic appraisal of the actual costs associated with employee turnover was done at our RPIC and considered the following items: Advertising and recruiting expenses; interviewing expenses; processing costs; orientation and training expenses; and overtime costs including fringe benefits and premium shift differentials. The over-all tangible costs related to turnover of an individual who is certified or qualified to be certified as a specialist in poison information is approximately $17,486. The specific cost categories included advertising/recruiting, $326; interviewing expenses, $360; orientation and training, $9,250; processing, $350; overtime monies, $7,200. The less tangible effects of turnover cannot be strictly measured in dollars, but can be reflected in reduced quality assurance factors, increased sick time, and decreased morale. While staff salaries and benefits usually account for 75% to 85% of a RPIC's operating budget, and since external sources of revenue do not offset the operational expenses, it is becoming increasingly difficult to remain competitive in today's current professional salary climate. While the loss of talent and its cumulative effect on quality is impossible to quantitatively measure, we have attempted to calculate the real financial burden associated with replacing personnel.(ABSTRACT TRUNCATED AT 250 WORDS)

Poison center funding--who should pay?

To illustrate costs associated with poison center closure a survey of lay callers to the poison center and emergency department costs was conducted. For 21 days all callers to a Regional Poison Information Center receiving home treatment were asked the type of health insurance coverage the patient had. This information was documented on the medical record and tabulated. Health care costs were determined by surveying local hospitals. Of the callers, 1,276 (43%) provided insurance information: 928 (73%) of the patients were covered by private insurers; 258 (20%) received state medical assistance and 90 (7%) had no medical coverage. The average emergency department cost of an ingestion exposure was $210.75, ocular $172.22, and inhalation $298.03. In the absence of a Regional Poison Information Center responding to 61,000 calls annually, the state would incur a debt ranging from 1.27 to 2.20 million dollars if 60% of those covered under state assistance went to the emergency department. Private insurers would forfeit 4.58 to 7.93 million dollars per year. These cost estimates consider only the emergency department charges, not unnecessary admissions. State government and private insurers clearly are the financial beneficiaries of poison center services which save several times their operating costs.

Ceramic lead glaze ingestions in nursing home residents with dementia.

Three cases of acute lead ceramic glaze ingestions that occurred in elderly patients during art therapy classes in nursing homes are reported. Initial blood lead levels were 109 micrograms/dL (5.23 mumol/L), 259 micrograms/dL (10.43 mumol/L), and 85 micrograms/dL (4.08 mumol/L), respectively, and all patients underwent chelation therapy. Two individuals tolerated therapy well and showed no discernable changes from baseline state. One patient with a lead encephalopathy died and is, to the best of our knowledge, the first report of a death directly related to a ceramic lead glaze ingestion. Ceramic lead glaze ingestions among institutionalized patients may be more common than generally appreciated and occasionally are associated with significant morbidity or, rarely, mortality. Simple preventive measures could eliminate the majority of such occurrences.

Coma reversal with cerebral dysfunction recovery after repetitive hyperbaric oxygen therapy for severe carbon monoxide poisoning.

The accepted beneficial effects of hyperbaric oxygen (HBO) include a greatly diminished carboxyhemoglobin (COHgb) half-life, enhanced tissue clearance of residual carbon monoxide (CO), reduced cerebral edema, and reversal of cytochrome oxidase inhibition, and prevention of central nervous system lipid peroxidation. Debate regarding the criteria for selection of HBO versus 100% normobaric oxygen therapy continues, and frequently is based solely on the level of COHgb saturation. Patients who manifest signs of serious CO intoxication (unconsciousness, neuropsychiatric symptoms, cardiac or hemodynamic instability) warrant immediate HBO therapy. An unresponsive 33-year-old woman was found in a closed garage, inside her automobile with the ignition on. Her husband admitted to seeing her 6 hours before discovery. 100% normobaric oxygen was administered in the prehospital and emergency department settings. The patient had an initial COHgb saturation of 46.7%, a Glasgow coma score of 3, and was transferred for HBO therapy. Before HBO therapy, the patient remained unresponsive and demonstrated decerebrate posturing and a positive doll's eyes (negative oculocephalic reflex). The electroencephalogram pattern suggested bilateral cerebral dysfunction consistent with a toxic metabolic or hypoxic encephalopathy. The patient underwent HBO therapy at 2.4 ATA for 90 minutes twice a day for 3 consecutive days. On day 7, the patient began to awaken, was weaned from ventilatory support, and was not soon verbalizing appropriately. A Folstein mental status examination showed a score of 26 of 30. Neurological examination demonstrated mild residual left upper extremity weakness and a normal gait. There was no evidence of significant neurological sequelae at 1 month follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)

Illiteracy: a contributing factor to poisoning.

It is estimated that over 60 million Americans (1/3 of the adult population) are functionally or marginally illiterate. To recognize and gain an understanding of illiteracy and its impact on poisoning, we determined if the illiterate in our community could recognize potential poisons. A prospective study involving 29 male and 21 female adult illiterates was undertaken. A personal interview was conducted to determine their ability to purchase medication and household products, their understanding of the uses and associated dangers of medications, and their manner of storage of these products in their homes. Of the participants, 66% were at reading levels of 0-3rd grade and 34% were at 3rd through 6th grade reading level. Each participant was shown 3 separate products and asked to distinguish and interpret caution statements and directions. In the 0-3rd grade group, 30% were unable to identify any of the products and none could explain the cautions or directions. In the second group (3rd-6th grade), all were able to identify the products and 76% could explain the cautions; everyone in this group correctly read the directions. We concluded that a large percentage of the adult population are potential poisoning victims due to their inability to read and comprehend label instructions. Poison Centers should recognize illiteracy as a contributing factor in poisonings and consider education and prevention programs for this segment of our population.

Home exposures to chlorine/chloramine gas: review of 216 cases.

Chlorine and chloramine gas are frequently produced in the home when cleaning products are mixed. These gases are strong irritants with the potential for tissue damage. Numerous literature citations report industrial exposures to chlorine/amine gas, but there are few reports regarding home exposures. The purpose of this study was to determine symptoms, treatment, and outcome in individuals exposed to these gases in the home. All exposures to chlorine/amine gas produced as a result of mixing cleaning products in the home and reported to a Regional Poison Information Center (RPIC) over a 12-month period were reviewed. All calls were documented and follow-up was done at appropriate intervals. All patients with respiratory embarrassment either at the initial contact or on follow-up were referred to a medical facility. Of the 216 patients (ages 12 to 81 years), 200 had resolution of symptoms within 6 hours, whereas only 16 had symptoms for more than 6 hours after exposure; 145 patients were treated at home and 71 received further medical care. Ten symptoms were identified, with the majority of patients experiencing more than one. Emergency room treatment included oxygen (62 patients), bronchodilators (9 patients), and steroid therapy (3 patients). Of the 70 patients who had chest x-ray films, only one had a positive finding; 41 had arterial blood gas measurements done, and all were within normal limits. Only one patient in the study group required admission for continued respiratory distress, but he had a preexisting chronic respiratory problem as well as an upper respiratory tract infection at the time of exposure. Although the gas produced by mixing cleaning products in the home can cause severe respiratory irritation, most of the patients exposed to chlorine and chloramine gas can safely be treated at home with comfort measures. Appropriate follow-up must be done to determine resolution of symptoms.

Air bags: lifesaving with toxic potential?

Federal Motor Vehicle Safety Standard No. 208, "Occupant Crash Protection", requires that all passenger cars manufactured after September 1, 1989 be equipped with automatic crash protection. Car manufacturers met this requirement by installing automatic safety belts or air bags. No chemical injuries have been reported as a result of air bag deployment in motor vehicle accidents (MVA). A 6-month retrospective study was conducted to evaluate the toxic effects of the white powdery residue from air bags, a combination of talc and sodium hydroxide, found in the driver compartment after an MVA. The study reviewed time to onset of symptoms, symptomatology, and treatment. The study included seven patients exposed to deployed air bags after an MVA. Four cases resulted in dermal burns and three patients were diagnosed with unrelated injuries. Three patients presented to an emergency department within 48 hours of the exposure complaining of burns to the skin. Two patients attempted home therapy but became concerned when the symptoms did not subside. One patient was discharged with the diagnosis of first degree burns of the chin and left hand. Another patient experienced bilateral hand erythema and blisters. Standard burn therapy was instituted in both instances. A third patient arrived 1 hour post-exposure to the emergency department complaining of a burning sensation to the hands, but the skin appeared normal. Thorough irrigation was initiated and Silvadene (Marion, Kansas City, MO) applied. One patient notified the poison center 1 hour post-exposure complaining of erythema and burning to his hands after an MVA.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute nickel carbonyl poisoning.

Nickel carbonyl [Ni(CO)4], is formed when metallic nickel combines with carbon monoxide. It is used in the refining process of nickel and as a catalyst in petroleum, plastic, and rubber production. Nickel carbonyl is considered to be one of the most toxic chemicals used industrially and the magnitude of its morbidity and mortality has been compared to that of hydrogen cyanide. A 46-year-old man presented to the emergency department 24 hours after accidental occupational exposure to nickel carbonyl. He admitted to dermal contamination and inhaling the vapor from his clothing after his respiratory protection was removed. On presentation the patient was alert and oriented, complained of shortness of breath, chest tightness, and paresthesias. Examination revealed decreased breath sounds bilaterally and arterial blood gas PO2 of 39% with calculated O2 saturation of 75%. After face mask O2 at 60% his PO2 increased to 85%. The patient required 60% O2 with continuous positive airway pressure of 5 for 4 days. Disulfiram (Antabuse) was administered for the first 2 days until sodium diethyldithiocarbamate (dithiocarb) was obtained. Disulfiram was used because it is metabolized to two molecules of dithiocarb and is hypothetically of value. Dithiocarb was obtained and continued over the next several days. The patient's urine nickel level on the day of admission was 172 micrograms/dL (normal < 5 micrograms/dL) and a serum level of 14.6 micrograms/dL (normal .26-.46 micrograms/dL). The patient's condition gradually improved over the next 10 days. Nickel carbonyl exposure produces mild transient initial symptoms which are followed within 24 hours by more severe life-threatening events.(ABSTRACT TRUNCATED AT 250 WORDS)

Orthotopic liver transplants necessitated by acetaminophen-induced hepatotoxicity.

BACKGROUND: Acetaminophen-induced hepatotoxicity has been recognized since 1966. Patients experiencing a massive hepatic insult due to acetaminophen (APAP) may recover with minimal residual complications or develop fulminant hepatic necrosis. We report 3 patients with hepatic failure due to an APAP overdose who received orthotopic liver transplants and survived. CASE REPORTS: An 18-y-o female ingested 60 500 mg APAP tablets (30 g). She presented with tachycardia and lethargy stating that she had taken amoxipine, carbamazepine, and lorazepam. She began to recover but on day 2 experienced an upper gastrointestinal bleed and became hypotensive and hyperpyrexic. She developed hepatic encephalopathy and it was then determined she had ingested APAP. Her APAP level was 13 micrograms/ml 96 h post-ingestion. She was successfully transplanted 19 d post-ingestion with recovery. A 40-y-o female was admitted for flu-like symptoms persisting for 7 d. She was jaundiced, hyperventilating and hypotensive. She admitted ingesting approximately 17 g APAP over 36 h. Her APAP level was 12.2 micrograms/ml. Her condition worsened and on day 3 she was in grade IV coma. She was successfully transplanted 4 d post-arrival with recovery. A 16-y-o female ingested an unknown amount of APAP. She presented approximately 24 h post-ingestion with a serum APAP level of 130 micrograms/ml. Her condition deteriorated and she became encephalopathic with grade IV coma. She was successfully transplanted on day 7 post-arrival. DISCUSSION: Hepatotoxicity can occur as a result of either acute or chronic APAP overdose. Although n-acetylcysteine (NAC) is effective antidotal therapy, it must be used within 8-12 h post-ingestion to be optimally effective. Inaccurate patient histories may prevent NAC administration resulting in hepatotoxicity. CONCLUSION: Liver transplantation is a viable option to be considered in those APAP overdose patients who experience rapidly progressing encephalopathy, hemolysis, and hepato-renal failure.