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Maintenance immunosuppression for lung transplantation includes cyclosporine or tacrolimus, mycophenolate mofetil or azathioprine, and prednisone. Some centers rely on induction agents including OKT3 (murine monoclonal antibody, OKT3), ATG (antithymocyte globulin), or thymoglobulin. In addition, a number of new agents including sirolimus (SRL) and the interleukin (IL)-2 receptor antagonists, daclizumab and basiliximab, have become available. Management of chronic rejection typically consists of augmented immunosuppression using many of the standard agents, and other potent agents such as methotrexate or cytoxan or more novel strategies including photopheresis, radiation, and total lymphoid irradiation (TLI).

Objective: To report a case demonstrating the importance of monitoring unbound valproic acid (VPA) serum concentrations in a patient with hypoalbuminemia., Case Summary: A 53-year-old white woman status-post heart transplantation was admitted to the hospital for declining cardiac function, possible rejection, and increased lethargy requiring intubation. An extensive workup of the patient's profound lethargy was initiated, including an evaluation of her VPA regimen. Initially, VPA dosages were adjusted based on the total serum concentration of VPA. Hypoalbuminemia compounded with increased lethargy prompted the measurement of unbound serum concentrations of VPA. The VPA dosage was then adjusted based on the unbound rather than the total VPA serum concentration; the patient eventually improved and was discharged from the hospital., Discussion: Lethargy is a concentration-related adverse effect of VPA. The nonlinear pharmacokinetic and protein saturation characteristics of VPA may result in nonproportional elevations in unbound drug, and subsequent increases in adverse effects, when dosage adjustments are based solely on measurement of total VPA serum concentrations in patients with hypoalbuminemia., Conclusions: This case report suggests that appropriate monitoring of unbound drug concentrations of VPA may prevent unrecognized concentration-related adverse effects. Awareness of the pharmacokinetic relationship and adverse effects of VPA will aid clinicians in identifying the etiology of symptoms.

Cannabinoids, including the endogenous ligand arachidonyl ethanolamide (anandamide), elicit not only neurobehavioral but also cardiovascular effects. Two cannabinoid receptors, CB1 and CB2, have been cloned, and studies with the selective CB1 receptor antagonist SR141716A have implicated peripherally located CB1 receptors in the hypotensive action of cannabinoids. In rat mesenteric arteries, anandamide-induced vasodilation is inhibited by SR141716A, but other potent CB1 receptor agonists, such as HU-210, do not cause vasodilation, which implicates an as-yet-unidentified receptor in this effect. Here we show that "abnormal cannabidiol" (Abn-cbd) is a neurobehaviorally inactive cannabinoid that does not bind to CB1 receptors, yet causes SR141716A-sensitive hypotension and mesenteric vasodilation in wild-type mice and in mice lacking CB1 receptors or both CB1 and CB2 receptors. Hypotension by Abn-cbd is also inhibited by cannabidiol (20 microgram/g), which does not influence anandamide- or HU-210-induced hypotension. In the rat mesenteric arterial bed, Abn-cbd-induced vasodilation is unaffected by blockade of endothelial NO synthase, cyclooxygenase, or capsaicin receptors, but it is abolished by endothelial denudation. Mesenteric vasodilation by Abn-cbd, but not by acetylcholine, sodium nitroprusside, or capsaicine, is blocked by SR141716A (1 microM) or by cannabidiol (10 microM). Abn-cbd-induced vasodilation is also blocked in the presence of charybdotoxin (100 nM) plus apamin (100 nM), a combination of K(+)-channel toxins reported to block the release of an endothelium-derived hyperpolarizing factor (EDHF). These findings suggest that Abn-cbd and cannabidiol are a selective agonist and antagonist, respectively, of an as-yet-unidentified endothelial receptor for anandamide, activation of which elicits NO-independent mesenteric vasodilation, possibly by means of the release of EDHF.

Depression is a significant post-transplant complication often necessitating drug therapy. Many of the newer selective serotonin reuptake inhibitor (SSRI) antidepressants are metabolized by the same cytochrome P450IIIA isoenzyme system that is responsible for the metabolism of cyclosporine, and these agents pose an interactive risk in transplant patients. We have observed nearly a 10-fold increase in whole blood cyclosporine concentrations in a cardiac transplant patient shortly after the addition of nefazodone antidepressant therapy. We suggest there is a clinically significant drug-drug interaction between nefazodone and cyclosporine due to inhibition of cytochrome P-450 IIIA4 isoenzymes by nefazodone.

Whether hepatitis C virus (HCV)-positive candidates or donor organs should undergo transplantation remains controversial. Seventy-two thoracic transplantation centers responded to a survey soliciting specific information about policies regarding the listing of HCV-positive candidates and the use of HCV-positive donor organs. Most centers (64%) list HCV-positive candidates for heart transplantation. Twenty-six percent of centers refuse to use HCV-positive organs, whereas the remainder restrict the use of HCV-positive organs to status 1 recipients or HCV-positive candidates. More information is needed regarding the clinical outcomes of HCV-positive candidates and recipients of HCV-positive organs before clear-cut candidate selection and organ allocation policies can be established.

Previous studies indicate that the CB1 cannabinoid receptor antagonist, N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-met hyl-1H-pyrazole-3-carboxamide HCl (SR141716A), inhibits the anandamide- and delta9-tetrahydrocannabinol- (THC) induced hypotension and bradycardia in anesthetized rats with a potency similar to that observed for SR141716A antagonism of THC-induced neurobehavioral effects. To further test the role of CB1 receptors in the cardiovascular effects of cannabinoids, we examined two additional criteria for receptor-specific interactions: the rank order of potency of agonists and stereoselectivity. A series of cannabinoid analogs including the enantiomeric pair (-)-11-OH-delta9-THC dimethylheptyl (+)-11-OH-delta9-THC dimethylheptyl were evaluated for their effects on arterial blood pressure and heart rate in urethane anesthetized rats. Six analogs elicited pronounced and long lasting hypotension and bradycardia that were blocked by 3 mg/kg of SR141716A. The rank order of potency was (-)-11-OH-delta9-THC dimethylheptyl > or = (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol > (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol > THC > anandamide > or = (-)-3-[2-hydroxy-4-(1,1-dimethyl-heptyl)phenyl]-4-[3-hydroxy-propyl]c yclohexan-1-ol, which correlated well with CB1 receptor affinity or analgesic potency (r = 0.96-0.99). There was no hypotension or bradycardia after palmitoylethanolamine or (+)-11-OH-delta9-THC dimethylheptyl. An initial pressor response was also observed with THC and anandamide, which was not antagonized by SR141716A. We conclude that the similar rank orders of potency, stereoselectivity and sensitivity to blockade by SR141716A indicate the involvement of CB1-like receptors in the hypotensive and bradycardic actions of cannabinoids, whereas the mechanism of the pressor effect of THC and anandamide remains unclear.

We studied the effects of the endogenous cannabinoid ligand anandamide on blood pressure, single unit activity of barosensitive neurons in the rostral ventrolateral medulla, and postganglionic splanchnic sympathetic nerve discharge in urethane-anesthetized rats. In rats with an intact baroreflex, an intravenous bolus of 4 mg/kg anandamide caused a triphasic blood pressure response: transient hypotension, followed by a brief pressor and more prolonged depressor phase. Anandamide evoked a "primary" increase in neuronal firing coincident with its pressor effect and a "secondary," baroreflex-mediated rise coincident with its depressor effect at both sites. Pretreatment of rats with phentolamine or trimethaphan did not inhibit either the pressor response or the primary increase in splanchnic nerve discharge elicited by anandamide. In barodenervated rats, electrical stimulation of the rostral ventrolateral medulla increased blood pressure and splanchnic nerve discharge. Anandamide treatment blunted the rise in blood pressure without affecting the increase in splanchnic nerve discharge. Anandamide did not affect the rise in blood pressure in response to an intravenous bolus dose of phenylephrine. The results indicate that (1) the brief pressor response to anandamide is not sympathetically mediated, and (2) the prolonged hypotensive response to anandamide is not initiated in the central nervous system, in ganglia, or at postsynaptic adrenergic receptors but is due to a presynaptic action that inhibits norepinephrine release from sympathetic nerve terminals in the heart and vasculature.

Drug interactions involving cyclosporine following transplantation are a challenging issue for the transplant clinician. This is especially true when ketoconazole is the second agent used in conjunction with cyclosporine. Because both agents are metabolized by the cytochrome P-450 IIIA4 enzyme system, cyclosporine levels rise dramatically in the presence of ketoconazole. Many other agents interact with ketoconazole, either by competitive enzyme inhibition in the liver and gastrointestinal tract, or by reducing the absorption of ketoconazole by agents that increase the pH of the gastrointestinal tract. Despite the potential cost savings when using ketoconazole to reduce cyclosporine doses, adverse effects associated with ketoconazole put patients at risk when using this combination. Close monitoring of cyclosporine levels is imperative when adding ketoconazole to cyclosporine, and once the dosage adjustments are complete, the addition of a third drug that interacts with either cyclosporine or ketoconazole could result in an unexpected rejection episode or toxic cyclosporine side effect.

Objective: To report the price of a drug interaction between azathioprine and allopurinol that resulted in pancytopenia in a patient who had undergone a heart transplant., Case Summary: A 63-year-old white man who received an orthotopic heart transplant in 1987 was hospitalized in June 1991 with a diagnosis of pancytopenia. His immunosuppressive medications on admission included cyclosporine 125 mg bid, azathioprine (AZA) 200 mg/d, and prednisone 2.5 mg/5 mg every other day. Six weeks prior to admission, the patient's local physician prescribed allopurinol for left wrist pain suspected to be gout. It was determined that the pancytopenia was caused by the drug interaction between AZA and allopurinol, both of which were withheld on admission. During hospitalization, the patient's white blood cell count dropped to 1.1 x 10(3)/mm3 with an absolute neutrophil count of less than 0.5 x 10(3)/mm3, a platelet count of less than 20 x 10(3)/mm3, and a hemoglobin of 3.7 g/dL. Four units of packed red blood cells were transfused and regramostim (GM-CSF) therapy was begun on hospital day 3 to speed the marrow recovery process. The patient was discharged on hospital day 8 and AZA, which had been withheld since admission, was restarted. The dosage was titrated to 200 mg/d over the following 2 weeks. The price of this patient's hospital stay was $13,042., Discussion: Not included in this price was the effect this drug interaction had on the patient's quality of life. Even after discharge from the hospital, it was estimated that it would take up to 3 months for the patient to fully recover his previous level of strength and functional capability. This interaction between AZA and allopurinol could easily have been avoided. Both the physician and the pharmacist missed this well-documented and potentially life-threatening drug interaction. Also, the patient failed to notify the transplant team when allopurinol was prescribed by his local physician. The importance of patient responsibility for medication therapy must be stressed to help avoid unnecessary drug interactions., Conclusions: Undetected drug interactions can be life-threatening to patients as well as costly to the healthcare system. Drug interactions also can have a profound negative effect on the patients' quality of life, the price of which cannot be measured in dollars alone. It is vital that the physician, pharmacist, and patient work together to optimize therapeutic outcomes and avoid unnecessary drug interactions.

1. Activation of CB1 receptors by plant cannabinoids or the endogenous ligand, anandamide, causes hypotension via a sympathoinhibitory action in anaesthetized rats. In mouse isolated vas deferens, activation of CB1 receptors inhibits the electrically evoked twitch response. To determine if these effects are related to presynaptic inhibition of noradrenaline (NA) release, we examined the effects of delta 9-tetrahydrocannabinol (delta 9-THC), anandamide and the CB1 antagonist, SR141716A, on exocytotic NA release in rat isolated atria and vasa deferentia. 2. In isolated atria and vasa deferentia preloaded with [3H]-NA, electrical field stimulation caused [3H]-NA release, which was abolished by tetrodotoxin 0.5 microM and concentration-dependently inhibited by delta 9-THC or anandamide, 0.3-10 microM. The inhibitory effect of delta 9-THC and anandamide was competitively antagonized by SR 141716A, 1-10 microM. 3. Tyramine, 1 microM, also induced [3H]-NA release, which was unaffected by tetrodotoxin, delta 9-THC or anandamide in either atria or vasa deferentia. 4. CB1 receptor mRNA is present in the superior cervical ganglion, as well as in whole brain, cerebellum, hypothalamus, spleen, and vas deferens and absent in medulla oblongata and atria, as demonstrated by reverse transcription-polymerase chain reaction. There was no evidence of the presence of CB1A receptor mRNA in ganglia, brain, or cerebellum. These results suggest that activation of presynaptic CB1 receptors located on peripheral sympathetic nerve terminals mediate sympathoinhibitory effects in vitro and in vivo.

Background: The intent of this study was to measure health-related quality of life and depression in 94 heart transplant recipients., Methods: Changes in health-related quality of life and depression were examined by administering the Sickness Impact Profile and the Beck Depression Inventory before heart transplantation, as well as 4, 8, 12, 24, 36, 48, and 60 months after surgery., Results: Sickness Impact Profile scores obtained before heart transplantation highlighted the greatest health-related quality of life dysfunction in work, sleep and rest, home management, and recreation and pastimes. Posttransplantation measures suggested improvement (p < 0.05) in emotional behavior, home management, mobility, ambulation, depression, eating behavior, social interaction, body care and movement, sleep and rest, recreation and pastimes, depression, and physical, overall, and psychosocial functioning. Continued improvement was noted up to 5 years after transplantation although patients continued to have marked work-related dysfunction. Age, medication regimen, rejection episodes, and a variety of preoperative medical variables were not related to health-related quality of life. Actuarial survival rates at 1, 2, 3, 4, and 5 years were 89%, 87%, 80%, 79%, and 79%, respectively., Conclusions: Our results suggest that as early as 4 months after heart transplantation, patients show excellent functioning in most health-related quality of life areas. Survival rates are encouraging. Patients did not generally experience problems with depression within the first 4 months after heart transplantation. Notable problems remain after transplantation in rate of return to work where only 53% returned to work by 5 years after heart transplantation.

We estimated the free fraction (fu) of cyclosporine (CyA) in the plasma from concentrations of CyA in urine (Cu) and plasma (Cp), urine flow rate (UF), and glomerular filtration rate in rabbits and in heart transplant patients. Following intravenous administration of CyA (5-30 mg kg-1) in ten NZW rabbits and oral administration of CyA (4.8-12.1 mg kg-1) in nine heart transplant patients, CyA concentrations in urine and plasma were measured by HPLC. The ratios of Cu to Cp and UF data were fitted to a physiological model of renal clearance using NONMEM. The free fraction of cyclosporine in the rabbits and the heart transplant patients was 0.0122 and 0.14, respectively. Because of the relatively low permeability of CyA across the tubular epithelium, no apparent equilibrium between Cu and Cp at any urine flow rate was reached and, therefore, the Cu to Cp ratio will not be equal to fu.

The purpose of this survey was to determine current practices of cardiothoracic transplant centers regarding transplantation of hearts and lungs into hepatitis C (HCV)-seropositive candidates and the use of organs from HCV-seropositive donors. A telephone survey of 48 cardiothoracic transplant centers was conducted in October 1992. Questions included the center's policy for listing HCV-seropositive candidates; if, and under what conditions, organs from HCV-seropositive donors would be used; and which HCV assays were used. Forty-five programs responded; 75% will list an HCV-seropositive candidate, either directly or by lack of routine screening to exclude such patients; only 16% will not accept HCV-seropositive candidates; 9% had no policy. Overall, 69% will accept organs from HCV-seropositive donors, at least for selected recipients (22% for any recipient, 45% for HCV-seropositive and/or status I recipients; 2% do not screen donors). A total of 27% will never accept organs from an HCV-seropositive donor, and 4% had no policy. Thirty centers provided information on HCV methodology. All but one use a second generation ELISA or EIA as a first-line test. A positive result will be followed by a confirmatory assay/liver biopsy in 42%. The variation in practices reflects the ambiguity in the literature. Adequate evaluation of morbidity and mortality due to HCV infection in this population has not yet been possible, although currently available reports do not show a substantial increase. Prospective controlled trials in cardiothoracic transplant patients are necessary.

Objective: To provide the reader with a review of the literature that evaluates whether a pharmacokinetic or pharmacodynamic drug interaction exists between ciprofloxacin and cyclosporine., Data Sources: A MEDLINE search was used to identify pertinent review articles, pharmacokinetic studies, and case reports., Study Selection: As both pharmacokinetic trials and case reports were few in number, all available sources were reviewed., Data Extraction: A few case reports were reviewed; however, data were extracted primarily from prospective human studies involving cyclosporine pharmacokinetic profiles., Data Synthesis: Ciprofloxacin has been reported to interact with cyclosporine during concomitant use through an interaction with the cytochrome P-450 system or by additive nephrotoxicity. Because ciprofloxacin may be used to treat a variety of infections in transplant recipients who receive cyclosporine, it is important to determine whether an interaction exists. Although cyclosporine is known to cause nephrotoxicity, only a few reports of ciprofloxacin-induced acute renal failure exist, all involving an immune-mediated interstitial nephritis. Four case reports have suggested a possible pharmacokinetic or pharmacodynamic drug interaction between cyclosporine and ciprofloxacin; however, many pharmacokinetic studies have refuted these reports. Several studies performing cyclosporine pharmacokinetic profiles have documented no increased cyclosporine concentrations, thus supporting the premise that ciprofloxacin does not interact with cyclosporine., Conclusions: Controlled studies involving cyclosporine pharmacokinetic profiles do not support a pharmacokinetic or pharmacodynamic drug interaction between ciprofloxacin and cyclosporine. Although anecdotal case reports have suggested synergistic nephrotoxicity, no clear correlation can be made. Based on our review of the literature, it can be concluded that cyclosporine and ciprofloxacin may be used together safely at the recommended dosages without increased cyclosporine monitoring.

Hyperlipidemia and obesity are common problems after heart transplantation, which may increase the risk of chronic graft atherosclerosis. The intent of this study was to (1) determine the impact of a history of hyperlipidemia on the occurrence of lipid abnormalities after transplantation, (2) compare lipid profiles of those patients being treated with triple-drug immunosuppression versus those patients weaned from prednisone therapy, and (3) identify any factors that would predict which patients are at highest risk for the development of hyperlipidemia after transplantation. Of 89 patients who lived for more than 12 months, 35 patients had a history of hyperlipidemia before heart transplantation (cholesterol level of more than 240 mg/dl; low-density lipoprotein cholesterol level of more than 160 mg/dl). The most dramatic rise in cholesterol level was observed in patients with no history of hyperlipidemia who were treated with triple-drug immunosuppression, in whom a 64% increase occurred versus a 24% increase in patients receiving steroid-free immunosuppression (p < 0.001). In patients with a history of hyperlipidemia, cholesterol level increased by 20% with triple-drug immunosuppression versus 14% with steroid-free immunosuppression (p = 0.613); however, 83% of the patients in the triple-drug group and 92% in the steroid-free group had elevated cholesterol levels. Multiple regression analysis revealed that significant independent and additive (p < 0.00001) contributions with respect to percent change in cholesterol level were evident for (1) a negative history of hyperlipidemia (p = 0.005), (2) triple-drug immunosuppression (p = 0.0021), and (3) female sex (p = 0.0113). A negative history of hyperlipidemia was predictive of the percent change in low-density lipoprotein cholesterol level (p = 0.0049), and triple-drug immunosuppression administration predicted the percent change in high-density lipoprotein cholesterol (p = 0.0119). Patients with a positive history of hyperlipidemia had higher lipid values at 12 and 24 months after transplantation; however, patients with no previous history of hyperlipidemia experienced the greatest percent change in both cholesterol and low-density lipoprotein levels. Patients receiving prednisone therapy gained more weight (9.0 +/- 7.0 kg) as compared with those patients tapered from prednisone therapy (5.9 +/- 8.6 kg); however, neither the increase in actual weight (p = 0.120) nor the increase in percent ideal body weight (14% +/- 11% versus 9% +/- 13%, respectively) were significant (p = 0.133). This study identified that postoperative weight gain is best predicted by premorbid habitus, rather than the type of immunosuppression used.(ABSTRACT TRUNCATED AT 400 WORDS)

Objective: The purpose of this article is to review the pathophysiology of the denervated heart and the factors that need to be considered before recommending the use of over-the-counter (OTC) medications in the cardiac transplant recipient., Data Sources: Pharmacology and therapeutic textbooks, English-language journal articles, and physiology textbooks published between 1969 and 1991., Data Extraction: Case reports, controlled case studies, and textbook chapters evaluating drug interactions with immunosuppressive agents were reviewed. The effects of various OTC medications on the denervated heart were examined and relevant material was extrapolated., Data Analysis: The number of cases or studies in which a particular effect or interaction occurred was reported. Those findings that were less well documented were either identified as such or were not included in the review., Data Synthesis: Common pharmacokinetic and pharmacodynamic interactions with the primary immunosuppressive agents (e.g., cyclosporine, azathioprine, prednisone) are reviewed. The physiology and altered responses of the denervated heart to various medications are also explained. Using this information recommendations are given for the use and monitoring of OTC analgesics, antacids, laxatives, sleep aids, stimulants, and other medications that may be used in the cardiac transplant recipient., Conclusions: Many OTC medications can be used safely in the cardiac transplant recipient. In each situation, risk/benefit assessments must always be made and therapy should be monitored closely. Most important, patients should always notify the transplant team before adding an OTC product to their immunosuppressive regimen.

Designing immunosuppressive regimens for the pediatric transplant patient is challenging because one must balance the need to provide adequate immunosuppression without interfering with normal growth processes or causing long-term adverse consequences. To optimize immunosuppressive therapy and minimize toxicity, it is necessary for the nurse to be knowledgeable of the pharmacokinetic and pharmacodynamic characteristics of the various agents. It is also important to understand which drugs interact with immunosuppressive agents and how to manage these interactions.

Objective: To review the mechanisms and sequence of events that occur during ischemia and cell death and following death of the human body. The impact of these postmortem events on the distribution and pharmacokinetic behavior of drugs is described. The case study presented illustrates a possible situation where such postmortem changes could have affected the pharmacokinetics of procainamide., Data Sources: English-language journal articles and reference texts identified from pertinent data sources., Data Synthesis: Postmortem changes in the human body begin at the cellular level with the onset of ischemia. As the length of time of ischemia increases and death ensues, more changes occur and lead to deterioration in tissue and organ function. These changes may affect the pharmacokinetic and distribution behavior of certain drugs. Drugs particularly affected are those whose distribution is dependent on molecular size, lipophilicity, pH, energy-dependent transport, and tissue binding. Such drugs include the tricyclic antidepressants, digoxin, and cimetidine. Other drugs with similar characteristics, such as procainamide, may also demonstrate like changes in distribution and pharmacokinetics., Conclusions: When measuring drug concentrations after death, it is important to consider the phenomenon of postmortem redistribution. Postmortem drug concentrations may not be a true reflection of antemortem concentrations and as a result, wrong conclusions could be made about the cause of death. More studies characterizing the postmortem distribution and pharmacokinetic characteristics of specific drugs are necessary.

Recent advances in immunotherapy have resulted in improved survival after heart transplantation. The use of OKT3 as an induction agent has allowed the identification of a subset of patients who can be successfully withdrawn from prednisone and maintained on only cyclosporine and azathioprine. The latter regimen offers several theoretic advantages in terms of freedom from complications of long-term steroid therapy. To compare both the long-term efficacy and toxicity of steroid-free maintenance immunosuppression with triple-drug therapy, the medical records of 68 patients undergoing transplantation at the Minneapolis Heart Institute during a 3-year period (1988 through 1990) were reviewed. Thirty-six patients were treated with OKT3 induction immunotherapy, 29 were successfully tapered off prednisone by 114 +/- 44 days after transplantation, whereas 32 patients were maintained on triple-drug therapy. The incidence of treated rejection was equivalent in both groups; however, the time to first rejection was longer in patients treated with OKT3/steroid-free maintenance (205 +/- 214 vs 27 +/- 17 days) (p = 0.02). Bacterial infections during the early posttransplant period were more common in the OKT3/steroid-free maintenance group (p = 0.008); however, fungal and viral infections were equally distributed between both groups. The incidence of hypertension was slightly higher in patients maintained on prednisone (67% vs 51%; p = 0.242).(ABSTRACT TRUNCATED AT 250 WORDS)

A group of high-risk heart transplant patients (n = 35) were treated from May 1987 through June 1990, with murine-derived monoclonal CD3 antibody (OKT3) induction therapy and steroid-free maintenance immunosuppression. This group was compared with a group of transplant patients (n = 47) who were not considered high risk and who were treated simultaneously with triple-drug immunosuppression (cyclosporine, azathioprine, and prednisone). The 1- and 3-year actuarial survival rates were similar: 97% and 91% for the OKT3 and 92% and 85% for the triple-drug immunosuppression groups, respectively. The overall incidence of rejection was equal for both groups (56%). No rejection occurred during the OKT3 course and rejection episodes occurred significantly later in patients treated with OKT3, with a mean first rejection episode of 111 +/- 104 days versus 27 +/- 21 days for the triple-drug immunosuppression group (p less than or equal to 0.05). Bacterial infections were seen more frequently (29% vs 6% of the patients treated) in the early period (less than 3 months) in the OKT3 group (p = 0.01) and were associated with the use of mechanical assistance in this group. The incidence of late infections or cytomegalovirus disease was similar for both groups. Patients treated with OKT3 and subsequent steroid-free maintenance immunosuppression had no significant posttransplantation increases of serum cholesterol levels, and hypertension was less common. Initial hospitalization was longer (p less than or equal to 0.05) in the OKT3 group (23 +/- 19 vs 13 +/- 5 days) but after the initial discharge the number of hospital days for the first year was similar for both groups (8 +/- 14 vs 9 +/- 13 days). Ventricular function at 1 year after transplantation was similar for both groups with average ejection fraction of 57% and 59% for the OKT3 and triple-drug immunosuppression groups, respectively. In conclusion, high-risk patients treated with OKT3 and steroid-free maintenance immunosuppression were managed on smaller doses of immunosuppressive drugs in the early postoperative period, and had excellent long-term survival rates. In this group of patients, rejection was delayed and the incidence of hypercholesterolemia, hypertension, and steroid-induced complications was decreased. Such a regimen offers a relatively drug-free period in the early posttransplant stages and freedom from the long-term complications of steroids.

From October 1985 through December 1989, 92 heart transplant procedures were performed in 89 patients. Nine patients (aged 19 to 66 years; 7 male, 2 female) required mechanical circulatory support after transplantation because of primary idiopathic organ failure (n = 2), implant difficulty (2), poor organ quality (2), or acute right heart failure (3). Devices used included the intraaortic balloon pump (6), centrifugal right ventricular assist device (2), left ventricular assist (1), biventricular assists (2), and total artificial heart (1). Two patients required multiple devices. One patient underwent retransplantation. Implant time ranged from 1 to 18 days. One early death occurred owing to right heart failure 6 days after transplantation, 7 hours after removal of a right ventricular assist device, for an overall mortality of 11%. The remaining 8 patients are alive 4 months to 28 months after transplantation. The actuarial 1-year survival of 89% +/- 10% compares well with the survival of 87% +/- 4% for the entire transplant group. All surviving patients are in functional class I. Echocardiographic examination in all patients revealed left ventricular ejection fraction to be normal in 7 and depressed in 1. Extending the criteria for organ donors or difficulty with the implant procedure can lead to early organ failure, which may be reversible with circulatory assistance allowing excellent survival.

Major advances in transplantation and in the treatment of autoimmune disorders have been achieved with the use of cyclosporine (CsA). During the past 10 years a variety of drug interactions have been reported to occur with CsA. These may be classified as either pharmacokinetic or pharmacodynamic in origin. Pharmacokinetic interactions are manifested by either an increase or decrease in the CsA concentration. The predominant mechanism of interaction is alteration in the cytochrome P-450 metabolism of CsA, however, some of the drugs may also affect its absorption, distribution, and elimination. Pharmacodynamic interactions include enhanced nephrotoxicity. Management of these events mandates proactive measures such as assessing the interactive potential of each new agent, measuring CsA concentrations more frequently when either initiating or discontinuing other agents, adjusting the dosage of CsA as necessary, and monitoring patients' clinical status to ensure efficacy and minimize the risk of toxicity.

Vancomycin dosing regimens should be individualized for each patient. The routine use of standard doses 500 mg every 6 hours or 1.0 g every 12 hours regardless of patients' age, weight or kidney function is no longer appropriate. A simplified method for initiating vancomycin therapy was developed and evaluated prospectively in 30 patients. Average doses of 8.3 +/- 0.6 mg/kg lean body weight (rounded to the nearest 50 mg) were administered to patients with varying degrees of renal function (estimated creatinine clearances 19-113 ml/min). The dosing interval was predicted by the patient's estimated creatinine clearance. Our simplified schedule resulted in desired serum levels and required no modification in 25 of 30 patients. Only slight dosage changes were needed in the remaining five patients. Mean peak and trough serum concentrations of vancomycin were 26.9 +/- 5.8 micrograms/ml (range 18.8-39.7 micrograms/ml) and 7.7 +/- 2.0 micrograms/ml (range 4.5-11.8 micrograms/ml) respectively. Our regimen is practical and simple and requires limited patient information.

Kidney stones have an overall incidence of two to three percent in western countries. In many patients, the disease process is difficult to control and recurrence rates are high: 20 to 50 percent over the subsequent ten years. The pathogenesis and standard methods of treatment for the five major types of stones (i.e., calcium oxalate, struvite, calcium phosphate, uric acid, and cystine) are reviewed. Three new drugs are reviewed in the context of their roles in the selective treatment of kidney stones. Cellulose sodium phosphate (Calcibind) is a nonabsorbable ion-exchange resin with a limited indication for the treatment of calcium stones associated with absorptive hypercalciuria Type I. Acetohydroxamic acid (Lithostat) is an urease-inhibitor that is indicated as adjunctive therapy in patients with chronic urea-splitting urinary tract infections and struvite stones. Potassium citrate (Urocit) is an investigational agent that has clinical efficacy in patients with calcium oxalate and calcium phosphate stones who are hypocitraturic. In addition, potassium citrate is an alkalinizing agent that can be used in patients with uric acid stones.

The efficacy of cefamandole and cefuroxime in preventing postoperative wound infections was compared in 3037 patients undergoing open-heart surgery. Antibiotic prophylaxis in 1467 patients having coronary artery bypass and valve replacement surgery was cefamandole 2 g iv preoperatively followed by 2 g q6h for five days postoperatively; 1570 patients received cefuroxime 1.5 g iv preoperatively then 1.5 g iv q 12h for three days postoperatively. Postoperative wound infections (sternal and leg wounds) were studied in each treatment group. In the cefamandole study group, 27 patients (1.8 percent) developed postoperative wound infections (9 sternal and 18 leg wounds). In the cefuroxime treatment group, 19 patients (1.2 percent) developed postoperative wound infections (9 sternal and 10 leg wounds). Overall, no statistical difference was found between the two antibiotics in preventing postoperative wound infections. However, in patients having valve replacement surgery, cefuroxime was found statistically more effective than cefamandole prophylaxis in preventing sternal wound infections (no infections in 284 patients compared with five infections in 205 patients, respectively, p = 0.01). The most common organism isolated from infected wounds with cefamandole was Staphylococcus aureus followed by S. epidermidis compared with cefuroxime which had S. epidermidis followed by S. aureus. Cefuroxime was found to be as effective as cefamandole and considerably less expensive in preventing postoperative wound infections in patients undergoing open-heart surgery.

No substance should be administered unnecessarily during pregnancy. However, when a pregnant woman is not immune to serious disease, the risk of maternal and fetal infection must be weighed against the risk of vaccination. Whenever possible, an inactivated (killed) vaccine should be selected and immunization delayed until the second trimester. Only rarely is an attenuated (live) vaccine indicated.

A project was undertaken to demonstrate significant drug cost savings from clinical pharmacy services. The method of identifying and documenting the problem and the presentation and implementation of the project are discussed. The cost savings of the project are presented, including the economic impact on the patient and institution. The clinical pharmacist, the key figure in the success of the project, presented a complete pharmacological and financial analysis of the project to the medical staff. The project resulted in a financial savings of approximately $600 000/yr to patients in decreased drug charges, $200 000/yr in decreased drug purchases/inventory, and $105 000/yr to the hospital in an improved revenue/expense statement. This project represents an example of the important role of the clinical pharmacist in helping a hospital identify areas to reduce drug therapy costs. A future role for clinical pharmacists will be to work closely with the director of pharmacy, hospital administration, and medical staff in identifying and implementing cost-effective drug therapy.

This study evaluated a dosing method for initiating vancomycin therapy in a large population based on patients' age, weight, and renal function. The aims were to determine the method's efficacy in achieving predetermined peak and trough serum concentrations, and to calculate the cost savings incurred by individualizing therapy. Average doses +/- 1 SD of 7.93 +/- 0.29 mg/kg corrected body weight (lean body weight + 40% excess weight) were administered at intervals predicted by the patients' estimated creatinine clearances (range 22-130 ml/min). The calculated mean dose +/- SD was 558 +/- 83 mg (range 350-750 mg) and the calculated median interval was 12 hours (range 6-24 hr). Peak and trough concentrations +/- SD measured at steady state averaged 26.0 +/- 5.4 and 7.3 +/- 2.3 micrograms/ml, respectively. Peak and trough serum concentrations fell within the predetermined therapeutic range in 311 (76%) of 410 samples. Peak concentrations were in the range of 20-30 micrograms/ml in 145 (71%) of 205 samples. Trough concentrations were in the range of 5-10 micrograms/ml in 166 (81%) of the 205 samples. This simplified dosing method successfully individualized therapy in most patients, and produced a significant savings to the pharmacy in reduced drug acquisition costs and to patients in reduced drug charges.