Cardiovascular effects of anandamide in anesthetized and conscious normotensive and hypertensive rats.

We previously showed that in anesthetized rats anandamide elicits bradycardia and a triphasic blood pressure response: transient hypotension secondary to a vagally mediated bradycardia, followed by a brief pressor and prolonged depressor response, the latter two effects being similar to those of delta 9-tetrahydrocannabinol (THC). The prolonged depressor but not the pressor response was reduced after alpha-adrenergic receptor blockade or cervical spinal cord transection and was inhibited by the cannabinoid type 1 (CB1) receptor antagonist SR141716A, suggesting CB1 receptor-mediated sympathoinhibition as the underlying mechanism. Here we examined the relationship between sympathetic tone and the cardiovascular effects of anandamide by testing these effects in both conscious and anesthetized, normotensive and spontaneously hypertensive rats. In urethane-anesthetized normotensive rats, SR141716A inhibited the prolonged depressor and bradycardic effects of anandamide and THC with similar potency, whereas it did not affect the pressor response to either agent. Anadamide caused similar hypotension in spontaneously breathing and in paralyzed, mechanically ventilated rats, suggesting that the hypotension is not secondary to respiratory effects. In conscious normotensive rats, anandamide elicited transient vagal activation and a brief pressor response, but the prolonged hypotensive component was absent. SR141716A potentiated and prolonged the brief pressor response to anandamide, suggesting that the depressor response may have been masked by an increased pressor response. All three phases of the anadamide response were present in both anesthetized and conscious spontaneously hypertensive rats, and the hypotensive component, inhibited by SR141716A in both, was more prolonged in the absence (> 50 minutes) than the presence (10 to 15 minutes) of anesthesia. We conclude that anandamide causes a non-CB1 receptor-mediated pressor and a CB1 receptor-mediated prolonged depressor response. The depressor response can be elicited in both conscious and anesthetized animals, but its magnitude depends on preexisting sympathetic tone.

Mechanism of the hypotensive action of anandamide in anesthetized rats.

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.

Practices of cardiothoracic transplant centers regarding hepatitis C-seropositive candidates and donors.

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.

Treatment of hyperlipidemia after heart transplantation and rationale for the Heart Transplant Lipid Registry.

Hyperlipidemia occurs frequently after heart transplantation, and accelerated coronary artery disease remains the major cause of morbidity and mortality in patients who survive more than 1 year after heart transplantation. However, the risks and benefits of lipid-lowering therapy after heart transplantation remain poorly defined, and national guidelines for lipid-lowering drug therapy do not specifically address treatment of dyslipidemia in transplant recipients. Since the initial reports in the 1980s of rhabdomyolysis in heart transplant patients receiving high-dosage lovastatin, results of 11 post-transplantation series that used lovastatin, simvastatin, or pravastatin at lower dosages as drug monotherapy have been published. These studies have shown an overall 1% incidence of rhabdomyolysis, defined as creatine kinase > 10 times the upper limit of normal plus muscle symptoms. One randomized, controlled prospective trial has investigated the effects of lipid-lowering pharmacotherapy on patient outcome in cardiac transplant recipients. At 1-year follow-up in this nonblinded, single-center trial, patients treated with pravastatin (20 or 40 mg/day) initiated within 2 weeks of transplantation had a significant reduction in mortality rate and a significantly lower incidence of transplant arteriopathy. A number of important issues remain unanswered regarding treatment guidelines in patients with hyperlipidemia after heart transplantation. In January 1995 we began the Heart Transplant Lipid Registry, with 12 participant centers, to gather data prospectively on the efficacy and safety of lipid-lowering drugs in the treatment of dyslipidemia after heart transplantation.

Inhibition of exocytotic noradrenaline release by presynaptic cannabinoid CB1 receptors on peripheral sympathetic nerves.

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.

Changes in health-related quality of life and depression in heart transplant recipients.

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.

The impact of steroid withdrawal on the development of lipid abnormalities and obesity in heart transplant recipients.

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)

Nefazodone and cyclosporine drug-drug interaction.

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.

A retrospective assessment of safety, efficacy, and pharmacoeconomics of generic azathioprine in heart-transplant recipients.

Although a generic formulation of azathioprine (AZA) has been available since 1996, safety, efficacy and pharmacoeconomic implications following conversion from Imuran (AZA) to generic AZA in heart-transplant patients remains to be determined. A retrospective, safety and efficacy assessment, in addition to a cost comparison, was performed in 30 heart-transplant patients who had been switched from Imuran to generic AZA. In heart-transplant patients converted from Imuran to generic AZA, no compromise in safety and efficacy, as measured by white blood cell (WBC) count, infections, rejections, malignancies, and hospitalizations was observed. Generic substitution of Imuran results in an annual cost savings of $318 per patient.

Steroid-free maintenance immunotherapy: Minneapolis Heart Institute experience.

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)

Policies regarding the transplantation of hepatitis C-positive candidates and donor organs.

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.

OKT3 induction and steroid-free maintenance immunosuppression for treatment of high-risk heart transplant recipients.

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.

Mechanical circulatory assistance after heart transplantation.

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.

Management of drug interactions with cyclosporine.

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.

Evaluation of a method for initiating vancomycin therapy: experience in 205 patients.

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.

A simplified dosing method for initiating vancomycin therapy.

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.

Immunizing the pregnant woman. Risks versus benefits.

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.

The pharmacokinetics and pharmacodynamics of immunosuppressive agents.

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.