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Biomedical subjects

R J Cipolle

Publications and source records attributed to R J Cipolle.

At least 37 records · Page 2Linked to original sources
PubMed1989

Local immunosuppression with reduced systemic toxicity in a canine renal allograft model.

We compared the efficacy of continuous intraarterial versus intravenous 6-mercaptopurine (6-MP) infusion in a mongrel canine renal allograft model with regard to overall survival, incidence of systemic and renal toxicity, and systemic drug exposure. Arterial anastomoses were done end-to-end, and infusion catheters were placed in the iliac artery or vena cava and connected to a subcutaneously placed programmable pump. A dose of 0.5 mg/kg/day 6-MP did not prolong survival over heparin-treated or untreated controls (MST = 7 days for both groups) when administered either locally or systemically. However, 0.75 mg/kg/day 6-MP i.a. (MST = 20 days) significantly prolonged survival over both untreated (P = 0.007) and heparin-treated controls (P = 0.02), with all dogs eventually dying of rejection. In contrast, 0.75 mg/kg/day i.v. (MST = 7 days) failed to prolong survival over controls (P greater than 0.1) and produced death from systemic toxicity in 3 of 7 animals. Six of 7 dogs receiving 2.0 mg/kg/day 6-MP i.a. (MST = 12 days) developed azotemia secondary to drug-induced nephrotoxicity. Identical renal histologic changes occurred in the same time frame in autotransplants treated similarly. Of 7 animals receiving 2.0 mg/kg/day i.v. (MST = 12 days), 5 died from early, severe systemic drug toxicity and 2 from early rejection. During 6-MP infusion at 0.5 mg/kg/day, systemic exposure was significantly less in the locally treated than in the systemically treated dogs when Cr concentrations were normal or moderately elevated (P less than 0.0005 and P = 0.01, respectively) but not when renal function became severely impaired (P = 0.34). In contrast to i.v. infusion, i.a. 6-MP delivery dissociated immunosuppressive efficacy from systemic toxicity, supporting previous work demonstrating high first-pass renal elimination of 6-MP. We conclude that tightly controlled local delivery of an immunosuppressive agent can effectively prolong graft survival with reduced systemic toxicity in a large animal model employing a pump/catheter system applicable to man.

Animals↗
PubMed1988

Time-dependent disposition of cyclosporine after pancreas transplantation, and application of chronopharmacokinetics to improve immunosuppression.

We studied the circadian influences on cyclosporine pharmacokinetics in five recipients of pancreatic allografts. Results from these patients demonstrate a slightly increased area under the concentration-time curve (p = 0.156) resulting from decreased apparent clearance during the resting (PM) versus activity (AM) period (p = 0.199). A significant delay in mean residence time was observed after the PM dose (p = 0.039), and the PM area under the moment curve was larger than the AM value (p = 0.063). We propose three chronopharmacokinetic dosing methods that alter either the PM dose administration time or redistribute the daily dose to produce equal exposure to cyclosporine during the active and resting periods. These trends and differences suggest that more sophisticated time-dependent cyclosporine dosing methods are needed to balance AM and PM drug exposure and thereby improve immunosuppression.

Administration, Oral↗
PubMed1988

An implantable pump for intrarenal infusion of immunosuppressants in a canine autotransplant model.

We developed a canine renal allograft model utilizing implantable infusion pumps and biocompatible catheters to investigate the pharmacokinetics of local immunosuppressive drug administration. Seven mongrel dogs underwent bilateral nephrectomy and autotransplantation of one kidney to the iliac vessels. The proximal end of an infusion catheter directed into the iliac artery was tunneled to a subcutaneously placed programmable pump. A second, sampling catheter was placed with its tip in the iliac vein. Simultaneous regional (iliac vein) and systemic (jugular vein) venous concentrations of 6-mercaptopurine (6-MP), the immunosuppressive metabolite of azathioprine, were determined during a continuous 24-h intraarterial infusion (10 mg/kg/24 hr). The gradient between regional and systemic 6-MP concentrations was maximal initially when the pump was turned on, continuously decreased until steady state was reached, and disappeared immediately after the pump was turned off. The mean ratio of steady-state iliac vein to systemic 6-MP concentrations was 5.0 +/- 1.4, demonstrating a pharmacokinetic advantage of continuous intraarterial 6-MP infusion to the autotransplanted kidney. The novel canine renal allograft model described herein overcomes the technical limitations of earlier models and represents a foundational step in the design of intrarenal infusion patterns of immunosuppressive agents which we expect to prolong survival of the allotransplanted kidney with minimal systemic drug exposure and side effects.

Animals↗
PubMed1988

Medical treatment of transient ischemic attacks: does it influence mortality?

All randomized studies published on the medical treatment of transient ischemic attacks in which controls received no treatment or placebo and in which mortality was reported were reviewed. Using the odds ratio method, we analyzed the results to determine if treatment had an effect on expected mortality. Studies were analyzed separately according to the treatment modality used. Chronic anticoagulation was used in four studies and platelet inhibitors in 12 (14 trials). This meta-analysis showed that neither treatment modality significantly reduces mortality. Chronic anticoagulation may have an adverse effect, and even though platelet inhibitors appeared to reduce mortality, no significance can be demonstrated, and the 95% confidence intervals did not allow us to rule out the possibility, albeit small, of an adverse effect or no effect at all.

Anticoagulants↗
PubMed1988

Documenting the clinical pharmacist's activities: back to basics.

The profession of pharmacy has applied the term "documentation" to count activities that more closely approximate descriptive protocols or administrative reports. This extended nonclinical use of the term documentation has resulted in the profession losing sight of a necessary step in the development, justification, and successful implementation of clinical pharmacy services. An instrument that helps to standardize the documentation of a clinical pharmacist's database, patient-care activities, and therapeutic plans is presented. This process, the pharmacist's workup of drug therapy (PWDT), consists of the following six interrelated steps: (1) establish a comprehensive patient-specific database; (2) identify patient-specific, drug-related problems; (3) describe desired therapeutic outcomes; (4) list all therapeutic alternatives that might produce the desired outcomes; (5) select the drug recommendation(s) that most likely will result in the desired outcomes; and (6) establish a plan for therapeutic drug monitoring that documents that desired effects occur and undesired effects are minimized. A formative method of documenting the clinical pharmacist's activities such as the PWDT must be functional on a daily basis in order to generate meaningful summative management reports.

Documentation↗
PubMed1987

Can embolic stroke be diagnosed on the basis of neurologic clinical criteria?

Diagnosis of embolic stroke is based on identification of a source of embolus (SOE) and on neurologic symptoms acknowledged as "clinical criteria." To test the validity of these criteria, we analyzed the symptoms at onset in 193 patients hospitalized after acute cerebral infarction. Patients were grouped according to identification of a cardiac SOE (106 patients), an arterial SOE (38 patients), or no SOE (49 patients). Cross-tabulations demonstrated that only rapidity and loss of consciousness at onset were associated with the presence of a cardiac SOE to a significant degree. Although these symptoms were highly specific for cardiac SOE, they were not sensitive. A distinct clinical neurologic profile from the symptoms and mode of onset was not identified.

Adult↗
PubMed1987

Procedures for emergency or treatment use of investigational drugs.

The procedures for obtaining and dispensing investigational drugs for single-patient compassionate use are described, and roles for pharmacists in this process at a university medical center are identified. To obtain an investigational drug, a physician must contact a pharmaceutical-company study monitor to discuss the details of the case. Other responsibilities of the physician include obtaining institutional review board approval; completing FDA form 1572 or 1573, or both; and securing written informed consent from the patient. The responsibilities of the pharmacist are to ensure that informed consent has been obtained; inform nursing, pharmacy, and medical staffs about the use, admixture requirements, and administration of the investigational agent; provide a therapeutic drug monitoring plan; and store, handle, and prepare the medication. The pharmacist also keeps inventory of all shipped drugs and returns all unused drugs to the manufacturer. Pharmacists should be knowledgeable about the proper procedure for obtaining and dispensing investigational drugs on an emergency or treatment basis.

Drug Evaluation↗
PubMed1984

Value of computed tomographic scan in the evaluation of adult patients after their first seizure.

The role of the computed tomographic (CT) scan in evaluating adults after their first seizure(s) was determined by reviewing the hospital records of 148 patients studied within 30 days of their ictus. Patients with alcohol or drug intoxication or withdrawal or with known brain tumor, craniotomy, or open skull fracture were excluded. Type of seizure; neurological, CT, and electroencephalographic findings; final diagnosis; and hospital outcome were cross correlated. The cause of seizure was established in 71 patients (48%); a structural lesion was identified by CT in 55 (37%), and 16 (11%) had metabolic seizures. CT findings agreed with the results of neurological examination 82% of the time. Structural lesions (including three tumors) were found by CT in 14 patients (15%) with nonfocal findings and in 12 (22%) of those with generalized electroencephalographic abnormalities. Our findings are similar to those reported in adult epileptics and lead us to conclude that the CT scan is a valuable aid in establishing the cause of seizures and in disclosing early lesions.

Adolescent↗
PubMed1984

Heparin-induced thrombocytopenia in patients with cerebrovascular ischemic disease.

We studied 137 patients who were treated with heparin for cerebral infarction (73), partially reversible ischemic neurologic deficit (22), or transient ischemic attack (42). Platelet counts were performed before therapy, twice weekly, and at cessation of therapy. Platelets decreased in 118 patients (86%). In 21 (15.3%), platelets dropped greater than or equal to 40%; 9 of 14 new ischemic events and three of six deaths occurred in this group of patients. Because there was a significant association between poor outcome and platelet drop greater than or equal to 40% (p less than 0.001), we believe that platelets should be monitored frequently when patients are treated with heparin for ischemic cerebrovascular disease.

Adult↗
PubMed1983

Toward optimal drug therapy. Benefits of therapeutic drug monitoring.

Over the past two decades, therapeutic drug monitoring has repeatedly been found to improve efficacy and minimize toxicity. Monitoring is needed in patients with conditions that alter their responses to drugs, such as congestive heart failure or old age. It is also necessitated by such drug factors as variable distribution or elimination and by such clinical situations as when compliance or efficacy is questioned. For drug monitoring to achieve its potential benefits, serum concentrations of drug must be measured at the appropriate time. In most clinical situations, a single trough measurement at steady state is adequate to assess therapy.

Dose-Response Relationship, Drug↗
PubMed1983

Heparin-associated thrombocytopenia: a prospective evaluation of 211 patients.

Two hundred eleven consecutive patients treated for acute thromboembolic disease were evaluated prospectively for the incidence of thrombocytopenia while receiving heparin treatment. One hundred patients received beef lung heparin and 111 patients received porcine intestinal mucosal heparin. All patients received a minimum of 4 consecutive days of continuous intravenous heparin, and platelet counts were determined prior to, at least twice weekly, and at the cessation of heparin therapy. Heparin-associated thrombocytopenia was defined as a decline from a normal platelet count (100,000-400,000/mm3) to less than 100,000/mm3 with a return to above 100,000/mm3 after the discontinuation of heparin. Heparin-associated thrombocytopenia developed in 11 patients (5.2% incidence). Ten of the thrombocytopenic patients had received beef lung heparin and one received porcine mucosal heparin. Chi-square analysis of these data was significant (p = 0.007). Plasma from seven of nine thrombocytopenic patients demonstrated a plasma factor compatible with a heparin-sensitive antiplatelet antibody. Heparin-associated thrombocytopenia appeared on days 2 to 10 of therapy. Cessation of heparin resulted in remission of thrombocytopenia within 4 days in all patients. Serial quantitative platelet count determinations are indicated in all patients receiving therapeutic heparinization for the early recognition and resolution of heparin-associated thrombocytopenia.

Adolescent↗
PubMed1982

Wide interpatient variations in gentamicin dose requirements for geriatric patients.

Substantial interpatient variations were demonstrated in the daily doses required to obtain therapeutic gentamicin sulfate serum concentrations in 417 elderly patients. Dosages ranged from 0.3 to 22.0 mg/kg/day in patients with a normal serum creatinine level. Twenty-five percent of these patients required daily doses higher than the standard regimen of 5 mg/kg/day, and 33% required less than 3 mg/kg/day. The drug half-lives in these patients ranged from 0.3 to 32.7 hours, compared with previous reports of 2.5 to four hours. The distribution volumes of these patients ranged from 0.07 to 0.53 L/kg, compared with reported values of 0.20 to 0.25 L/kg. These wide variations in kinetic variables in elderly patients and the need to obtain narrow ranges in serum concentrations required measuring serum concentrations and individually calculating each patient's dosage requirement early in the treatment course. Doing this consistently produced optimal peak and trough serum levels. Ototoxicity did not occur in any of the patients, and nephrotoxicity may have been drug related in 2% of the elderly patients.

Aged↗
PubMed1982

Gentamicin pharmacokinetics in 1,640 patients: method for control of serum concentrations.

The pharmacokinetics and dosage requirements of gentamicin were studied in 1,640 patients receiving treatment for gram-negative infections. A wide interpatient variation in the kinetic parameters of the drug occurred in all patients and in patients who had normal serum creatinine or normal creatinine clearance. The half-life ranged from 0.4 to 32.7 h in 331 patients who had normal creatinine clearance. The factors related to the elimination rate constant were creatinine clearance, age, distribution volume, weight, gender, and hematocrit. The daily dose necessary to obtain therapeutic serum concentrations ranged from 0.5 to 25.8 mg/kg in patients with normal serum creatinine and from 0.7 to 25.8 mg/kg in patients with normal creatinine clearance. In 13 patients (0.9%), a significant change in base-line serum creatinine (greater than or equal to 0.5 mg/dl) occurred during or after treatment, which may have been gentamicin-associated toxicity. Overt cochlear or vestibular toxicity did not occur in these patients. The method of individualizing dosage regimens provided a clinically useful means of rapidly attaining therapeutic peak and trough serum concentrations.

Adolescent↗