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At least 919 records · Page 51Linked to original sources
PubMed2001

The effect of different doses of cyclosporin A on the systemic exposure of orally administered paclitaxel.

The objective of this study was to define the minimally effective dose of cyclosporin A (CsA) that would result in a maximal increase of the systemic exposure to oral paclitaxel. Six evaluable patients participated in this randomized cross-over study in which they received at two occasions two doses of 90 mg/m(2) oral paclitaxel 7 h apart in combination with 10 or 5 mg/kg CsA. Dose reduction of CsA from 10 to 5 mg/kg resulted in a statistically significant decrease in the area under the plasma concentration-time curve (AUC) and time above the threshold concentrations of 0.1 microM (T>0.1 microM) of oral paclitaxel. The mean (+/-SD) AUC and T>0.1 microM values of oral paclitaxel with CsA 10 mg/kg were 4.29+/-0.88 microM x h and 12.0+/-2.1 h, respectively. With CsA 5 mg/kg these values were 2.75+/-0.63 microM x h and 7.0+/-2.1 h, respectively (p=0.028 for both parameters). In conclusion, dose reduction of CsA from 10 to 5 mg/kg resulted in a significant decrease in the AUC and T>0.1 microM values of oral paclitaxel. Because CsA 10 mg/kg resulted in similar paclitaxel AUC and T>0.1 microM values compared to CsA 15 mg/kg (data which we have published previously), the minimally effective dose of CsA is determined at 10 mg/kg.

Adenocarcinoma↗
PubMed1990

[A comparison of digital luminescence radiography and the conventional film-screen technic in pulmonary coin lesions--a clinical study].

The aim of this investigation is the evaluation of DLR for the radiological diagnosis of intrapulmonary coin lesions. For this, a DLR system was used which had been specially developed for chest radiography. Early results were unsatisfactory and therefore specific image parameters were developed. The scope for dose reduction was also investigated. Oncology patients were examined by DLR and by our reference system. Results show that DLR is better than conventional images if edge enhancement is carried out, using the specific parameters. The superiority of the optimised digital images is apparent particularly in those portions of the lung that are obscured by the cardiac or diaphragmatic shadows. Because of image noise, a dose reduction of only 28% is possible, compared with our reference system.

Evaluation Studies as Topic↗
PubMed2003

Efficacy of vinblastine, bleomycin, methotrexate (VBM) combination chemotherapy with involved field radiotherapy in early stage (I-IIA) Hodgkin disease patients.

Vinblastine, bleomycin, methotrexate (VBM) combination chemotherapy (CT) with involved field radiotherapy (IFRT) was first described by the Stanford group as an active regimen in early stage Hodgkin's disease (HD). Here, we report our retrospective experience of a modified VBM schedule + IFRT in a similar group of patients. From 1988, 49 patients with stage I-IIA HD received vinblastine (VBL) 6 mg/m2, bleomycin (BLM) 10 IU/m2, methotrexate (MTX) 30 mg/m2 day 1,8 every four weeks for three cycles; IFRT was delivered four weeks later followed by three additional cycles of VBM with a dose reduction of BLM (6 IU/m2). The regimen was well tolerated, with grade 3-4 neutropenia occurring in 20 patients. No acute or late pulmonary toxicity was recorded in our series. Estimated Freedom from Progression (FFP) and Overall Survival (OS) at five years are 75% (95% CI, 60.1%-92.2%) and 85% (95% CI, 73.6%-98.1%), respectively. In this retrospective analysis, VBM + IFRT treatment with bleomycin dose reduction seems safe and active. Such combination could be considered as first line treatment for early stage HD patients with favorable prognosis and/or not suitable for anthracyclines-containing regimens.

Adolescent↗
PubMed1999

[Tolerance and feasibility of adjuvant treatment of stage II malignant melanoma with high-dose interferon-alpha].

BACKGROUND: The use of high-dose interferon alpha as adjuvant therapy has been shown for the first time to improve recurrence-free and overall survival in stage II malignant melanoma. The aim of our work was to evaluate the toxicity of this therapeutic scheme during a 1-year period in 13 patients with malignant melanoma. PATIENTS AND METHODS: Thirteen patients, mean age 56 years, with stage II melanoma were included. Interferon alpha was administered at the dose of 20 MU per m2 body surface area five days per week for four weeks during the induction phase and at the dose of 10 MU subcutaneously three times a week for 48 weeks in the maintenance phase. Patients underwent clinical assessment daily and had blood tests twice a week during the induction phase. Weekly blood tests and monthly examinations were then performed during the maintenance phase. Clinical and biological toxicity was evaluated in accordance with the WHO scores. Grade 3 toxicity led to a 30 p. 100 dose reduction and treatment was interrupted in case of grade 4 toxicity. RESULTS: A flu-like syndrome (grade 1-2) and digestive disorders, nausea, anorexia related to dysgeusia or dry mouth were observed in most of the patients during the induction phase and persisted in 30% of the patients during the maintenance phase. Six patients developed a state of depression (grade 2-3) which persisted during the maintenance phase, inciting us to prescribe an antidepressor regimen for all our patients. One patient developed major reversible alopecia at dose reduction. Nine patients had grade 1 or grade 2 neutropenia and four had grade 3 neutropenia. Seven patients developed grade 1-2 thrombocytopenia, six had elevated transaminase levels (grade 1-2) and two moderately elevated CPK. CONCLUSION: At the end of the induction phase of interferon alpha therapy in 13 patients with malignant melanoma, 8/13 had received 100 p. 100 of the theoretical dose and 11/13 had received 80 p. 100. At the end of the treatment protocol, 5/10 patients had received 100 p. 100 of the theoretical dose and 8/10 more than 80 p. 100. The proposed protocol appears to be feasible without major risk. Rigorous clinical and biological surveillance is mandatory.

Adult↗
PubMed1991

Cyclophosphamide pulse therapy in Wegener's granulomatosis.

Twenty-three patients with Wegener's granulomatosis, 15 with daily oral cyclophosphamide therapy and eight with intravenous cyclophosphamide pulse therapy, were studied retrospectively. All patients had involvement of the kidneys and systemic symptoms. Mean monthly cyclophosphamide dose was 1.0 g in the pulse group and 2.7 g in the daily treated group. In all patients remission could be achieved. During 207.5 months of daily oral therapy the following complications were observed: leukopenia, necessitating dose reduction in seven patients, severe infection in one patient, relapses in three patients. During 103 months of intravenous pulse therapy one patient developed leukopenia. No patient had a severe infection. Two relapses were seen. Our data suggest that cyclophosphamide pulse therapy is an effective treatment strategy in patients with Wegener's granulomatosis and kidney involvement. It offers the chance of bladder protection and marked total dose reduction, possibly decreasing the risk of malignancies.

Administration, Oral↗
PubMed1999

Association between alopecia and response to aggressive chemotherapy in patients with Hodgkin's disease.

The clinical significance and implications of absence of alopecia and/or neutropenia in patients treated with chemotherapy for malignant disease is unknown. We hypothesized that there is a common mechanism of resistance to the effects and the adverse effects of anticancer treatment, which may have clinical implications. To evaluate this hypothesis, we conducted a retrospective analysis of the charts of 17 consecutive patients with Hodgkin's disease who received at least 4 courses of combination chemotherapy (ABVD or MOPP/ABV). Twelve patients underwent complete alopecia while 5 patients retained their hair or had only minimal hair loss. The two groups had similar pretreatment characteristics. Ten (83%) of the patients with alopecia achieved complete remission as compared with 2 (40%) of the patients who retained their hair (P = 0.11). Also, patients without alopecia had fewer episodes of neutropenia (0% vs 33%, P = 0.02), delays of scheduled treatments (0% vs 66%, P = 0.02) or number of courses with dose reductions (20% vs 41%, P = 0.39). These differences shows a clear trend which did not reach statistical significance due to the small number of patients. We suggest that, in intensively treated patients with Hodgkin's disease, the absence of alopecia may predict a poor response to treatment. Also, patients without alopecia probably have fewer episodes of leukopenia, deferral of treatment courses or number of courses with dose reductions. We hypothesize that there is a common mechanism of resistance to cytotoxic agents that may prevent apoptotic death in both normal and malignant cells.

Adult↗
PubMed2006

[Interferon causes ischemic ocular diseases--case studies and review of the literature].

BACKGROUND: Reports of interferon-associated retinopathy mainly originate from Japanese working groups. Only a few cases have been described in Europe. PATIENTS AND METHODS: We have performed a retrospective analysis of the patients who were examined in the University Eye Clinic in Mainz complaining of visual loss associated with systemic interferon therapy in the time span between January 2001 and December 2003. RESULTS: 12 patients (age 35 - 67 years), undergoing treatment with interferon alpha for hepatitis C, metastatic renal cell carcinoma, leukaemia and malignant melanoma of the skin, complained of blurred vision 2 - 10 weeks after the start of interferon therapy. Fundus examination revealed retinal haemorrhages and cotton-wool spots in all eyes. Additionally in some eyes macular edema, retinal arteriolar occlusion or anterior ischemic optic neuropathy was seen. As underlying risk factors we found diabetes mellitus (6 x) and systemic hypertension (3 x). After interruption (10 x) or dose reduction (2 x) of interferon therapy in all eyes the ischemic changes disappeared rapidly. Permanent visual loss or visual field defects remained in 3 out of 24 eyes. CONCLUSIONS: Patients under interferon therapy should be monitored closely by an ophthalmologist, especially those with systemic vascular risk factors. In the case of development of ischemic microangiopathy of the retina or optic nerve, interferon therapy should be stopped or dose reduction is recommended.

Adult↗
PubMed2006

[A case of non-curatively resected gastric cancer successfully treated over 3 years with biweekly paclitaxel therapy].

We report a case of non-curatively resected gastric cancer successfully treated over 3 years with biweekly administration of paclitaxel. A 69-year-old man underwent non-curative resection with distal gastrectomy for advanced gastric cancer with remarkable lymph node metastasis on June 10, 2002. The metastatic lymph node (No. 8 a, 8 p and 12 a) linked up with the retroperitoneal node, making resection impossible. Postoperatively, he was initially treated with weekly administration of paclitaxel 100 mg/body (68 mg/m(2)) per week. However, due to grade 3 neutropenia in the first course, weekly administration was changed to biweekly administration with dose reduction to 60 mg/body (41 mg/m(2)), resulting in the continuation of paclitaxel therapy. Since then, no grade 3 or more severe adverse reactions have been observed. He has maintained NC for 3 years, and is still being treated on an outpatient basis at present. We believe that, in paclitaxel therapy for advanced gastric cancer, it is important for long-term survival to continue it perseveringly by dose reduction or change of schedule, when major adverse reactions are seen.

Aged↗
PubMed1998

Detection of simulated chest lesions with normal and reduced radiation dose: comparison of conventional screen-film radiography and a flat-panel x-ray detector based on amorphous silicon.

RATIONALE AND OBJECTIVES: The authors compared a solid-state amorphous silicon (a-Si) detector and screen-film radiography (SFR) with regard to the detection of simulated pulmonary lesions. Evaluation of the impact of a dose reduction of 50% with this digital flat-panel detector was of special interest. METHODS: A self-scanning flat-panel detector, based on a-Si technology with 143 x 143 microm pixel size, 1 k x 1 k matrix and 12-bit digital output was used. An asymmetric state-of-the-art screen-film system was compared with a-Si images taken at the same dose as SFR-images and at a dose reduced by 50%. An anthropomorphic chest phantom was superimposed by templates containing nodules, linear structures, reticular, and micronodular opacities in a random distribution. Receiver operating characteristic analysis was performed for 23,040 observations made by four independent observers. Student's t test (95% confidence-level) was used for statistical analysis. RESULTS: Receiver operating characteristic analysis showed that a-Si images taken at the same dose as SFR-images were significantly superior to SFR with respect to the detectability of lines (P = 0.01) and micronodular opacities (P < 0.01). For the other objects and the a-Si images taken at a reduced dose, it yielded no statistically significant differences between both imaging modalities. CONCLUSIONS: The results of this phantom study indicate that a-Si detector technology holds promise in terms of dose reduction in chest radiography without loss of diagnostic accuracy compared with SFR.

Humans↗
PubMed1992

A phase II study of ifosfamide in combination with etoposide and cisplatin in the treatment of extensive small cell lung cancer.

The combination of etoposide and cisplatin has become one of the standard treatments for small cell lung cancer. Ifosfamide, an analogue of cyclophosphamide, has demonstrated single-agent antitumor activity comparable with that of the most active agents used to treat small cell lung cancer. Because ifosfamide is relatively nonmyelosuppressive and its principal dose-limiting toxicity, urotoxicity, has largely been eliminated with the introduction of the uroprotective agent mesna, we undertook a phase II study of the combination of all three agents (etoposide/ifosfamide/cisplatin) in good-performance-status, extensive-disease patients 70 years of age or younger. Twenty-five patients (17 men and eight women; median age, 58 years) were treated with 75 mg/m2 etoposide, 20 mg/m2 cisplatin, and 1.0 g/m2/d ifosfamide administered intravenously for 5 days. Mesna (200 mg/m2) was given as a bolus prior to the first day of chemotherapy and then daily by continuous infusion (900 mg/m2 over 24 hours) between administrations of chemotherapy. Mesna was continued for 12 hours after the last dose of ifosfamide. Treatment cycles were planned every 4 weeks for four cycles. Due to severe toxicities in the first eight patients, subsequent patients received only 4 days of treatment (20% dose reduction). Of the 25 extensive-disease patients studied, 23 are evaluable for response. Seven (30%) achieved a complete response and 10 (43%) had a partial response (overall response rate, 73%). Five patients (22%) had stable disease (< 50% decrease and no evidence of disease progression for at least 4 weeks), and disease progressed in 1 patient (4%). The median survival time was 42 weeks (range, 2 to 160+ weeks). Granulocytopenia was dose-limiting: median granulocyte count was 0.486 x 10(9)/L, 21% of cycles had a granulocyte nadir below 0.2 x 10(9)/L, and four patients died of sepsis. Three patients required platelet transfusion and nine needed blood transfusion. Microscopic hematuria occurred in eight patients (11% of treatment cycles) but was reversible in all cases. A number of central nervous system symptoms were reported but could not be definitely attributed to ifosfamide/mesna. Gastrointestinal toxicity was generally mild, which is attributed to the use of an aggressive antiemetic program. The etoposide/ifosfamide/cisplatin regimen is active and produced a complete response rate of 30% in extensive small cell lung cancer; the duration of response and survival appears similar to that of other standard regimens. The 5-day schedule produced excessive toxicity in this patient population, necessitating a 20% dose reduction (by using a 4-day schedule). The method of administration required a minimum of 5 hospital days per cycle.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1997

Dose-dependent reduction of retinal vessel changes associated with diabetic retinopathy in galactose-fed dogs by the aldose reductase inhibitor M79175.

The onset and progression of retinal vascular changes associated with early diabetic retinopathy has been delayed in beagles fed 30% galactose diet for 38 months by treatment with the aldose reductase inhibitor M79175 (2-methyl-6-fluoro-spirochroman-4-5'- imidazolidine-2',4'-dione). Forty 9-month old male beagles were fed a daily diet containing either 30% non-nutrient filler or 30% galactose. One group of galactose-fed dogs was untreated while the others received M79175 at an average group dose of either 10 or 16 mg/kg/day. After 38 months one eye from 4 dogs from each group was enucleated and the isolated retinal vasculatures were objectively evaluated using an Olympus Cue-3 color image analysis system. Measurements of endothelium/pericyte (E/P) ratios, pericyte ghosts/1000 cells, pericytes and endothelial densities, and % acellularity per area and % acellularity per capillary length were conducted on a 0.1 mm square area surrounding the midpoints of 12 previously defined subregions. With the exception of endothelial densities which were not changed in galactose-fed dogs, M79175 treatment resulted in smaller changes in all parameters examined with the E/P ratio in dogs treated with 16 mg/kg/day M79175 not significantly different from that of age-matched non-galactose-fed dogs. These studies indicate that aldose reductase inhibitors provide dose-dependent protection against pericyte degeneration and subsequent microaneurysms formation.

Aldehyde Reductase↗
PubMed1997

Weekly paclitaxel with epirubicin as second-line therapy of metastatic breast cancer: results of a clinical phase II study.

Phase I/II trials have shown that combination of an anthracycline with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) represents a high-potency therapy for treatment of patients with metastatic breast cancer, with response rates exceeding 90%. This phase II trial was conducted to test the tolerability and efficacy of weekly epirubicin plus paclitaxel as second-line therapy for patients with pretreated metastatic breast cancer. In this study, 35 patients with previous hormone therapy and/or chemotherapy were treated at a weekly dose of paclitaxel 80 mg/m2 with epirubicin 35 mg/m2 (10 patients, 123 cycles) or paclitaxel 80 mg/m2 with epirubicin 25 mg/m2 (25 patients, 218 cycles). The dose reduction of anthracyclines became necessary due to severe hemotoxicity (neutropenia World Health Organization grade 3 to 4 in 30.2% of cycles). The therapy schema included a 2-week therapy interval after each treatment period of 6 weeks, with treatment continued until response or disease progression. Overall, 18 patents (51.4%) presented with responses (complete response or partial response) to therapy, with seven (20%) achieving a complete response after six to 18 cycles. In three cases (8.6%), tumor state was unchanged for a median interval of 11 weeks (range, 5 to 20 weeks). Progressive disease was observed in seven cases (20%), and seven patients (20%) were not evaluable. Following epirubicin dose reduction, neutropenia World Health Organization grade 3 to 4 occurred in only 18.1% of cycles. Referring to nonhematologic toxicity, alopecia exceeded World Health Organization grade 2. Other nonhematologic toxicities exceeding grade 2 were observed in only a few courses and were not statistically relevant. No clinically relevant deterioration of cardiac function was observed at a median cumulative dose of epirubicin 285 mg/m2 (maximum cumulative dose, 630 mg/m2). This study has substantiated that the schedule used is highly efficient and well tolerated as second-line chemotherapy for patients with metastatic breast cancer.

Adult↗
PubMed2003

Development of clinical pathway in S-1 chemotherapy for gastric cancer.

We have developed a clinical pathway to enable the safe continuous administration of S-1 (TS-1) in ambulatory care for patients with advanced gastric cancer. The S-1 clinical pathway includes a pathway for clinicians, a pathway for patients, and such assist tools as a medication diary, an explanatory document containing instructions relating to patient compliance, a table of associations between adverse reactions and prodromes, and general principles for dose reduction and withdrawal. These pathways and assist tools will improve the patient's perception of adverse reactions, thereby contributing to early discovery and rapid action against adverse events. The S-1 clinical pathway has been used with ten patients. S-1 administration has been continued in seven patients. In four of the seven patients, continued administration on the occurrence of adverse reactions was made possible by the use of appropriate measures such as drug withdrawal or dose reduction. It was confirmed that the S-1 clinical pathway was a useful tool for cancer chemotherapy in ambulatory care.

Adult↗
PubMed2006

Efficacy and toxicity of the novel chemotherapeutic agent KW-2170 in recurrent epithelial ovarian cancer.

OBJECTIVES: KW-2170 is a novel DNA intercalating agent whose mechanism of action is similar to doxorubicin HCl, yet is associated with less cardiac toxicity. The objective of this study was to evaluate the activity and toxicity of this novel chemotherapeutic agent in patients with recurrent ovarian carcinoma. METHODS: A prospective phase II trial was performed in patients with persistent or recurrent epithelial ovarian or primary peritoneal carcinoma and measurable disease. Patients could have platinum-sensitive or refractory disease and could have received any number of prior treatments. One treatment cycle consisted of KW-2170 administered at a dose of 18 mg/m(2) weekly for 3 weeks followed by a 21-day rest period. Toxicity was assessed using the NCI Common Toxicity Criteria (Version 2.0), and dose reduction was allowed for significant toxicity. Response to therapy was assessed in patients who completed at least 2 cycles using RECIST criteria. RESULTS: A total of 28 patients were enrolled in this phase II trial at 5 separate centers. Of the 28 patients evaluated, all had stage III/IV disease at initial diagnosis. The median number of prior therapeutic regimens in these patients was 4 (range 1-8). The median number of KW-2170 cycles administered was 2 (range 1-5). Treatment-related toxicity in this heavily pretreated population was acceptable as only 6 patients (21%) had grade 3-4 neutropenia. Dose reductions occurred in 6 patients (21%) for grades 1-4 neutropenia, and no patient had febrile neutropenia. Four patients completed less than 1 cycle; 3 secondary to progressive disease, and one due to Gram-positive sepsis. Of patients receiving at least 2 full cycles, 10 patients (55%) had stable disease with a median of 4.5 months (range 3-10) to disease progression. All other patients were removed from the study after 1-2 cycles of therapy with no significant clinical effect noted. CONCLUSIONS: Although associated with relatively little toxicity, KW-2170 at the dose and schedule evaluated demonstrated little clinical activity in this heavily pretreated population of recurrent ovarian cancer patients. Whether KW-2170 would have greater clinical activity in a more treatment naive group of patients at an increased dose awaits clinical trial evaluation.

Acridines↗
PubMed2002

The panorama of opioid-related cognitive dysfunction in patients with cancer: a critical literature appraisal.

BACKGROUND: Opioids have an essential role in the management of pain in cancer patients, particularly those with advanced disease. Cognitive dysfunction is a recognized complication of opioid use. However, misconceptions and controversy surround the nature and prevalence of its occurrence. A projected increase in the aging cancer population highlights the need for a better understanding of this phenomenon. METHODS: A critical appraisal of the literature evidence in relation to the pattern, pathophysiology, assessment, impact, and management of cognitive dysfunction due to opioid use in cancer pain management is given. RESULTS: Studies in cancer patients with less advanced disease reveal subtle evidence of cognitive impairment, largely related to initial dosing or dose increases. In advanced cancer, opioid-induced cognitive dysfunction usually occurs in the form of delirium, a multifactorial syndrome. The presence of both cognitive impairment and delirium frequently is misdiagnosed or missed. Potential risk factors include neuropathic and incidental pain, opioid tolerance, somatization of psychologic distress, and a history of drug or alcohol abuse. Elevation of opioid metabolites with renal impairment may contribute to cognitive dysfunction. Recognition of opioid-related cognitive dysfunction is improved by objective screening. Successful management requires either dose reduction or a change of opioid, in addition to addressing other reversible precipitants such as dehydration or volume depletion. CONCLUSIONS: Opioid-related cognitive dysfunction tends to be subtle in the earlier stages of cancer, whereas delirium, a more florid form with behavioral disturbance is likely to be present in the advanced cancer population. In patients with advanced disease, an optimal management approach requires careful clinical assessment, identification of risk factors, objective monitoring of cognition, maintenance of adequate hydration, and either dose reduction or switching to a different opioid.

Adult↗
PubMed2006

A phase II trial of weekly topotecan for patients with secondary platinum-resistant recurrent epithelial ovarian carcinoma following the failure of second-line therapy.

OBJECTIVE: To determine the response rate, progression-free survival and toxicity associated with weekly topotecan administered to patients with platinum-sensitive recurrent epithelial ovarian (EOC) in the third-line setting. METHODS: Patients with measurable platinum-sensitive EOC following failure of second-line chemotherapy were eligible for this phase II study. All patients were initially treated with cytoreductive surgery and platinum/paclitaxel-based chemotherapy. Continuous, weekly topotecan was administered at a starting dose of 4 mg/m(2). Toxicity and efficacy were assessed at various time points after initiation of therapy. RESULTS: Twenty nine patients were enrolled in this prospective study. Toxicity was acceptable with grade 1/2 nausea being the most commonly experienced side effect (52%). Nine patients (31%) had grade 3/4 leukopenia; however, only 3 patients had febrile neutropenia. Thirteen patients had a treatment delay and six required dose reductions. Twenty two patients were evaluable for efficacy. The overall response rate for weekly topotecan was 13.6% [95% CI; -0.7-27.9%] with 1 complete response, and 2 partial responses. Twelve patients (54.5%), including 2 with minor responses, had stable disease for a median duration of 18 weeks. CONCLUSIONS: Weekly topotecan at the current schedule in the third-line setting in patients with platinum-sensitive recurrent EOC has modest clinical activity. Toxicity associated with this regimen is acceptable but growth factor support, dose reductions, or schedule alterations may need to be considered in many of these patients.

Adult↗
PubMed1995

Cocaethylene causes dose-dependent reductions in cardiac function in anesthetized dogs.

Twelve million Americans abuse both cocaine and ethanol each year because this drug combination produces a pronounced and prolonged euphoria. However, these substances in combination are substantially more toxic than either drug alone. This toxicity may be due to cocaethylene, which has been detected in the serum of patients who have used cocaine and ethanol and two require emergency treatment. Cocaethylene is a pharmacologically active cocaine metabolite formed in the liver only in the presence of ethanol. To investigate the cardiovascular effects of cocaethylene, we randomized 15 mongrel dogs to receive 11.25 mg/kg (n = 4), 7.5 mg/kg (n = 6), or 3.75 mg/kg (n = 5) of cocaethylene as an intravenous (i.v.) bolus. These doses were chosen to achieve serum concentrations of cocaethylene consistent with those observed in patients with cocaine and ethanol toxicity. The ECG and the femoral arterial, left ventricular (LV), and pulmonary artery pressure were measured continuously, and cardiac output (CO) and serum levels of cocaethylene were monitored at specific intervals before and after drug administration. The maximal rate of increase and decrease in LV pressure (LVP), i.e., (dP/dt)max and (dP/dt)min, were determined as our indexes of ventricular contractility and relaxation. Cocaethylene concentrations peaked 2-4 min after each bolus and then decreased in a curvilinear manner. Cocaethylene's half-life (t1/2) was 150 +/- 15.1 min (mean +/- SEM). The greatest hemodynamic changes occurred at the peak cocaethylene serum concentrations in each group. In comparison with control measurements, cocaethylene in concentrations of 11.25 and 7.5 mg/kg decreased (dP/dt)max by 81 and 43% and decreased (dP/dt)min by 80 and 36%, respectively. In these two groups, cocaethylene decreased stroke volume (SV) by 29 and 33% and reduced mean arterial pressure (MAP) by 65 and 30%, respectively. Cocaethylene increased pulmonary artery wedge pressure (PAWP) by 70 and 67% in the 11.25- and 7.5-mg/kg groups. These hemodynamic changes persisted for 60 min after the bolus administration. In each of the three groups, cocaethylene increased the QRS interval duration by 60, 32, and 44% and the QTc interval by 38, 21, and 17%. These ECG changes persisted for 120 min. These experiments suggest cocaethylene depresses the myocardium. Cocaethylene may be a major contributor to the delayed but substantial cardiotoxicity that occurs in individuals who use both cocaine and ethanol.

Animals↗
PubMed1990

Metyrapone-induced withdrawal symptoms.

The metyrapone test is widely used in endocrinological testing to assess the integrity of hypothalamic-pituitary-adrenal axis function; we have used it to study the metabolic basis of addictive disease and opioid dependence. In recent studies, we have observed that metyrapone administration in long-term methadone-maintained patients and in patients undergoing slow dose reduction to drug-free status following chronic treatment may induce a narcotic withdrawal-like syndrome. Although metyrapone is known to produce mild adverse reactions in non-opiate dependent subjects, narcotic withdrawal-like symptoms have not been previously observed or reported. The metyrapone test was administered to 15 former heroin addicts: 10 (8 male, 2 female) in steady-state methadone maintenance therapy (30 to 90 mg/d) and 5 (3 male, 2 female) in the final phase of a slow methadone dose reduction procedure (0 to 10 mg/d). Eight out of 15 methadone maintenance subjects exhibited a narcotic withdrawal-like syndrome ranging from 'moderate' to 'severe' and four additional subjects had 'mild' symptoms, occurring within 1 h after metyrapone administration, and resolving within 2 h of onset. No significant symptoms were seen in 3 methadone maintained subjects nor in any of 9 normal volunteers (7 male, 2 female). The mechanism by which metyrapone induces symptoms resembling narcotic withdrawal in opiate-dependent individuals is unknown but physicians performing this test should be aware of this possible response.

Adult↗