Cumulative clinics

Presence or absence of active metabolites and their contribution to clinical effects Immediate or cumulative clinical effects Drug-induced inhibition or induction of PK processes... 

All modalities, from electroconvulsive therapy (ECT) to psychotherapy, can be incorporated into our approach when empirical data support their utility. When sufficient data are lacking, we offer suggestions based on our cumulative clinical and research experience. 

Flurazepam is administered orally as the dihydrochloride salt. It is rapidly N-dealkylated to give the 2 -fluoro derivative of N-desmethyIdiazepam, and it subsequently follows the same metabolic pathways as chlordiazepoxide and diazepam (Fig. 22.18). The half-life of flurazepam is fairly long ( 7 hours) consequently, it has the same potential as chlordiazepoxide and diazepam to produce cumulative clinical effects and side effects (e.g., excessive sedation) and residual pharmacological activity, even after discontinuation. Chlorazepate is yet another benzodiazepine that is rapidly metabolized (3-decarboxylation) to N-desmethyIdiazepam and so shares similar clinical and pharmacokinetic properties to chlordiazepoxide and diazepam. 

The basic elements and considerations for assay development, validation, and specification assignment are reviewed briefly. Assay development produces a method that requires validation for the analysis and release of materials (bulk or formulated finished product) for use in clinical development. The cumulative analysis of materials and stability considerations is then used to established specifications for internal and regulatory submission. 

Idarubicin inhibits both DNA and RNA polymerase, as well as topoisomerase II. The pharmacokinetics of idarubicin can best be described by a three-compartment model, with an a half-life of 13 minutes, a (3 half-life of 2.4 hours, and a terminal half-life of 16 hours.22 Idarubicin is metabolized to an active metabolite, idarubicinol, which has a half-life of 41 to 69 hours. Idarubicin and idarubicinol are eliminated by the liver and through the bile. Idarubicin has shown clinical activity in the treatment of acute leukemias, chronic myelogenous leukemia, and myelodysplastic syndromes. Idarubicin causes cardiomyopathy at cumulative doses of greater than 150 mg/m2 and produces cumulative cardiotoxic effects with other anthracyclines. Idarubicin is a vesicant and causes red-orange urine, mucositis, mild to moderate nausea and vomiting, and bone marrow suppression. 

This royal-blue-colored drug is an anthracenedione that inhibits DNA topoisomerase II. The pharmacokinetics of mitoxantrone may best be described by a three-compartment model, with an a half-life of 3 to 10 minutes, a 3 half life of 0.3 to 3 hours, and a median terminal half-life of 12 days. Biliary elimination appears to be the primary route of elimination, with less than 10% of the drug eliminated by the kidney.23 Mitoxantrone has shown clinical activity in the treatment of acute leukemias, breast and prostate cancer, and non-Hodgkin s lymphomas. Myelosuppression, mucositis, nausea and vomiting, and cardiac toxicity are side effects of this drug. The total cumulative dose limit is 160 mg/m2 for patients who have not received prior anthracycline or mediastinal radiation. Patients who have received prior doxorubicin or daunorubicin therapy should not receive a cumulative dose greater than 120 mg/m2 of mitoxantrone. Patients should be counseled that their urine will turn a blue-green color. 

In leukemia, the intensified use of methotrexate and glucocorticoids is responsible for causing an increased frequency of neurotoxicity and, in older children and adults, avascular necrosis of bone. High cumulative doses of anthracyclines can cause cardiomyopathy. Cranial irradiation causes neuropsychologic deficits and endocrine abnormalities that lead to obesity, short stature, precocious puberty, and osteoporosis.3 As newer and more intensive treatments enter clinical trials, close observation for long-term side effects will assume even greater importance.24... 

Fig. 10. Cumulative number of preclinical and clinical publications on rifaximin (courtesy of Lorin Johnson, PhD). Only papers quoted in Medline are presented.

Table 4.4 The clinical trial process. A drug must satisfactorily complete each phase before it enters the next phase. Note that the average duration listed here relates mainly to traditional chemical-based drugs. For biopharmaceuticals, the cumulative duration of all clinical trials is, on average, under 4 years...

In a second experiment (Hanhijarvi, Nevalainen, and Mannisto, 1985), the chronic, cumulative dermal effects of anthralin chemicals were studied in minipigs. Using only 12 animals, they were able, by having 32 sites per animal, to study the effects of two different chemicals (dithranol and butantrone both anthralins) in three different formulations at three different concentrations each. The protocol also included observations for systemic toxicity, clinical laboratory measurements, plasma drug analyses, and gross and histopathological examinations. 

Doxorubicin is a chemotherapeutic onthrocycline antibiotic, which may cause cordiotoxicity through the free-radical mechanism. Cardiotoxicity limits the clinical usefulness as a result of which doxorubicin has a total cumulative dose of about 450 mg/m body surface area. Patients with pre-existing cardiac disease, elderly patients and patients who have received myocardial irradiation must be treated cautiously and cardiac monitoring may be required. 

The hazard to the population therefore increases throughout the trial process as more people are given greater cumulative amounts of the drug in a less-controlled and monitored manner. However, with each additional patient treated, the clinical experience with the drug also increases, providing a greater safety database in the most relevant species, that is, man. The risk... 

Persons with aplastic anemia due to benzene exposure have been found to be at a much greater risk for developing leukemias. A follow-up of 51 benzene-exposed workers with pancytopenia revealed 13 cases of leukemia. The cumulative incidence of leukemia among individuals with clinically ascertained benzene hemopathy has ranged from 10% to 17% in various studies. ... 

MYKO 63 (P generation) was found to be significantly effective on all the animal tumors it was tested on and would have been really promising for clinical trials if it had not induced any cumulative toxicity when inoculated in daily polyinjections. In other words, the molecular structure of MYKO 63 was actually too stable to attack the tumor rapidly and to be excreted fast enough before a next injection would occur. 

Rhinocerebral p/iycomycos/s A cumulative dose of at least 3 g amphotericin B is recommended. Although a total dose of 3 to 4 g will infrequently cause lasting renal impairment, it is a reasonable minimum where there is clinical evidence of deep tissue invasion. Rhinocerebral phycomycosis usually follows a rapidly fatal course therapy must be more aggressive than that for more indolent mycoses. 

Evaluation of left ventricular ejection fraction (LVEF) is recommended prior to administration of the initial dose of mitoxantrone. Subsequent LVEF evaluations are recommended if signs or symptoms of CFIF develop, and prior to all doses administered to patients who have received a cumulative dose of 100 mg/m or more. Do not administer mitoxantrone to MS patients who have received a cumulative lifetime dose of 140 mg/m or more, or those with either LVEF of less than 50% or a clinically significant reduction in LVEF. 

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