Escalating dose

Foltin RW, Ward AS, Haney M, et al The effects of escalating doses of smoked cocaine in humans. Drug Alcohol Depend 70 149—157, 2003... 

Segal DS, Kuczenski R Behavioral alterations induced by an escalating dose-binge pattern of cocaine administration. Behav Brain Res 88 251—260, 1997 Serper MR, Chou JC, Allen MH, et al Symptomatic overlap of cocaine intoxication and acute schizophrenia at emergency presentation. Schizophr Bull 25 387—394, 1999... 

Balan V Nelson DR, Sulkowski MS, Everson GT, Lambiase LR, Wiesner RH, Dickson RC, Post AB, Redfleld RR, Davis GL, Neumann AU, Osborn BE, Ereimuth WW, Subramanian GM (2006) A Phase I/II study evaluating escalating doses of recombinant human albumin-interferon-alpha fusion protein in chronic hepatitis C patients who have failed previous interferon-alpha-based therapy, Antivir Ther 11 35 5... 

Six months later, BA s pain is controlled with the escalating doses of the combination product however, he has reached the maximum dose of acetaminophen. What would you suggest at this time ... 

Opioid rotation is the switch from one opioid to another to achieve a better balance between analgesia and treatment-limiting adverse effects. This practice is often used when escalating doses (greater than 1 g of morphine per day) become ineffective. In some settings opioid rotation is utilized routinely to prevent the development of analgesic tolerance.48... 

Intravesical infusion of linear PEI/pDNA polyplexes was evaluated in patients with superficial bladder cancer where intravesical therapy with bacillus Calmette-Guerin had failed [6, 224]. Patients had low grade superficial bladder cancer, which expressed H19. The therapeutic pDNA contains H19 gene regulatory sequences that drive the expression of an intracellular toxin. Escalating doses of 2-20 mg plasmid per intravesical treatment were applied, with responders continuing to receive polyplexes once a month every month for 1 year. The treatment resulted in complete ablation of the marker tumor, without any new tumors in four of the 18 patients (22% overall complete response rate). Eight of the 18 patients (44%) had complete marker tumor ablation or a 50% reduction of the marker lesion. 

Chronic opiate treatment results in complex adaptations in opioid receptor signaling. Much has been learned from studies on mechanisms of tolerance to the analgesic effects of opiates. This is a major clinical problem, as it means that ever-escalating doses are required for the treatment of chronic pain. The classic view was that tolerance reflects a decrease in functional opioid receptors via desensitization and internalization. Desensitization occurs when receptors are uncoupled from G proteins as a result of phosphorylation by G-protein-coupled receptor... 

Chadwick SL, Kingston HD, Stem M, et al. Safety of a single aerosol administration of escalating doses of the cationic lipid GL-67/DOPE/DMPE-PEG5000 formulation to the lungs of normal volunteers. Gene Ther 1997 4(9) 937-942. 

The design of the MTD study in the nonpregnant rabbit is variable depending on the type of test item and preferences of the testing laboratory. In our laboratory, this study is performed in two phases. In the first phase, two groups of three females each are given escalating dose levels every 2 days (see Note 3) until a reaction to treatment is observed (see Note 4). 

The treatment duration in the escalating dose phase of the Maximum-Tolerated-Dose study can be extended from 2 days to several days depending of the mechanism of action of the test compound and on the basis of data available with this compound in other species. 

Long-term use is not recommended in most children and adolescents, but when it does occur, patients may develop tolerance to many of the side effects, particularly sedation. Tolerance does not appear to develop toward the anxiolytic effects, and the vast majority of patients do not require escalating doses once a therapeutic effect is found (Lader, 1987 Hobbs et al., 1996). 

The NME can now be administered to humans. The first step in clinical evaluation is one or more phase I studies designed to assess the drug s safety and pharmacokinetic profile. Phase I studies usually involve a small number of healthy volunteers who are closely monitored after receiving escalating doses of the drug candidate. Phase I studies of drugs for cancer or HIV infection must be carried out in patients, not in healthy subjects. Ordinarily, until more information is available, the minimum dose to induce side effects is stipulated as the upper dose limit for subsequent administration to human subjects. 

Case Example Zolpidem was abused by a 33-year-old man who had been prescribed 10 mg/day for insomnia associated with depression. The patient took 30 mg and noticed improvement of depressive symptoms. With continued escalated doses (up to 150 to 280 mg/day), tolerance developed. He occasionally noticed signs of intoxication with severe ataxia after doses of 80 to 100 mg but never experienced the more common side effects of high-dose zolpidem. Dose reduction caused depressive mood recurrence with apathy and drug-craving. A grand mal seizure after ingesting 60 to 80 mg resolved without supportive measures (155). 

Shah N, Pasquini R, Rousselot P et al. Dasatinib (SPRYCEL) vs. escalated dose of imatinib (IM) in patients (pts) with ehronie phase chronic myeloid leukemia (CP-CML) resistant to imatinib results of the CA180-017 START-R randomized study (Abstract 167). B/ooii2006 108 53a. 

Tolerance is the state in which escalating doses of a drug are needed to maintain an effect, such as pain relief (analgesia). 

A number of issues, however, prove to be problematic with the use of caffeine. First, tolerance appears to rapidly develop with repeated doses (50). Second, there is substantial interindividual variability in the rate of metabolism and in the frequency of undesired effects such as tremor, jitteriness, and insomnia. Interestingly, despite the widespread use of caffeine, and the strong reluctance of many users to forgo consumption and their inclination to typically escalate dose (i.e., number of servings of coffee or cola), routine caffeine consumption is usually not viewed as drug use, much less drug abuse. 

Based upon these observations and following Phase I safety studies, a Phase II randomized, double-blind, controlled clinical trial was undertaken to treat active ulcerative colitis with escalating doses of ISIS 2302. Based on an intent-to-treat analysis, 59% (13/22) of patients treated daily with 240 mg ISIS 2302 enema over six weeks achieved a positive response, as measured by Disease Activity Index (DAI)... 

PK data for cetuximab were derived from 19 clinical studies performed up to 2003 [16]. Ten of these studies were conducted as dose-escalation/dose-finding studies, while the remaining nine were conducted at the approved dosing regimen of 400 mg/m2 initially, followed by weekly doses of 250 mg/m2. 

Bloomington, Indiana, U.S.A.) coated with escalating doses of paclitaxel (0,2, 0,7, 1.4, and 2.7 jig/mm2 of stent surface area) applied directly to stent surface. In both trials, there was a dose-dependent effect on the angiographic parameters of restenosis (64). However, clinical outcomes at 6 and 12 months were not improved in these studies (65). The subsequent Drug ELuting coronary stent systems in the treatment of patients with de noVo nativE coronaRy lesions... 

---