Safety and Tolerability

A major reason for the widespread adoption of HMG-CoA reductase inhibitors is their excellent patient tolerability, which enhances compli- 

In the context of therapy with an inhibitor of HMG-CoA reductase, the term myopathy is used to indicate unexplained muscle pain or weak- 

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Finally, drug treatment in the elderly is of great importance and warrants special attention with regard to safety and tolerability, since systolic blood pressure is recognized as an important target for treatment, particularly in older persons. The benefits of antihypertensive treatment in the elderly and in patients with isolated systolic hypertension are greater than in younger persons. 

Hanna G, Lalezari J, HelUnger J, Wohl D, Masterson T, Fiske W, Kadow J, Lin P, Giordano M, Colonno R, Grasela D (2004) Antiviral activity, safety, and tolerability of a novel, oral smaU-molecule HlV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects a novel, oral small-molecule HlV-1 attachment inhibitor, BMS-488043, in HIV-1-infected subjects. In 11th conference on retroviruses and opportunistic infections, San Francisco, CA... 

Navarro F, Hanauer SB. Treatment of inflammatory bowel disease Safety and tolerability issues. Am J Gastroenterol 2003 98(12 Suppl) S18-S23. 

Baena-Cagnani CE. Safety and tolerability of treatments for allergic rhinitis in children. Drug Safety 2004 27 883-898. 

FIGURE 69-3. Treatment algorithm3 for acute bacterial rhinosinusitis in patients with mild disease without recent antibiotic exposure.31 aAntibiotics are listed in order of predicted efficacy based on predicted clinical and bacteriologic efficacy rates, clinical studies, safety, and tolerability. Doses can be found in Table 69-4. 6Cephalosporins should be considered for patients with non-type I hypersensitivity to penicillins they are more likely to be effective than the alternative agents. cHigh doses (90 mg/kg per day) are recommended for most children, especially those with day-care contacts or frequent infections. 

MJ Parnham. Safety and tolerability of intravenously administered phospholipids and emulsions. In RH Muller, S Benita, BHL Bohm, eds. Emulsions and Nanosuspensions for the Formulation of Poorly Soluble Drugs. Stuttgart Medpharm Scientific Publishers, 1998, pp 131-140. 

Treatment of symptomatic diverticular disease of the colon is aimed at the relief of symptoms and the prevention of major complications. The efficacy of fiber supplementation and of anticholinergic and spasmolytic agents remains controversial. Antibiotics are commonly used in the treatment of inflammatory complications of diverticular disease. Data from open labelled and randomized controlled trials do suggest the efficacy of rifaximin in obtaining symptomatic relief in patients with diverticular disease. Approximately 30% therapeutic gain compared to fiber supplementation only can be expected after one year of intermittent treatment with rifaximin. Considering the safety and tolerability of rifaximin, this drug can be recommended for patients with symptomatic uncomplicated diverticular disease. 

Rifaximin, a virtually nonabsorbed antibiotic, is a semisynthetic rifamycin derivative, with a broad antimicrobial spectrum that includes most Gram-positive and Gram-negative bacteria, both aerobes and anaerobes [1, 2], Unlike systemically available antibiotics, this antimicrobial allows localized targeting (e.g. enteric or cutaneous) of pathogens and is associated with a minimal risk of systemic toxicity or side effects [3, 4], Provided that nonabsorbed antibiotics are as effective as systemically absorbed drugs for the target illness, their safety and toler-... 

Both enantiomers and the racemate of l-(3,4-dichlorophenyl)-3-azabicyclo [3.1.0]hexane, 27a-c, have been reported to be in development. The racemate, DOV 216,303, inhibits the reuptake of NE, 5-HT and DA with IC50 values of 20, 14 and 78 nM, respectively [85]. DOV 216,303 is active in tests predictive of antidepressant activity, including the mouse FST (minimum effective dose = lOmg/kg), reversal of tetrabenazine-induced ptosis and locomotor depression. DOV 216,303 was also reported to be well tolerated in phase I clinical trials [85,86], In a phase II study designed to explore safety and tolerability in depressed individuals, patients received either DOV 216,303 (50 mg, b.i.d.) or citalopram (20 mg, b.i.d.) for two weeks [85]. It was found that the side effect profile was not remarkably different between the two treatment groups. In addition, time-dependent reductions in Hamilton Depression Scores (HAM-D) were similar for both groups. 

Pruvanserin hydrochloride (41, EMR-62218/LY-2422347) is a 5-HT2A antagonist in phase II for the treatment of insomnia [99]. Safety and tolerability studies of 5 and 15 mg compared with placebo are ongoing and completion was expected in November 2006. 

In man, minaprine at doses of 150-300 mg/day (p.o.) is well tolerated, and extensive safety and tolerance studies have been performed [ 153 and references cited therein]. Clinical evaluations of minaprine have been published [154-158 and literature cited therein]. 

Preclinical studies Animal studies that support Phase I safety and tolerance studies and must comply with Good Laboratory Practice (GLP). Other preclinical studies are done in discovery research laboratories to support drug efficiency claims. 

Estimation of Initial Safety and Tolerability. The initial and subsequent administration of an investigational new drug into humans is usually intended to determine the tolerability of the does range expected to be needed for later clinical studies and to determine the nature of adverse reactions that can be expected. These studies typically include both single and multiple dose administration. 

Glund, K., Hoffmann, T., Demuth, H.-U., Banke-Bochita, J., Rost, K.-L. and Fuder, H. (2000) Single dose-escalation study to investigate the safety and tolerability of the DP IV inhibitor P32/98 in healthy volunteers. Experimental and Clinical Endocrinology and Diabetes, 108, 159. 

In 1983, the first SSRI, fluvoxamine (Luvox), debuted in Switzerland. Five years later, fluoxetine (Prozac) was introduced in the United States. The SSRIs revolutionized the treatment of depression. They improved safety and tolerability, removing much of the stigma of taking an antidepressant. In fact, some think that it has become too easy to take antidepressants and that psychotherapy is being neglected or discouraged. 

Methylphenidate is now the most widely used of the stimulants. It has a well-established record of safety and tolerability and has been used in children throughout the school years and in adults as well. In preschool children, the effects of methylphenidate can vary. 

Teppler H, Gesser RM, Friedland IR, Woods GL, Meibohm A, Herman G Mistry G Isaacs R. (2004) Safety and tolerability of ertapenem. J Antimicrob Chemother 53 75-81. 

Johnson JR, Bumell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. (2010) Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC CBD extract and THC extract in patients with intractable can correlated pain. J Pain Symptom Manage 39 167-179. 

Medicinal products for diseases predominantly or exclusively affecting paediatric patients -when a full development programme with the possible exception of initial safety and tolerability would be required at an early stage. 

Another issue is whether to conduct Phase 1 safety and tolerability studies only in elderly subjects if the drug is specifically for use in that age group. It may be argued that it is unethical to conduct such studies in young healthy volunteers if such an age group will never receive the drug. 

Flutamide was the first drug used in prostate cancer therapy for which the withdrawal syndrome was reported. In that study, 40% of patients showed a decline in prostate specific antigen (PSA) levels after cessation of flutamide from the therapeutic protocol. The decline in PSA levels was associated with an improvement of the clinical symptoms. Based on these paradoxical observations, the concept of sequenced androgen ablation was proposed [217]. Several phase II clinical studies were performed, demonstrating safety and tolerability, however, a direct comparison in randomised phase III trials is necessary [218]. 

This compound is effective in tumor xenograft models when dosed orally or IV. Compoimd 42 is in safety and tolerability studies in humans. 

Irinotecan is an active chemotherapeutic agent that has been used in esophageal cancer and is also a potent radiosensitizer. In vitro studies have shown activity in esophageal cancer cell lines. A Phase I study has demonstrated its safety and tolerability with cisplatin. Phase I/II studies are currently underway determining the maximum tolerated weekly dose of irinotecan combined with concurrent radiation for locally advanced esophageal cancer (MSKCC 99081). 

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