Dose Determination Study Research Articles

Dose determination and confirmation of a long-acting formulation of ceftiofur (ceftiofur crystalline free acid) administered subcutaneously for the treatment of bovine respiratory disease.

The objective of this work was to determine and confirm an effective dose of ceftiofur crystalline free acid sterile oil suspension (CCFA-SS, 100 mg ceftiofur equivalents (CE)/mL], a long-acting single-administration ceftiofur formulation, for the treatment of the bacterial component of bovine respiratory disease (BRD). Study 1 was a dose determination study that used an intratracheal Mannheimia haemolytica (Pasteurella haemolytica) challenge model to evaluate single-administration doses of CCFA-SS at 0.0, 1.1, 2.2, 3.3, 4.4 or 5.5 mg CE/kg body weight (BW) for the treatment of BRD. Data from this study were used to select doses for field testing in three multi-location clinical studies. In Study 2, the efficacy of a single administration dose of CCFA-SS at 4.4 mg CE/kg BW was compared with a negative control for the treatment of naturally occurring BRD in feedlot cattle. Treatments were administered when uniform clinical signs of BRD were present. Study 3 used a design similar to Study 2, and compared single-administration doses of CCFA-SS at 3.0 or 4.4 mg CE/kg BW with the positive-control tilmicosin (Micotil(R) 300 Injection, Elanco Animal Health) at 10 mg/kg BW. Study 4 compared the efficacy of single doses of CCFA-SS of 1.1-8.8 mg CE/kg BW with tilmicosin at 10 mg/kg BW. A total of 1176 cattle were included in these clinical studies. In Study 1, a dose of 4.55 mg CE/kg BW was determined to be effective. This was rounded to 4.4 mg CE/kg for field testing. In Study 2, a single dose of CCFA-SS at 4.4 mg CE/kg BW had a higher treatment success rate on day 14 (61%) than negative controls (26%, P < 0.01). However, in Study 3 this dose was judged to be at the beginning of an efficacious dose range for the treatment of BRD when compared with tilmicosin. In Study 4, day 28 treatment success rates were higher for CCFA-SS at 4.4-8.8 CE/kg BW than for tilmicosin (P=0.002) or the noneffective CCFA-SS dose of 1.1 mg CE/kg BW (P < 0.001). Based on decision criteria for Study 4, the effective dose was determined to be 4.4-5.5 mg CE/kg BW. These clinical studies demonstrated that a single dose of CCFA-SS (100 mg CE/mL) administered subcutaneously (s.c.) in the neck at 4.4-5.5 mg CE/kg BW is an effective treatment for BRD in feedlot cattle. However, this route of administration is no longer being considered for this formulation because of the ceftiofur residues that are present at the injection site for extended periods of time.

Intravenous immunoglobulin therapy in the treatment of patients with pemphigus vulgaris unresponsive to conventional immunosuppressive treatment

Background: Severe pemphigus vulgaris (PV) is conventionally treated with high-dose oral prednisone, usually in combination with an immunosuppressive agent (ISA). Some patients experience significant side effects, which are sometimes fatal, from prolonged immunosuppression. Objective: Intravenous immunoglobulin (IVIg) was administered to 21 patients with severe cutaneous and mucosal PV who had not responded to the prolonged use of oral prednisone and multiple ISAs. Methods: A preliminary dose-determination study tested 7 additional volunteers to ascertain the optimal IVIg dose of 2 g/kg per cycle. Parameters to assess clinical outcome were recorded before and after IVIg therapy. Variables tested were highest dose, total dose, and duration of prednisone and ISAs, their side effects, frequency of recurrence and relapse, duration of IVIg therapy, clinical response, induction and duration of remission, number of hospitalizations, total days of hospital stay, and quality of life. Results: Use of IVIg monotherapy resulted in effective control of disease and produced a sustained remission in the 21 patients. The patients became free of lesions and remained so after finishing IVIg therapy. IVIg had a steroid-sparing effect and produced a high quality of life. Serious side effects from the use of IVIg were not observed. IVIg needs to be gradually withdrawn after achievement of clinical control. Conclusion: In patients with PV who do not respond to conventional immunosuppressants, IVIg appears to be an effective treatment alternative. Its early use is of significant benefit in patients who may experience life-threatening complications from immunosuppression. IVIg is effective as monotherapy. (J Am Acad Dermatol 2001;45:679-90.)

Polyethylene glycol (PEG) 4000 in constipated children (6 months – 15 years): A dose determination study

Polyethylene glycol (PEG) 4000 in constipated children (6 months – 15 years): A dose determination study

Is it Possible to Differentiate between Angiotensin II Type 1 (AT1) Receptor Blockers in Normotensive Volunteers?

Variability of blood pressure responses to inhibition of the renin-angiotensin system is influenced by factors inherent in the patient, such as renin status, and by drug-specific factors, such as pharmacokinetics. The pharmacokinetic-pharmacodynamic interactions of two doses of candesartan cilexetil, which is an ester prodrug of the insurmountable angiotensin II type 1 (AT 1 ) receptor blocker candesartan, were compared with those of the standard dose of losartan in normotensive volunteers whose renin status was controlled by mild sodium depletion. In a double-blind, placebo-controlled crossover study, the effects of single oral doses of candesartan cilexetil, 8 mg and 16 mg, and losartan, 50 mg, were compared for 24 h in 16 healthy individuals pretreated with a single 40-mg dose of furosemide. Mean blood pressure was recorded by repeated measurements using the oscillometric method. In addition, measurements were made of plasma active renin, angiotensin I and angiotensin II, and plasma levels of candesartan and EXP-3174, the active metabolites of candesartan cilexetil and losartan, respectively, were determined by high-performance liquid chromatography and correlated to pharmacodynamic changes. The large interindividual variability of EXP-3174 levels in subjects who received losartan revealed a significant correlation between active renin and peak drug levels ( r = 0.77, n = 16, p < 0.01). Such a correlation was not found within either group of individuals who received candesartan cilexetil, because of lower interindividual pharmacokinetic variability. A dose-response relationship was found between plasma renin and candesartan when both doses of candesartan cilexetil were analysed. The pharmacodynamic effects of a single oral dose of candesartan cilexetil, 16 mg, were superior to those of candesartan cilexetil, 8 mg, and losartan, 50 mg (see Table). This conclusion has been confirmed by the results of a parallel-group, dose-determination study performed in hypertensive patients. The less variable pharmacokinetic-pharmacodynamic interaction for candesartan cilexetil than for losartan could account for the smooth 24-h reduction in blood-pressure found in patients treated with candesartan cilexetil. These results suggest not only that AT 1 -receptor antagonists can be differentiated, but that they will not be equally useful in clinical practice where, in contrast to clinical research, clear evidence is more difficult to obtain because of variability in renin status.

Dose determination study of azithromycin for treatment of pneumonia

Dose determination study of azithromycin for treatment of pneumonia

Double‐blind dose determination study of a new antidepressant—sertraline

AbstractAs part of a multicenter dose determination study designed to evaluate the safety and therapeutic activity of four fixed dose levels of sertraline—a new antidepressant with biochemical characteristics different from tricyclics—17 patients with diagnoses of major depressive disorder were treated with active medication under double‐blind conditions for 4 weeks following a 1‐week washout period. Patients receiving the two higher dose levels of sertraline exhibited almost no symptomatic improvement and manifested more adverse events that patients receiving the two lower dose levels. No statistically significant differences between the low‐dose groups and the placebo group were found. Thus, the efficacy of sertraline could not be demonstrated under these design constraints, although differential dose level effects were indicated. Dosage levels up to 100 mg/day would appear to be more clinically appropriate than higher dosage levels.