Minimal Daily Dose Research Articles

Evaluation of parenteral diluent contamination by caprolactam.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. A leachable cyclic amide (caprolactam) can be found in normal saline (NS) and 5% dextrose in water (D5W) plastic bags widely used in clinical practice if they contain polyamide in a multilayer sheeting. This contamination and the parameters that could influence its content have never been studied in a public work such as a scientific publication. Two independent laboratories validated a caprolactam dosing method and studied contamination levels in several containers. Caprolactam content in multilayer polypropylene/polyamide/polypropylene plastic bags ranged from a mean (SD) of 5.43 (0.21) mg/L (D5W 1,000mL) to 22.83 (1.26) mg/L (NS 50mL). NS and D5W can be intravenously administered with a total daily dose of 3L, corresponding to a minimal daily dose of 16.3mg of caprolactam. The high levels of contamination we have reported and the possibility of administering caprolactam to high-risk patients (eg, neonates, the elderly) should make it imperative for pharmaceutical companies to communicate publicly on the safety of caprolactam.

Chlorpromazine-induced status epilepticus: A case report

It is largely known that some antipsychotic agents could have proconvulsive and proepileptogenic effects in some patients and could induce EEG abnormalities as well. However, the association of status epilepticus with certain antipsychotic drugs has been very rarely reported. A case of an 18-year-old adolescent girl, with chlorpromazine therapy started for anxiety-phobic disorder was reported. Her personal history disclosed delayed psychomotor development. Shortly after the introduction of the neuroleptic chlorpromazine therapy in minimal daily dose (37.5 mg), she developed myoclonic status epilepticus, confirmed by the EEG records. Frequent, symmetrical bilateral myoclonic jerks and altered behavior were associated with bilateral epileptiform discharges of polyspikes and spike-wave complexes. This epileptic event lasted 3.5 hours and it was stopped by the parenteral administration ofvalproate and lorazepam; she was EEG monitored until stable remission. Status epilepticus as initial epileptic event induced by neuroleptic agent was not previously reported in our national literature. Introduction of chlorpromazine to a patient without history of seizures is associated with the evolution of an epileptic activity, including the occurrence of status epilepticus. Clinical evaluation of the risk factors possibly related to chlorpromazine-induced seizure is recommended in individual patients before administering this drug.

An Open-Label, Positron Emission Tomography Study to Assess Adenosine A2A Brain Receptor Occupancy of Vipadenant (BIIB014) at Steady-State Levels in Healthy Male Volunteers

Adenosine A2A receptor antagonists are potential new treatments for Parkinson disease. We used positron emission tomography (PET) of the A2A receptor radiotracer, [C]SCH442416, to assess binding of the novel A2A antagonist, vipadenant (previously known as BIIB014), to human brain A2A receptors and to investigate the relationship among dose, steady-state plasma levels, and receptor occupancy. We used PET to compare [C]SCH442416 uptake before and after blockade with daily oral vipadenant (2.5-100 mg/d for 10 or 11 days) in healthy volunteers (n = 15). We estimated receptor occupancy in brain regions of interest, particularly the putamen, by kinetic modeling of PET data. We estimated the dose, minimal plasma concentration at steady state (Cmin), and area under the plasma concentration curve (AUC0-tau) at the steady state required for saturation (> or =90% receptor occupancy) using Bayesian Emax and logistic regression models. The estimated receptor occupancy of vipadenant in the brain regions of interest varied from 74% to 94% at the lowest daily dose (2.5 mg) and reached saturation in all regions at 100 mg. In the putamen, the estimated minimal daily dose, steady-state Cmin, and steady-state AUC0-tau required for receptor saturation were 10.2 mg (interquartile range, 28%), 0.097 microg/mL (27%), and 6 microg h/mL (21%), respectively. This study provides the first evidence that vipadenant occupies A2A receptors in the human brain. Receptor occupancy was related to both dose and plasma levels of vipadenant. These results, coupled with previous efficacy results in animals, justify continued development of vipadenant as a potential treatment for Parkinson disease.

Pharmacological and Clinical Basis of Treatment of Familial Mediterranean Fever (FMF) with Colchicine or Analogues: An Update

Familial Mediterranean Fever (FMF), an autosomal recessive disorder, is characterised by recurrent attacks of fever and serositis, lasting 24-72 hours. Since 1972 colchicine has become the drug of choice for prophylaxis against FMF attacks and amyloidosis FMF-associated. Colchicine, an alkaloid neutral, is absorbed in the jejunum and ileum. It metabolised by liver and only small amounts are recovered unchanged in the urine. Really plasma half-life is prolonged in patients with liver or renal failure. Colchicine is able to prevent activation of neutrophils, binding beta-tubulin and making beta-tubulin-colchicine complexes; this way inhibits assembly of microtubules and mitotic spindle formation; moreover its mode of action includes modulation of chemokines, prostanoids production, inhibition of neutrophil and endothelial cell adhesion molecules. The minimal daily dose in adults is 1.0 mg/die, but in children there is not a definite dose. Since in vitro high dosages of colchicine stop mitosis, this drug might interfere with male and female fertility and with children growth, but, according to current guidelines and because of rare side effects of the drug, FMF patients are recommended to take colchicine. Since colchicine treatment is often complicated by frequent gastrointestinal side effects, by our experience, in order to improve colchicine tolerance we recommend: lactose-free diet and treatment of intestinal bacterial overgrowth and/or Hp-infection, assessed by breath tests. Since our data showed that 10-15% of FMF patients seem are non-responders or intolerant to colchicine, today we are working in the design of colchicine analogues which may have lesser toxicities and a larger therapeutic window.

Guideline for the treatment of leprosy by new quinolones

Ofloxacin(OFLX) is often applied today as a substitution drug of MDT for drug resistance to dapsone, rifampicin or clofazimine. However, OFLX resistance is also becoming a great concern. Low and/or irregular administration are considered to be the major causes of OFLX resistance. OFLX should be used as a combined therapy, and minimal daily dose of 400 mg of OFLX or 200-300 mg of levofloxacin is required. Quinolone resistance should be considered when no improvement of clinical and/or bacterial index is observed after the treatment for 6 months. In such cases, resistance gene detection is necessary.

Dose-finding study of triptorelin acetate for prevention of a premature LH surge in IVF: a prospective, randomized, double-blind, placebo-controlled study

Gonadotrophin-releasing hormone agonists (GnRHa) are routinely used in IVF programmes to prevent an unwanted LH surge and consequent ovulation. Despite its widespread use in IVF, a convincing dose recommendation for GnRHa in IVF does not exist. In our opinion, the lowest possible dose of GnRHa should be used. Thus, we performed a prospective, randomized, double-blind, placebo-controlled study to determine the minimal daily dose of triptorelin acetate needed to suppress a premature LH surge during IVF treatment in a long protocol. A total of 240 women (60 in each group) was randomized to either placebo or to one of three doses of triptorelin, i.e. 15, 50 or 100 microg daily. Ovarian stimulation was performed with two or three ampoules of FSH daily. A premature LH surge occurred in 23% of placebo-treated patients, but in none of the triptorelin acetate-treated patients. There were significantly more oocytes and embryos in the 50 and 100 microg triptorelin groups. There was no dose relationship in rates of either implantation, pregnancy, ongoing pregnancy, live birth or baby take-home. In this study we showed that daily administration of 15 microg triptorelin is sufficient to prevent a premature LH surge, and that 50 microg is equivalent to 100 microg in terms of IVF results.

Influence of Dienogest on Ovulation in Young Fertile Women

Objective: To determine the minimal oral dose of dienogest that will reliably and safely inhibit ovulation in healthy women with normal menstrual cycles. Design and Setting: Randomised, open, four-arm, phase II study involving one control cycle followed by one treatment cycle. Over 21 days patients received one of four oral doses of dienogest 0.5, 1.0, 1.5 or 2.0mg daily. Blood sampling for several hormones was performed on 13 days of each cycle. Participants: Forty-two healthy women were enrolled in the study. Because of an anovulatory control cycle and other reasons, nine of these volunteers did not start the treatment. 33 participants (mean age 24 ± 2 years) completed the study according to the protocol. Main Outcome Measures: Inhibition of ovulation was assessed by serum levels of progesterone, oestradiol, luteinising hormone and follicle-stimulating hormone. Safety and tolerability was measured by pre- and post-study medical examinations, cycle control, laboratory (blood and urine) tests, and incidence and severity of adverse events. Results: Dienogest 0.5mg inhibited ovulation in two-thirds of the participants. Doses of dienogest ranging from 1.0 to 2.0mg inhibited ovulation in all patients who completed the study. No serious adverse events were observed at any dose. The frequency of dysmenorrhoea was lower during the treatment cycle than during the control cycle. Increases in cycle duration and reductions in the duration of menstrual flow and serum dienogest levels were dose dependent. Conclusions: Dienogest 1.0mg is the minimal daily dose needed to inhibit ovulation in healthy individuals with normal ovulatory cycles. Dienogest was well tolerated at doses of up to 2.0mg and showed good control of withdrawal bleeding and dysmenorrhoea. Dienogest is suitable for use as the progestin compound in oral contraceptives.

Effects of differing absolute and relative doses of progesterone and estrone on implantation and fetal survival in ovariectomized rats.

Rats were inseminated, then ovariectomized and treated with different doses of progesterone (P) and estrone (E), to determine the minimal and optimal daily doses of P and E required for implantation and fetal survival in ovariectomized rats. The minimal daily dose of P and E required for an optimal rate of implantation and fetal survival in ovariectomized rats was between 0.4 and 4.0 mg of P, and 0.1 and 1.0 microgram of E. The daily 5.0 micrograms E dose was too high to realize implantation or fetal survival when it was injected with P beginning on the day after insemination. If, however, 7 days of daily P treatment preceded the daily 5.0 micrograms E, combined with 20 mg P, delayed implantation was realized but subsequent fetal survival was not. High P doses alone did not substitute for combining E with lower P doses.

Reassessment of the daily dose of oral thyroxine for replacement therapy in hypothyroid children

The optimal daily requirement of sodium L-thyroxine for replacement therapy of hypothyroidism was evaluated in 11 hypothyroid children ranging from one to 14 years of age. The "optimal" dose of L-T4, defined as the minimal daily dose necessary to suppress the serum concentration of TSH to normal, was determined in each patient and individual growth rates were assessed for periods up to 12 months during the time this dose was being administered. The mean "optimal" dose of L-T4 was 3.78 +/- 0.6 mug/kg or 104.6 +/- 5.2 mug/m2. This dose was considerably lower than the doses of L-T4 generally recommended. All patients appeared clinically euthyroid, and their serum concentrations of T3 and T4 as well as their height velocities remained within the normal range while the "optimal" dose of L-T4 was being adminstered.

Thyroid physiology during the postnatal period in the rat: A study of the development of thyroid function and of the morphogenetic effects of thyroxine with special reference to cerebellar maturation

In the young rat, the concentration of thyroxine in the plasma progressively augments from birth to the third postnatal week. The plasma thyroxine turnover is also significantly higher during this period than at 30 days or in the adult. In the propylthiouracil-treated animal, the minimal daily dose of exogenous thyroxine able to correct the structural maturation of the cerebellar Purkinje cells and of their afferents also returns the electrophysiological maturation of the Purkinje cells to normal. Furthermore, this minimal daily dose prevents the enlargement of the thyroid gland, and it corresponds to the amount of hormone normally produced per day by the thyroid. The sensitivity of the cerebellar structures appears earlier and consequently is higher than that of the structures giving birth to the postnatal ossification centers.