A novel home-based method for preparing suspensions of anti-TB drugs.

BACKGROUND: Tablets are the most widely available dosage form for the treatment of TB; however, adult tablets fail to meet the needs of young children who cannot swallow these tablets or require dose titration. We tested a new, simple device (XTEMP-R®) and the methodology for converting tablets of TB drugs into a homogeneous suspension for home use by children and caregivers.METHODS: XTEMP-R is a new device used for converting tablets into liquid preparations. Four TB drugs - pretomanid, delamanid, clofazimine and bedaquiline - were dispersed in the device utilizing water and simple syrup. The reproducibility of accurately delivering aliquots from the suspension upon preparation and upon redispersion after storing for 2 days was studied.RESULTS: Suspensions of each of the drugs tested were easily prepared in about 10 min and were visually uniform in consistency. Dosages in 2 and 5 mL were assessed in suspension, and those in 5 mL tested upon redispersion after 2 days. The observed range for these dosages spanned from 94.6% to 101.1% of the theoretical concentration for the suspensions under examination. The cleaned device had no detectable residual drug.CONCLUSION: XTEMP-R can be used at home by caregivers to prepare doses of suspensions accurately for children and patients who cannot swallow tablets.

Stable, compounded bedaquiline suspensions to support practical implementation of pediatric dosing in the field.

BACKGROUND: Bedaquiline (BDQ) tablets are indicated as part of a combination regimen for the treatment of multidrug-resistant TB in adults, adolescents and children. A dispersible tablet formulation is now approved but is not currently available in all settings. The aim of this study was to develop stable extemporaneous liquid formulations of BDQ that can be stored at room temperature or 30°C for several weeks, to support pragmatic pediatric dosing in the field and reduce wastage.METHODS: BDQ tablets were suspended in simple syrup and a sugar-free vehicle. Each 20 mg/mL formulation was stored at room temperature or 30°C for 30 days in amber dispensing bottles. Appearance, BDQ potency, pH and microbial counts were determined on Days 0, 15 and 30.RESULTS: The BDQ potency in both formulations remained at 98-101% of the theoretical concentration for 30 days. The appearance, pH and microbial count of sugar-free formulation did not change during the 30-day storage. The simple syrup formulation was stable for 15 days as microbial growth was observed on Day 30.CONCLUSIONS: BDQ may be prepared in syrup or sugar-free suspensions: syrup suspensions can be stored for 15 days at room temperature and 30C, whereas sugar-free suspensions can be stored for 30 days at room temperature and 30C. This information will support practical BDQ dosing for children in the field.

Extemporaneously compounded liquid formulations of clofazimine.

BACKGROUND: Clofazimine (CFZ) is routinely used worldwide for the treatment of leprosy and TB. However, no liquid or dispersible tablet formulations of CFZ are currently available commercially for patients with challenges ingesting soft gelatin capsules or solid formulations. The aim of this research was to develop stable extemporaneous liquid formulations of CFZ that can be stored at room temperature for several weeks to enable practical dosing in the field. METHODS: Two formulations were prepared in syrup and sugar-free vehicles with CFZ tablets using a simple method that can be used in a routine pharmacy. Suspensions were stored at room temperature and at 30°C for 30 days. Formulation aliquots were tested on Days 0, 15 and 30 for appearance, pH, potency and microbial counts. RESULTS: Appearance remained unchanged during storage. The pH of both formulations was between 4.0 and 6.0. Potency was between 90% and 110% for 30 days in the syrup formulation and for 15 days in the sugar-free formulation. Microbial counts met United States Pharmacopeia 1111 limits for oral aqueous liquids and specific organisms were absent. CONCLUSIONS: A simple field-friendly method was successfully developed for the preparation of CFZ liquid formulations using commonly available ingredients. This will permit practical dosing and titration for children and other patients with swallowing challenges.

Sugar and sugar-free liquid formulations of delamanid for patients with rifampicin-resistant TB.

BACKGROUND: Delamanid (DLM) tablets are recommended for the treatment of rifampicin-resistant TB. However, no liquid or dispersible tablet formulation of DLM is currently commercially available for patients with challenges ingesting these tablets. The aim of this study was to develop stable extemporaneous liquid formulations of DLM that can be stored at room temperature for several weeks.METHODS: DLM tablets were suspended in 1) simple syrup and 2) a specially formulated sugar-free vehicle. These suspensions containing DLM 5 mg/mL were stored in plastic prescription bottles at room temperature or 30°C for 30 days. These suspensions were evaluated for appearance, potency, pH, and microbial counts at Days 0, 15, and 30.RESULTS: The potency of DLM in each formulation remained at 98-104% of the theoretical concentration for 30 days. The appearance, pH, and microbial count did not change for the sugar-free formulation during the 30-day storage period. Microbial growth, however, was observed in the simple syrup formulation on Day 30 but not on Day 15.CONCLUSION: DLM can be formulated in sugar or sugar-free suspensions and stored at room temperature or 30°C for at least 15 and 30 days, respectively.

Stable sugar and sugar-free suspensions of pretomanid.

BACKGROUND: Pretomanid (PMD) tablets are indicated as part of a combination regimen for the treatment of adults with pulmonary extensively drug-resistant, treatment-intolerant or non-responsive multidrug-resistant TB. No commercial liquid formulation is currently available for patients unable to swallow these tablets.OBJECTIVE: To develop stable extemporaneous liquid formulations of PMD that can be stored at room temperature or 30°C for at least 4 weeks.METHODS: Crushed PMD tablets were formulated into 20 mg/mL suspensions in a simple syrup and sugar-free formulation. The PMD formulations were stored at room temperature and at 30°C for 30 days in dispensing bottles. Appearance, pH, potency and microbial counts of the suspensions were determined on Days 0, 15 and 30.RESULTS: The potency of PMD remained at 99.7-103.4% of the theoretical concentration in each formulation. The appearance, pH and microbial count did not change during the 30-day storage period. Simple syrup formulations did not require preservatives for microbial stability.CONCLUSIONS: PMD oral suspension formulations in simple syrup or in sugar-free vehicle were easily prepared by utilising commonly available equipment and ingredients and were stable for 30 days. These formulations are appropriate alternatives for patients with swallowing difficulties.

Prescription order risk factors for pediatric dosing alerts.

OBJECTIVES: To determine dosing alert rates based on prescription order characteristics and identify prescription order risk factors for the occurrence of dosing alerts. METHODS: A retrospective analysis of inpatient medication orders and dosing alerts occurring during October 2011 and January, April, and July 2012 at a pediatric institution. Prescription orders and alerts were categorized by: medication class, patient age, route of administration, and month of the year. RESULTS: There were 228,259 orders during the studied period, with 11,072 alerted orders (4.9%). The most frequently alerted medication class was the non-analgesic central nervous system agent class (14% of alerts). Age, route, medication class, and month all independently affected dosing alert rates. The alert rate was highest for immunosuppressive agents (54%), neonates (6.7%), and orders for rectal administration (9.5%). The alert rate was higher in adult patients receiving their care at a pediatric institution (5.7%) compared to children (4.7%), but after multivariate analysis, pediatric orders had higher odds for an alert (OR 1.1, 95% CI 1.05-1.16). Mercaptopurine had the highest alert rate when categorized by active ingredient (73.9%). Albuterol 2.5mg/mL continuous aerosol and heparin 1000 units in 0.9% sodium chloride injection solution were the unique medications with the highest alert rates (100.0% and 97.7%, respectively). CONCLUSIONS: Certain types of prescription orders have a higher risk for causing dosing alerts than others. Patient age, medication class, route of administration, and the month of year can affect dosing alert rates. Design and customization efforts should focus on these medications and prescription order characteristics that increase the risk for dosing alerts.

Treatment of irritable bowel syndrome.

WHAT IS KNOWN AND OBJECTIVE: The complexity and diversity of irritable bowel syndrome's (IBS) presentation make treatment difficult. Although there are reviews and guidelines for treating IBS, they focus on the efficacy of medications for IBS symptoms using high-priority endpoints, leaving those of lower priority largely unreported. Therefore, the aim of this review is to provide a comprehensive evidence-based review of the efficacy of medications to treat IBS symptoms, reported by IBS subtype, including secondary symptom endpoints that are often underreported. METHODS: A review of PubMed for articles published through December 2009 using the keywords: 'irritable bowel syndrome', 'therapeutics', 'antidiarrhoeals', 'laxatives', 'loperamide', 'dietary fibre', 'psyllium', 'calcium polycarbophil', 'bulking agents', 'lubiprostone', 'antidepressant agents, tricyclics' and its representative entities, 'serotonin reuptake inhibitors' and its representative entities, 'dicyclomine', hyoscyamine', 'peppermint oil', 'parasympatholytics' and its representative entities, 'rifaximin', 'pregabalin', 'gabapentin', 'clonidine', 'octreotide', 'atropine' and 'probiotics' is provided. Placebo-controlled trials were evaluated for the strength of evidence supporting the efficacy of each medication for explicit IBS symptoms. The efficacy of each medication for the symptoms of abdominal pain, bloating, stool form, mucus, urgency, feeling of incomplete evacuation, flatulence, frequency, or borborgymi and overall symptoms are reported by IBS subtype. RESULTS AND DISCUSSION: The literature search identified 58 placebo-controlled trials of the efficacy of medications for treating IBS symptoms, which were critically evaluated and reported. The available studies suggest improvement in various IBS symptoms with loperamide, fibre supplements, lubiprostone, tricyclic antidepressants (TCAs), selective serotonin receptor inhibitors (SSRIs), antispasmotics, rifaximin, pregabalin, gabapentin, clonidine, octreotide and probiotic treatments. WHAT IS NEW AND CONCLUSION: This review is the first to compile the available evidence on the efficacy of the various pharmacological treatments for IBS on the basis of IBS subtype and specific symptoms. This evidence is limited and more well-designed studies are required to better inform therapeutic decision-making in the management of this difficult syndrome.

Pharmacokinetics of gabapentin in paediatric patients with uncontrolled seizures.

PURPOSE: The pharmacokinetics of gabapentin in paediatric patients with uncontrolled seizures was studied. METHODS: Thirteen paediatric patients (mean age: 9.4 years) with uncontrolled partial seizures were included. Patients received gabapentin orally until doses were individualized to 9.6-39.8 mg/kg/day. Blood samples were obtained just prior to the dose and over 8 h after gabapentin was administered in the fasting state. The plasma concentration of gabapentin was measured by a high-performance liquid chromatography assay. Pharmacokinetic parameters for gabapentin were determined by non-compartment methods using multivariate regression analysis. RESULTS: Data from nine patients were suitable for pharmacokinetic analysis. The C(max) from 0.9 to 5.8 microg/mL (mean: 2.6 +/- 1.7 microg/mL) and T(max) from 0.5 to 2.0 h (mean: 1.6 +/- 1.0 h). The apparent clearance (Cl/F) ranged from 0.12 to 1.12 L/h/kg (mean: 0.50 +/- 0.29 L/h/kg), and the elimination half-life from 3.2 to 12.2 h (mean: 5.5 +/- 0.8 h). Five patients experienced moderate (n = 4) to severe (n = 1) aggressive behaviour and another gained weight on gabapentin. CONCLUSIONS: Our data suggests that gabapentin pharmacokinetics can vary substantially among paediatric patients. Gabapentin was well tolerated in patients with uncontrolled partial seizures up to 6 months of therapy.

Safety of intravenous bolus administration of gentamicin in pediatric patients.

OBJECTIVE: To determine the safety of gentamicin administered intravenously as a bolus. METHODS: All patients (n = 123, ages: up to 18y, 121; 21y, 1; 31y, 1) who received gentamicin intravenously as a bolus over a four-month period were studied retrospectively. Patient demographics, type of infection, dosing regimen, length of therapy, peak and trough serum concentrations, blood urea nitrogen, serum creatinine, and urine output were reviewed. Patients were stratified into four groups and data analyzed statistically. RESULTS: Mean initial dose (5.32 +/- 2.38 mg/kg/d) was consistent with established guidelines for age and kidney development, with subsequent adjustments based on serum concentrations. Susceptible organisms were eradicated with a mean length of therapy of 6.9 +/- 6.9 days (range 1-35). Patients received a median of nine doses: 42% received doses every eight hours and 33% received doses every 24 hours. No relationship between dosing and abnormal serum creatinine were found (p = 0.69). The estimated cost savings mainly from less nursing time and lower equipment and supply use were $50/patient with bolus administration of gentamicin. CONCLUSIONS: Intravenous bolus administration was safe in pediatric patients and was associated with lower costs.

Efficacy and safety of aerosolized tobramycin in cystic fibrosis.

Aerosolized tobramycin has been extensively used in cystic fibrosis (CF) patients in order to directly deliver the antibiotic to the endobronchial site of infection, and decrease toxicity by limiting systemic absorption. Aerosolized tobramycin doses ranging from 80 mg twice or three times daily to 600 mg three times daily have been used in various clinical trials. At an 80-mg dose, preservation of pulmonary function with little or no improvement over the baseline was reported. Tobramycin, nebulized at 600 mg three times daily, significantly improved clinical and pulmonary functions and reduced the density of Pseudomonas aeruginosa in the sputum. No ototoxicity or nephrotoxicity was reported at either dose. TOBI, a tobramycin solution for inhalation, received Food and Drug Administration approval for maintenance treatment of P. aeruginosa lung infections in CF patients at least 6 years of age. Patients received TOBI nebulize 300 mg of tobramycin every 12 hr daily for 28 days, followed by 28 days off the drug in alternating cycles. In phase III trials, TOBI improved pulmonary function and decreased sputum density of P. aeruginosa compared to placebo. Serum creatinine was minimally, transiently elevated in both groups. More patients in the TOBI group reported voice alterations. All reports of tinnitus were in the TOBI group. An increased risk of emergence of resistant strains of P. aeruginosa was noted at all doses, after prolonged use.

Publication of clinical drug trials.

Clinical drug trials are the best means for establishing the efficacy and safety of drug therapy. Peer-reviewed publications are the most efficient and reliable means for wide dissemination of the results. The investigators and industry have an obligation to publish the data obtained from these trials so that patients may receive the most effective treatment in the safest possible way.

Gastrostomy tube placement in nonadherent HIV-infected children.

OBJECTIVE: To determine the benefits of gastrostomy tube (G-tube) placement in HIV-infected children receiving highly active antiretroviral therapy (HAART). METHODS: Children who had a G-tube placed due to medication adminsitration difficulties were followed to determine changes in medication adherence and changes in laboratory parameters. Medication adherence and laboratory parameters were reviewed for three months prior to G-tube placement and then were followed for six months after G-tube placement. Viral RNA and CD4+ counts were assessed between the two time periods. Medication adherence was followed by review of pharmacy refill records and pill counts. Parents were surveyed about their opinion regarding the G-tube placement and medication administration in their children. RESULTS: Six children had G-tubes placed due to medication administration difficulties. The G-tube was tolerated in all six cases, although one child developed a staphylococcal infection 13 months after G-tube placement. Before G-tube placement, the medication adherence to HAART averaged 47% +/- 20% SD, with a range of 15-90%. After G-tube placement, medication adherence improved to 90-100%. All parents were satisfied with the G-tube and all reported shorter medication administration times and fewer behavioral problems. Five of six patients had at least a 2-log10 decrease in viral load, and CD4+ percentages improved by an average of 6.4%. CONCLUSIONS: G-tubes were well tolerated by HIV-infected children. Although G-tube placement is not needed in most children with HIV, it may provide an option for parents and children where administration of antiretroviral medication poses extreme difficulty and all other avenues have been exhausted.

The safety and antiviral effect of protease inhibitors in children.

STUDY OBJECTIVE: To determine the safety and antiviral effect of protease inhibitors (PIs) over 36 months in pediatric patients infected with the human immunodeficiency virus (HIV). DESIGN: Observational study SETTING: Pediatric immunodeficiency clinic. PATIENTS: Twenty-one children. INTERVENTION: Demographics, dosage regimens, genotype data, viral RNA and CD4+ lymphocyte counts, adverse drug events (ADEs), laboratory tests, and compliance were evaluated over 3 years. Data were analyzed by chi2, repeated measures analysis of variance, and paired t tests. MEASUREMENTS AND MAIN RESULTS: Twenty-one pediatric patients (aged 3 mo-15 yrs) received PIs over the study period. Average daily doses were ritonavir 26 mg/kg in 12 patients, nelfinavir 94 mg/kg in 16, indinavir 49 mg/kg in 5, and saquinavir 43 mg/kg in 4. Five patients developed resistance to an existing PI. Overall compliance was 70%. Baseline HIV-1 RNA plasma concentrations were significantly higher than average follow-up concentrations during 3-36 months in patients taking ritonavir (p<0.001) and nelfinavir (p<0.001). Sample size was insufficient for indinavir or saquinavir. Sixty ADEs occurred, diarrhea being most common. Of patients with ADEs, 55% required increased monitoring and 43% treatment. Ritonavir was associated with the most ADEs (28), followed by nelfinavir (16), indinavir (11), and saquinavir (5). Significant increases between baseline and follow-up cholesterol levels were found with ritonavir (p=0.02) and nelfinavir (p=0.001), and for serum creatinine (p=0.02) and triglycerides (p=0.02) with ritonavir. Follow-up triglycerides were significantly higher than baseline for indinavir (p=0.003). CONCLUSION: Nelfinavir and ritonavir were effective in decreasing HIV-1 viral loads and improving CD4+ lymphocyte counts. Ritonavir was associated with more ADEs than other PIs. Changes in cholesterol, serum creatinine, and triglycerides were noted with some PIs.

Periorbital cellulitis secondary to Conidiobolus incongruus.

A previously healthy, 18-month-old girl developed edema and erythema around her left eye 1 week after getting sand in that eye. The patient did not respond to oral or intravenous antibiotics. A mass developed around the eye, and biopsy revealed Conidiobolus incongruus. The patient failed to respond to amphotericin B 1 mg/kg, and susceptibility tests indicated multiantifungal resistance. A combination of antifungal therapy, hyperbaric oxygen, and surgery was required for successful treatment. Three months after treatment the child was disease free. There is no definitive therapy for Conidiobolus incongruus infections, although various drugs have been administered with some success. When susceptibility tests determine multidrug resistance, radical resection with antifungal chemotherapy and hyperbaric oxygen may be necessary as well as lifesaving.

Acute hepatitis and bleeding possibly induced by zidovudine and ritonavir in an infant with HIV infection.

Acute hepatitis led to abnormal coagulopathy, bleeding, and death in a nonhemophiliac infant infected with the human immunodeficiency virus, possibly due to zidovudine or ritonavir or both. Acute hepatitis during ritonavir treatment and episodes of spontaneous bleeding have been reported in patients with hemophilia. Zidovudine is associated with elevated liver enzymes, elevated bilirubin, and hepatomegaly leading to abnormal coagulopathy, bleeding, and death in adults. A temporal relationship between the start of combination antiretroviral therapy and onset of hepatosplenomegaly and rise in liver enzymes suggests that zidovudine or ritonavir, or both, are the likely cause of this adverse event. Ritonavir is believed to cause direct hepatotoxicity, probably by inducing acute mitochondrial toxicity, and may hasten reverse transcriptase inhibitor-induced liver toxicity. Liver function of patients receiving a combination of nucleoside reverse transcriptase inhibitor and protease inhibitors should be closely monitored.

Stability of dapsone in two oral liquid dosage forms.

OBJECTIVE: Dapsone use in pediatric patients is increasing; however, the currently available tablet dosage form cannot be used in young children. The objective of our study was to determine the stability of dapsone in two oral suspensions stored at two temperatures. METHODS: Commercially available dapsone tablets (25 mg) were used to prepare the suspensions: the first in simple syrup and water with citric acid, the second in 1:1 Ora Sweet:Ora Plus to yield a concentration of 2.0 mg/mL. The dosage forms were stored in 10 amber plastic prescription bottles. Five were stored at 25 degrees C and five at 4 degrees C. Three samples were taken from each of five bottles at 0, 7, 14, 28, 42, 56, 70, and 91 days (n = 15). Dapsone concentrations in each sample were measured in duplicate by a validated and stability-indicating HPLC method; the pH of each sample was also determined. The drug was considered stable if the mean concentration > or =90% of the original concentration. RESULTS: The mean concentrations of dapsone were >95% of the initial concentrations for 91 days at both 4 degrees C and 25 degrees C in each suspension. There was a slight darkening of the samples stored at 25 degrees C. CONCLUSIONS: Dapsone was stable in two suspensions prepared from commercially available tablets for at least three months at 4 degrees C and 25 degrees C.

Clinical use of fluoroquinolones in children.

OBJECTIVE: To review the pharmacokinetics, efficacy, and safety of fluoroquinolones in children. DATA SOURCES: A MEDLINE search (January 1966-March 1998) was conducted for relevant literature. STUDY SELECTION AND DATA EXTRACTION: Data from compassionate use and published studies were reviewed for the assessment of pharmacokinetics, efficacy, and safety of fluoroquinolones in children. DATA SYNTHESIS: Fluoroquinolones have a broad spectrum coverage of gram-positive and gram-negative bacteria, including Pseudomonas aeruginosa and intracellular organisms. Fluoroquinolones are well absorbed from the gastrointestinal tract, have excellent tissue penetration, low protein binding, and long elimination half-lives. These antibiotics are effective in treating various infections and are well tolerated in adults. However, the use of fluoroquinolones in children has been restricted due to potential cartilage damage that occurred in research with immature animals. Fluoroquinolones have been used in children on a compassionate basis. Ciprofloxacin is the most frequently used fluoroquinolone in children, most often in the treatment of pulmonary infection in cystic fibrosis as well as salmonellosis and shigellosis. Other uses include chronic suppurative otitis media, meningitis, septicemia, and urinary tract infection. Safety data of fluoroquinolones in children appear to be similar to those in adults. Fluoroquinolones are associated with tendinitis and reversible arthralgia in adults and children. However, direct association between fluoroquinolones and arthropathy remains uncertain. CONCLUSIONS: Fluoroquinolones have been found to be effective in treating certain infections in children. Additional research is needed to define the optimal dosage regimens in pediatric patients. Although fluoroquinolones appear to be well tolerated, further investigations are needed to determine the risk of arthropathy in children. However, their use in children should not be withheld when the benefits outweigh the risks.

Aerosolized furosemide in the treatment of acute respiratory distress and possible bronchopulmonary dysplasia in preterm neonates.

OBJECTIVE: To review the efficacy and safety of inhaled furosemide in the treatment of acute respiratory distress and possible bronchopulmonary dysplasia (BPD) in preterm neonates receiving ventilator and oxygen support. DATA SOURCES: A MEDLINE search was performed from January 1966 to December 1998 using the key words inhaled or aerosolized furosemide, BPD, preterm, neonate, and infant newborn. STUDY SELECTION AND DATA EXTRACTION: All clinical trials involving the use of inhaled furosemide in ventilator- and oxygen-dependent preterm neonates with acute respiratory distress and possible BPD were evaluated. DATA SYNTHESIS: Inhaled furosemide 1 and 2 mg/kg has improved pulmonary function in preterm neonates without significant adverse effects. However, only a single dose of inhaled furosemide was used in these trials, and pulmonary functions were monitored for only two or four hours after administration. CONCLUSIONS: Inhaled furosemide may be effective, but studies are needed to determine the optimal dosage regimen and long-term risks and benefits of its use in these patients.