Thomas G. Wells

Influence of Diurnal Blood Pressure Variations on Target Organ Abnormalities in Adolescents With Mild Essential Hypertension

As hypertensive target-organ damage has been associated with diminished diurnal blood pressure (BP) variation in adults, we compared diurnal BP patterns of hypertensive adolescents with left ventricular hypertrophy with normotensive and hypertensive adolescents with normal left ventricular mass. In addition, the frequency of microalbuminuria (Malb), hyperfiltration, and reduced renal functional reserve (RFR) was evaluated in adolescents with normal BP and untreated borderline and mild essential hypertension. Thirty-three normotensive (NT) adolescents, 14.5+/-2.1 years (mean +/- SD), and 29 untreated borderline and mildly hypertensive (HT) adolescents, 14.6+/-2.4 years, wore the SpaceLabs 90207 ambulatory BP monitor for 24 h. Left ventricular mass was measured by M-mode echocardiography and then indexed (LVMI) to the cube of height. Creatinine clearance (Clcr) and urine Malb was measured on 24 h collection and RFR by change in creatinine clearance after an oral protein load. Diurnal BP change was expressed as the absolute and percent day-night BP fall and cusum derived plot height (CPH) and circadian alteration magnitude (CDCAM). Groups were compared using analysis of covariance with adjustments for race, gender, and body mass index. All NT and 19 HT subjects (HT-1) had normal LVMI at 22.2+/-5.3 and 25.8+/-3.8 g/m3, respectively. Ten HT (HT-2) had increased LVMI of 36.9+/-5.2 g/m3. No significant difference was found for absolute or percent day-night BP fall or CDCAM between groups. Nocturnal systolic BP was correlated most closely with LVMI (r = 0.41, p = .001). Clcr, Malb, and RFR did not differ between the groups. In conclusion, adolescents with borderline and mild essential hypertension and left ventricular hypertrophy have similar levels of diurnal BP fall, urine Malb excretion, and RFR compared to normotensive and hypertensive adolescents with normal left ventricular mass.

A Double‐Blind, Placebo‐Controlled, Dose‐Response Study of the Effectiveness and Safety of Enalapril for Children with Hypertension

Despite widespread use to treat childhood hypertension, enalapril has never been studied systematically to determine effectiveness, dose response, and safety in a pediatric population. This study was conducted prospectivelyin 110hypertensive children ages 6 to 16 years in two sequential phases. The primary outcome variable for both phases of the study was trough (24‐h postdose) sitting diastolic blood pressure. The primary objective of the first phase of the study was to determine whether enalapril lowered blood pressure in children in a dose‐dependent manner. During a 2‐week, double‐blind, randomized, dose‐response period, patients were stratified by weight (< 50 kg or ≥50 kg), then assigned to one of three dosing groups: low (0.625 or 1.25 mg), middle (2.5 or 5 mg), or high dose (20 or 40 mg). Reduction in blood pressure was examined as a function of dose ratio (1:4:32) and on a weight‐adjusted basis. On completion of the dose‐response phase of the study, patients entered a 2‐week, double‐blind, randomized withdrawal to either enalapril or placebo. Antihypertensive effectiveness, defined as the difference in sitting diastolic blood pressure between the placebo and enalapril groups, was determined. Adverse events were carefully recorded throughout the study. The dose‐response relationship for enalapril had a negative slope and was linear over the chosen dosingrange, suggesting that larger doses of enalapril were associated with a greater reduction in blood pressure. Randomized withdrawal to active drug or placebo confirmed the antihypertensive effectiveness of enalapril in the middle‐ and high‐dose groups. The antihypertensive effect of enalapril was maintained across age, gender, race, and Tanner stage. Enalapril appears to be an effective and generally well‐tolerated antihypertensive agent in children ages 6 to 16 years. An initial dose of 2.5 mg in children weighing < 50 kg and 5 mg in children weighing ≥50 kg (mean = 0.08 mg/kg) administered once daily effectively lowered blood pressure within 2 weeks in most patients. Blood pressure was reduced in a dose‐dependent fashion, with larger doses resulting in a greater reduction.

A prospective randomized comparison of cefotaxime vs ampicillin and chloramphenicol for bacterial meningitis in children

Fifty children with bacterial meningitis were prospectively randomized to receive cefotaxime (50 mg/kg/dose every 6 hours) or ampicillin and chloramphenicol in standard doses. Twenty-three patients received cefotaxime and 27 received standard therapy. Bacterial isolates included: Haemophilus influenzae (29), Streptococcus pneumoniae (eight), Neisseria meningitidis (eight), group B streptococci (three), and Salmonella enteritidis (two). Ten (34%) of the H. influenzae isolates were resistant to ampicillin, nine on the basis of beta-lactamase production. All strains were susceptible to cefotaxime. Clinical cure rates for the cefotaxime (100%) and standard therapy (96%) groups were similar; survival without detectable sequelae was similar, at 78% and 77%, respectively. The duration of therapy, 11.1 +/- 2.4 days (range 10 to 21 days) vs 11.9 +/- 3.9 days (range 10 to 21 days), and days to defervescence, 4.7 +/- 2.6 days (range 1 to 14 days) vs 5.6 +/- 2.9 days (range 2 to 17 days), were similar in the cefotaxime and standard therapy groups, respectively. No adverse drug reactions or side effects were noted in either group. Cefotaxime was found to be as safe and effective as standard therapy for the treatment of bacterial meningitis in children.

Early bladder outlet obstruction in fetal lambs induces renal dysplasia and the prune-belly syndrome

A model of posterior urethral valves in fetal lambs was developed in order to evaluate the effect of intrauterine urinary obstruction on the developing kidney. Complete urethral obstruction was induced in five fetal lambs at 43 to 45 days of gestation. Two control fetal lambs underwent sham operations. At full term (140 days), two of the five experimental lambs and both control lambs were available for postmortem examination. Results of gross and histological examination of the control lambs were normal. In contrast, the kidneys of the experimental lambs were markedly asymmetrical in size. Histological examination of the kidneys in experimental lambs showed cystic dilatation of the collecting ducts and occasional cystic dilatation of Bowmans spaces, features compatible with obstruction. Also noted were peripheral cortical cysts and primitive tubules lined with cuboidal epithelium and surrounded by fibromuscular collarettes, characteristic of renal dysplasia. One of the infant lambs had many characteristics of the prune-belly syndrome, including a wrinkled, markedly distended abdomen, deficient abdominal wall musculature, flared chest wall, limb deformities, and undescended testes. These results suggest that early in utero urethral obstruction (at the beginning of the second third of gestation) causes renal dysplasia. The results also support the hypothesis that the prune-belly syndrome results from abdominal distention that occurs early in gestation.

The Pharmacokinetics of Irbesartan in Hypertensive Children and Adolescents

An open‐label study was conducted to characterize the pharmacokinetics and antihypertensive response to irbesartan in children (1–12 years) and adolescents (13–16 years) with hypertension. Patients received single once‐daily oral doses of irbesartan 2 mg/kg (maximum of 150 mg once daily) for 2 to 4 weeks (nifedipine or hydrochlorothiazide). Plasma irbesartan concentrations were determined by a validated high‐performance liquid chromatography/fluorescence method from blood samples taken predose, up to 24 hours after dosing on Day1, and up to 48 hours after the final dose. The plasma concentration‐time profiles were similar between the 6‐ to 12‐year and the 13‐ to 16‐year age groups and to that previously determined from a study of adult subjects receiving 2 mg/kg (i.e., 150 mg) oral irbesartan once daily. Mean reductions in systolic/diastolic blood pressure were 16/10 mmHg at Day 28 with irbesartan monotherapy (n = 8). Irbesartan was well tolerated and maybe a treatment option for pediatric hypertensive patients.

Cefotaxime and desacetylcefotaxime pharmacokinetics in infants and children with meningitis.

The pharmacokinetics and cerebrospinal fluid (CSF) penetration of cefotaxime (Ctx) and desacetylcefotaxime (dCtx) were evaluated in 13 infants and children with meningitis after dose 6 of Ctx in a multiple-dose intermittent intravenous infusion regimen (50 mg/kg every 6 h). Model-dependent and noncompartmental pharmacokinetic parameters were determined and were found to be congruous. The disposition of both Ctx and dCtx was described adequately by a one-compartment, open model. Noncompartmental pharmacokinetic parameters are reported. The mean Ctx serum concentration at 0.25 h postinfusion was 121.2 micrograms/ml, and the mean CSF concentration at 1 h postinfusion was 6.2 micrograms/ml. The CSF/serum ratio was variable (0 to 20%), with a mean penetration of 10.1%. The mean Ctx elimination half-life, apparent steady-state volume of distribution, and total body clearance were 0.8 h, 0.361 liter/kg, and 0.289 liter/h per kg, respectively. For Ctx, 61% of the dose was excreted unchanged in the urine during the 6-h postinfusion period, and the estimated renal clearance was 0.174 liter/h per kg. No significant correlations were observed between Ctx pharmacokinetic parameters and demographic parameters. The mean peak concentration of dCtx in serum (21.6 micrograms/ml) occurred at approximately 1.5 h postinfusion, and the mean concentration in CSF at 1 h postinfusion was 5.6 micrograms/ml. The CSF/serum ratio was extremely variable (0 to 103%), and the mean penetration was 28.8%. The mean apparent elimination half-life for dCtx was 2.1 h. In infants and children with normal renal function, a 50-mg/kg dose of Ctx administered every 6 h should provide adequate concentrations in serum and CSF in the majority of patients with meningitis.

24-Hour Ambulatory Blood Pressure Monitoring in Male Children Receiving Stimulant Therapy

OBJECTIVE: To determine whether cardiac indices are altered as assessed by 24-hour ambulatory blood pressure monitoring (ABPM) in male children receiving either chronic methylphenidate or dextroamphetamine/levoamphetamine (Adderall) therapy. METHODS: Boys 7–11 years old who were receiving methylphenidate or Adderall for a minimum of 2 months were asked to participate. Subjects wore ambulatory blood pressure monitors for 24-hour periods both off and on stimulant therapy. RESULTS: Subjects (n = 17; 8 methylphenidate, 9 Adderall) were well matched. Systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate differed between off and on stimulant therapy (p < 0.05). DBP load calculated from ABPM reference data was increased significantly (9.0% ± 5.6% on and 4.8% ± 4.5% off therapy; p < 0.05) while subjects were taking Adderall. There was a trend toward a greater elevation in blood pressure load during awake hours and a more pronounced decrease during the asleep hours for periods on compared with off-stimulant therapy. This trend resulted in significant (p < 0.05) nocturnal dipping on-stimulant phases compared with off-stimulant therapy for both SBP and DBP (Adderall) and SBP (methylphenidate). Two subjects (1 Adderall, 1 methylphenidate) met the criteria to be considered hypertensive based both on mean awake and 24-hour blood pressure load assessments during their on-treatment period. One additional subject receiving Adderall therapy met the criteria to be considered hypertensive based on blood pressure load criteria while off therapy only. Positive correlation coefficients (p < 0.05) were found when comparing stimulant dose (mg/kg) with the percent change of mean SBP, DBP, and heart rate between off and on therapy (r = 0.56, 0.61, and 0.58, respectively). CONCLUSIONS: These preliminary data suggest that blood pressure and heart rate appear to be altered in male patients while receiving stimulant therapy for attention-deficit hyperactivity disorder. Blood pressure and heart rate screening and monitoring during stimulant therapy to determine whether alterations become clinically significant is encouraged.

Levofloxacin pharmacokinetics in children.

Levofloxacin is a broad‐spectrum fluoroquinolone antibiotic with activity against many pathogens that cause bacterial infections in children, including penicillin‐resistant pneumococci. To provide dosing guidance for children, 3 single‐dose, multicenter pharmacokinetic studies were conducted in 85 children in 5 age groups: 6 months to <2 years, 2 to <5 years, 5 to<10 years, 10 to <12 years, and 12 to 16 years. Each child received a single 7‐mg/kg dose of levofloxacin (not to exceed 500 mg) intravenously or orally. Plasma and urine samples were collected through 24 hours after dose. Pharmacokinetic parameters were estimated and compared among the 5 age groups and to previously collected adult data. Levofloxacin absorption (as indicated by Cmax and tmax) and distribution in children are not age dependent and are comparable to those in adults. Levofloxacin elimination (reflected by t1/2 and clearance), however, is age dependent. Children younger than 5 years of age clear levofloxacin nearly twice as fast (intravenous dose, 0.32 ± 0.08 L/h/kg; oral dose, 0.28 ± 0.05 L/h/kg) as adults and, as a result, have the total systemic exposure (area under the plasma drug concentration‐time curve) approximately one half that of adults. The levofloxacin area under the plasma drug concentration‐time curve (dose normalized) in children receiving a single dose of the oral liquid formulation is comparable to that in children receiving the intravenous formulation. To provide compatible levofloxacin exposures associated with clinical effectiveness and safety in adults, children <5 years need a daily dose of 10 mg/kg, whereas children 6 months to <5 years should receive 10 mg/kg every 12 hours.

The Pharmacokinetics of Enalapril in Children and Infants with Hypertension

Forty children with hypertension between the age of 2 months and 15 years received 0.07 to 0.14 mg/kg of enalapril as a single daily dose. Enalapril was administered orally as a novel extemporaneous suspension in children younger than 6 years of age and as tablets in older children. First‐dose and steady‐state pharmacokinetics were estimated in children ages 1 to 24 months, 25 months to < 6 years, 6 to < 12 years, and 12 to < 16 years. Maximum serum concentrations for enalapril occurred approximately 1 hour after administration. Serum concentrations of enalaprilat, the active metabolite of enalapril, peaked between 4 and 6 hours after the first dose and 3 and 4 hours after multiple doses. The area under the concentration versus time curve (AUC), adjusted for body surface area, did not differ between age groups. Based on comparison of first‐dose and steady‐state AUCs, the accumulation of enalaprilat in children ranged from 1.13‐ to 1.45‐ fold. For children ages 2 to 15 years, mean urinary recovery of total enalaprilat ranged from 58.3% in children ages 6 to < 12 years to 71.4% in children ages 12 to < 16 years. Urinary recovery for children ages 2 to < 6 years was 66.8%. The mean percentage conversion of enalapril to enalaprilat ranged from 64.7% for children ages 1 to 24 months to 74.6% for children ages 6 to < 12 years. The median effective half‐life for accumulation ranged from 14.6 hours in children ages 12 to < 16 years to 16.3 hours in children ages 6 to < 12 years. There were two serious adverse events, neither of which was attributed to enalapril or resulted in discontinuation of the study drug. The extemporaneous suspension used in this study was tolerated well. The pharmacokinetics of enalapril and enalaprilat in hypertensive children ages 2 months to 15 years with normal renal function appears to be similar to that previously observed in healthy adults.

Considerations in the Rational Design and Conduct of Phase I/II Pediatric Clinical Trials: Avoiding the Problems and Pitfalls

Over the past decade, there has been a heightened awareness of the need to include children in the drug development process. With this awareness has come an expansion of the infrastructure for conducting studies in children and an increase in the sponsorship of pediatric clinical trials. However, the growth in pediatric research has, in many cases, not been accompanied by an increase in the involvement of trained pediatric investigators when it comes to trial design and/or interpretation. Pediatric phase I/II protocols continue to span a spectrum from those that are carefully constructed to those that are poorly designed. This paper highlights the basic elements of phase I/II protocols that merit unique consideration when the clinical trial involves children. Illustrations are provided from our experience, which highlight problems that may arise when trials are not designed with the pediatric patient in mind.