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M J Shelton

Publications and source records attributed to M J Shelton.

At least 19 recordsLinked to original sources
PubMed2001

If taken 1 hour before indinavir (IDV), didanosine does not affect IDV exposure, despite persistent buffering effects.

Concurrent administration of indinavir and didanosine significantly reduces the level of exposure to indinavir, but it is unclear how soon after didanosine administration indinavir may be given safely. We compared indinavir pharmacokinetics and gastric pH in 12 human immunodeficiency virus-positive patients by use of 800 mg of indinavir alone versus 800 mg of indinavir administered 1 h after didanosine administration. Median gastric pH was significantly higher when indinavir was taken after didanosine administration; however, no significant difference in the maximum concentration in plasma or the area under the concentration-time curve from time zero to 8 h was observed. Indinavir may be taken with a light meal 1 h following the administration of 400 mg of didanosine.

Adolescent↗
PubMed2001

Effects of grapefruit juice on pharmacokinetic exposure to indinavir in HIV-positive subjects.

The objective of this study was to determine the effects of double-strength grapefruit juice on gastric pH and systemic bioavailability of indinavir in HIV-infected subjects receiving indinavir. Fourteen HIV-infected subjects took 800 mg of indinavir with 6 ounces (180 ml) of water or double-strength grapefruit juice. Gastric pH was measured and blood samples were collected for 5 hours after indinavir dosing. Grapefruit juice increased the mean gastric pH (from 1.39 +/- 0.4 to 3.20 +/- 0.3; p < 0.05) and slightly delayed the absorption of indinavir (tmax increased from 1.12 +/- 0.8 h to 1.56 +/- 0.6 h; p < 0.05). However, there were no significant differences in indinavir exposure. Cmax was 16.7 +/- 7.3 microM with water versus 13.9 +/- 4.2 microM with grapefruit juice (p = NS), and AUC0-8 was 37.5 +/- 19 with water versus 36.9 +/- 15 with grapefruit juice (p = NS). The authors concluded that concomitant administration of grapefruit juice increases gastric pH and delays indinavir absorption but does not uniformly affect the systemic bioavailability of indinavir in HIV-infected subjects.

Adult↗
PubMed1999

Prevention of disseminated Mycobacterium avium complex infection with reduced dose clarithromycin in patients with advanced HIV disease.

OBJECTIVE: To evaluate the ability of once daily reduced dose clarithromycin to prevent disseminated Mycobacterium avium complex (dMAC) infection in patients with advanced HIV disease. DESIGN: Non-randomized, retrospective study. SETTING: Outpatient clinic of an urban university-affiliated municipal hospital. PATIENTS: A group of 192 HIV-infected patients with a CD4 count < 100 x 10(6) cells/l who were followed for at least 90 days during a 6-year period (1991-1996) before the use of protease inhibitors. INTERVENTIONS: Clarithromycin 500 mg orally once daily (n = 84), rifabutin 300 mg orally once daily (n = 47) or no prophylaxis (n = 61). MAIN OUTCOME MEASURES: Positive blood culture for M. avium complex (MAC), time to development of dMAC, and time to death. RESULTS: When compared with no prophylaxis or rifabutin, the incidence of dMAC and time to development of dMAC were improved among those patients receiving clarithromycin (P < 0.001). Prolonged survival was associated with both clarithromycin and rifabutin use when compared with no prophylaxis (P < 0.002). In patients who failed prophylaxis, resistance to clarithromycin and rifabutin was observed. CONCLUSIONS: In the era prior to protease inhibitor use, once daily clarithromycin at a dose of 500 mg was associated with a reduction in the incidence of dMAC, appeared to be superior to rifabutin, and was associated with prolonged survival in patients with advanced HIV disease.

AIDS-Related Opportunistic Infections↗
PubMed1999

Comparison of a neural network approach with five traditional methods for predicting creatinine clearance in patients with human immunodeficiency virus infection.

STUDY OBJECTIVE: To compare the results of an artificial neural network approach with those of five published creatinine clearance (Cl(cr)) prediction equations and with the measured (true) Cl(cr) in patients infected with the human immunodeficiency virus (HIV). DESIGN: Six-month prospective study. SETTINGS: Two university medical centers. PATIENTS: Sixty-five HIV-infected patients: 18 relatively healthy outpatients and 47 inpatients. INTERVENTIONS: All subjects had urine collected for 24 hours to determine Cl(cr). MEASUREMENTS AND MAIN RESULTS: The 16 input variables were age, ideal body weight, actual body weight, body surface area, height, and the following blood chemistries: sodium, potassium, aspartate aminotransferase, alanine aminotransferase, red blood cell count, platelet count, white blood cell count, glucose, serum creatinine, blood urea nitrogen, and albumin. The only output variable was Cl(cr). A training set of 55 subjects was used to develop the relationship between input variables and the output variable. The trained neural network was then used to predict Cl(cr) of a validation set of 10 subjects. Mean differences between predicted Cl(cr) and actual Cl(cr) (bias) were 4.1, 28.7, 29.4, 26.0, 31.8, and 55.8 ml/min/1.73 m2 for the artificial neural network, Cockcroft and Gault, Jelliffe 1, Jelliffe 2, Mawer et al, and Hull et al methods, respectively. CONCLUSION: The accuracy of predicting Cl(cr) in subjects with HIV infection by the artificial neural network is superior to that of the five equations that are currently used in clinical settings.

Adult↗
PubMed1998

Production of serum immunoglobulins and T cell antigen binding molecules specific for cow's milk antigens in adults intolerant to cow's milk.

The immune response to three cow's milk antigens, beta-lactoglobulin (BLG), alpha-lactalbumin (AL), and casein (CA) was studied in 15 milk-intolerant adult patients and 11 adult controls. IgG, IgE, and IgG subclasses (IgG1, IgG2, IgG3, IgG4) and T cell-derived antigen-binding molecules (TABM) specific for each antigen were measured in both groups. In the patient group, a significant elevation of total IgG and TABM against each of the milk antigens was found as well as raised levels of IgG1 to BLG and CA, IgG4 to BLG, and IgE to CA. TABM specific for BLG were isolated by affinity for BLG and found to be Mr 28,000-46,000 polypeptides functionally and physically associated with TGF-beta1 and TGF-beta2. These results indicate a Th2-type immune response to the milk antigens in milk-intolerant individuals compared with the control group which shows a pattern typical of anergy or deletion.

Adult↗
PubMed1998

Previous infection with Helicobacter pylori is the primary determinant of spontaneous gastric hypoacidity in human immunodeficiency virus-infected outpatients.

To investigate the incidence and demographics of gastric hypoacidity among persons infected with human immunodeficiency virus (HIV), 146 asymptomatic subjects were evaluated with use of a radiotelemetry device (Heidelberg capsule). Gastric hypoacidity (minimum gastric pH of > or = 3) occurred in 24 subjects (17%). Demographic characteristics, CD4 cell counts, and Helicobacter pylori serological status were evaluated for an association with gastric pH. Subjects with hypoacidity were more likely to have positive H. pylori serology than were subjects without hypoacidity (15 of 24 vs. 23 of 74, respectively; P = .004). Multivariate analysis indicated that a positive H. pylori serology was the most significant predictor of hypoacidity, accounting for an increase in gastric pH of 39%. A history of injection drug use, heterosexual transmission of HIV, and male gender were also associated with an elevated gastric pH. CD4 cell counts did not contribute to predictions of gastric pH. A history of H. pylori infection is relatively common in HIV-positive black and Hispanic populations and is a predictor of gastric pH.

AIDS-Related Opportunistic Infections↗
PubMed1998

Zalcitabine population pharmacokinetics: application of radioimmunoassay.

Zalcitabine population pharmacokinetics were evaluated in 44 human immunodeficiency virus-infected patients (39 males and 5 females) in our immunodeficiency clinic. Eighty-one blood samples were collected during routine clinic visits for the measurement of plasma zalcitabine concentrations by radioimmunoassay (1.84+/-1.24 samples/patient; range, 1 to 6 samples/patient). These data, along with dosing information, age (38.6+/-7.13 years), sex, weight (79.1+/-15.0 kg), and estimated creatinine clearance (89.1+/-21.5 ml/min), were entered into NONMEM to obtain population estimates for zalcitabine pharmacokinetic parameters. The standard curve of the radioimmunoassay ranged from 0.5 to 50.0 ng/ml. The observed concentrations of zalcitabine in plasma ranged from 2.01 to 8.57 ng/ml following the administration of doses of either 0.375 or 0.75 mg. A one-compartment model best fit the data. The addition of patient covariates did not improve the basic fit of the model to the data. Oral clearance was determined to be 14.8 liters/h (0.19 liter/h/kg; coefficient of variation [CV] = 23.8%), while the volume of distribution was estimated to be 87.6 liters (1.18 liters/kg; CV = 54.0%). We were also able to obtain individual estimates of oral clearance (range, 8.05 to 19.8 liters/h; 0.11 to 0.30 liter/h/kg) and volume of distribution (range, 49.2 to 161 liters; 0.43 to 1.92 liters/kg) of zalcitabine in these patients with the POSTHOC option in NONMEM. Our value for oral clearance agrees well with other estimates of oral clearance from traditional pharmacokinetic studies of zalcitabine and suggests that population methods may be a reasonable alternative to these traditional approaches for obtaining information on the disposition of zalcitabine.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Relationship between didanosine exposure and surrogate marker response in human immunodeficiency virus-infected outpatients.

We used information available from routine clinic visits to characterize the pharmacokinetics of didanosine in 82 human immunodeficiency virus-infected patients. A total of 271 blood samples were collected for the measurement of didanosine concentrations in plasma (mean +/- standard deviation [SD], 3.30 +/- 2.21 samples/patient). Bayesian estimates of didanosine oral clearance (CL[oral]) were obtained for these patients by the POSTHOC option within the NONMEM software package. Population priors from a previous NONMEM analysis of didanosine pharmacokinetics were used. The mean +/- SD CL(oral) was 132 +/- 27.7 liters/h, which agrees reasonably well with estimates obtained from previous pharmacokinetic studies of didanosine. Estimates of individual didanosine exposure were then used to consider potential relationships between drug exposure and surrogate marker response over a 6-month period. No correlations were found between the didanosine area under the concentration-time curve from 0 to 6 months and the absolute CD4 cell count (r = 0.305; 0.1 < P < 0.2), weight response (r = 0.0857; P > 0.4), or percentage of CD4 lymphocytes (r = 0.0559; P > 0.4). Future efforts to characterize didanosine exposure in outpatients by random sampling methods should involve more directed efforts to limit residual variability in the data.

Adult↗
PubMed1997

Single-dose pharmacokinetics of delavirdine mesylate and didanosine in patients with human immunodeficiency virus infection.

Delavirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 (HIV-1) that is currently being evaluated in combination regimens with various nucleoside analogs, including didanosine. Due to the pH-dependent solubility of delavirdine, the buffering agents in didanosine formulations may reduce delavirdine absorption. To evaluate the potential interaction between these agents, 12 HIV-infected patients (mean [+/- standard deviation] CD4+ cell count, 304 +/- 213/mm3) were enrolled in a three-way crossover single-dose study. Didanosine (125 to 200 mg given as buffered tablets) and delavirdine mesylate (400 mg) pharmacokinetics were evaluated when each drug was given alone (treatments A and B, respectively), when the two drugs were given concurrently (treatment C), and when didanosine was given 1 h after delavirdine (treatment D). Delavirdine exposure was reduced by concurrent administration of didanosine. The maximum drug concentration in serum (Cmax) was reduced from 7.22 +/- 4.0 to 3.51 +/- 1.9 microM, and the area under the concentration-time curve from 0 h to infinity (AUC0-->infinity) was reduced from 22.5 +/- 14 to 14 +/- 5.7 microM.h. The extent of N-dealkylation, as indicated by the ratio of the N-dealkylated delavirdine AUC0-->infinity to the delavirdine AUC0-->infinity, was unchanged across study treatments (P = 0.708). Reductions in didanosine exposure were observed during concurrent administration with delavirdine with a Cmax reduction from 4.65 +/- 2.0 to 3.22 +/- 0.59 microM and an AUC0-->infinity reduction from 7.93 +/- 3.9 to 6.54 +/- 2.3 microM.h. Thus, concurrent administration of delavirdine and didanosine may reduce the AUC0-->infinity of both drugs, although the clinical significance of this reduction is unknown. Administration of delavirdine 1 h before didanosine avoided the interaction. Due to the single-dose nature of this study, these findings require further evaluation at steady state.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Didanosine reduces atevirdine absorption in subjects with human immunodeficiency virus infections.

Atevirdine is a nonnucleoside reverse transcriptase inhibitor with in vitro activity against human immunodeficiency virus type 1 and is currently in phase II clinical trials. Atevirdine is most soluble at a pH of < 2, and therefore, normal gastric acidity is most likely necessary for optimal bioavailability. Because of the rapid development of resistance in vitro, atevirdine is being evaluated in combination with didanosine and/or zidovudine in both two- and three-drug combination regimens. To examine the influence of concurrent didanosine (buffered tablet formulation) on the disposition of atevirdine, 12 human immunodeficiency virus type 1-infected subjects (mean CD4+ cell count, 199 cells per mm3; range, 13 to 447 cells/mm3) participated in a three-way, partially randomized, crossover, single-dose study to evaluate the pharmacokinetics of didanosine and atevirdine when each drug was given alone (treatments A and B, respectively) versus concurrently (treatment C). Concurrent administration of didanosine and atevirdine significantly reduced the maximum concentration of atevirdine in serum from 3.45 +/- 2.8 to 0.854 +/- 0.33 microM (P = 0.004). Likewise, the mean atevirdine area under the concentration-time curve from 0 to 24 h after administration of the combination was reduced to 6.47 +/- 2.2 microM.h (P = 0.004) relative to a value of 11.3 +/- 4.8 microM.h for atevirdine alone. Atevirdine had no statistically significant effect on the pharmacokinetic parameters of didanosine. Concurrent administration of single doses of atevirdine and didanosine resulted in a markedly lower maximum concentration of atevirdine in serum and area under the concentration-time curve, with a minimal effect on the disposition of didanosine. It is unknown whether an interaction of similar magnitude would occur under steady-state conditions; thus, combination regimens which include both atevirdine and didanosine should be designed so that their administration times are separated. Since the duration of the buffering effect of didanosine formulations is unknown, atevirdine should be given prior to didanosine.

Adolescent↗
PubMed1995

Pharmacokinetics of zidovudine and didanosine during combination therapy.

While the combination of zidovudine and didanosine is used in HIV-infected patients with more advanced disease, the possibility of a pharmacokinetic interaction between these two drugs remains controversial. Zidovudine doses of 50, 100, and 200 mg, combined with 67, 167, and 250 mg of didanosine were evaluated in 11 asymptomatic HIV-infected patients after receiving 24 weeks of combination therapy in AIDS Clinical Trials Group protocol 143. The pharmacokinetic parameters of zidovudine and didanosine were similar to those obtained with each drug given as monotherapy in other previously published studies. The renal clearance and urinary recovery of glucuronidated zidovudine was reduced when zidovudine was given in combination with didanosine, possibly due to competition for renal tubular secretion. These data suggest that no clinically important pharmacokinetic interaction occurs when zidovudine and didanosine are given together.

Adult↗
PubMed1995

A low allergen diet is a significant intervention in infantile colic: results of a community-based study.

BACKGROUND: The effect of diet change in 38 bottle-fed and 77 breast-fed "colicky" infants, referred from community-based pediatric facilities was studied over a 1-week period in a double-blind (within each feeding mode), randomized, placebo-controlled trial. METHODS: Bottle-fed infants were assigned to either casein hydrolysate or cow's milk formula. All mothers of breast-fed infants were started on an artificial color-free, preservative-free, additive-free diet and also randomized to an active low allergen diet (milk-, egg-, wheat-, nut-free) or a control diet. RESULTS: The response to diet was assessed on day 1 and day 8 with the use of a previously validated infant distress chart on which parents recorded distress levels. If successful outcome was defined as a reduction in distress of 25% or more, after adjusting for age and feeding mode, infants on active diet had a significantly higher rate of improvement than those on the control diet (odds ratio, 2.32; 95% confidence interval, 1.07-5.0; p = 0.03). Analysis of the day 8 to day 1 distress ratio, again adjusted for age and feeding mode, showed that infants on the active diet had distress reduced by 39% (95% confidence interval, 26-50) compared with 16% (95% confidence interval, 0-30) for those on the control diet (p = 0.012). CONCLUSION: The results suggest a period of dietary modification with a low allergen diet and appropriate nutritional support should be considered in healthy infants with colic.

Age Factors↗
PubMed1994

A major continuous allergenic epitope of bovine beta-lactoglobulin recognized by human IgE binding.

Hexapeptides of sequential overlapping sequences of beta-lactoglobulin (BLG) were used to probe serum from children with immediate-type cow milk allergy for IgE binding to continuous epitopes of BLG in an enhanced enzyme-linked immunosorbent assay (ELISA). Six regions of IgE binding were identified on the BLG molecule and these were synthesized as dodecapeptides. Inhibition of IgE binding to whole BLG was used to confirm the BLG-specific binding of IgE to each of the synthesized peptides. One of the peptides, peptide 4, showed inhibition in an IgE anti-BLG radioimmunoassay to all 16 sera tested. The patterns of inhibition with the native BLG molecule and peptide 4 were significantly correlated (P = 0.005), suggesting that this peptide contains a major continuous IgE binding epitope of BLG.

Allergens↗
PubMed1994

Features of transient hypogammaglobulinaemia in infants screened for immunological abnormalities.

The incidence of transient hypogammaglobulinaemia of infancy (THI) detected in a major paediatric centre over a 10 year period was examined. A total of 2468 subjects less than 2 years of age had an IgG measurement taken between July 1979 and March 1990. Subjects with known immunodeficiencies were excluded. Fifteen patients were classified as having THI with an initial IgG level less than the fifth centile followed by a second measurement within the normal range. A further 24 patients were identified as having possible THI with a single low IgG concentration. There were 60,174 live births each year in Victoria in the years 1979-88. This gives an incidence of proved THI of 23 per 10(6) births, and including proved and probable THI an incidence of 61 per 10(6) live births. Of those patients with proved THI 12/15 had symptoms of either atopic disease or food allergy/intolerance and three had gastrointestinal symptoms without any evidence of atopic disease. At presentation 12/15 (80%) were IgA deficient and 9/15 had IgM concentrations less than the 20th centile for age. It is suggested that in view of the preponderance of atopic and food intolerant patients that subclinical protein loss from the bowel due to allergic inflammation may be a contributing factor to the development of THI in some patients.

Agammaglobulinemia↗
PubMed1993

Zalcitabine.

OBJECTIVE: To review the chemistry, intracellular metabolism, pharmacokinetics, and clinical trials of zalcitabine (2'3'-dideoxycytidine, ddC). DATA SOURCES: English-language articles and conference procedings. The indexing terms used were zalcitabine, 2'3'-dideoxycytidine, and ddC. STUDY SELECTION: In addition to the manufacturer's package insert, available Phase I and Phase I/II studies were reviewed. DATA EXTRACTION: Clinical experience with ddC has been limited to uncontrolled studies and an expanded-access program. Efficacy was evaluated solely on surrogate markers of HIV disease: CD4+ lymphocyte counts and p24 antigen determinations. Clinical endpoints, such as disease progression and survival rates, must be provided to the Food and Drug Administration (FDA) for continued approval. DATA SYNTHESIS: The FDA has approved use of ddC in combination with zidovudine (ZDV) as therapy of HIV infection for patients with CD4+ lymphocyte counts < or = 300 cells/mm3 who have experienced significant clinical or immunologic deterioration. Although ddC has the same mechanism of action as other nucleoside analogs, it is more potent on a molar basis. The drug is stable in gastric pH and has good bioavailability (approximately 70-90 percent), but is rapidly cleared from plasma (half life approximately 1-3 h). Intracellular concentrations of ddC triphosphate, the active form, are probably related to plasma concentrations, yet may persist in cells longer than the parent drug persists in plasma. When used as primary therapy in patients with CD4+ < or = 300 cells/mm3, ddC/ZDV increased CD4+ lymphocyte counts and reduced plasma p24 antigen concentrations. In comparison to ZDV monotherapy data taken from other studies, ddC/ZDV appeared to demonstrate a more pronounced and sustained increase in CD4+ cell counts; however, this observation cannot be confirmed until the results of ZDV-controlled comparisons are available. Overall, 17-31 percent of the patients receiving the currently recommended initial dosage of ddC experience peripheral neuropathy. CONCLUSIONS: In combination with ZDV, ddC appears to augment the CD4+ cell response of ZDV monotherapy in the treatment of HIV infection for ZDV-naive patients, although controlled studies and rigorous statistical analyses are lacking at present. The efficacy of ddC/ZDV in patients who received prior treatment with ZDV monotherapy is unclear at the present.

Adolescent↗
PubMed1993

Comparative pharmacokinetics of antiviral nucleoside analogues.

The recent development of nucleoside analogues with antiviral activity has expanded the small but useful armamentarium for the treatment of certain viral diseases such as the human immunodeficiency virus, cytomegalovirus and others. Their intracellular site of action and need for sequential phosphorylation require that traditional pharmacokinetic parameters be used in conjunction with an understanding of intracellular metabolism when designing dosage regimens. This review summarises the available pharmacokinetic literature for zidovudine, didanosine, zalcitabine, aciclovir, ganciclovir, vidarabine and ribavirin. After oral administration, didanosine, aciclovir and ribavirin are < 50% bioavailable and ganciclovir is < 6% absorbed. In contrast, zidovudine and zalcitabine are > 60% bioavailable, although zidovudine undergoes considerable and variable first-pass hepatic glucuronidation while zalcitabine has no first-pass effect. Zidovudine, zalcitabine and didanosine are absorbed rapidly in the fasted state, with peak plasma concentrations exceeding their respective in vitro antiretroviral inhibitory concentrations. All reviewed agents except ribavirin have a relatively short plasma half-life (approximately 0.5 to 4h), with each agent demonstrating a different intracellular enzymatic activation scheme. For example, the rate-limiting step for formation of zidovudine triphosphate is the conversion of the monophosphate to the diphosphate, while didanosine is ultimately converted to dideoxyadenosine triphosphate which has the longest intracellular half-life (approximately 12 to 24h) among these agents. These drugs are not highly protein bound and they distribute into tissues with an apparent volume of distribution at steady-state ranging from 0.3 to 1.2 L/kg. They vary in the extent to which they enter cerebrospinal fluid, ranging from a low of < 25% for didanosine to a high of > 70% of a concurrent plasma concentration for ribavirin and vidarabine. These agents also vary with regard to degree of renal excretion of the parent drug, with the lowest noted for vidarabine (1 to 3%) and the highest for zalcitabine (approximately 75%) and ganciclovir (> 90%). With the increasing number of clinically useful nucleoside analogues, it is essential for the clinician to appreciate the subtle differences among these agents to ensure that optimal therapeutic outcomes may be attained with minimal toxicity.

Antiviral Agents↗