Ralph H. Raasch

Effects of intraluminal epidermal growth factor on mucosal proliferation in the small intestine of adult rats

To determine whether intraluminal administration of epidermal growth factor (EGF) has a trophic effect on small bowel mucosa, catheters were surgically placed in the ileum of adult rats and infused with EGF. Comparing animals receiving EGF (5 micrograms/48 h) with controls, in the ileum mean mucosal ornithine decarboxylase specific activity increased by greater than 200% (p less than 0.001), mean deoxyribonucleic acid specific activity and crypt labeling index increased by greater than or equal to 100% (p less than 0.001), and mean deoxyribonucleic acid content of the mucosa increased by 25% (p less than 0.05). During these studies, the jejunum was not exposed to ileal infusate, as shown with the use of a phenol red marker. Nevertheless, all measurements except deoxyribonucleic acid content increased in the jejunum as well, although to a lesser extent. A greater rise in mucosal ornithine decarboxylase and deoxyribonucleic acid specific activity could be demonstrated in the jejunum when EGF was infused directly into this segment. Mucosal ornithine decarboxylase activity was found to be dose-dependent and to increase in the ileum only after a latent period of 12-24 h. We conclude that intraluminal administration of EGF stimulates a mucosal proliferative response in the small intestine. Intraluminal EGF appears likely to be one of a number of endogenous trophic factors in the small bowel.

Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole

To determine the effect of multiple dosing of combined sulfamethoxazole and trimethoprim on the single‐dose pharmacokinetics of lamivudine.

Treatment of calcinosis universalis with low-dose warfarin

Patients with calcinosis universalis secondary to dermatomyositis or systemic sclerosis have increased levels of the calcium-binding amino acid, gamma-carboxyglutamic acid. The enzyme that effects gamma carboxylation of glutamic acid is warfarin-sensitive. Four patients with calcinosis universalis were treated with 1 mg per day of warfarin for 18 months in a non-blind initial study. Two patients had both decreased gamma-carboxyglutamic acid urinary concentration and decreased extra-skeletal uptake on technetium 99m-diphosphonate whole-body nuclear scanning. In a subsequent double-blind placebo study, two thirds of the patients receiving 1 mg per day of warfarin had decreases in extra-skeletal nuclear tracer uptake after 18 months, compared with none of the four patients receiving placebo. No patient had a change in clinical assessment, bleeding complication, or baseline normal prothrombin time. This low-dose warfarin regimen appears to have no demonstrable adverse effects, and these results suggest a beneficial effect on the progression of calcinosis in these rheumatic diseases.

Efficacy of Tube Feeding in Supplying Energy Requirements of Hospitalized Patients

During a 6-week period, all adult patients in a university hospital receiving ready-to-feed nasoenteric tube feeding formula were prospectively studied. The study objective was to determine each patients caloric intake from tube feeding relative to their energy needs and to identify factors causing decreased feeding intake. Each of 35 patients was visited at least once daily to determine their volumetric intake of tube feeding formula. Daily review of patient care records and nursing interviews were used to identify interruptions in therapy. Patients basal energy expenditures (BEE) were calculated using the Harris-Benedict equation. Calorie goals were set by members of the Nutrition Support Service or clinical dietitians. Intakes averaged 1095 +/- 41 Kcal (SEM) per day or 61% of their mean calorie goal of 1791 +/- 41 Kcal. Mean daily calorie intake was statistically different (p less than 0.05) from mean energy goal on patient study days 1 through 5, 7, and 8. Only 16 of the 35 patients achieved an intake of 100% of their energy goal on any day of therapy. Calorie goals averaged 1.4 times BEE. Mean daily calorie intake did not exceed BEE until study day 10. Eighteen % of potential feeding time was lost due to temporary feeding interruptions; primarily inadvertent extubation (4.6%), gastrointestinal intolerance (4.7%), medical procedures requiring discontinuation of feeding (2.8%), and feeding tube positioning difficulties (1.5%). In addition, physicians ordered only 75% of calculated energy goals. These data indicate that tube feeding therapy, when provided under usual hospital conditions, does not meet patients energy requirements.

Competing drug-drug interactions among multidrug antiretroviral regimens used in the treatment of HIV-infected subjects : ACTG 884

ObjectiveTo evaluate the steady state concentrations of saquinavir, ritonavir, nelfinavir, delavirdine, and adefovir in six different three- and four-drug combination regimens. DesignRandomized, partially double-blinded, multicenter study in a population of indinavir-experienced subjects with virologic failure. The first seven subjects enrolled in each of the six treatment arms from 10 participating sites were entered into this pharmacokinetic evaluation. SettingMulticenter study of the AIDS Clinical Trials Group (ACTG). PatientsHIV-infected subjects. InterventionsA 12-hour pharmacokinetic study was conducted after 2 weeks of drug administration. Main outcome measuresArea under the concentration–time curve with statistical comparisons to evaluate the effect of the second protease inhibitor and the effect of the non-protease inhibitors. ResultsThere was no difference in saquinavir concentrations according to whether the second protease inhibitor was ritonavir or nelfinavir. Saquinavir concentrations in the groups receiving the combination of delavirdine plus adefovir dipivoxil were reduced by approximately 50% compared with those receiving delavirdine. Delavirdine concentrations were reduced by approximately 50%, in the delavirdine plus adefovir dipivoxil arms compared with the delavirdine arms. ConclusionsSaquinavir concentrations were significantly lower in the arms containing the combination of delavirdine and adefovir dipivoxil compared with the arms containing delavirdine. Delavirdine concentrations were significantly lower when coadministered with adefovir dipivoxil. These drug–drug interactions were not expected, the mechanism(s) is (are) not clear, and additional studies are warranted. This study illustrates the need to understand more fully the pharmacokinetic characteristics of complex combination antiretroviral regimens prior to use in patient management.

Pharmacokinetics and bioavailability of zidovudine and its glucuronidated metabolite in patients with human immunodeficiency virus infection and hepatic disease (AIDS Clinical Trials Group protocol 062).

The pharmacokinetics of zidovudine (ZDV) are established in patients with various stages of human immunodeficiency virus (HIV) disease. This study was conducted to determine the pharmacokinetic parameters of ZDV in patients with asymptomatic HIV infection and liver disease. HIV-infected volunteers with normal renal function were stratified according to the severity of liver disease (seven of eight were classified as mild). Each subject received a single intravenous dose of ZDV (120 mg) on the first day, followed by a single oral dose of ZDV (200 mg) on the second day. Blood samples were obtained over a 8-h collection interval, and concentrations of ZDV and its glucuronidated metabolite (GZDV) were determined by high-performance liquid chromatography. The following pharmacokinetic parameters were obtained after oral administration of ZDV to HIV-infected patients with mild hepatic disease; these values were compared with previously reported data in healthy volunteers. The area under the curve (AUC) (1,670 +/- 192 ng.h/ml), maximum concentration of drug in serum (1,751 +/- 180 ng/ml), and half-life (2.04 +/- 0.38 h) of ZDV were increased, while the apparent oral clearance (1.57 +/- 0.31 liter/h/kg of body weight) was decreased; AUC (7,685 +/- 1,222 ng.h/ml) and maximum concentration of drug in serum (5,220 +/- 1,350 ng/ml) of GZDV and the AUC ratio of GZDV to ZDV (2.79 +/- 0.43) after oral administration were decreased. ZDV absolute bioavailability was 0.75 +/- 0.15 in HIV-infected patients with hepatic disease. Although the ZDV apparent oral clearance was not impaired as significantly as in patients with biopsy-proven cirrhosis, our results suggest that ZDV, could accumulate in HIV-infected patients with mild hepatic disease because of impaired formation of GZDV. Patients with mild hepatic disease may require dosage adjustment to avoid accumulation of ZDV after extended therapy.

Ticlopidine and Antiplatelet Therapy

OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical efficacy, and toxicity of ticlopidine. Comparisons with other antiplatelet agents are presented, with an emphasis on efficacy, and a recommendation is provided regarding ticlopidines place in therapy. DATA SOURCES: A MEDLINE literature retrieval of English-language journal articles from 1987 to January 1993 and references identified from bibliographies of review articles and clinical trials. STUDY SELECTION: Randomized, blind, controlled studies of ticlopidine and other antiplatelet agents were preferentially selected. DATA EXTRACTION: Clinical trials were reviewed in terms of study design, efficacy results, and toxicity. DATA SYNTHESIS: Ticlopidine is a new antiplatelet agent with a distinct mechanism of action. In the largest trial of the drug for the prevention of stroke, it was found to be more effective than aspirin in reducing the risk of stroke or death. Clinical trials have also shown ticlopidine to decrease the rate of vascular death and myocardial infarction in patients with unstable angina, and to maintain venous graft patency after coronary artery bypass grafting. The use of ticlopidine in diabetic microangiopathy and peripheral vascular disease appears promising, but further studies are needed. Adverse reactions most commonly reported with ticlopidine are gastrointestinal complaints; the most severe reaction is transient neutropenia, which is seen in approximately 2.3 percent of patients and is severe in nearly 1 percent. CONCLUSIONS: Ticlopidine is a reasonable alternative for use in preventing stroke among patients unable to take aspirin or those who do not benefit from aspirin therapy. Its use as first-line therapy is limited by its high cost and the occurrence of hematologic adverse effects.

Disposition of didanosine in HIV‐seropositive patients with normal renal function or chronic renal failure: Influence of hemodialysis and continuous ambulatory peritoneal dialysis

To evaluate the pharmacokinetics of didanosine in patients with normal kidney function or chronic kidney failure.

Single Versus Combined Antibiotic Therapy for Gram-Negative Infections

OBJECTIVE To evaluate the available clinical data regarding single versus combination antimicrobial therapy for treatment of gram-negative infections, focusing on the more recent data in predominantly nonneutropenic hosts. In vitro and in vivo data regarding various antimicrobial combinations are also discussed. DATA SOURCES Clinical trials, review articles, and meta-analyses were identified from a MEDLINE search (1960–July 2003). Special attention was given to clinical outcome trials performed since 1989. Search terms included gram-negative infections, drug synergism, Pseudomonas aeruginosa, monotherapy, combination therapy, carbapenems, β-lactams, cefepime, aminoglycosides, and fluoroquinolones. DATA SYNTHESIS Although most of the studies were not randomized, double-blind, or controlled, the most recent literature indicates that monotherapy with agents that are active against isolated organisms, including P. aeruginosa, may be appropriate for most patients. Efficacy outcomes, including mortality, did not significantly differ in most studies comparing single and combination therapies. Some trials suggest that combination therapy may be preferred in neutropenic patients and those with pseudomonal infections. CONCLUSIONS Hospitalized patients with gram-negative infections are often treated with combination antimicrobial agents; however, some of the recently available data, although limited, suggest that administration of monotherapy is a feasible alternative in certain patient populations.

Tolerance and Pharmacokinetic Interactions of Rifabutin and Azithromycin

ABSTRACT This multicenter study evaluated the tolerance and potential pharmacokinetic interactions between azithromycin and rifabutin in volunteers with or without human immunodeficiency virus infection. Daily dosing with the combination of azithromycin and rifabutin was poorly tolerated, primarily because of gastrointestinal symptoms and neutropenia. No significant pharmacokinetic interactions were found between these drugs.