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Biomedical subjects

M E Morgan

Publications and source records attributed to M E Morgan.

At least 19 recordsLinked to original sources
PubMed2001

Frontal horn thin walled cysts in preterm neonates are benign.

BACKGROUND: Screening cranial ultrasound led to the discovery of isolated frontal horn cysts quite distinct from periventricular leucomalacia cysts. AIM: To clarify their significance, incidence, characteristics, causal factors or aetiology, and effect on long term outcome. DESIGN: A retrospective observational study of all first cranial ultrasound scans (total of 2914) performed during the period 1984-1994 inclusive found 21 neonates with smooth thin walled frontal horn cysts: 18 of 2629 scanned were of birth weight < 1500 g or gestation < 33 weeks, and three of 285 were > 33 weeks gestation. Sequential ultrasound, maternal records, and neonatal events were retrospectively assessed. In survivors, routine neurodevelopmental evaluations were obtained. Postmortem studies of one cyst were performed to determine the nature and origin of these lesions. RESULTS: Of the 21 subjects, 15 had isolated frontal horn cysts and six had additional ultrasound scan abnormalities, including four with subependymal haemorrhage. The sonographic features of frontal horn cysts were of distinctive morphology (elliptical, smooth, thin walled, ranging in size from 3 to 20 mm) and position (adjacent to the tip of the anterior horns). The cysts enlarged and then regressed by a median corrected age of 2 months. Subjects of < 33 weeks gestation (n = 18) had a median birth weight of 1465 g (range 720-1990) and median gestation of 30 weeks (range 24-32). There was no consistent perinatal course. The neurodevelopmental outcome in 10 of the 11 survivors with isolated frontal horn cysts was normal. Five subjects died from causes unrelated to brain pathology in the neonatal period, and one subject died after infancy. Histological examination of a cyst at autopsy in one additional subject subsequent to the period of study confirmed the cyst to be lined by neuroblasts and ependymal cells. CONCLUSIONS: The incidence of frontal horn cysts in this low birthweight population was 7 per 1000 (0.7%) subjects scanned. They are present in the first week of life, enlarge, and resolve spontaneously. Survivors with isolated frontal horn cysts appear to have normal neurodevelopmental outcome. The prognosis of these distinct frontal horn cysts therefore appears to be benign.

Brain Neoplasms↗
PubMed1999

An outbreak of Bacillus cereus respiratory tract infections on a neonatal unit due to contaminated ventilator circuits.

An outbreak of Bacillus cereus respiratory tract infections affecting six ventilated preterm neonates over a two-week period is described. Reusable ventilator circuits were identified as the cause of the outbreak. Ordinarily these were reprocessed on the Neonatal Unit (NNU), first through a washing machine and then through a low-temperature steam (LTS) disinfector. The onset of the outbreak coincided with a breakdown of the LTS facility, which necessitated sending the washed circuits off site for LTS disinfection. The washing machine was shown to be contaminated with the same serovars of B. cereus as those isolated from patients. Two critical steps in the off site LTS disinfection process allowed exsporulation and multiplication of B. cereus: the circuits were inadequately dried after processing, whilst return of the moist circuits to the NNU was often delayed. The outbreak was terminated by withdrawal of the heat-disinfected ventilator circuits. This outbreak emphasizes the need for high standards where medical equipment is reprocessed, especially for use in vulnerable patients.

Bacillaceae Infections↗
PubMed1998

Microscale titrimetric and spectrophotometric methods for determination of ionization constants and partition coefficients of new drug candidates.

This study describes the adaptation of conventional titrimetric and spectrophotometric techniques to a microscale for the determination of drug ionization constants (pKa) and partition coefficients (log P). The apparatus for determining pKa and compound purity (or equivalent weight) consists of a three-port conical glass microvial maintained at 25 degrees C, a pH microelectrode, and a microinjection pump equipped with a 10 microL gastight syringe for titrant delivery. Sample mixing and protection from atmospheric CO2, which is particularly important at the microscale, is accomplished using a fine stream of water-saturated N2 bubbles. Simple titrimetric procedures combined with ionic equilibria models which allow the accurate determination of pKa and purity (or equivalent weight) using sample sizes in the microgram range and solution volumes of 10-100 microL were developed and validated using acetic acid and tromethamine. Simultaneous determinations of pKa, purity or equivalent weight, and octanol/water partition coefficient were shown to be possible from a single sample of a test solute by adapting the pH-metric technique to a microscale. Using benzoic acid as a model compound, a pKa of 4.24 and octanol/water partition coefficient of 64 were obtained, in close agreement with the literature values. The principles employed in titrimetric analysis were also applied to demonstrate the spectrophotometric determination of benzoic acid's pKa and partition coefficient using only 6 micrograms of compound. The microscale titration method was then used to determine the two pKa values of an "unknown" diprotic acid containing a carboxyl and an aromatic SH group. The phenyl thiol pKa was confirmed using the microscale spectrophotometric procedure.

1-Octanol↗
PubMed1997

Difference gel electrophoresis: a single gel method for detecting changes in protein extracts.

We describe a modification of two-dimensional (2-D) polyacrylamide gel electrophoresis that requires only a single gel to reproducibly detect differences between two protein samples. This was accomplished by fluorescently tagging the two samples with two different dyes, running them on the same 2-D gel, post-run fluorescence imaging of the gel into two images, and superimposing the images. The amine reactive dyes were designed to insure that proteins common to both samples have the same relative mobility regardless of the dye used to tag them. Thus, this technique, called difference gel electrophoresis (DIGE), circumvents the need to compare several 2-D gels. DIGE is reproducible, sensitive, and can detect an exogenous difference between two Drosophila embryo extracts at nanogram levels. Moreover, an inducible protein from E. coli was detected after 15 min of induction and identified using DIGE preparatively.

Animals↗
PubMed1997

Role of brain tissue localized purine metabolizing enzymes in the central nervous system delivery of anti-HIV agents 2'-beta-fluoro-2',3'-dideoxyinosine and 2'-beta-fluoro-2',3'-dideoxyadenosine in rats.

PURPOSE: This study examines the central nervous system (CNS) delivery of 2'-beta-fluoro-2',3'-dideoxyadenosine (F-ddA) and 2'-beta-fluoro-2',3'-dideoxyinosine (F-ddI), acid stable analogues of dideoxyadenosine (ddA) and dideoxyinosine (ddI) having reduced susceptibility to purine salvage pathway enzymes important in the metabolism of ddA and ddI, adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP), respectively. Their CNS delivery compared to that for ddI provides insight into the role of brain tissue ADA and PNP in these processes. METHODS: Brain and cerebrospinal fluid (CSF) concentration-time profiles were obtained for F-ddI during and after intravenous infusions of F-ddI, and for both F-ddA and F-ddI after F-ddA infusions in normal rats or rats pre-treated with the ADA inhibitor 2'-deoxycoformycin (DCF). Rate constants for CNS entry, efflux and metabolism were estimated by computer fits using plasma concentration-time profiles as the driving force functions. RESULTS: The CNS delivery of F-ddI did not differ significantly from that for ddI. F-ddA, which is more lipophilic than F-ddI, provided higher brain (approximately 8x) and CSF (approximately 11x) concentrations of total dideoxynucleoside (F-ddA and F-ddI) compared to F-ddI. Deamination by brain tissue ADA to form F-ddI reduced CNS levels of intact F-ddA but provided higher brain parenchyma (5x) and CSF/plasma (3x) ratios of F-ddI relative to F-ddI controls. Thus, F-ddA functions in part as a CNS-activated prodrug of F-ddI. DCF pre-treatment inhibited brain tissue ADA, abolishing the prodrug effect, and enhancing F-ddA concentrations in both brain parenchyma (5x) and CSF (6x). CONCLUSIONS: PNP metabolism does not appear to play a role in the low CNS delivery of ddI. On the other hand, deamination of F-ddA by brain tissue ADA is an important process, such that F-ddA functions in part as a CNS-activated prodrug of F-ddI. Enhanced CNS uptake of intact F-ddA can be achieved with ADA inhibition.

Adenosine Deaminase↗
PubMed1996

Nosocomial infection with Rhizopus microsporus in preterm infants: association with wooden tongue depressors.

BACKGROUND: We report four cases of cutaneous infection with Rhizopus microsporus in vulnerable preterm infants in one neonatal nursery. METHODS: There was no overlap in hospital stay between the first two cases and an extensive programme of environmental sampling was therefore initiated, with special attention being paid to items that had close contact with infants' skin. Samples were cultured by standard techniques, including fungal culture with Sabouraud's medium. Filamentous fungi with non-septate hyphae were presumptively identified as agents of mucormycosis and referred to the Mycology Reference Laboratory, Bristol, UK, for speciation. FINDINGS: The source of infection was identified as wooden tongue depressors, which were used on the nursery to construct splints for intravenous and arterial cannulation sites. The outbreak was ended by the removal of these items from the nursery. INTERPRETATION: Wooden tongue depressors can be a vehicle for transmission of mucormycosis. The combination of warm, humid conditions in neonatal incubators, particularly in association with occlusive dressings, may favour cutaneous fungal invasion and put small, sick babies at risk of infection.

Cross Infection↗
PubMed1996

Gastric emptying and gastro-oesophageal reflux in preterm infants.

Gastro-oesophageal reflux is common in preterm infants, but the role of gastric emptying as a causal factor has not been studied before. Gastric emptying was therefore measured in 19 healthy preterm infants (median gestational age 32 weeks) while concurrently measuring 24 hour lower oesophageal pH, using an antimony pH electrode, positioned manometrically. Real time ultrasonic images of the gastric antrum were obtained, and measurements of antral cross-sectional area (ACSA) were made immediately before a nasogastric feed and then during subsequent gastric emptying until ACSA returned to its pre-feed value. Half emptying time (50% delta ACSA) was calculated as the time taken for the ACSA to fall to half the maximal postprandial increment. Mean (SEM) reflux index for the group was 11.9 (2.0)%; number of reflux episodes per 24 hours: 15.4 (1.7); and number of reflux episodes longer than five minutes 5.5 (0.8). Average half emptying times for an individual infant were: median (range) 46 (18-105) minutes. There was no association between gastric emptying rates and any of the indices of gastro-oesophageal reflux, either during the entire 24 hour period for which the lower oesophageal pH was recorded, or in the postprandial periods after the feeds which were studied ultrasonically. Gastro-oesophageal reflux was also unrelated to feed volume and feed type. Asymptomatic gastro-oesophageal reflux is common in preterm infants, but gastric emptying time is not a determinant of it. Inappropriate relaxation of the lower oesophageal sphincter or abnormal oesophageal motility offer more plausible explanations.

Esophagus↗
PubMed1996

Quantitative assessment of blood-brain barrier damage during microdialysis.

In view of the increasing use of microdialysis for monitoring drug uptake into the brain, the consequences of tissue/blood-brain barrier (BBB) damage that occurs on microdialysis probe insertion on the extent and rate of solute uptake need to be more carefully examined. In this study, both microdialysis and a classic method were used to compare the apparent brain uptake of two polar permeants, [3H]sucrose and [14C]urea. The blood-to-brain transfer constants of these compounds differ significantly, with the value of urea exceeding that of sucrose by a factor of approximately 20 when compared by the classic one-point-per-animal method. The BBB selectivity to these nonmetabolized permeants as assessed by microdialysis provides a sensitive measure of the integrity of the BBB to polar nonelectrolytes within the molecular size range of most drugs. The following evidence for blood-brain barrier damage during microdialysis sampling was obtained: (1) the loss of [3H]sucrose from the extracellular fluid in brain on termination of an intravenous infusion is biphasic, with the initial phase evident immediately on termination by the infusion, suggesting that a fraction of the microdialysis probe resides in a region in rapid equilibrium with plasma; (2) complete loss of selectivity in the rate constants for CNS entry of sucrose vs. urea and (3) there were substantially higher area under the concentration vs. time curve AUCECF/AUCplasma ratios for both sucrose and urea generated by microdialysis than the corresponding ratios (AUCCSF/AUCplasma or AUCbrain/AUCplasma) obtained by classic methods. These results suggest that the BBB to small molecule transport likely remains compromised for some time after microdialysis probe insertion.

Animals↗
PubMed1996

Role of altered metabolism in dideoxynucleoside pharmacokinetics. Studies of 2'-beta-fluoro-2',3'-dideoxyinosine and 2'-beta-fluoro-2',3'-dideoxyadenosine in rats.

Enzymes of the purine salvage pathway play an important role in altering the in vivo pharmacokinetics of 2',3'-dideoxypurine nucleosides. This study examines the pharmacokinetics of enzyme-resistant 2'-beta-fluoro analogues of 2',3'-dideoxyinosine (ddI) and 2',3'-dideoxyadenosine (ddA). 2'-beta-Fluoro-2',3'-dideoxyinosine (F-ddI) is an acid-stable analogue of ddI that is highly resistant to purine nucleoside phosphorylase, the principal enzyme in ddI metabolism. 2'-beta-Fluoro-2',3'-dideoxyadenosine (F-ddA), an acid-stable and purine nucleoside phosphorylase-resistant analogue of ddA, is converted in vivo to F-ddI by adenosine deaminase (ADA) but is a much poorer substrate for this enzyme than is ddA. Both F-ddA and F-ddI have been shown to have activity against human immunodeficiency virus in vitro, and F-ddA has been selected by the National Cancer Institute for clinical trials as a new human immunodeficiency virus reverse transcriptase inhibitor. The pharmacokinetics of F-ddI and ddI were compared at equivalent doses in chronically catheterized rats. Because ddI and F-ddI are isosteres having nearly identical lipophilicity, this comparison is likely to reflect primarily metabolic differences. The clearance of F-ddI was substantially reduced, in comparison with that of ddI (27.3 ml/min/kg vs. 90.9 ml/min/kg), resulting in higher systemic concentrations at steady state and prolonged retention of F-ddI after termination of infusions, consistent with a significant metabolic component in the clearance of ddI. Concentrations of F-ddA and F-ddI during and after infusions of F-ddA were determined in both untreated and 2'-deoxycoformycin-pretreated rats. In untreated rats, F-ddA was rapidly eliminated from plasma, with a total clearance of 68.5 ml/kg/min. Metabolic clearance of F-ddA to F-ddI accounted for 58% of this value (bioconversion t1/2 = 9.8 +/- 1.9 min). Pretreatment with 2'-deoxycoformycin, an ADA inhibitor, reduced the clearance of F-ddA to 23.8 ml/min/kg, leading to 2.9 +/- 0.4-fold higher steady-state plasma concentrations of F-ddA, in agreement with a 2.5-fold enhancement predicted by a compartmental model assuming complete ADA inhibition.

Adenosine Deaminase Inhibitors↗
PubMed1995

Enhanced oral bioavailability of DDI after administration of 6-Cl-ddP, an adenosine deaminase-activated prodrug, to chronically catheterized rats.

PURPOSE: 6-Cl-2',3'-dideoxypurine (6-Cl-ddP), an adenosine deaminase (ADA) activated prodrug of ddI, may be an effective antiretroviral agent for the treatment of AIDS dementia due to its ability to deliver increased concentrations of ddI to brain tissue. To examine the feasibility of administering this drug orally, the oral and hepatic portal bioavailabilities of 6-Cl-ddP were determined. In addition, the oral and portal bioavailabilities of ddI after administration of the prodrug were compared to those from administration of ddI itself. METHODS: Pharmacokinetic and bioavailability studies were conducted in fully conscious, chronically catheterized rats in a randomized crossover design. Plasma ddI and 6-Cl-ddP concentration-time profiles were determined by HPLC. RESULTS: 6-Cl-ddP has poor apparent oral bioavailability (7% +/- 3%, n = 3) but high bioavailability after portal administration (97% +/- 11%), suggesting either poor absorption or extensive gut wall metabolism. The appearance of > 50% of the dose as ddI in the systemic circulation after an oral dose of 6-Cl-ddP rules out poor absorption of the prodrug, and confirms expectations of high ADA activity in the gastrointestinal tract. Gastric administration of 6-Cl-ddP resulted in a > 10-fold increase in the oral bioavailability of ddI, from 3-7% to > 50%, and a significant decrease in the variability in apparent bioavailability. CONCLUSIONS: These data indicate that lipophilic adenosine deaminase activated prodrugs of dideoxypurine nucleosides may have limited utility for improving CNS delivery after oral administration but may be useful in enhancing the oral bioavailability of highly polar and therefore poorly absorbed dideoxynucleosides.

Adenosine Deaminase↗
PubMed1995

Catch up growth and pancreatic function in growth retarded neonates.

To test the hypothesis that relative pancreatic dysfunction is a determinant of catch up growth in small for gestational age (SGA) babies, 47 such babies (median gestation 38 weeks; range 27-41) and 41 appropriate for gestational age (AGA) babies matched for sex, race, and gestational age were recruited. Anthropometry was performed within 48 hours of birth and at 6 months. Faecal chymotrypsin activities were measured at 0-2 days, 14 days, 6 weeks and 6 months. At 6 months 30 SGA infants and 25 AGA infants were remeasured. In each group, median stool chymotrypsin activities doubled between 0-2 days and 6 months (9.0-25.5 IU/g SGA group; 11.6-25.3 IU/g AGA group). SGA babies had significantly lower chymotrypsin activities at 14 days (10.9 U/g) than AGA babies (15.5 U/g). In the SGA group faecal chymotrypsin activities at 0-2 days were strongly correlated with both catch up weight and with catch up length when corrected for the effects of birthweight. These data show that impaired pancreatic exocrine function at birth is associated with severe intrauterine malnutrition and with impaired catch up growth during the first 6 months of life.

Case-Control Studies↗
PubMed1994

Thoracic splenosis.

The authors present a case that demonstrates the continued high sensitivity of Tc-99m SC liver-spleen imaging for thoracic splenosis. A patient with profound weight loss, positive PPD and left upper lobe lung density on a chest radiograph was felt to have a strong clinical suspicion of a malignant pulmonary lesion. Two needle biopsies of the lesion were consistent with splenic tissue. Transbronchial biopsy of the right lower lobe lung revealed metastatic adenocarcinoma of an unknown origin. A Tc-99m SC liver-spleen scan of the abdomen and thorax indicated the lung density was consistent with thoracic splenosis.

Adenocarcinoma↗
PubMed1994

Gastric emptying in preterm infants.

An ultrasonic technique was used to compare gastric emptying after a feed of expressed breast milk and formula milk in a blind, cross over study of preterm infants. Fourteen infants (median gestational age 33 weeks) were studied on 46 occasions. Each infant received a nasogastric feed of either expressed breast milk or formula milk, and the alternative at the next feed. Real time ultrasound images of the gastric antrum were obtained and measurements of antral cross sectional area (ACSA) were made before the feed and then sequentially after its completion until the ACSA returned to its prefeed value. The half emptying time (50% delta ACSA) was calculated as the time taken for the ACSA to decrease to half the maximum increment. On average, expressed breast milk emptied twice as fast as formula milk: mean 50% delta ACSA expressed breast milk 36 minutes; formula milk 72 minutes. The technique was reproducible and there was no significant difference between the emptying rates of feeds of the same type for an individual infant. These data show that breast milk has a major effect on gastric emptying, which may have important implications for preterm infants who have a feed intolerance due to delayed gastric emptying.

Animals↗
PubMed1993

Species comparison of adenosine and beta-adrenoceptors in mammalian atrial and ventricular myocardium.

The antagonist radioligand 1,3-[3H]dipropyl-8-cyclopentylxanthine ([3H]DPCPX) was used to characterize adenosine A1 receptors in membrane preparations from atrial and ventricular myocardium of rat, rabbit, guinea pig and pig. Kd values in crude membranes from guinea pig atria and ventricles (3.3 and 3.0 nM) were higher than those in the other species (ranges, 1.5-1.8 and 1.5-1.9 nM). Bmax values were greater in atria than in ventricles in all four species, and in atria and ventricles of guinea pig (76 and 34 fmol/mg), than in the other species (ranges, 15-17 and undetectable to 12 fmol/mg). In contrast, guinea pig Kd and Bmax values for beta-adrenoceptors, which were labelled with (-)3-[125I]iodocyanopindolol, fell within the range of values for the other three mammalian species. In semipurified membrane preparations from pig, [3H]DPCPX and the agonist radioligand [125I]-N6-4-aminobenzyladenosine appeared to label a similar population of receptors and gave comparable Kd values in atria (0.73 and 0.66 nM) and in ventricles (0.57 and 0.70 nM). In semipurified preparations from pig, the agonist R-(-)-N6-(2-phenylisopropyl)adenosine (R-PIA) displaced [3H]DPCPX in a manner consistent with the presence of both high- and low-affinity adenosine A1 receptors. The data from this study indicate that the density of adenosine A1 receptors in atria is greater than in ventricles, but similar Kd values suggest that the A1 receptor population is the same in the two cardiac tissues. Also, the data demonstrate that the [3H]DPCPX antagonist binding characteristics of guinea pig myocardium differ from those in rat, rabbit and pig.

Adenylyl Cyclases↗
PubMed1992

Doppler assessment of human neonatal gut blood flow velocities: postnatal adaptation and response to feeds.

Duplex pulsed Doppler ultrasound was used to study changes in gut blood flow velocities during the first week of life in a group of 14 term babies. There was a significant increase in fasting peak systolic velocity in the superior mesenteric artery between days 1 and 2 with a further upward trend until day 5; no such changes were seen in the coeliac axis. Fasting velocities were 20% lower in breast-fed babies than bottle-fed babies. Following feeds, there was a significant increase in velocity in the superior mesenteric artery that was 35% greater in the bottle-fed than breast-fed babies. Changes in the coeliac axis were qualitatively similar but substantially smaller. The peak velocity in both vessels occurred 50 min after a feed. We conclude that Doppler ultrasound can be readily used to measure gut blood flow velocities in the human newborn. It provides a noninvasive technique for investigating adaptive postnatal changes in the splanchnic circulation, and, in particular, the response to feeds.

Adaptation, Physiological↗
PubMed1992

Abnormal gut blood flow velocities in neonates at risk of necrotising enterocolitis.

Duplex pulsed Doppler ultrasound was used to determine blood flow velocities in the coeliac axis and superior mesenteric artery in three groups of neonates: a group at high risk of developing necrotising enterocolitis (n = 27) and two control groups, i.e., a nonasphyxiated, appropriately grown group of preterm infants (n = 18) and a group of nonasphyxiated term infants (n = 14). Subjects were studied on the first, second, and fourth days of life. The median peak systolic velocities in the superior mesenteric artery were between 20 and 51% lower in the at-risk group than in the term control group on all 3 days of measurement (p less than 0.05-p less than 0.002). The ratio of peak systolic velocity in the coeliac axis to that in superior mesenteric artery, an index of relative downstream vascular resistance in the superior mesenteric artery, was 42-65% greater in the at-risk group compared with the other two groups on days 1 and 2 (p less than 0.05-p less than 0.001) and significantly greater than the term group on day 4 (73%, p less than 0.002). These data demonstrate that neonates at risk of developing necrotising enterocolitis have abnormal gut blood flow velocities. Furthermore, they provide evidence that an alteration in the splanchnic circulation may be an important factor in the final common pathway that links diverse risk factors for necrotising enterocolitis with clinical disease.

Blood Flow Velocity↗
PubMed1992

Central nervous system targeting of 2',3'-dideoxyinosine via adenosine deaminase-activated 6-halo-dideoxypurine prodrugs.

AIDS dementia complex is a neurologic disorder, characterized by increasingly severe cognitive, behavioral, and motor impairment, which is associated with human immunodeficiency virus (HIV) infection in the central nervous system (CNS). Many of the dideoxynucleosides effective systemically in the treatment of HIV infections, such as 2',3'-dideoxyinosine (ddI), exhibit limited penetration into the CNS and limited or variable effectiveness in reversing the symptoms of AIDS dementia. Thus, approaches for increasing the CNS uptake of ddI and other dideoxynucleosides are needed. The CNS uptake of a series of 6-halo-2',3'-dideoxypurine ribofuranosides (6-halo-ddPs) previously shown to be active against HIV because of their conversion to ddI through the action of adenosine deaminase was examined in rats. In vitro studies in rat blood and brain tissue homogenate suggested a favorable selectivity for bioconversion in brain tissue, but with bioconversion half-lives varying widely within the series. In vivo infusions of 6-chloro-ddP (6-Cl-ddP), 6-bromo-ddP (6-Br-ddP), and 6-iodo-ddP (6-I-ddP) resulted in significant increases (20- to 34-fold) in the ddI concentration ratios in brain parenchyma/plasma when compared with those after an infusion of ddI alone. Absolute concentrations of ddI in brain parenchyma were increased 10- and 4-fold, respectively, following 30-min infusions of 6-Cl-ddP or 6-Br-ddP, but were 2.4-fold lower after an infusion of 6-I-ddP relative to that after a control infusion of ddI. Detailed studies of the plasma pharmacokinetics, CNS uptake kinetics, and bioconversion of 6-Cl-ddP were conducted to compare in vivo transport and bioconversion parameters with those predicted from in vitro measurements and to rationalize the efficiency of CNS delivery of ddI from 6-Cl-ddP. The results show that increased lipophilicity alone does not ensure that a given prodrug will deliver higher levels of a parent compound to the CNS. Both the selectivity and absolute rate of bioconversion in the brain are important factors.

Animals↗