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Biomedical subjects

D I Friedman

Publications and source records attributed to D I Friedman.

At least 19 recordsLinked to original sources
PubMed1995

Enhanced transdermal delivery of diazepam by submicron emulsion (SME) creams.

Diazepam, a lipophilic drug with CNS activity, serves here as a model to investigate the efficacy of SubMicron Emulsion (SME) as a novel transdermal vehicle. Diazepam was formulated in various topical regular creams and SubMicron Emulsion creams of different compositions. The different formulations were applied topically and protection against Pentamethylenetetrazole induced convulsive effects in mice was monitored. The efficacy of Diazepam applied topically in emulsion creams strongly depends on the oil droplet size and to a lesser degree--on the formulation composition and the oil type. Processing medium-chain-triglyceride (MCT) emulsion with a high-pressure homogenizer causes a drastic reduction in the droplet size, thereby significantly increasing the transdermal activity of Diazepam. In this case both the high-pressure homogenization and the presence of lecithin, an efficient dispersant, contribute to the effective droplet size reduction of below 1 micron, usually between 100-300 nm. The SubMicron Emulsions as vehicles for transdermal delivery of Diazepam generate significant systemic activity of the drug as compared with regular creams or ointments. Transdermal delivery of Diazepam via SME formulations is very effective, and the activity may reach the range of parenteral delivery. A single application of Diazepam in SME cream to mice skin provides pronounced transdermal drug delivery and prolonged protective activity up to 6 hours.

Administration, Cutaneous↗
PubMed1992

Interaction between bacteriophage lambda and its Escherichia coli host.

Bacteriophage lambda relies to a large extent on processes requiring interactions between viral- and host-encoded proteins for its lytic growth, establishment of lysogeny, and release from the prophage state. Both biochemical and genetic studies of these interactions have yielded new information about important host and lambda functions. In particular, mutations in Escherichia coli that compromise lambda DNA replication, genome packaging, transcription elongation, and site-specific recombination have led to the identification of bacterial genes whose products are chaperones, transcription factors, or DNA-binding proteins.

Bacterial Proteins↗
PubMed1992

Identification of the rph (RNase PH) gene of Bacillus subtilis: evidence for suppression of cold-sensitive mutations in Escherichia coli.

A shotgun cloning of Bacillus subtilis DNA into pBR322 yielded a 2-kb fragment that suppresses the cold-sensitive defect of the nusA10(Cs) Escherichia coli mutant. The responsible gene encodes an open reading frame that is greater than 50% identical at the amino acid level to the E. coli rph gene, which was formerly called orfE. This B. subtilis gene is located at 251 degrees adjacent to the gerM gene on the B. subtilis genetic map. It has been named rph because, like its E. coli analog, it encodes a phosphate-dependent exoribonuclease activity, RNase PH, that removes the 3' nucleotides from precursor tRNAs. The cloned B. subtilis rph gene also suppresses the cold-sensitive phenotype of other unrelated cold-sensitive mutants of E. coli, but not the temperature-sensitive phenotype of three temperature-sensitive mutants, including the nusA11(Ts) mutant, that were tested.

Amino Acid Sequence↗
PubMed1992

Neuro-ophthalmic findings in progressive supranuclear palsy.

We studied 104 patients with progressive supranuclear palsy (PSP), 38 of whom were examined by both a neurologist and a neuro-ophthalmologist. Neuro-ophthalmic findings that may help differentiate PSP from Parkinson's disease include vertical supranuclear ophthalmoparesis and fixation instability. Eyelid abnormalities, particularly lid retraction, blepharospasm, and "apraxia" of eyelid opening and closure, were important distinguishing signs. Although downgaze palsy is felt to be the clinical hallmark of PSP, upgaze and downgaze were equally affected at the time of diagnosis in our patients.

Aged↗
PubMed1991

Functional importance of sequence in the stem-loop of a transcription terminator.

Intrinsic transcription terminators of prokaryotes are distinguished by a common RNA motif: a stem-loop structure high in guanine and cytosine content, followed by multiple uridine residues. Models explaining intrinsic terminators postulate that the stem-loop sequence is necessary only to form structure. In the tR2 terminator of coliphage lambda, single-nucleotide changes reducing potential RNA stem stability eliminated tR2 activity, and a compensatory change that restored the stem structure restored terminator activity. However, multiple changes in the stem sequence that should have either maintained or increased stability reduced terminator activity. These results suggest that the ability of the stem-loop structure to signal transcription termination depends on sequence specificity and secondary structure.

Bacteriophage lambda↗
PubMed1991

Labeling of human retinohypothalamic tract with the carbocyanine dye, DiI.

The carbocyanine dye, DiI, was used to demonstrate human retinohypothalamic tract (RHT) projections in 6 normal human postmortem brains. In 5 of 6 brains, labeling was seen extending from the site of implantation in the distal optic nerve to both the ipsilateral and contralateral suprachiasmatic nuclei. This study confirms the presence of RHT projections in humans, and demonstrates the usefulness of DiI for neuronal tracing in human postmortem tissue.

Cadaver↗
PubMed1991

Neuro-ophthalmic complications of interleukin 2 therapy.

We describe three patients who experienced several types of visual problems while receiving interleukin 2 therapy for melanoma or lymphoma. Their symptoms included diplopia, binocular negative scotomata, scintillating scotomata, and palinopsia. All symptoms eventually resolved following discontinuation of therapy. It appears that focal neurologic deficits that affect the visual system may complicate interleukin 2 administration.

Adult↗
PubMed1991

Oral absorption of peptides: influence of pH and inhibitors on the intestinal hydrolysis of leu-enkephalin and analogues.

Leu-enkephalin (YGGFL) and several analogues were chosen as model peptides for the study of peptide absorption and hydrolysis in the rat jejunum. An HPLC assay was adapted to detect YGGFL or the analogues and metabolites. Peptide hydrolysis was studied in the rat jejunum using a single-pass perfusion method. Extensive hydrolysis of YGGFL was observed in the rat jejunum and approaches to reduce its metabolism were studied. The brush border enzymes are a major site of enkephalin hydrolysis. Lumenal peptidases were secondary to the brush border enzymes in hydrolyzing the enkephalins in this system. In the in situ perfusion system, YGGFL is hydrolyzed primarily to Tyr and GGFL by the brush border aminopeptidase and to YGG and FL by brush border endopeptidase. Lowering the jejunal pH below 5.0 significantly reduces aminopeptidase activity and, to a lesser extent, endopeptidase activity. An aminopeptidase inhibitor, amastatin, produced more pronounced inhibitory effects at higher pH and the endopeptidase inhibitors, tripeptides YGG and GGF, are effective even below pH 5.0. Coperfusion of YGGFL with a combination of aminopeptidase and endopeptidase inhibitors, e.g., amastatin and YGG, is more effective in inhibiting hydrolysis since both metabolic pathways are inhibited. Leu-D(Ala)2-enkephalin, while showing enhanced stability against aminopeptidase hydrolysis, is hydrolyzed at the Gly-Phe bond by the endopeptidase. Its hydrolysis is not affected by pH changes or amastatin but is decreased by YGG. The YGGFL wall permeability was estimated and is not a limiting factor for oral absorption.

Administration, Oral↗
PubMed1991

Analysis of the Escherichia coli nusA10(Cs) allele: relating nucleotide changes to phenotypes.

The Escherichia coli nusA gene product, known to influence transcription elongation, is essential for both bacterial viability and growth of lambdoid phages. We report the cloning and sequencing of the conditionally lethal nusA10(Cs) allele. Changes from nusA+ were observed at nucleotides 311 and 634. Functional studies showed that both nucleotide changes are necessary for the cold-sensitive phenotype, although bacteria with the change at 634 grew more slowly at 30 degrees C than the nusA+ controls. The mutant nusA10(Cs) gene product is not as active as nusA+ in supporting transcription antitermination mediated by the N regulatory protein of bacteriophage lambda. The change at nucleotide 634 is shown to be solely responsible for this phenotype. Four differences were found between the nusA+ gene that we sequenced and the published nusA sequence. These changes alter the reading frame of nusA in a functionally important domain [as identified by the nusA1 and nusA11(Ts) mutations], resulting in an arginine-rich region that may be involved with RNA binding.

Amino Acid Sequence↗
PubMed1991

Neuro-ophthalmic manifestations of human immunodeficiency virus infection.

Both the afferent visual pathways and ocular motor system may be affected by human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS). Coexisting infections and neoplastic processes in the eye and brain create a diagnostic challenge for the clinician. This article discusses neuroophthalmic manifestations associated with HIV and AIDS, with emphasis on clinical presentation, diagnosis, and treatment.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Transcription-dependent competition for a host factor: the function and optimal sequence of the phage lambda boxA transcription antitermination signal.

Ordered development of lambdoid phages relies on systems of transcription termination and antitermination. The phage-encoded N early regulatory proteins, acting with the Nus proteins of Escherichia coli, modify RNA polymerase to a form that overrides many transcription termination signals. These modifications require cis-acting sites, nut, located downstream of the early phage promoters. The nut sites in phages lambda, 21, and P22, which share similarities but are not identical, contain two signals, boxA and boxB. We demonstrate that although a consensus sequence for the boxA signal (boxAcon), 5'CGCTCTTTA, is found only in P22, changes to consensus in the nutR sites of lambda and 21 create more effective antitermination signals than the wild-type signals. An in vivo competition assay demonstrates that a lambda nut region with boxAcon outcompetes nut regions with wild-type, as well as other variations of the boxA sequence, for the host NusB protein. This suggests that boxA influences NusB activity in N-mediated antitermination. Successful competition by boxAcon requires transcription of the nut site as well as N activation. Nucleotide replacement further demonstrates that bases at both ends of boxA are important for antitermination.

Bacterial Proteins↗
PubMed1990

Identification of a second promoter for the metY-nusA-infB operon of Escherichia coli.

The metY-nusA-infB operon of Escherichia coli encodes functions involved in both transcription and translation. Previous studies have identified a single promoter, P0, that directs transcription of the entire operon. We have identified a second promoter, P-1, that also is positioned to transcribe the complete operon. P-1 is located 50 base pairs upstream of and oriented in the same direction as P0. Sequences associated with P-1 have features suggestive of regulatory elements. P-1 differs from any previously described naturally occurring E. coli promoter by having -35 and -10 sequences that perfectly match the procaryotic promoter consensus hexamer sequences, although the spacing between the two elements is 1 base pair more than optimal. We demonstrate that P-1 is active in vivo.

Base Sequence↗
PubMed1990

Progressive cranial polyneuropathy caused by primary central nervous system melanoma.

Primary malignant melanoma of the central nervous system (CNS) is exceedingly rare. The earliest description by Virchow in 1859 has been followed by approximately 50 autopsy-proven cases reported in the literature. These tumors are considered to arise from leptomeningeal melanocytes whose embryonic origin is neural crest tissue. Given the rarity of primary CNS melanoma, the diagnosis requires a thorough search to exclude a dermatologic, ocular, or visceral site of tumor origin. We report an unusual case of primary CNS melanoma in a patient with painful, progressive cranial polyneuropathy that eluded antemortem diagnosis despite extensive clinical, radiographical, and laboratory investigations.

Adult↗
PubMed1989

Intestinal absorption mechanism of dipeptide angiotensin converting enzyme inhibitors of the lysyl-proline type: lisinopril and SQ 29,852.

The intestinal absorption mechanism of two nonsulfhydril lysyl-proline angiotensin converting enzyme (ACE) inhibitors, lisinopril (1) and SQ 29,852 (2; [(S)-1-[6-amino-2-[[hydroxy (4-phenylbutyl)-phosphinyl]oxy[-1-oxohexyl]-L-proline) were investigated in rats using a single-pass perfusion method. Compound 2 is well absorbed from rat jejunum, whereas lisinopril absorption is relatively low. The permeability of both ACE inhibitors is concentration dependent and is decreased by the dipeptide Tyr-Gly and by cephradine, indicating a nonpassive absorption mechanism via the peptide carrier-mediated transport system. Compound 2 is well absorbed by a nonpassive mechanism, in parallel with a small passive component. The estimated dimensionless carrier parameters for 2 are J*max = 0.16, Km = 0.08 mM, P*c = 2.0, and P*m = 0.25; for lisinopril, passive absorption is not significant and its absorption is nonpassive: J*max = 0.032, Km = 0.082 mM, and P*c = 0.39 (where J*max is the maximal flux, Km is the Michaelis constant, P*c is the carrier permeability, and P*m is the passive permeability). These results offer a mechanistic explanation for the prolonged ACE inhibition and the low oral bioavailability of lisinopril, and for the nonlinear pharmacokinetics of 2.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Passive and carrier-mediated intestinal absorption components of two angiotensin converting enzyme (ACE) inhibitor prodrugs in rats: enalapril and fosinopril.

The intestinal absorption mechanism of two ACE inhibitor prodrugs, enalapril and fosinopril, was investigated in rats using a single-pass perfusion method. A modified boundary layer solution was applied to determine the apparent intestinal wall permeability. The prodrug enalapril is well absorbed from rat jejunum, whereas the parent drug, enalaprilat, is poorly absorbed. The permeability of enalapril is concentration dependent and is decreased by the dipeptide Tyr-Gly and by cephradine but not by the amino acids L-leucine or L-phenylalanine, indicating a nonpassive absorption mechanism via the small peptide carrier-mediated transport system. In contrast, fosinopril is readily absorbed by a concentration-independent mechanism without the involvement of the peptide carrier.

Angiotensin-Converting Enzyme Inhibitors↗