Search PubMed⌕ Search

Biomedical subjects

S S Patel

Publications and source records attributed to S S Patel.

At least 19 recordsLinked to original sources
PubMed1998

Increased DNA unwinding efficiency of bacteriophage T7 DNA helicase mutant protein 4A'/E348K.

Bacteriophage T7 4A' protein is a DNA helicase that unwinds DNA in a reaction coupled to dTTP hydrolysis. To understand better its mechanism of DNA unwinding, we characterized a set of 4A' mutant proteins (Washington, M. T., Rosenberg, A. H., Griffin, K., Studier, F. W., and Patel, S. S. (1996) J. Biol. Chem. 271, 26825-26834). We showed here, using single turnover DNA unwinding assays, that the 4A'/E348K mutant protein had the unusual property of unwinding DNA (with a 5-6-fold slower rate) despite a significant defect in its dTTPase activity (a 25-30-fold slower rate). Comparing the DNA unwinding rates to the dTTPase rates, we estimated the DNA unwinding efficiencies of both wild-type (about 1 base pair unwound per dTTP hydrolysis) and mutant (4 to 6 base pairs unwound per dTTP hydrolysis). Thus the mutant had a 4-6-fold improvement in its DNA unwinding efficiency over that of the wild-type. We believe that this mutant undergoes less slippage (uncoupled dTTP hydrolysis) than the wild-type. We speculate that nature has selected for a high rate of DNA unwinding rather than a high efficiency of DNA unwinding. Thus even though the mutant is more efficient at DNA unwinding, the wild-type probably was selected because it unwinds DNA faster.

Amino Acid Sequence↗
PubMed1997

Asymmetric interactions of hexameric bacteriophage T7 DNA helicase with the 5'- and 3'-tails of the forked DNA substrate.

Bacteriophage T7 DNA helicase requires two noncomplementary single-stranded DNA (ssDNA) tails next to a double-stranded DNA (dsDNA) region to initiate DNA unwinding. The interactions of the helicase with the DNA were investigated using a series of forked DNAs. Our results show that the helicase interacts asymmetrically with the two tails of the forked DNA. When the helicase was preassembled on the forked DNA before the start of unwinding, a DNA with 15-nucleotide (nt) 3'-tail and 35-nt 5'-tail was unwound with optimal rates close to 60 base pairs/s at 18 degrees C. When the helicase was not preassembled on the DNA, a >65-nt long 5'-tail was required for maximal unwinding rates of 12 base pairs/s. We show that the helicase interacts specifically with the ssDNA region and maintains contact with both ssDNA strands during DNA unwinding, since conversion of the two ssDNA tails to dsDNA structures greatly inhibited unwinding, and the helicase was unable to unwind past a nick in the dsDNA region. These studies have provided new insights into the mechanism of DNA unwinding. We propose an exclusion model of DNA unwinding in which T7 helicase hexamer interacts mainly with the ssDNA strands during DNA unwinding, encircling the 5'-strand and excluding the 3'-strand from the hole.

Bacteriophage T7↗
PubMed1997

Kinetic mechanism of GTP binding and RNA synthesis during transcription initiation by bacteriophage T7 RNA polymerase.

We have used stopped-flow and rapid chemical quench-flow methods to investigate the kinetics of the early steps during transcription initiation by bacteriophage T7 RNA polymerase. Most promoters of T7 RNA polymerase initiate with two GTPs. The kinetics of GTP binding was investigated by monitoring the fluorescence changes resulting from GTP binding to polymerase and fluorescent 2-aminopurine-containing promoter DNA complex. Scheme 1 was determined from studies of T7 Phi10 promoter at 25 degrees C, where (E.D)n represents the polymerase.DNA complex in different conformations. GTPE and GTPI represent the elongating and initiating GTP molecules incorporated at the +2 and +1 positions, respectively. Our studies show that GTP at the elongation site binds with at least 10-fold tighter affinity than the GTP at the initiation site. Two conformational changes were revealed upon GTP binding to the polymerase.2-aminopurine DNA complex. The first conformational change occurred upon GTP binding to the elongation site. This conformational change was reversible, and studies with partially melted DNA and incorrect NTPs suggested that it may represent a DNA melting and/or base pairing step. A second rate-limiting conformational change whose rate was same as the maximum rate of pppGpG synthesis occurred after two GTPs were bound. As with DNA polymerases, this rate-limiting conformational change probably occurs at each NMP incorporation event and may be involved in proper positioning of the initiation and the elongating GTPs within the polymerase active site to achieve efficient and accurate RNA synthesis.

2-Aminopurine↗
PubMed1997

Inhibition of T7 RNA polymerase: transcription initiation and transition from initiation to elongation are inhibited by T7 lysozyme via a ternary complex with RNA polymerase and promoter DNA.

The mechanism of transcription repression of T7 RNA polymerase by T7 lysozyme was investigated using a combination of kinetic and equilibrium methods. HPLC gel-filtration experiments demonstrated complex formation between T7 lysozyme, T7 RNA polymerase, and promoter DNA. The interactions between the two proteins were quantitated by measuring in real time the changes in protein fluorescence upon binary complex formation using stopped-flow kinetics. Complex formation between T7 lysozyme and the RNA polymerase was found to occur by a one-step process, with a bimolecular association rate constant of 38 microM-1 S-1 and a dissociation rate constant of 3.5 S-1. These constants provided an equilibrium dissociation constant, Kd, of 92 nM for the polymerase lysozyme complex. The interactions of the polymerase with the DNA were studied by stopped-flow kinetics and nitrocellulose equilibrium DNA binding experiments in the absence and in the presence of T7 lysozyme. The results showed that T7 lysozyme did not prevent or change the kinetic or thermodynamic interactions of the RNA polymerase with the DNA. T7 lysozyme by itself did not bind to the DNA, but since it bound to the RNA polymerase as well as to the polymerase DNA complex, transcription repression must involve the formation of the ternary complex between T7 lysozyme, T7 RNA polymerase and the promoter DNA. The effect of T7 lysozyme was most striking on runoff product synthesis which was greatly inhibited whereas the steady-state synthesis of abortive products, limited by polymerase cycling or RNA dissociation, was relatively unaffected by the presence of T7 lysozyme. Investigation of the pre-steady-state kinetics of transcription in the presence and absence of T7 lysozyme indicated that the inhibition of runoff product synthesis was largely due to inhibition of transcription initiation and transition from initiation to elongation.

Bacteriophage T7↗
PubMed1997

DNA polymerase beta: multiple conformational changes in the mechanism of catalysis.

Stopped-flow fluorescence assay was applied to identify conformational changes in the catalytic cycle of DNA polymerase beta (Pol beta), using a synthetic DNA primer/template containing 2-aminopurine (2-AP) at the template position opposite the incoming dNTP. Two phases of fluorescence change were observed in the stopped-flow fluorescence assay of the incorporation of the correct nucleotide dTTP. The rate of the slow phase corresponds to that of product formation. This slow phase was identified as the result of a rate-limiting conformational change step before chemistry because this slow phase was also observed with a dideoxynucleotide at the 3' end of the primer which prevents chemical bond formation. The fast phase was also attributed to a conformational change step since its dependence on [dTTP] is hyperbolic. The rates of the two phases and their dependence on [dTTP] and [Mg2+] suggest that the fast conformational change is induced by the binding of MgdNTP and the slow conformational change is induced by the binding of the catalytic Mg2+ ion. The same biphasic kinetics with different rates were also observed with the thio analog dTTPalphaS and incorrect nucleotides dATP, dGTP, and dCTP. The structural nature for the two conformational changes has been discussed in relation to the available structural information of this enzyme. The results could help to explain how a polymerase controls and achieves its fidelity with a multiple conformational change mechanism.

2-Aminopurine↗
PubMed1997

The dTTPase mechanism of T7 DNA helicase resembles the binding change mechanism of the F1-ATPase.

Bacteriophage T7 DNA helicase is a ring-shaped hexamer that catalyzes duplex DNA unwinding using dTTP hydrolysis as an energy source. Of the six potential nucleotide binding sites on the hexamer, we have found that three are noncatalytic sites and three are catalytic sites. The noncatalytic sites bind nucleotides with a high affinity, but dTTPs bound to these sites do not dissociate or hydrolyze through many dTTPase turnovers at the catalytic sites. The catalytic sites show strong cooperativity which leads to sequential binding and hydrolysis of dTTP. The elucidated dTTPase mechanism of the catalytic sites of T7 helicase is remarkably similar to the binding change mechanism of the ATP synthase. Based on the similarity, a general mechanism for hexameric helicases is proposed. In this mechanism, an F1-ATPase-like rotational movement around the single-stranded DNA, which is bound through the central hole of the hexamer, is proposed to lead to unidirectional translocation along single-stranded DNA and duplex DNA unwinding.

Bacteriophage T7↗
PubMed1997

Kinetic mechanism of transcription initiation by bacteriophage T7 RNA polymerase.

The kinetic mechanism of transcription initiation by bacteriophage T7 RNA polymerase was investigated using transient state kinetic methods. Transcription by bacteriophage T7 RNA polymerase occurs in three stages consisting of initiation, promoter clearance, and elongation. Abortive products, up to 6-8-mer, were synthesized during the initiation phase; the transition from initiation to elongation occurred between the synthesis of 6-8-mer and 11-12-mer, and the processive elongation phase began after the synthesis of 12-mer RNA. Our results show that the synthesis of elongation product from the phi 10 promoter is limited both by the efficiency of initiation and by the frequency at which the polymerase escapes the promoter. Studies with heparin trap suggest that the polymerase maintains contact with the promoter region during multiple turnovers of abortive RNA synthesis; thus, the polymerase does not completely dissociate from the promoter after each event of abortive RNA synthesis. The pre-steady-state kinetics of RNA synthesis indicate that initiation occurs at a rate constant (3.5 s(-1)) that is about 30 times faster than the steady-state rate constant of RNA synthesis (0.1 s(-1)). The steady-state rate constant of RNA synthesis is limited largely by the cycling of the RNA polymerase, whereas initiation is limited by the formation of pppGpG, the first RNA product. We show that the synthesis of pppGpG is not limited by steps associated with GTP binding, DNA binding, or the melting of the promoter DNA. Instead, the kinetic results indicate that initiation at the phi10 promoter is limited either by the first phosphodiester bond formation step or more likely by a conformational change prior to pppGpG formation. Such a conformational change could play a role in proper alignment of the initiating and elongating NTPs for efficient phosphodiester bond formation and in maintaining the fidelity of RNA synthesis.

Bacteriophage T7↗
PubMed1997

High-speed, random-access fluorescence microscopy: I. High-resolution optical recording with voltage-sensitive dyes and ion indicators.

The design and implementation of a high-speed, random-access, laser-scanning fluorescence microscope configured to record fast physiological signals from small neuronal structures with high spatiotemporal resolution is presented. The laser-scanning capability of this nonimaging microscope is provided by two orthogonal acousto-optic deflectors under computer control. Each scanning point can be randomly accessed and has a positioning time of 3-5 microseconds. Sampling time is also computer-controlled and can be varied to maximize the signal-to-noise ratio. Acquisition rates up to 200k samples/s at 16-bit digitizing resolution are possible. The spatial resolution of this instrument is determined by the minimal spot size at the level of the preparation (i.e., 2-7 microns). Scanning points are selected interactively from a reference image collected with differential interference contrast optics and a video camera. Frame rates up to 5 kHz are easily attainable. Intrinsic variations in laser light intensity and scanning spot brightness are overcome by an on-line signal-processing scheme. Representative records obtained with this instrument by using voltage-sensitive dyes and calcium indicators demonstrate the ability to make fast, high-fidelity measurements of membrane potential and intracellular calcium at high spatial resolution (2 microns) without any temporal averaging.

Animals↗
PubMed1997

Neural network model of short-term horizontal disparity vergence dynamics.

We present a neural network model of short-term dynamics of the human horizontal vergence system (HVS) and compare its predictions qualitatively and quantitatively with a large variety of horizontal disparity vergence data. The model consists of seven functional stages, namely: (1) computation of instantaneous disparity; (2) generation of a disparity map; (3) conversion of the disparity into a velocity signal; (4) push-pull integration of velocity to generate a position signal; (5) conversion of the position signal to motoneuron/plant activity for each eye; (6) gating of velocity overdrive signal to motoneuron/plant system; and finally (7) discharge path for position cells. Closed-loop (normal binocular viewing) symmetric step and staircase disparity vergence data were collected from three subjects and model parameters were determined to quantitatively match each subject's data. The simulated closed-loop as well as open-loop (disparity clamped viewing) symmetric step, sinusoidal, pulse, staircase, square and ramp wave responses closely resemble experimental results either recorded in our laboratory or reported in the literature. Where possible, the firing pattern of the neurons in the model have been compared to actual cellular recordings reported in the literature. The model provides insights into neural correlates underlying the dynamics of vergence eye movements. It also makes novel predictions about the human vergence system.

Convergence, Ocular↗
PubMed1997

Fosfomycin tromethamine. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections.

Fosfomycin tromethamine is a phosphonic acid bactericidal agent with in vitro activity against most urinary tract pathogens. It is particularly active against Escherichia coli, and Citrobacter, Enterobacter, Klebsiella, Serratia and Enterococcus spp. There appears to be little cross-resistance between fosfomycin and other antibacterial agents, possibly because it differs from other agents in its general chemical structure and site of action. In its new formulation as the oral tromethamine salt, fosfomycin has 34 to 41% oral bioavailability, has a mean elimination half-life of 5.7 hours, and is primarily excreted unchanged in the urine. Following a single 3 g oral dose, peak urinary concentrations occur within 4 hours and remain high (> 128 mg/L) for 24 to 48 hours, which is sufficient to inhibit most urinary tract pathogens. In clinical trials in patients with acute uncomplicated lower urinary tract infection, single-dose fosfomycin tromethamine therapy was effective, and comparable with several other antibacterial agents given either as single-dose or multiple-dose treatments [e.g. beta-lactam and fluoroquinolone agents, cotrimoxazole (trimethoprim-sulfamethoxazole), nitrofurantoin and pipemidic acid]. Bacteriological eradication rates of 75 to 90% were achieved 5 to 11 days after therapy, with eradication rates of 62 to 93% 4 to 6 weeks after therapy. In 3 large double-blind comparisons with ciprofloxacin, cotrimoxazole and nitrofurantoin, 99% of fosfomycin tromethamine recipients and 100% of patients receiving comparator agents were considered clinically cured or improved after therapy. Fosfomycin tromethamine is well tolerated, with a low incidence of adverse events. These comprise mainly gastrointestinal symptoms that are transient, mild and self-limiting. Thus, fosfomycin tromethamine achieves high clinical and bacteriological cure rates in patients with acute uncomplicated lower urinary tract infection and is well tolerated. The single-dose administration regimen and favourable US pregnancy category rating of fosfomycin tromethamine should also encourage its use in this indication.

Acute Disease↗
PubMed1996

Equilibrium and stopped-flow kinetic studies of interaction between T7 RNA polymerase and its promoters measured by protein and 2-aminopurine fluorescence changes.

The mechanism of bacteriophage T7 RNA polymerase binding to its promoter DNA was investigated using stopped-flow and equilibrium methods. To measure the kinetics of protein-DNA interactions in real time, changes in tryptophan fluorescence in the polymerase and 2-aminopurine (2-AP) fluorescence in the promoter DNA upon binary complex formation were used as probes. The protein fluorescence changes measured conformational changes in the polymerase whereas the fluorescence changes of 2-AP base, substituted in place of dA in the initiation region (-4 to +4), measured structural changes in the promoter DNA, such as DNA melting. The kinetic studies, carried out in the absence of the initiating nucleotide, are consistent with a two-step DNA binding mechanism, [formula: see text] where the RNA polymerase forms an initial weak EDa complex rapidly with an equilibrium association constant K1. The EDa complex then undergoes a conformational change to EDb, wherein RNA polymerase is specifically and tightly bound to the promoter DNA. Both the polymerase and the promoter DNA may undergo structural changes during this isomerization step. The isomerization of EDa to EDb is a fast step relative to the rate of transcription initiation and its rate does not limit transcription initiation. To understand how T7 RNA polymerase modulates its transcriptional efficiency at various promoters at the level of DNA binding, comparative studies with two natural T7 promoters, Phi10 and Phi3.8, were conducted. The results indicate that kinetics, the bimolecular rate constant of DNA binding, kon (K1k2), and the dissociation rate constant, koff (k-2), and thermodynamics, the equilibrium constants of the two steps (K1 and k2/k-2) both play a role in modulating the transcriptional efficiency at the level of DNA binding. Thus, the 2-fold lower kon, the 4-fold higher koff, and the 2-5-fold weaker equilibrium interactions together make Phi3.8 a weaker promoter relative to Phi10.

2-Aminopurine↗
PubMed1996

Biochemical analysis of mutant T7 primase/helicase proteins defective in DNA binding, nucleotide hydrolysis, and the coupling of hydrolysis with DNA unwinding.

We characterized nine helicase-deficient mutants of bacteriophage T7 helicase-primase protein (4A') prepared by random mutagenesis as reported in the accompanying paper (Rosenberg, A. H., Griffin, K., Washington, M. T., Patel, S. S., and Studier, F. W. (1996) J. Biol. Chem. 271, 26819-26824). Mutants were selected from each of the helicase-conserved motifs for detailed analysis to understand better their function. In agreement with the in vivo results, the mutants were defective in helicase activity but were active in primase function. dTTP hydrolysis, DNA binding, and hexamer formation were examined. Three classes of defective mutants were observed. Group A mutants (E348K, D424N, and S496F), defective in dTTP hydrolysis, lie in motifs 1a, 2, and 4 and are possibly involved in NTP binding/hydrolysis. Group B mutants (R487C and G488D), defective in DNA binding, lie in motif 4 and are responsible directly or indirectly for DNA binding. Group C mutants (G116D, A257T, S345F, and G451E) were not defective in any of the activities except the helicase function. These mutants, scattered throughout the protein, appear defective in coupling dTTPase activity to helicase function. Secondary structural predictions of 4A' and DnaB helicases resemble the known structures of RecA and F1-ATPase enzymes. Alignment shows a striking correlation in the positions of the amino acids that interact with NTP and DNA.

Amino Acid Sequence↗
PubMed1996

Selection, identification, and genetic analysis of random mutants in the cloned primase/helicase gene of bacteriophage T7.

T7 gene 4 specifies two overlapping proteins 4A, a 566-amino acid primase/helicase, and 4B, a 503-amino acid helicase whose initiation codon is the 64th codon of the 4A protein. The 4A' gene, which has a leucine codon replacing the 4B initiation codon, specifies a single 566-amino acid protein that can provide the primase and helicase functions required for normal T7 growth. We selected N-methyl-N'-nitro-N-nitrosoguanidine mutants in the cloned 4A' gene that no longer support the growth of a phage that completely lacks gene 4. Genetic mapping of the 76 mutations found them to be distributed throughout the protein, including both the N-terminal and C-terminal halves of the molecule thought to represent primase and helicase domains, respectively. Complementation tests with partially and completely defective phage showed that all but five of the mutants lacked helicase function but retained primase function. The other five, which lacked both functions, all made short proteins, including one missing only 60 amino acids. No mutations lacked only primase function, and none mapped within the first 105 amino acids, which includes the 63-amino acid region unique to 4A that contains elements required to recognize primase sites. Forty-six mutations were sequenced and included 27 missense mutations affecting 25 amino acids. Many mutations in the N-terminal half of the protein affected its solubility in cell extracts. Mutations in the C-terminal half clustered in or near five helicase consensus sequences. Biochemical analysis of nine of the mutant proteins is described in the accompanying paper (Washington, M. T., Rosenberg, A. H., Griffin, K., Studier, F. W., and Patel, S. S. (1996) J. Biol. Chem. 271, 26825-26834).

Amino Acid Sequence↗
PubMed1996

Cooperative interactions of nucleotide ligands are linked to oligomerization and DNA binding in bacteriophage T7 gene 4 helicases.

The equilibrium nucleotide binding and oligomerization of bacteriophage T7 gene 4 helicases have been investigated using thymidine 5'-triphosphate (dTTP), deoxythymidine 5'-(beta, gamma-methylenetriphosphate)(dTMP-PCP), thymidine 5'-diphosphate (dTDP), adenosine 5'-triphosphate (ATP), and adenosine 5'-O-(3-thiotriphosphate) (ATP gamma S). In the presence of nucleotide ligands, T7 helicases self-assemble into hexamers with six potential nucleotide binding sites that are nonequivalent both in the absence and in the presence of single-stranded DNA. All nucleotides tested bind with high affinity to three sites (K(d) = 5 x 10(-6) M, dTTP; 6 x 10(-7) M, dTMP-PCP; 4 x 10(-6) M, dTDP; 3 x 10(-5) M, ATP; 2 x 10(-6) M, ATP gamma S), while binding to the remaining sites is undetectable. Interestingly, nucleotide binding to the high-affinity sites exhibits positive cooperativity which is sensitive to protein concentration. This effect is a result of ligand binding-linked oligomerization wherein helicase oligomer equilibrium changes as a function of both nucleotide and protein concentration. A study of DNA binding shows that 1-2 NTPs bound per hexamer are sufficient for stoichiometric interaction between the helicase and DNA. Thus, the ring-shaped helicase hexamers assemble around DNA with one, two, or three NTPs bound to each hexamer. This study also examines the preferred use of dTTP for T7 helicase-catalyzed DNA unwinding by comparison with ATP, the more commonly used nucleotide ligand. ATP binds to the helicase with 6-fold weaker affinity than dTTP and promotes hexamerization as well as DNA binding. Nevertheless, DNA unwinding with ATP is at least 100-fold slower than with dTTP. Thus, the difference in ATP and dTTP utilization probably lies in a highly specific step in the coupling of NTP hydrolysis to DNA unwinding.

Bacteriophage T7↗
PubMed1996

Use of the ganciclovir implant in the treatment of recurrent cytomegalovirus retinitis.

OBJECTIVE: To evaluate the efficacy of the ganciclovir implant in the treatment of recurrent cytomegalovirus (CMV) retinitis. METHODS: Patients with acquired immunodeficiency syndrome and recurrent CMV retinitis were evaluated for entry into the study. A ganciclovir implant was inserted in 91 eyes of 70 patients between October 1992 and October 1995. The efficacy of the implant and visual results were retrospectively reviewed. RESULTS: Fifty-three (76%) of 70 eyes had inactive CMV retinitis 1 month postoperatively (positive initial response). Twenty-one eyes of 19 patients had less than 1 month of follow-up. Nineteen (36%) of 53 eyes developed recurrent CMV retinitis. The median time to recurrence for those patients with a positive initial response was 7 months. Forty-eight (84%) of 57 patients with follow-up longer than 1 month after implant insertion in the first eye received systemic anti-CMV medication during the study. The cumulative risk for developing a retinal detachment was 23% at 6 months following implant insertion. Other complications included vitreous hemorrhage, hyphema, and suprachoroidal implantation of the device. CONCLUSION: The ganciclovir implant is effective as an adjunct to continued systemic therapy in those patients with recurrent CMV retinitis.

AIDS-Related Opportunistic Infections↗
PubMed1996

Cytomegalovirus papillitis in patients with acquired immune deficiency syndrome. Visual prognosis of patients treated with ganciclovir and/or foscarnet.

BACKGROUND: Of those patients with acquired immune deficiency syndrome in whom cytomegaloviral retinitis develops, cytomegaloviral papillitis reportedly develops in up to 4% as well. Although occasionally patients have a good visual outcome, the majority have a poor visual prognosis, with a visual acuity of 20/200 or worse, even with treatment. METHODS: To evaluate the effects of prolonged induction with foscarnet or ganciclovir on the visual prognosis of cytomegalovirus (CMV) papillitis, the records of 22 patients seen between 1990 and 1995 at the Los Angeles County-University of Southern California Eye Clinic were reviewed. Papillitis was defined as greater than 270 degrees of disc edema/blurring of the disc margins as seen on direct examination and on color fundus photographs. RESULTS: Eighteen patients with a mean initial visual acuity of 20/69 (range, 20/ 15-20/400) were treated with induction doses of intravenous ganciclovir (range, 5-7.5 mg/kg twice daily) or foscarnet (range, 60-90 mg/kg twice or 3 times daily) for a mean of 3.3 weeks. The mean follow-up period was 4.8 months (range, 1-13 months). These patients maintained a mean final visual acuity of 20/68 (range, 20/ 25-20/400) with greater than 90% resolution of the papillitis. The remaining four patients had poor outcomes (visual acuity < 20/400) because of progressive CMV papillitis or retinitis. The median survival time was 4.5 months from the diagnosis of papillitis, but 7 months from the onset of CMV ocular infection. CONCLUSION: Patients with CMV papillitis have good visual prognosis when managed with high and prolonged doses of intravenous foscarnet and/or ganciclovir.

AIDS-Related Opportunistic Infections↗
PubMed1996

Latanoprost. A review of its pharmacological properties, clinical efficacy and tolerability in the management of primary open-angle glaucoma and ocular hypertension.

Latanoprost is an ester prodrug analogue of prostaglandin F2 alpha which effectively reduces intraocular pressure (IOP) by increasing uveoscleral outflow rather than altering conventional trabeculo-canalicular) aqueous outflow. The IOP-lowering effect of latanoprost lasts for 20 to 24 hours after a single dose, which allows a single daily dosage regimen. Data from 4 randomised double-masked multicentre studies indicate that a once daily dose of topical latanoprost 0.005% is as effective as timolol 0.5% twice daily in the treatment of patients with primary open-angle glaucoma or ocular hypertension. A number of studies also demonstrate that latanoprost enhances IOP-lowering effects when applied in combination with other antiglaucoma agents. Latanoprost is well tolerated with no, or barely detectable, conjunctival hyperaemia, and, unlike timolol, is not associated with systemic adverse effects. However, 3 to 10% of patients treated with latanoprost 0.005% have shown increased iris pigmentation after 3 to 4.5 months' treatment. In summary, the available data show that latanoprost is a potent IOP-lowering agent with a number of positive features including a single daily dosage regimen, a novel mechanism of action that enhances the IOP-lowering effect of contemporary agents, and a lack of systemic adverse effects. These properties suitably poise latanoprost for a prominent position in the management of patients with primary open-angle glaucoma and ocular hypertension.

Glaucoma, Open-Angle↗