Biomedical subjects

S Cox

Publications and source records attributed to S Cox.

At least 19 recordsLinked to original sources

PubMed1999

Dissection of the nucleotide and metal-phosphate binding sites in cAMP-dependent protein kinase.

The catalytic (C) subunit of cAMP-dependent protein kinase (cAPK) is more stable by several criteria when it is part of a holoenzyme complex. By measuring the thermal stability of the free C subunit in the presence and absence of nucleotides and/or divalent metal ions, it was found that most of the stabilizing effects associated with the type I holoenzyme could be attributed to the nucleotide. The specific requirements for this enhanced stability were further dissected: Adenosine stabilized the C subunit up to 5 degrees C; however, divalent cations (i.e., Mg2+, Ca2+, and Mn2+) do not increase heat stability in combination with adenosine and adenine (1). Divalent cations as well as ATP and ADP have no effect by themselves (2). The enhanced stability derived from both ATP and ADP requires divalent cations. MnATP (12 degrees C) shows a much stronger effect than CaATP (7 degrees C) and MgATP (5 degrees C) (3). In the holoenzyme complex or the protein kinase inhibitor/C subunit complex, metal/ATP is also required for enhanced stability; neither the RI or RII subunits nor PKI alone stabilize the C subunit significantly (4). For high thermal stability, the occupation of the second, low-affinity metal-binding site is necessary (5). From these results, we concluded that the adenine moiety works independently from the metal-binding sites, stabilizing the free C subunit by itself. When the beta- and gamma-phosphates are present, divalent metals are required for positioning these phosphates, and two metals are required to achieve thermostability comparable to adenosine alone. The complex containing two metals is the most stable. A comparison of several conformations of the C subunit derived from different crystal structures is given attributing open and closed forms of the C subunit to less and more thermostable enzymes, respectively.

Binding Sites↗

PubMed1999

Percutaneous revascularization of atherosclerotic obstruction of aortic arch vessels.

OBJECTIVES: To compare stenting of aortic arch vessel obstruction with surgical therapy and to establish recommendations for treatment. BACKGROUND: Though surgery has been considered to be the procedure of choice for subclavian and brachiocephalic obstruction, little work has been done to compare it with stenting. METHODS: Eighteen patients with symptomatic aortic arch vessel stenosis or occlusion were treated with stenting, followed by periodic clinical follow-up and noninvasive arterial Doppler studies. Data were compared with the results as shown in a systematic review of a published series of surgery and stenting procedures which included comparison of technical success, complications, mortality and patency. RESULTS: Primary success in our series was 100% with improvement in mean stenosis from 84+/-11% to 1+/-5% and mean arm systolic blood pressure difference from 44+/-16 mm Hg to 3+/-3 mm Hg. There were no major complications (death, stroke, TIA, stent thrombosis or myocardial infarction). At follow-up (mean 17 months), all patients were asymptomatic with 100% primary patency. Literature review demonstrates equivalent patency and complications in the other published series of stenting. In contrast, there was a similar patency but overall incidence of stroke of 3+/-4% and death of 2+/-2% in the published surgical series. CONCLUSIONS: Subclavian or brachiocephalic artery obstruction can be effectively treated by primary stenting or surgery. Comparison of stenting and the surgical experience demonstrates equal effectiveness but fewer complications and suggests that stenting should be considered as first line therapy for subclavian or brachiocephalic obstruction.

Aged↗

PubMed1999

Prevalence of herpes simplex virus types 1 and 2, cytomegalovirus, and varicella-zoster virus infections in Eritrea.

BACKGROUND: Herpesviruses establish latent infections in their hosts for life. The scarcity of data that exists in regard to herpesvirus infections in many African regions, could partly be due to the mild nature of their primary infections and the lack of means for their proper diagnosis. However, in recent decades the alarming spread of HIV infection in Africa and associated frequent reactivation of herpesvirus infections is leaving less room for neglect. This seroprevalence study is intended to help in the evaluation of the prevalence of herpesvirus infections in Eritrea. OBJECTIVE: To evaluate the spread of herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), cytomegalovirus (CMV), and varicella-zoster virus (VZV) infections. STUDY DESIGN: The study population groups comprise female sex workers (FSW), former guerrilla fighters, truck drivers, port workers, a tribe called Rashaida, pregnant women, children under 5 years of age, and children over 5 years of age. The groups of pregnant women and children under and over 5 years of age were included to form a background for the evaluation of groups considered at risk for sexually transmitted or blood borne infections. RESULTS: All study groups had a high seroprevalence of HSV-1 infections ( > 80%), except for the children under 5 years of age. The FSW had the highest prevalence of HSV-2 infections, 80%, followed by guerrilla fighters, truck drivers, port workers, pregnant women, children, and the Rashaidas. Positivity for antibodies against CMV was > 90% in all studied populations. The prevalence of VZV infections was surprisingly low in the tribe of Rashaida, 44% compared to more than 90% in the other adult groups tested for VZV (P = 0.0001). CONCLUSION: The study shows that the prevalence of HSV-2 in the risk group of FSW was high, which could partly be explained by their sexual behaviours. HSV-2 was particularly low in the Rashaida group and, as expected, in the children. The low prevalence of VZV observed in the Rashaida is of importance since it makes them vulnerable to infection with varicella during their inevitable integration with the other tribes in their society.

Adult↗

PubMed1998

Analysis of HIV-1 reverse transcriptase gene mutations in infected children treated with zidovudine.

Prolonged treatment with antiretroviral agents directed against reverse transcription (RT) in patients with HIV-1 infection results in the emergence of virus variants with reduced sensitivity containing mutations in the HIV-1 RT gene. Development of zidovudine (ZDV)-related mutations was studied in a cohort of 24 vertically infected pediatric patients receiving ZDV therapy. Monthly clinical and immunologic evaluation was accompanied by direct sequencing of the HIV-1 RT gene every 4 months. A correlation was observed between the emergence of mutations and the duration of therapy. Mutation at codon 41 was found only in the presence of mutation at codon 215. The presence of the mutations Met41-->Leu and Thr215-->Tyr/Phe did not appear to be related to disease progression. These findings suggest that the mere presence of mutations in the HIV-1 RT gene alone during ZDV monotherapy is not a reliable prognostic marker in the absence of other clinical and virologic information.

Anti-HIV Agents↗

PubMed1998

Backbone flexibility of five sites on the catalytic subunit of cAMP-dependent protein kinase in the open and closed conformations.

To develop an alternative approach to measure peptidyl backbone flexibility and to expand our understanding of the segmental flexibility of cAMP-dependent protein kinase (cAPK), the effect of protein kinase inhibitor peptide, PKIalpha(5-24), and MgATP on the mobility of fluorescein selectively conjugated to five sites on the catalytic subunit of cAPK was examined. Specifically, five full-length, single-site catalytic subunit mutants (K16C, K81C, I244C, C199A, and N326C) were prepared, and fluorescein maleimide was selectively attached to the side chains of each substituted cysteine or, in the case of the C199A mutant, to the unprotected native C343. The time-resolved anisotropy decay profiles of the five fluorescein maleimide-conjugated mutants were well fit to a biexponential equation. The fast rotational correlation times of the fluorescein conjugates ranged between 1.9 and 2.8 ns and were inversely correlated (r = -0.87) to the averaged crystallographic main-chain atom B factors around each site of conjugation. The slow correlation times ranged between 25 and 28 ns and were about the same magnitude as the value of 21 ns estimated from the Stokes-Einstein equation. The presence of MgATP and PKIalpha(5-24), which induces the closed conformation of cAPK, was associated with a reduction of the fast rotational correlation time of the K81C conjugate, indicating that the peptidyl backbone around K81 is measurably less flexible when the C subunit is in the closed compared with the open conformation. The results suggest (i) that time-resolved fluorescence anisotropy can assess the nanosecond flexibility of short segments of the peptidyl backbone around each site of labeling and (ii) that the substrate/pseudosubstrate binding differentially affects the backbone flexibility of cAPK.

Animals↗

PubMed1998

Conserved water molecules contribute to the extensive network of interactions at the active site of protein kinase A.

Protein kinases constitute a large family of regulatory enzymes, each with a distinct specificity to restrict its action to its physiological target(s) only. The catalytic (C) subunit of protein kinase A, regarded as a structural prototype for this family, is composed of a conserved core flanked by two nonconserved segments at the amino and carboxyl termini. Here we summarize evidence to show that (i) the active site consists of an extended network of interactions that weave together both domains of the core as well as both segments that flank the core; (ii) the opening and closing of the active site cleft, including the dynamic and coordinated movement of the carboxyl terminal tail, contributes directly to substrate recognition and catalysis; and (iii) in addition to peptide and ATP, the active site contains six structured water molecules that constitute a conserved structural element of the active site. One of these active-site conserved water molecules is locked into place by its interactions with the nucleotide, the peptide substrate/inhibitor, the small and large domains of the conserved core, and Tyr-330 from the carboxyl-terminal "tail."

Animals↗

PubMed1998

Drug susceptibility of subtypes A,B,C,D, and E human immunodeficiency virus type 1 primary isolates.

We determined the susceptibility to antiviral drugs of clinical isolates of human immunodeficiency virus type 1 (HIV-1) subtypes A, B, C, D, and E. Isolates from treated and untreated patients were tested for sensitivity to zidovudine (ZDV), lamivudine (3TC), didanosine (ddI), nevirapine (NVP), foscarnet (PFA), and ritonavir (RNV). The susceptibility to these different drugs was broadly similar between the different subtypes of HIV-1. Isolates of subtype D showed a tendency toward slightly lower susceptibility to all the antiviral drugs, which could be related to the rapid growth characteristics of these isolates.

Anti-HIV Agents↗

PubMed1998

Solid phase ELISA for determination of the virus dose dependent sensitivity of human cytomegalovirus to antiviral drugs in vitro.

The main problems in determining the true in vivo susceptibility of human cytomegalovirus (CMV) to antiviral compounds are the influence of the size of the viral inoculum, the variation in the replication capacity of different CMV strains and the subjective evaluation of the inhibition of viral growth in the plaque assay. In this study, a specific assay was developed which reproducibly determines the sensitivity of primary isolates of CMV. The assay includes simultaneous virus titration and determination of the antiviral sensitivity. When individual virus doses were evaluated, the IC50 was generally dependent on the virus dose, except for resistant isolates, where the IC50 did not change irrespective of the dose of virus. The novel method of IC50 calculation takes into account all values derived from the linear part of the inhibition curve. This may better reflect the in vivo conditions, where the antiviral drug encounters different amounts of virus in different organs. Two human fibroblast-derived cell lines showed similar results.

Antiviral Agents↗

PubMed1998

Prevalence of infection with HIV, hepatitis B and C viruses, in four high risk groups in Eritrea.

BACKGROUND: Little is known about the prevalence of infections in different population groups in Africa, and about the influence of living conditions on the spread of infections. This study is the first of its kind in the state of Eritrea and is expected to serve as an evaluation of the situation in the country. OBJECTIVE: A serosurvey for human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) was carried out during the summer of 1995 in Massawa, a small sea port in Eritrea (East Africa) in four groups considered to be at risk for these infections. STUDY DESIGN: The study subjects were former Guerrilla Fighters, Female Sex Workers, Truck Drivers, and Port Workers. Participants from a tribe called Rashaida were believed to be at low risk, and thus served as a control. RESULTS: The Female Sex Workers had the highest incidence of HIV-1 infection, 29%, compared to 10% for Port Workers, and 3% for Guerrilla Fighters. On the other hand presence of HBsAg, indicating a high prevalence of hepatitis B carrier status, was highest in the Guerrilla Fighters, followed by the Rashaidas, and lowest in the Female Sex Workers. The Female Sex Workers were further tested for antibodies against HBV and the results revealed that 53% of them, 5%, had antibodies against HBcoreAg. Excluding the possibility of an acute infection at sampling time, three of them became HBsAg carriers. Surprisingly, our group of Truck Drivers did not show HIV-1 infection, and no HIV-2 infections were seen in the whole cohort. CONCLUSION: The study shows that the described groups have different prevalences of infection with HIV, hepatitis B and C which can partly be explained by their living conditions.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Pharmacokinetics and safety of tobramycin after once-daily administration in patients with cystic fibrosis.

STUDY OBJECTIVE: Tobramycin is commonly used to treat respiratory tract infections in patients with cystic fibrosis. We designed a study to determine the pharmacokinetics and safety of once-daily dosing of tobramycin in this population. DESIGN: Multiple blood samples were collected from each patient, and serum concentrations of tobramycin were determined by a fluorescence polarization immunoassay. Blood urea nitrogen and serum creatinine levels were measured every 2 to 3 days, and audiometric evaluations were performed at the start and end of therapy. MEASUREMENTS AND RESULTS: Eighteen patients (mean age, 24.6 years) received tobramycin at doses of 7 to 15 mg/kg/d as a single-dose infusion over 20 min. The maximum serum concentration of tobramycin ranged from 40.1 to 64.6 mg/L. A mean dose of 11.9+/-1.9 mg/kg was needed to obtain a theoretical mean peak serum concentration of 42.4+/-4.5 mg/L. The mean total body clearance, apparent volume of distribution, and elimination half-life was 1.7+/-0.4 mL/min/kg, 0.27+/-0.06 L/kg, and 1.8+/-0.3 h, respectively. The period of time that the serum concentration exceeded eight times the theoretical minimum inhibitory concentration of 1 mg/L ranged from 2.1 to 4.4 h, which was nearly five times longer compared with the use of divided daily doses in the same patients during previous hospitalizations. No nephrotoxicity, ototoxicity, or adverse effects occurred in any patient. CONCLUSION: Based on our data, tobramycin may be used safely in once-daily doses to treat exacerbations of respiratory tract infections in patients with cystic fibrosis.

Adolescent↗

PubMed1997

A binary complex of the catalytic subunit of cAMP-dependent protein kinase and adenosine further defines conformational flexibility.

BACKGROUND: cAMP-dependent protein kinase (cAPK), a ubiquitous protein in eukaryotic cells, is one of the simplest members of the protein kinase family. It was the first protein kinase to be crystallized and continues to serve as a biochemical and structural prototype for this family of enzymes. To further understand the conformational changes that occur in different liganded and unliganded states of cAPK, the catalytic subunit of cAPK was crystallized in the absence of peptide inhibitor. RESULTS: The crystal structure of the catalytic subunit of mouse recombinant cAPK (rC) complexed with adenosine was solved at 2.6 A resolution and refined to a crystallographic R factor of 21.9% with good stereochemical parameters. This is the first structure of the rC subunit that lacks a bound inhibitor or substrate peptide. The structure was solved by molecular replacement and comprises two lobes (large and small) which contain a number of conserved loops. CONCLUSIONS: The binary complex of rC and adenosine adopts an 'intermediate' conformation relative to the previously described 'closed' and 'open' conformations of other rC complexes. Based on a comparison of these structures, the induced fit that is necessary for catalysis and closing of the active-site cleft appears to be confined to the small lobe, as in the absence of the peptide the conformation of the large lobe, including the peptide-docking surface, does not change. Three specific components contribute to the closing of the cleft: rotation of the small lobe; movement of the C-terminal tail; and closing of the so-called glycine-rich loop. There is no induced fit in the large lobe to accommodate the peptide and the closing of the cleft. A portion of the C-terminal tail, residues 315-334, serves as a gate for the entry or exit of the nucleotide into the hydrophobic active-site cleft.

Adenosine↗

PubMed1997

Structure of poliovirus type 2 Lansing complexed with antiviral agent SCH48973: comparison of the structural and biological properties of three poliovirus serotypes.

BACKGROUND: Polioviruses are human pathogens and the causative agents of poliomyelitis. Polioviruses are icosahedral single-stranded RNA viruses, which belong to the picornavirus family, and occur as three distinct serotypes. All three serotypes of poliovirus can infect primates, but only type 2 can infect mice. The crystal structures of a type 1 and a type 3 poliovirus are already known. Structural studies of poliovirus type 2 Lansing (PV2L) were initiated to try to enhance our understanding of the differences in host range specificity, antigenicity and receptor binding among the three serotypes of poliovirus. RESULTS: The crystal structure of the mouse neurovirulent PV2L complexed with a potent antiviral agent, SCH48973, was determined at 2.9 A resolution. Structural differences among the three poliovirus serotypes occur primarily in the loop regions of the viral coat proteins (VPs), most notably in the loops of VP1 that cluster near the fivefold axes of the capsid, where the BC loop of PV2L is disordered. Unlike other known structures of enteroviruses, the entire polypeptide chain of PV2L VP4 is visible in the electron density and RNA bases are observed stacking with conserved aromatic residues (Tyr4020 and Phe4046) of VP4. The broad-spectrum antiviral agent SCH48973 is observed binding in a pocket within the beta-barrel of VP1, in approximately the same location that natural 'pocket factors' bind to polioviruses. SCH48973 forms predominantly hydrophobic interactions with the pocket residues. CONCLUSIONS: Some of the conformational changes required for infectivity and involved in the control of capsid stability and neurovirulence in mice may occur in the vicinity of the fivefold axis of the poliovirus, where there are significant structural differences among the three poliovirus serotypes in the surface exposed loops of VP1 (BC, DE, and HI). A surface depression is located at the fivefold axis of PV2L that is not present in the other two poliovirus serotypes. The observed interaction of RNA with VP4 supports the observation that loss of VP4 ultimately leads to the loss of viral RNA. A model is proposed that suggests dual involvement of the virion fivefold and pseudo-threefold axes in receptor-mediated initiation of infection by picornaviruses.

Adaptation, Physiological↗

PubMed1997

Crystal structure of a polyhistidine-tagged recombinant catalytic subunit of cAMP-dependent protein kinase complexed with the peptide inhibitor PKI(5-24) and adenosine.

The crystal structure of the hexahistidine-tagged mouse recombinant catalytic subunit (H6-rC) of cAMP-dependent protein kinase (cAPK), complexed with a 20-residue peptide inhibitor from the heat-stable protein kinase inhibitor PKI(5-24) and adenosine, was determined at 2.2 A resolution. Novel crystallization conditions were required to grow the ternary complex crystals. The structure was refined to a final crystallographic R-factor of 18.2% with good stereochemical parameters. The "active" enzyme adopts a "closed" conformation as found in rC:PKI(5-24) [Knighton et al. (1991a,b) Science 253, 407-414, 414-420] and packs in a similar manner with the peptide providing a major contact surface. This structure clearly defines the subsites of the unique nucleotide binding site found in the protein kinase family. The adenosine occupies a mostly hydrophobic pocket at the base of the cleft between the two lobes and is completely buried. The missing triphosphate moiety of ATP is filled with a water molecule (Wtr 415) which replaces the gamma-phosphate of ATP. The glycine-rich loop between beta1 and beta2 helps to anchor the phosphates while the ribose ring is buried beneath beta-strand 2. Another ordered water molecule (Wtr 375) is pentacoordinated with polar atoms from adenosine, Leu 49 in beta-strand 1, Glu 127 in the linker strand between the two lobes, Tyr 330, and a third water molecule, Wtr 359. The conserved nucleotide fold can be defined as a lid comprised of beta-strand 1, the glycine-rich loop, and beta-strand 2. The adenine ring is buried beneath beta-strand 1 and the linker strand (120-127) that joins the small and large lobes. The C-terminal tail containing Tyr 330, a segment that lies outside the conserved core, covers this fold and anchors it in a closed conformation. The main-chain atoms of the flexible glycine-rich loop (residues 50-55) in the ATP binding domain have a mean B-factor of 41.4 A2. This loop is quite mobile, in striking contrast to the other conserved loops that converge at the active site cleft. The catalytic loop (residues 166-171) and the Mg2+ positioning loop (residues 184-186) are a stable part of the large lobe and have low B-factors in all structures solved to date. The stability of the glycine-rich loop is highly dependent on the ligands that occupy the active site cleft with maximum stability achieved in the ternary complex containing Mg x ATP and the peptide inhibitor. In this ternary complex the gamma-phosphate is secured between both lobes by hydrogen bonds to the backbone amide of Ser 53 in the glycine-rich loop and the amino group of Lys 168 in the catalytic loop. In the adenosine ternary complex the water molecule replacing the gamma-phosphate hydrogen bonds between Lys 168 and Asp 166 and makes no contact with the small lobe. This glycine-rich loop is thus the most mobile component of the active site cleft, with the tip of the loop being highly sensitive to what occupies the gamma-subsite.

Adenine↗

PubMed1997

HIV-1 drug susceptibilities and reverse transcriptase mutations in patients receiving combination therapy with didanosine and delavirdine.

Previous studies have shown that the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase mutation Y181C, which confers high-level resistance to nonnucleoside reverse transcriptase inhibitors (NNRTIs), develops rarely during therapy with NNRTIs plus zidovudine. To determine whether didanosine (ddI) is also effective in preventing the emergence of Y181C, we analyzed delavirdine (DLV) susceptibilties and reverse transcriptase sequences of isolates obtained from patients enrolled in a pharmacokinetic study of DLV and ddI. Nine NNRTI-naive patients were evaluated. Seven received DLV/ddI and two received DLV/ddI/zidovudine. Median durations of prior zidovudine and ddI were 26 and 15 months, respectively. Isolates from eight of nine patients had a mutation(s) associated with nucleoside resistance at entry. After treatment with DLV and ddI alone, isolates from five of seven patients developed Y181C, four in combination with K103N. Thus, in this group of nucleoside-experienced patients, combination therapy with DLV/ddI did not prevent the emergence of Y181C.

Adult↗

PubMed1997

Counting the uncatchable? An epidemiological method for counting drug misusers.

Service provision and treatment outcome for problem drug users are receiving increased attention, although both are hindered by the lack of good epidemiological data. A technique of population enumeration called capture recapture methodology (CRM) is currently being advocated for use in populations that are otherwise hard to count. CRM is explained and some of its limitations discussed. Studies that have used this methodology are examined.

Catchment Area, Health↗

PubMed1997

SCH 43478 and analogs: in vitro activity and in vivo efficacy of novel agents for herpesvirus type 2.

SCH 43478 and analogs are a class of non-nucleoside antiviral agents that have potent and selective activity against herpes simplex virus type 2 (HSV-2). The IC50 for these compounds in plaque reduction analysis using Vero cells ranges from 0.8 to 2.0 microg/ml. All compounds have a LC50 > 100 microg/ml in cytotoxicity analysis. Mechanism of action studies suggest that these molecules have an effect on the transactivation of viral immediate early (alpha) gene expression. Time of addition studies indicate that antiviral activity of these analogs is limited to the initial 2-3 h after infection and is not due to inhibition of viral adsorption or penetration. Analysis of HSV protein expression demonstrates that SCH 49286 inhibits the accumulation of viral immediate early (alpha) gene products. SCH 43478 demonstrates statistically significant efficacy (P < 0.05) in the guinea pig genital model of HSV infection. Following subcutaneous administration in a therapeutic treatment regimen, SCH 43478 (90 mg/kg/day) is efficacious in reducing the number and severity of lesions and the neurological complications of acute HSV infection. Thus, SCH 43478 and analogs are anti-herpesvirus agents with a unique mechanism of action.

Adsorption↗

PubMed1997

Population pharmacokinetics of felbamate in children.

Information about the pharmacokinetics of felbamate in children is limited. Even though it is claimed that monitoring of felbamate concentrations is unnecessary, many neurologists have requested therapeutic drug monitoring (TDM) for various reasons. This study used the NONMEM program to describe the pharmacokinetics and the influence of other anticonvulsants on the pharmacokinetics of felbamate. Felbamate, carbamazepine (CBZ), phenytoin (PHY), valproate (VPA), and barbiturate serum levels were obtained by our TDM service as requested by the clinician. The clearance and volume of distribution of felbamate were 41.1 ml/h/kg and 908 ml/kg, respectively. CBZ and PHY increased the clearance 49 and 40% while VPA decreased it 21%. Barbiturate had no significant effect. Clearance also decreased with age.

Adolescent↗

PubMed1997

Increased activation of the combination of 3'-azido-3'-deoxythymidine and 2'-deoxy-3'-thiacytidine in the presence of hydroxyurea.

The intracellular phosphorylation of 3'-azido-3'-deoxythymidine and 2'-deoxy-3'-thiacytidine was increased two- to threefold by the addition of hydroxyurea (HU) to the single drugs or to the two drugs in combination. The ratios of drug triphosphate to competing cellular deoxynucleoside triphosphate were increased two- to threefold for both 3'-azido-3'-deoxythymidine and 2'-deoxy-3'-thiacytidine in the presence of HU. These HU-induced increases in 3'-azido-3'-deoxythymidine and 2'-deoxy-3'-thiacytidine metabolism may further enhance the anti-human immunodeficiency virus activity of these two drugs.

Anti-HIV Agents↗