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Evaluation of microangiopathy of the skin in patients with non-insulin-dependent diabetes mellitus by laser Doppler flowmetry; microvasodilatory responses to beraprost sodium.

To determine the relationship of skin microangiopathy and other diabetic microvascular complications, we measured changes in skin blood flow after the administration of the prostacyclin (PGI2) analogue, beraprost sodium (BPS), in 82 patients with non-insulin-dependent diabetes mellitus and 20 healthy subjects. The diabetic patients had various degrees of retinopathy and nephropathy. Using laser Doppler flowmetry we measured skin blood flow at the dorsum of the right big toe at various times after the administration of 40 micrograms BPS and calculated the blood flow change (delta flux = peak flux--basal flux). We also determined the ankle pressure index (API), an ankle/brachial systolic pressure ratio. The basal blood flow was higher in healthy subjects than in diabetic patients (P < 0.001). BPS significantly increased blood flow in both diabetic patients and healthy subjects (P < 0.001). In all 102 subjects delta flux was positively correlated with the API (R = 0.40, P < 0.001). Despite no differences in API among the diabetic retinopathy and nephropathy subgroups, the delta flux in diabetic patients with progressive retinopathy and macroalbuminuria was significantly lower than in healthy subjects or in diabetic patients with less severe retinopathy and nephropathy (P < 0.05). The results suggested that BPS increases skin blood flow and the flow increase induced by BPS is related partly to the levels of API. The effect of BPS on skin blood flow decreased with an increases in the severity of retinopathy and nephropathy. Diabetic skin microangiopathy appears to coexist with other microvascular diabetic complications and may be proportional to their severity.

Adult↗

The complete sequence of the mitochondrial genome of Daphnia pulex (Cladocera: Crustacea).

The sequence of the mitochondrial DNA (mtDNA) of the branchiopod crustacean Daphnia pulex has been completed. It is 15333bp with an A+T content of 62.3%, and contains the typical complement of 13 protein-coding, 22 transfer RNA (tRNA) and two ribosomal RNA (rRNA) genes. Comparison of this sequence with the sequences of the other eight completely sequenced arthropod mtDNAs showed that gene order and orientation are identical to that of Drosophila but different from Artemia due to the rearrangement of two tRNA genes. Nucleotide composition, codon usage, and amino acid composition are very similar in the crustaceans, but divergent from insects and chelicerates which show a much higher bias towards A+T. However, with few exceptions, the mitochondrial proteins of Daphnia are more similar to those of the dipteran insects (Drosophila and Anopheles) than to those of Artemia, at both the nucleotide and amino acid levels, suggesting that Artemia mtDNA is evolving at an accelerated rate. These results also show that sequence evolution and the evolution of nucleotide composition can be decoupled. Analysis of nucleotide substitution patterns in COII showed that there has been an unbiased acceleration of the overall substitution rate in Artemia. In contrast, the accelerated substitution rate in Apis is due partly to extreme A+T mutation pressure. Secondary structures are proposed for the Daphnia tRNAs and rRNAs. The tRNAs are similar to those of other arthropods but tend to have TPsiC arms that are only 4bp long. The rRNA secondary structures are similar to those proposed for insects except for the absence of a small number of helices in Daphnia. Phylogenetic analysis of second codon positions grouped Daphnia with Artemia, as expected, despite the latter's accelerated divergence rate. In contrast, the unusual pattern of mtDNA divergence in Apis led to a topology in which the holometabolous insects (Anopheles, Drosophila, Apis) appeared to be paraphyletic with respect to the hemimetabolous insect, Locusta, due to the early branching of Apis.

Animals↗

Comparison of the mechanical properties of the crystalline and amorphous forms of a drug substance.

PURPOSE: To better understand the influence of long-range molecular order on the processing characteristics of an active pharmaceutical ingredient (API). METHODS: Crystalline and amorphous samples of a model drug substance were isolated and their "true" density, crystallinity, melting point, glass transition temperature, particle size distribution, and powder flow characteristics determined. Compacts of a standard porosity were manufactured from each form and their dynamic indentation hardness, quasi-static indentation hardness, tensile strength and "compromised tensile strength" determined. X-ray powder diffraction was used to confirm that no changes were induced by compact formation or testing. RESULTS: The crystalline and amorphous forms of the drug substance had relatively high melting and glass transition temperatures (approximately 271 and 142 degrees C, respectively) and were physically and chemically stable under the conditions of the testing laboratory. Consistent with this there was no evidence of crystallinity in the amorphous samples or vice versa before, during or after testing. The two API lots were effectively equivalent in their particulate properties (e.g. particle size distribution), although differences in their particle morphologies were observed which influenced powder flow behavior. The compacts of the bulk drug samples exhibited moderate ductility, elasticity, and strength, and high brittleness, in keeping with many other drug substance samples. A significantly greater compression stress was required to form the compacts of the crystalline material, and these sample materials were more ductile, less brittle and less elastic than those made from the amorphous API. There were no major differences in the tensile strength or the viscoelasticity of the compacts made from the crystalline and amorphous samples. CONCLUSIONS: The mechanical properties of compacted amorphous and crystalline samples of a drug substance have been measured and the contributions due to the molecular ordering of the crystalline form proposed. Small but significant differences in the mechanical properties were noted which could potentially affect the processing performance of API.

Chemical Phenomena↗

Development and application of a universal method for quantitation of anionic constituents in active pharmaceutical ingredients during early development using suppressed conductivity ion chromatography.

A universal method for quantitation of anionic substances in active pharmaceutical ingredients (API) during early development was developed using ion chromatography (IC). The method was developed to allow rapid characterization of APIs in support of early clinical studies The method parameters were chosen to allow quantitation of monovalent, divalent, and trivalent inorganic ions as well as monvalent and divalent carboxylic acids. These parameters were also chosen to ensure appropriate performance for regulated analyses using less than 10mg of API per replicate. The method was applied to and validated for a range of anionic analytes in APIs of varying hydrophobicity to demonstrate applicability to various analyses encountered during early development of pharmaceuticals.

Anions↗

Studies of cargo delivery to the vacuole mediated by autophagosomes in Saccharomyces cerevisiae.

In the yeast Saccharomyces cerevisiae, aminopeptidase I (API), a vacuolar hydrolase, is selectively transported to the vacuole via the autophagosome. API forms a cytosol to vacuole targeting (Cvt) complex in the cytoplasm. The complex is engulfed by the autophagosome under starvation conditions. In this study, the Cvt complex is visualized as a dot in the cytoplasm by fluorescence microscopy with API-GFP. The Cvt complex associates with the preautophagosomal structure (PAS), which plays a central role in autophagosome formation. In a Deltacvt19 mutant, which is specifically defective in API transport, but not in autophagy, the Cvt complex forms normally but never associates with the PAS. This indicates that Cvt19p mediates association between the Cvt complex and the PAS.

Aminopeptidases↗

Products and mechanism of the reaction of OH radicals with 2,2,4-trimethylpentane in the presence of NO.

Alkanes are important constituents of gasoline fuel and vehicle exhaust, with branched alkanes comprising a significant fraction of the total alkanes observed in urban areas. Products of the gas-phase reactions of OH radicals with 2,2,4-trimethylpentane and 2,2,4-trimethylpentane-d18 in the presence of NO at 298+/-2 K and atmospheric pressure of air have been investigated using gas chromatography with flame ionization detection (GC-FID), combined gas chromatography-mass spectrometry (GC-MS), and in situ atmospheric pressure ionization tandem mass spectrometry (API-MS). Acetone, 2-methylpropanal, and 4-hydroxy-4-methyl-2-pentanone were identified and quantified by GC-FID from 2,2,4-trimethylpentane with molar formation yields of 54+/-7%, 26+/-3%, and 5.1+/-0.6%, respectively; upper limits to the formation yields of acetaldehyde, 2,2-dimethylpropanal, and 4,4-dimethyl-2-pentanone were obtained. Additional products observed from 2,2,4-trimethylpentane by API-MS and API-MS/MS analyses using positive and negative ion modes were hydroxy products of molecular weight 130 and 144, a product of molecular weight 128 (attributed to a C8-carbonyl), and hydroxynitrates of molecular weight 135, 177, and 191 (attributed to HOC4H8ONO2, HOC7H14ONO2, and HOC8H16-ONO2, respectively). Formation of HOC8H16ONO2 and HOC7H14-ONO2 is consistent with the observation of products of molecular weight 207 (HOC8D16ONO2) and 191 (HOC7D14-ONO2), respectively, in the API-MS analyses of the 2,2,4-trimethylpentane-d18 reaction (-OD groups rapidly exchange to -OH groups under our experimental conditions). These product data allow the reaction pathways to be delineated to a reasonable extent, and the reaction mechanism is discussed.

Free Radical Scavengers↗

Organization and potential function of the mrjp3 locus in four honeybee species.

Royal jelly is a nutritious secretion produced by nurse honeybees to provision queens and growing larvae. Major proteins of royal jelly are mutually similar, and they all belong to the MRJP/yellow protein family (pfam03022). The mrjp3 loci in four traditional honeybee species (Apis mellifera, Apis cerana,Apis dorsata, and Apis florea) were sequenced and found to share high sequence and structural similarities. PCR analyses confirmed the presence of an extensive repetitive region, which showed size and sequence polymorphisms in all species. The evolutionary history of mrjp genes and their repetitive regions was reconstructed from their nucleotide sequences. The analyses proved that the repeat region appeared early in the evolution of the mrjp gene family and that the extreme elongation of the repeat is mrjp3 specific. In the MRJPs was documented a correlation between nitrogen content and repeat length. Therefore, it is argued that the repeat occurred due to a selection for an increase in nitrogen storage for a more efficient nutrition of queens and larvae.

Amino Acid Sequence↗

Activity, structure, and diversity of Type II proline-rich antimicrobial peptides from insects.

Apidaecin 1b (Api), the first characterized Type II Proline-rich antimicrobial peptide (PrAMP), is encoded in the honey bee genome. It inhibits bacterial growth by binding in the nascent peptide exit tunnel of the ribosome after the release of the completed protein and trapping the release factors. By genome mining, we have identified 71 PrAMPs encoded in insect genomes as pre-pro-polyproteins. Having chemically synthesized and tested the activity of 26 peptides, we demonstrate that despite significant sequence variation in the N-terminal sequence, the majority of the PrAMPs that retain the conserved C-terminal sequence of Api are able to trap the ribosome at the stop codons and induce stop codon readthrough-all hallmarks of Type II PrAMP mode of action. Some of the characterized PrAMPs exhibit superior antibacterial activity in comparison with Api. The newly solved crystallographic structures of the ribosome complexed with Api and&#xa0;with the more active peptide Fva1 from the stingless bee demonstrate the universal placement of the PrAMPs' C-terminal pharmacophore in the post-release ribosome despite variations in their N-terminal sequence.

Animals↗

Raman spectroscopy as a process analytical technology tool for the understanding and the quantitative in-line monitoring of the homogenization process of a pharmaceutical suspension.

The aim of this study was to propose a Process Analytical Technology (PAT) strategy for the quantitative in-line monitoring of an aqueous pharmaceutical suspension using Raman spectroscopy. A screening design was used to study the significance of process variables (mixing speed and height of the stirrer in the reactor) and of formulation variables (concentration of the active pharmaceutical ingredient (API) ibuprofen and the viscosity enhancer (xanthan gum)) on the time required to homogenize an aqueous pharmaceutical model suspension as response variable. Ibuprofen concentration (10% and 15% (w/v)) and the height of stirrer (position 1 and 2) were discrete variables, whereas the viscosity enhancer (concentration range: 1-2 g L-1) and the mixing speed (700-1000 rpm) were continuous variables. Next, a multilevel full factorial design was applied to study the effect of the remaining significant variables upon the homogenization process and to establish the optimum conditions for the process. Interactions between these variables were investigated as well. During each design experiment, the conformity index (CI) method was used to monitor homogeneity of the suspension mixing system in real-time using Raman spectroscopy in combination with a fibre optical immersion probe. Finally, a principal component regression (PCR) model was developed and evaluated to perform quantitative real-time and in-line measurements of the API during the mixing process. The experimental design results showed that the suspension homogenization process is an irregular process, for which it is impossible to model the studied variables upon the measured response variable. However, applying the PCR model it is possible to predict in-line and real-time the concentration of the API in a suspension during a mixing process. In this study, it is shown that Raman spectroscopy is a suitable PAT tool for the control of the homogenization process of an aqueous suspension. Raman spectroscopy not only allowed real-time monitoring of the homogeneity of the suspension, but also helped (in combination with experimental design) to understand the process. Further, the technique allowed real-time and in-line quantification of the API during the mixing process.

Chemistry, Pharmaceutical↗

Validation of the official control method based on Polymerase Chain Reaction (PCR) for identification of authorised probiotic yeast in animal feed.

Council Directive 70/524/EEC regulates the application of probiotic (microorganisms) additives in feeding stuffs. In the present study a method for the differentiation and strain identification of authorised probiotic Saccharomyces cereviseae strains in feeding stuffs by Polymerase Chain Reaction (PCR) was validated. Four different samples of animal feeding stuffs containing yeast at levels between 10(5) to 10(7) CFU/g were examined. Samples were enumerated on chloramphenicol glucose yeast extract agar and colonies were selected from these plates for DNA extraction and subsequent analysis. The PCR method using delta sequence primers produced an 'amplified sequence polymorphism' characteristic for the test strain. Feeds supplemented with one of four probiotic yeast strains each were analysed by seven of nine invited laboratories. All laboratories returned valid results with the exception of one laboratory that had insufficiently separated bands on the gel. The method had a good reproducibility for probiotic yeast isolates from feed of all four authorised probiotic yeast strains (APYS) CBS 493.94, APYS CNCM 1-1079, APYS CNCM 1-1077, APYS NCYC SC47 and of a commercially available yeast reference strain, NCYC 81. The PCR method is to be considered by CEN and ISO as official control method for identification of authorised probiotic Saccharomyces cerevisiae strains from feeding stuffs.

Animal Feed↗

The anal position index: a simple method to define the normal position of the anus in neonate.

AIM: The purpose of this study was to determine the normal position of anus using anal position index (API) and the modified measurement method and to emphasize the importance of ectopic anus. This cross-sectional study was performed on 400 neonates equally, boys and girls who were all delivered at full term without any malformations. Anal position index, which is the ratio of anus-fourchette distance in girls and anus-scrotum distance in boys to the distance between coccyx and fourchette/scrotum, was calculated in all cases. To make correct measurements, transparent adhesive tape was used longitudinally on midperinum in a way that it covered the anus. Then fourchette/scrotum, anus center and the lower margin of coccyx were marked on it. Distances marked on each tape were then measured with the standard ruler. Mean+/-SD of API in girls was 0.45+/-0.08 (95% CI: 0.44-0.46) and in boys 0.54+/-0.07 (95% CI: 0.53-0.55). Mean+/-2 SD was considered as the normal range for an anus position. Six female and five male neonates who had abnormal APIs were investigated further. CONCLUSIONS: Our findings suggested a simple method for determination of normal position of anus in children, especially those who are referred for chronic constipation. API can never be considered as the sole indication for the surgical intervention.

Anal Canal↗

Powder-in-bottle formulation of SU011248. Enabling rapid progression into human clinical trials.

SU011248 is an oral, multitargeted receptor tyrosine kinase inhibitor (anti PDGFR, VEGFR, Kit, and Flt3) for the treatment of solid tumors. The powder-in-bottle (PIB) approach was used to accelerate development and introduction into Phase I clinical trials. This approach consists of extemporaneously compounding the active pharmaceutical ingredient (API) into a solution or a suspension in the clinic prior to oral administration. The development consisted of physico-chemical assessment, constitution fluid selection, weighing and dosing validation, and stability evaluation of API, before and after constitution with the fluid. Of the oral liquids evaluated, apple juice was selected as the constitution fluid. Particle size of SU011248 had an impact on the weighing validation and the dissolution time. Particle size specifications of breadth d90 < 180 microm and length d90 < 750 microm were set to achieve pharmaceutical acceptability. Dosing validation studies showed complete recovery of SU011248 from the bottle over a dose range of 10 to 2200 mg. SU011248 is stable as the solid API. Following constitution with apple juice, the product is stable through the predicted duration of compounding and dosing at the clinical site. This approach provided a high degree of dosing flexibility during the initial phase of clinical trials. Additionally, the PIB approach reduced the time and API required for clinical development and supplies to < 2 months and < 100 gm, respectively.

Antineoplastic Agents↗

Apg5p functions in the sequestration step in the cytoplasm-to-vacuole targeting and macroautophagy pathways.

The cytoplasm-to-vacuole targeting (Cvt) pathway and macroautophagy are dynamic events involving the rearrangement of membrane to form a sequestering vesicle in the cytosol, which subsequently delivers its cargo to the vacuole. This process requires the concerted action of various proteins, including Apg5p. Recently, it was shown that another protein required for the import of aminopeptidase I (API) and autophagy, Apg12p, is covalently attached to Apg5p through the action of an E1-like enzyme, Apg7p. We have undertaken an analysis of Apg5p function to gain a better understanding of the role of this novel nonubiquitin conjugation reaction in these import pathways. We have generated the first temperature-sensitive mutant in the Cvt pathway, designated apg5(ts). Biochemical analysis of API import in the apg5(ts) strain confirmed that Apg5p is directly required for the import of API via the Cvt pathway. By analyzing the stage of API import that is blocked in the apg5(ts) mutant, we have determined that Apg5p is involved in the sequestration step and is required for vesicle formation and/or completion.

Aminopeptidases↗

Comparison of automated and rapid manual methods for the same-day identification of Enterobacteriaceae.

The Vitek AMS automated instrument method for identification of Enterobacteriaceae was compared with two rapid manual methods intended for the same purpose, the Micro ID System and the API 20E Same-Day procedure, on a series of 400 consecutive fresh clinical isolates. Results were compared with identifications obtained using the API 20E System with overnight incubation and supplemental tube biochemicals (when needed). Both the final (8-hour) and a manually requested, presumptive 5-hour result from the AMS were compared with the 4-hour results provided by the Micro ID and the 5-hour results provided by the API. The Micro ID system proved to be the most rapid and accurate of the three test systems by correctly identifying 96.8% (387/400) of isolates. The API 20E using 5-hour readings identified 90.7% (363/400) of isolates, although 96.8% (387/400) could be identified if supplemental overnight tests were employed to separate profile codes with "good likelihood, but low selectivity." The AMS correctly identified 88.8% (355/400) isolates after 5 hours, and 95.0% (380/400) following 8 hours incubation.

Automation↗

Comparison between two thymol formulations in the control of Varroa destructor: effectiveness, persistence, and residues.

An apiary trial on the use of two acaricide formulations (gel-Apiguard and vermiculite and Api Life VAR) in the control of Varroa destructor (Anderson & Trueman) was conducted in summer 2001 in Sardinia (Italy). The main goals were 1) to determine their effectiveness against V. destructor, taking into account natural mite mortality in control hives; and simultaneously 2) to determine the persistence of both formulations and residues in honey and wax, by using a new extraction method. Both thymol formulations, after the treatments, reduced significantly the levels of mite infestations of adult bees and sealed brood, but their efficacy, expressed as percentage of mortality, was lower for both products (Api Life VAR 74.8 +/- 13.1 and 81.3 +/- 15.5, Apiguard 90.4 +/- 8.3 and 95.5 +/- 8.7 for sealed brood and adult bees, respectively) than the efficacy previously obtained with the same products in other experimental conditions. Moreover, a considerable colony-to-colony variability was recorded, and a significant negative effect of the thymol treatments on colony development was observed. During 2 wk of treatment, the bees removed nearly 95% of all the applied product (gel or vermiculite). Residues found in honey collected from the nest varied from 0.12 to 4.03 mg/kg for Api Life VAR and from 0.40 to 8.80 mg/kg for Apiguard. The residues were relatively higher in wax (Api Life VAR = 21.6 +/- 13.0; Apiguard = 147.7 +/- 188.9) than in honey, because thymol is a fat-soluble ingredient.

Animals↗

The coevolution of insect muscle TpnT and TpnI gene isoforms.

In bilaterians, the main regulator of muscle contraction is the troponin (Tpn) complex, comprising three closely interacting subunits (C, T, and I). To understand how evolutionary forces drive molecular change in protein complexes, we have compared the gene structures and expression patterns of Tpn genes in insects. In this class, while TpnC is encoded by multiple genes, TpnT and TpnI are encoded by single genes. Their isoform expression pattern is highly conserved within the Drosophilidae, and single orthologous genes were identified in the sequenced genomes of Drosophila pseudoobscura, Anopheles gambiae, and Apis mellifera. Apis expression patterns also support the equivalence of their exon organization throughout holometabolous insects. All TpnT genes include a previously unidentified indirect flight muscle (IFM)-specific exon (10A) that has evolved an expression pattern similar to that of exon 9 in TpnI. Thus, expression patterns, sequence evolution trends, and structural data indicate that Tpn genes and their isoforms have coevolved, building species- and muscle-specific troponin complexes. Furthermore, a clear case can be made for independent evolution of the IFM-specific isoforms containing alanine/proline-rich sequences. Dipteran genomes contain one tropomyosin gene that encodes one or two high-molecular weight isoforms (TmH) incorporating APPAEGA-rich sequences, specifically expressed in IFM. Corresponding exons do not exist in the Apis tropomyosin gene, but equivalent sequences occur in a high-molecular weight Apis IFM-specific TpnI isoform (TnH). Overall, our approach to comparatively analyze supramolecular complexes reveals coevolutionary trends not only in gene families but in isoforms generated by alternative splicing.

Amino Acid Sequence↗

Multiple antiphospholipid tests do not increase the diagnostic yield in antiphospholipid syndrome.

The family of antiphospholipid antibodies (aPL) includes a heterogeneous population of autoantibodies whose specificity is directed against not only phospholipids, but their complex with plasma proteins. Anticardiolipin antibodies (aCL) and lupus anticoagulant (LA) tests are widely performed to screen the aPL family which is associated with thrombotic complications in patients with systemic lupus erythematosus (SLE) or antiphospholipid syndrome (APS). The clinical significance of other aPL tests, including antibodies against phosphatidylserine (aPS), phosphatidylinositol (aPI), phosphatidic acid (aPA), phosphatidylcholine (aPC) and phosphatidylethanolamine (aPE), has not been established. The purpose of this study was to evaluate whether multiple aPL tests have enhanced diagnostic value for APS. We tested IgG/M/A aPS, aPI, aPA, aPC and aPE by ELISA using 10% bovine serum as blocking and sample diluent in 26 SLE patients with clinical manifestations of APS, but negative for both aCL and LA (Group 1). The results were compared with 32 SLE patients without any features of APS (Group 2) and 24 SLE patients with APS (aCL and/or LA positive) (Group 3). In Group 1, 1/26 (4%) was positive for IgA aPE, less frequent than in other groups, and none of the patients had any other aPL. In Group 2, 1/32 (3%) was positive for aPS, two (6%) for aPI, one (3%) for aPA and four (12.5%) for aPE. None was positive for aPC. In the third group, 13/24 (54%) were positive for aPS, 11 (46%) for aPI, 15 (63%) for aPA, four (17%) for aPC and seven (29%) for aPE. Since aPE was found in some patients, we extended the study, including 207 SLE patients, and tested aPE. IgG/M/A aPE was found in six (3%), 10(5%) and 21 (10%), respectively, but no association was found between aPE and any clinical features of APS. This study suggests that screening by multiple aPL tests does not increase the diagnostic yield in APS.

Adolescent↗

Examining the production costs of antiretroviral drugs.

OBJECTIVES: To present direct manufacturing costs and price calculations of individual antiretroviral drugs, enabling those responsible for their procurement to have a better understanding of the cost structure of their production, and to indicate the prices at which these antiretroviral drugs could be offered in developing country markets. METHODS: Direct manufacturing costs and factory prices for selected first and second-line antiretroviral drugs were calculated based on cost structure data from a state-owned company in Brazil. Prices for the active pharmaceutical ingredients (API) were taken from a recent survey by the World Health Organization (WHO). The calculated prices for antiretroviral drugs are compared with quoted prices offered by privately-owned, for-profit manufacturers. RESULTS: The API represents the largest component of direct manufacturing costs (55-99%), while other inputs, such as salaries, equipment costs, and scale of production, have a minimal impact. The calculated prices for most of the antiretroviral drugs studied fall within the lower quartile of the range of quoted prices in developing country markets. The exceptions are those drugs, primarily for second-line therapy, for which the API is either under patent, in short supply, or in limited use in developing countries (e.g. abacavir, lopinavir/ritonavir, nelfinavir, saquinavir). CONCLUSION: The availability of data on the cost of antiretroviral drug production and calculation of factory prices under a sustainable business model provide benchmarks that bulk purchasers of antiretroviral drugs could use to negotiate lower prices. While truly significant price decreases for antiretroviral drugs will depend largely on the future evolution of API prices, the present study demonstrates that for several antiretroviral drugs price reduction is currently possible. Whether or not these reductions materialize will depend on the magnitude of indirect cost and profit added by each supplier over the direct production costs. The ability to achieve price reductions in line with production costs will have critical implications for sustainable treatment for HIV/AIDS in the developing world.

Anti-Retroviral Agents↗