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PubMed2006

Alkali-metal-mediated zincation of anisole: synthesis and structures of three instructive ortho-zincated complexes.

The new concept of alkali-metal-mediated zincation (AMMZ), formally a zinc-hydrogen exchange reaction but one that requires the participation of an alkali metal, is applied here to the alkyl aryl ether anisole, an important molecule for studying directed ortho-metalation (DoM) chemistry. Treating one molar equivalent of anisole with the lithium dialkyl-TMP zincate reagent [THF.Li(mu-TMP)(mu-tBu)Zn(tBu)] (1) in hexane solution affords the mono-ortho-zincated complex [THF.Li(mu-TMP)(mu-o-C6H4OMe)Zn(tBu)] (2), which establishes that 1 functions as an alkyl base although previously it was regarded as an amido (TMP) base in other DoM applications. Treating two molar equivalents of anisole with 1, and increasing the reaction time, affords the bis-ortho-zincated complex [THF.Li(mu-TMP)(mu-o-C6H4OMe)Zn(o-C6H4OMe)] (3), which establishes that 1 can also function as a dual alkyl base. Omitting THF and rerunning the reaction with one or two molar equivalents of anisole affords [Ph(Me)O.Li(mu-TMP)(mu-o-C6H4OMe)Zn(tBu)] (4), which remarkably contains a combination of neutral and ortho-deprotonated anisole ligands. On isolating crystalline 4 from solution and adding THF, it converts to 2 and then to 3 on further stirring of the solution, as determined by NMR studies. This fact, along with other observations, would suggest that a complex-induced proximity effect does not need to be invoked to explain the observed zincation of anisole. The crystal structures of 2-4 are presented, as are their 1H, 13C, and 7Li NMR spectra recorded in C6D6 solution.

Journal Article↗
PubMed2006

Superoxo, peroxo, and hydroperoxo complexes formed from reactions of rhodium porphyrins with dioxygen: thermodynamics and kinetics.

Rhodium(II) porphyrin complexes react with dioxygen to form terminal superoxo and bridged mu-peroxo complexes. Equilibrium constants for dioxygen complex formation with rhodium(II) tetramesitylporphyrin ((TMP)Rh*) and a m-xylyl-tethered dirhodium(II) diporphyrin complex (*Rh(m-xylyl)Rh*) are reported. (TMP)Rh-H reacts with oxygen to form a transient hydroperoxy complex ((TMP)Rh-OOH), which reacts on to form the rhodium(II) complex ((TMP)Rh*) and water. Kinetic studies for reactions of (TMP)Rh-H with O2 suggest a near concerted addition of dioxygen to the (TMP)Rh-H unit. Reactivity studies for mixtures of H2/O2 and CH4/O2 with the dirhodium(II) complex (*Rh(m-xylyl)Rh*) are reported.

Journal Article↗
PubMed2004

Enzymatic and fungal treatments on sugarcane bagasse for the production of mechanical pulps.

Crude ligninolytic enzyme extracts from Phanerochaete chrysosporium fungi were applied to sugarcane bagasse, prior to thermomechanical (TMP) and chemithermomechanical pulping (CTMP), and their properties were compared with the normal TMP and CTMP and also with TMP and CTMP pretreated with Ceriporiopsis subvermispora and P. chrysosporium fungi. The sugarcane bagasse was impregnated with the crude enzyme extract containing lignin peroxidase (LiP), manganese peroxidase (MnP), and laccase (Lac). The results show that pretreatment with enzyme crude extract is an advantageous way to produce TMP and CTMP from sugarcane bagasse, as compared with only fungal pretreatment. Enzymatic pretreatments need only hours to enhance pulping and paper properties, compared with the weeks necessary for fungal treatments. Higher pulp yields were obtained compared with the fungal pretreatments. Enzymatic pretreatment reduced the energy consumption in a proportion similar to that of C. subvermispora fungal pretreatment and increased the pulp tensile index compared with the normal TMP and CTMP pulps, although the tensile strength was somewhat lower than that for pulps from C. subvermispora fungal pretreatment before CTMP processing. An advantage of enzymatic pretreatment is that brightness is increased compared with normal TMP and CTMP processes, whereas fungal pretreatments reduce the brightness.

Biomechanical Phenomena↗
PubMed1996

Synthesis and pharmacology of potential cocaine antagonists. 2. Structure-activity relationship studies of aromatic ring-substituted methylphenidate analogs.

As part of a program to develop medications which can block the binding of cocaine to the dopamine transporter, yet spare dopamine uptake, a series of aromatic ring-substituted methylphenidate derivatives was synthesized and tested for inhibitory potency in [3H]WIN 35,428 binding and [3H]dopamine uptake assays using rat striatal tissue. Synthesis was accomplished by alkylation of 2-bromopyridine with anions derived from various substituted phenylacetonitriles. In most cases, erythro compounds were markedly less potent than the corresponding (+/-)-threo-methylphenidate (TMP; Ritalin) derivatives. The ortho-substituted compounds were much less potent than the corresponding meta- and/or para-substituted derivatives. The most potent compound against [3H]WIN 35,428 binding, m-bromo-TMP, was 20-fold more potent than the parent compound, whereas the most potent compound against [3H]dopamine uptake, m,p-dichloro-TMP, was 32-fold more potent. Threo derivatives with m- or p-halo substituents were more potent than TMP, while electron-donating substituents caused little change or small loss of potency. All of the derivatives had Hill coefficients approaching unity, except m,p-dichloro-TMP, which had an nH of 2.0. Although the potency of the (+/-)-methylphenidate derivatives in the two assays was highly correlated (R2 = 0.986), the compounds m-chloro-,m-methyl-, and p-iodo-TMP were 4-5-fold more potent at inhibiting [3H]-WIN 35,428 binding than [3H]dopamine uptake (cocaine has a ratio of 2.3). These and other compounds may be promising candidates for further testing as potential partial agonists or antagonists of cocaine.

Animals↗
PubMed1996

Radical-initiated lipid peroxidation in low density lipoproteins: insights obtained from kinetic modeling.

We present kinetic models of various complexity for radical-initiated lipid peroxidation in low density lipoproteins (LDL). The models, comprised of simultaneous differential equations programmed in Mathematica, were used to evaluate the concentration profiles of the reactants of interest. Single-phase reaction schemes describing lipid peroxidation and antioxidation according to the "conventional" and tocopherol-mediated peroxidation (TMP) model were simulated for conditions of low and high radical fluxes produced by thermolabile azo initiators. The results show that the particular dependencies of the rates of lipid peroxidation (Rp) on the rates of initiation (Ri) for the two reaction schemes were accurately predicted by the simulations. Both models qualitatively predicted inhibition of lipid peroxidation in the presence of alpha-tocopherol (alpha-TOH) under high radical flux conditions, suggesting that both can describe inhibited lipid peroxidation in solution under these conditions. TMP, but not the conventional model, could also predict the experimentally observed complex behavior of LDL lipid peroxidation induced with different concentrations of azo initiators. Specifically, TMP faithfully reproduced the observed kinetic chain length of lipid peroxidation of > > 1 at low and < < 1 at high concentration of the initiator (i.e., 0.2 and 10 mM, respectively for LDL at 1 mumol apoB-100/L) during the alpha-TOH-containing period of oxidation. It also demonstrated the experimentally observed nondependence of RpTMP on Ri. Kinetic analysis of radical generation and initiation of lipid peroxidation in an extended, two-compartment model of TMP showed that phase separation of bimolecular reactions in a suspension of LDL particles can lead to a approximately 400-fold increase in the rate of lipid hydroperoxide formation. The experimentally observed co-antioxidant action of water-soluble ascorbate and lipid-soluble ubiquinol-10 were verified using this model. A simple biophysical model constituting the reactions of TMP and incorporating the compartmental nature of an LDL suspension is proposed. Together, the results demonstrate that TMP is the only model that fits the experimental data describing the early stages of LDL lipid peroxidation under various oxidizing conditions. The implications of our findings are discussed in relation to atherogenesis and a recently proposed alternative model of LDL lipid peroxidation (Abuja and Esterbauer (1995) Chem. Res. Toxicol. 8, 753).

Antioxidants↗
PubMed1998

A Brassica cDNA clone encoding a bifunctional hydroxymethylpyrimidine kinase/thiamin-phosphate pyrophosphorylase involved in thiamin biosynthesis.

We report the characterization of a Brassica napus cDNA clone (pBTHI) encoding a protein (BTHI) with two enzymatic activities in the thiamin biosynthetic pathway, thiamin-phosphate pyrophosphorylase (TMP-PPase) and 2-methyl-4-amino-5-hydroxymethylpyrimidine-monophosphate kinase (HMP-P kinase). The cDNA clone was isolated by a novel functional complementation strategy employing an Escherichia coli mutant deficient in the TMP-PPase activity. A biochemical assay showed the clone to confer recovery of TMP-PPase activity in the E. coli mutant strain. The cDNA clone is 1746 bp long and contains an open reading frame encoding a peptide of 524 amino acids. The C-terminal part of BTH1 showed 53% and 59% sequence similarity to the N-terminal TMP-PPase region of the bifunctional yeast proteins Saccharomyces THI6 and Schizosaccharomyces pombe THI4, respectively. The N-terminal part of BTH1 showed 58% sequence similarity to HMP-P kinase of Salmonella typhimurium. The cDNA clone functionally complemented the S. typhimurium and E. coli thiD mutants deficient in the HMP-P kinase activity. These results show that the clone encodes a bifunctional protein with TMP-PPase at the C-terminus and HMP-P kinase at the N-terminus. This is in contrast to the yeast bifunctional proteins that encode TMP-PPase at the N-terminus and 4-methyl-5-(2-hydroxyethyl)thiazole kinase at the C-terminus. Expression of the BTH1 gene is negatively regulated by thiamin, as in the cases for the thiamin biosynthetic genes of microorganisms. This is the first report of a plant thiamin biosynthetic gene on which a specific biochemical activity is assigned. The Brassica BTH1 gene may correspond to the Arabidopsis TH-1 gene.

Alkyl and Aryl Transferases↗
PubMed2002

[Urinary tract infections and antibiotic resistance].

Urinary tract infections (UTI) are diseases which differ considerably regarding pathogenesis, natural history and management. Complicated UTI as well as uncomplicated acute pyelonephritis in women are managed with pretherapy urine and, possibly, blood culture. This is not the case, however, with the most frequent UTI, acute uncomplicated cystitis in women. Empirical management strategies, without pretherapy culture, are well established and widely used. The treatment of choice is trimethoprim-sulfamethoxazole (TMP-SMZ) and fluoroquinolones. E. coli cause the vast majority of these infections, and resistance to TMP-SMZ has been observed to increase considerably during the last decade. Data from Europe and Switzerland regarding resistance of etiologic agents causing acute uncomplicated cystitis are very limited. Indeed, these empirical management strategies have resulted in poor microbiological information, since only selected groups of women with UTI undergo urine culture. Data derived from laboratory isolates usually lack the necessary clinical and epidemiological correlations. Preliminary data allow some estimates of the clinical and microbiological success rates when treating TMP-SMZ resistant uropathogens with TMP-SMZ. TMP-SMZ should probably no longer be used if the prevalence of TMP-SMZ resistance among uropathogens causing acute uncomplicated cystitis is 20% or higher. In these cases, a fluoroquinolone during three days, amoxicillin-clavulanate during three to five days or nitrofurantoin during seven days should be given empirically. Non-antibiotic means of preventing UTI, such as increasing colonization resistance with lactobacilli, or the use of vaccines which provide inhibition of adherence of uropathogens to uroepithelial cells, show very promising experimental results. In order to survey and correct the value of our empirical strategies, more appropriate data on antimicrobial resistance and risk factors in the community are needed. This data can only be produced by a strong collaboration effort with networks of general practitioners.

Anti-Infective Agents, Urinary↗
PubMed2000

The effect of PUVA on langerhans cells in rat oral epithelium photosensitized with systemic methoxsalen or topical trioxsalen.

BACKGROUND/PURPOSE: Ultraviolet-A radiation (UVA) of the oral mucosa after photosensitization with either systemic methoxsalen (8-MOP) or topical trioxsalen (TMP), i.e. mouth-PUVA, has been reported to be successful in the treatment of oral lichenoid lesions. In the case of PUVA treatment of skin disorders, local immune suppressive effects have been demonstrated, and the antigen presenting epithelial Langerhans cells (LCs) have been shown to be especially sensitive to ultraviolet treatments. Our aim was to compare the photobiological effects of PUVA in oral mucous membrane (OMM) using topical TMP or systemic 8-MOP photosensitization. METHODS: Rat OMM photosensitized with topical TMP or systemic 8-MOP was treated with PUVA using UVA doses of 1-8 J/cm2. The LCs were demonstrated in epithelial sheets of the treated OMM with ATPase staining. RESULTS: Both treatments caused a sim ilar, dose-dependent depletion of ATPase-positive LCs, with a maximal depletion of 80% or 73% with 8 J/cm2 at 2 days after irradiation as photosensitized with TMP or 8-MOP, respectively. This contrasts with earlier published findings in human skin, where topical TMP is an order of magnitude greater a sensitizer than 8-MOP, and PUVA-induced depletion of LCs occurs maximally 5 days after irradiation. CONCLUSION: The depletion of LCs of rat OMM after PUVA treatment is greater using topical TMP compared to systemic 8-MOP, but the difference is significantly smaller than reported earlier in human skin.

Administration, Oral↗
PubMed1996

Studies on the mechanism of trimethoprim-induced hyperkalemia.

We examined the effects of trimethoprim (TMP) on metabolic parameters and renal ATPases in rats after a 90 minute infusion (9.6 mg/hr/kg body wt, i.v.) and after 14 days (20 mg/kg body wt/day, i.p.). After one dose of TMP, plasma electrolytes, arterial pH and aldosterone levels were normal, but a natriuresis, bicarbonaturia, and decreased urinary potassium excretion occurred. Na-K-ATPase activity in microdissected segments from these animals was decreased by 36 +/- 0.9% in proximal convoluted tubule (PCT) (P < 0.005); decreases of 50 +/- 2.1% and 40 +/- 1.1% were seen in cortical and medullary collecting tubules (CCT and MCT), respectively (P < 0.005). Na-K-ATPase activity was unaffected in medullary thick ascending limb (MTAL). H-ATPase (in PCT and collecting duct) and H-K-ATPase (in CCT and MCT)-activities were not changed. Following chronic TMP administration, plasma potassium increased as compared to control (5.16 +/- 0.05 mEq/liter vs. 3.97 +/- 0.05 mEq/liter, P < 0.05), however, acid-base status and plasma aldosterone levels were normal. Na-K-ATPase activity was decreased by 45 +/- 2.6% in PCT (P < 0.005), 73 +/- 2.0% in CCT (P < 0.001), and 53 +/- 2.5% in MCT (P < 0.005). Na-K-ATPase, activity in MTAL and H-K-ATPase activity in CCT and MCT were unchanged. H-ATPase activity in PCT and MTAL was normal, but in the collecting tubule (CCT and MCT) it was decreased by approximately 25% (P < 0.05). TMP inhibited Na-K-ATPase activity in a dose-dependent fashion in PCT, CCT, and MCT when tubules from normal animals were incubated in vitro with the drug; TMP in vitro did not affect H-ATPase or H-K-ATPase activity. These results suggest that TMP-induced hyperkalemia may result from decreased urinary potassium excretion caused by inhibition of distal Na-K-ATPase, in the face of intact H-K-ATPase activity.

Adenosine Triphosphatases↗
PubMed1994

Kinetic studies with N2-phenylguanines and with L-thymidine indicate that herpes simplex virus type-1 thymidine kinase and thymidylate kinase share a common active site.

It is known that the Herpes simplex virus type 1 (HSV-1)-encoded thymidine kinase (TK) co-purifies with an associated thymidylate kinase (TMPK) activity and that thymidylate (TMP) inhibits the phosphorylation of thymidine by the HSV-1 TK. Here we demonstrate that: (i) TMP phosphorylation catalysed by the viral TMPK is competitively inhibited by thymidine (TdR) with a Ki equal to its Km as substrate for the viral TK; (ii) L-thymidine (L-TdR), the enantiomer of the naturally occurring D-TdR and a substrate for the HSV-1 TK [Spadari, Maga, Focher, Ciarrocchi, Manservigi, Arcamone, Capobianco, Caruso, Colonna, Iotti and Garbesi (1992) J. Med. Chem. 35, 4214-4220], is a powerful inhibitor of the HSV-1 TMPK activity with a Ki value identical with its Km as a substrate for the viral TK; (iii) both viral TK and TMPK activities are inhibited, in a competitive way and with identical Ki values, by novel, non-substrate inhibitors of HSV-1 TK, N2-phenylguanines; (iv) L-TdR is phosphorylated to L-TMP by the viral TK, but L-TMP is not phosphorylated to L-TDP by the viral TMPK activity; and (v) L-TMP inhibits competitively and with identical potencies the phosphorylation of TdR and TMP catalysed respectively by the HSV-1 TK and TMPK activities. In conclusion, our data demonstrate that both TK and TMPK activities encoded by HSV-1 share a common active site which is very tolerant in accepting modified nucleosides, but cannot readily accommodate modified nucleoside monophosphates.

Binding Sites↗
PubMed2002

Efficacy of trimethoprim-sulfadoxine against Escherichia coli in a tissue cage model in calves.

Tissue cages implanted subcutaneously in calves were infected with Escherichia coli. Twenty-four hours later, the calves were treated either with single doses of 2.5 + 12.5 or 5 + 25 mg/kg trimethoprim (TMP) + sulfadoxine (SDX) or with five doses of 7.5 + 37.5 mg/kg TMP + SDX at 12-h intervals. In addition, one cage in each of three calves in the highest dose group was infected 3 h after initiation of treatment. Untreated calves were kept as controls. Concentrations of TMP and SDX in plasma and tissue cage fluid (TCF) and counts of viable bacteria in TCF were determined. In the highest dose group, concentrations of TMP in TCF remained above the minimum inhibitory concentration of the test strain for 94-101 h and peak to minimum inhibitory concentration (MIC) ratio was close to 10. In spite of this, an effect of treatment was noted only in cages infected after initiation of treatment. In vitro studies and analysis of thymidine content in serum and TCF from calves suggest that levels of thymidine in TCF are high enough to antagonize the antibacterial effect of TMP. The results indicate that soft tissue infections in secluded infection sites of calves are refractory to treatment with TMP + SDX.

Animals↗
PubMed1994

Alpha 1-acid glycoprotein-binding as a factor in age-related changes in the pharmacokinetics of trimethoprim in piglets.

This study examined the effects of plasma alpha 1-acid glycoprotein (AGP) on the protein binding and pharmacokinetics of trimethoprim (TMP) in piglets. The piglets were given 5 mg/kg of TMP intravenously at 1, 14 and 28 days after birth. The plasma AGP level was highest at day 1. Fourteen days after birth, the level decreased by about 90% of that at day 1. The level at 28 days was almost the same as that at 14 days. Plasma protein bindings of TMP depended on the AGP level but not on the albumin level. The percentage of plasma protein binding decreased from 85 to 45%, and the AGP level also decreased from 6,000 to 700 micrograms/ml. The altered protein binding of TMP affected pharmacokinetic parameters such as total body clearance (CLtot), distribution volume and therefore the elimination rate constant. These parameters correlated well with the percentage binding to plasma proteins. Maturational development in the capacity to eliminate TMP was also indicated by the increase in total body clearance of unbound drug (CLtotub), which directly reflects the elimination capacity of the body. However, its contribution to the increase in CLtot was considered not to be large. CLtotub increased twofold 14 days after birth, whereas CLtot increased about ninefold. The increase in CLtot therefore, may result from both the maturational development in elimination capacity and the AGP-dependent decrease in plasma protein binding. It is concluded that the decrease in plasma AGP level observed in piglets is one of major factors affecting the pharmacokinetics of TMP.

Aging↗
PubMed2000

Efficacy of temporal musculopericranial flap for reconstruction of the anterior base of the skull.

Since March 1988 the temporal musculopericranial (TMP) flap has been used as our flap of choice to reconstruct defects of the anterior base of the skull that are larger than 2 x 3 cm, including the dura mater, in 33 patients. The primary diseases were malignant head and neck tumours (n = 16), trauma (n = 15), meningioma (n = 1), and teratoma (n = 1). The dura mater was reconstructed with a unilateral TMP flap, after which the cranial and nasal cavities were closed with the opposite TMP flap. In addition, bone was grafted by sandwiching the bone between the two flaps and fixing it to the surrounding residual bone. When a large area was resected, making it impossible to use a TMP flap, a frontal musculopericranial (FMP) flap or a free flap (usually the rectus abdominis myocutaneous flap) was used to close the cranial and nasal cavities. Thirty of the 33 patients recovered with no postoperative complications. Two patients developed extradural abscesses in the anterior base of the skull and one developed mild meningitis, but they were successfully treated conservatively. When bilateral TMP flaps were used for the reconstruction, no patient had aesthetic problems in the forehead region. The TMP flap is extremely effective for the reconstruction of the anterior base of the skull because it is minimally invasive and causes few aesthetic problems in the forehead region.

Adolescent↗
PubMed2001

Empirical therapy for uncomplicated urinary tract infections in an era of increasing antimicrobial resistance: a decision and cost analysis.

Infectious Diseases Society of America guidelines state that uncomplicated urinary tract infections (UTIs) should be treated empirically with trimethoprim-sulfamethoxazole (TMP-SMZ), unless the community resistance among uropathogens exceeds 10%-20%, in which case a fluoroquinolone (FQ) should be used. However, the data to support this threshold are limited. We performed a cost-minimization and sensitivity analysis to determine what level of TMP-SMZ resistance in a community should trigger FQ use. The mean cost of empirical treatment with TMP-SMZ was US$92 when the proportion of resistant Escherichia coli was 0%, $106 when it was 20%, and $120 when it was 40%. The mean cost of empirical FQ treatment was $107 at current levels of FQ resistance. When >22% of E. coli in a community are TMP-SMZ-resistant, empirical FQ therapy becomes less costly than TMP-SMZ therapy. Treatment guidelines for empirical treatment of UTIs may need modification, and the threshold trigger for empirical FQ use should be raised to >20% TMP-SMZ resistance.

Anti-Infective Agents↗
PubMed2005

Clonal groups and the spread of resistance to trimethoprim-sulfamethoxazole in uropathogenic Escherichia coli.

BACKGROUND: Antibiotic resistance is increasingly complicating the management of urinary tract infection. We investigated the extent to which a group of Escherichia coli called clonal group A (CGA), which is associated with resistance to trimethoprim-sulfamethoxazole (TMP-SMZ), accounted for TMP-SMZ resistance among a prospectively collected set of uropathogenic and rectal E. coli isolates from a university population in Michigan. METHODS: Resistant and susceptible uropathogenic E. coli isolates (45 each) and 79 randomly selected rectal E. coli isolates were evaluated for CGA status by use of 2 definitions of this group-- the enterobacterial repetitive intergenic consensus sequence 2 (ERIC2)-polymerase chain reaction (PCR) pattern A fingerprint and the C288T single nucleotide polymorphism (SNP) in the fumC gene. We compared virulence gene profiles and molecular mechanisms of resistance to TMP-SMZ between isolates classified as CGA by both approaches to better characterize the relationship between isolates. RESULTS: Of the 45 isolates that exhibited ERIC2-PCR pattern A, one-half (23 of 45) were resistant to TMP-SMZ, and 16 contained the C288T SNP. The pattern A isolates were diverse, exhibiting multiple mechanisms of resistance to TMP-SMZ and various combinations of virulence factors. C288T SNP isolates showed less variation, with 15 of 16 resistant to TMP-SMZ and a 1.8-kb class I integron bearing the dfrA17 gene present in 14 of 15 resistant isolates. Twelve of 16 exhibited the same combination of virulence genes. Pulsed-field gel electrophoresis patterns for these 12 isolates were unique. CONCLUSION: CGA, as defined by the fumC C288T SNP, appears to be distantly clonal but is not an outbreak-related group. The widespread group has likely evolved through lateral transfer of genes conferring virulence and antibiotic resistance.

Adolescent↗
PubMed1994

Effect of corticosteroids on the incidence of adverse cutaneous reactions to trimethoprim-sulfamethoxazole during treatment of AIDS-associated Pneumocystis carinii pneumonia.

We retrospectively studied all courses of treatment with trimethoprim-sulfamethoxazole (TMP-SMZ) alone and with adjuvant corticosteroids for AIDS-associated Pneumocystis carinii pneumonia. The corticosteroids were administered for 8-21 days (mean, 14 days) because of hypoxemia. We evaluated the influence of corticosteroids on the incidence of cutaneous adverse reactions to TMP-SMZ and on the course of AIDS during 3 months of follow-up. Of 38 patients treated with TMP-SMZ alone, 18 (47%) developed cutaneous side effects, whereas three (13%) of the 23 patients who received adjuvant corticosteroid therapy experienced such effects (P = .014). Of the 21 reactive patients, 14 were treated throughout the duration of hypersensitivity. Therapy was interrupted for seven patients (18%) treated with TMP-SMZ alone and for none of those who were given adjuvant corticosteroid therapy (P = .23). During follow-up, the incidence of mucocutaneous herpes simplex virus infection was higher among patients who received adjuvant corticosteroids than among those treated with TMP-SMZ alone (P = .005). Adjuvant corticosteroids thus reduce the incidence of adverse cutaneous reactions to TMP-SMZ in patients with AIDS who are treated for hypoxemic P. carinii pneumonia.

AIDS-Related Opportunistic Infections↗
PubMed1994

Trimethoprim-induced aseptic meningitis in a patient with AIDS: case report and review.

We report the case of a 41-year-old man infected with human immunodeficiency virus who had two episodes of aseptic meningitis that occurred 2 weeks apart; the first was associated with ingestion of trimethoprim-sulfamethoxazole (TMP-SMZ) and the second was associated with ingestion of TMP alone. Onset of fever, headache, and flushing was abrupt, followed by somnolence, hearing loss, and aphasia. Analysis of the CSF showed pleocytosis and an elevated protein level. The findings resolved within 48 hours after withdrawal of the drug. We also review 18 previously reported cases of TMP-SMZ- or TMP-induced meningitis, 17 of which occurred in women. In all of these cases, a similar abrupt onset and resolution were noted. Six of the 18 patients had collagen-vascular diseases. All but two of these patients had multiple recurrent episodes of meningitis before the diagnosis was made. We conclude that the diagnosis of TMP-SMZ- or TMP-induced meningitis should be considered when a patient receiving these drugs has recurrent episodes of aseptic meningitis.

Acquired Immunodeficiency Syndrome↗
PubMed1996

Clindamycin/primaquine as prophylaxis for Pneumocystis carinii pneumonia.

The records of 206 patients with advanced infection due to human immunodeficiency virus type 1 who were receiving prophylaxis with clindamycin/primaquine (C/P), trimethoprim-sulfamethoxazole (TMP-SMZ), or dapsone to prevent Pneumocystis carinii pneumonia (PCP) were retrospectively examined. Two hundred sixty-two patient-years of prophylaxis were accrued (176.2 of TMP-SMZ, 63.4 of dapsone, and 22.8 of C/P). The rates of PCP in the TMP-SMZ, dapsone, and C/P groups were 3.4, 11.0, and 30.7 per 100 patient-years, respectively. Pairwise comparisons showed C/P to be less effective than TMP-SMZ (relative risk [RR], 9.02; 95% confidence interval [CI], 3.03-26.83). A similar trend was apparent for C/P vs. dapsone (RR, 2.78; 95% CI, 0.98-7.93). When only those receiving primary prophylaxis were analyzed, C/P recipients remained at greater risk than TMP-SMZ recipients (RR, 13.19; 95% CI, 3.54-49.12) and dapsone recipients (RR, 3.85; 95% CI, 1.12-13.31). Failure of C/P prophylaxis could be due, at least in part, to underdosing (clindamycin, 300 mg/d; primaquine, 15 mg/d). C/P recipients had more nonspecific diarrhea than did TMP-SMZ recipients (RR, 2.99; 95% CI, 1.61-5.55).

Adult↗