Nirmatrelvir treatment of SARS-CoV-2-infected mice blunts antiviral adaptive immune responses.

Alongside vaccines, antiviral drugs are becoming an integral part of our response to the SARS-CoV-2 pandemic. Nirmatrelvir-an orally available inhibitor of the 3-chymotrypsin-like cysteine protease-has been shown to reduce the risk of progression to severe COVID-19. However, the impact of nirmatrelvir treatment on the development of SARS-CoV-2-specific adaptive immune responses is unknown. Here, by using mouse models of SARS-CoV-2 infection, we show that nirmatrelvir administration blunts the development of SARS-CoV-2-specific antibody and T cell responses. Accordingly, upon secondary challenge, nirmatrelvir-treated mice recruited significantly fewer memory T and B cells to the infected lungs and mediastinal lymph nodes, respectively. Together, the data highlight a potential negative impact of nirmatrelvir treatment with important implications for clinical management and might help explain the virological and/or symptomatic relapse after treatment completion reported in some individuals.

Evaluation of the absolute oral bioavailability of the anaplastic lymphoma kinase/c-ROS oncogene 1 kinase inhibitor lorlatinib in healthy participants.

PURPOSE: Lorlatinib is a third-generation tyrosine kinase inhibitor currently approved for the treatment of anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer. This open-label, phase 1, randomized two-sequence, two-treatment, two-period, crossover study investigated the absolute oral bioavailability of lorlatinib in healthy participants. METHODS: Eligible participants were randomized to receive two treatments in one of two sequences: lorlatinib 100 mg single oral dose followed by lorlatinib 50 mg intravenous (IV) dose, or lorlatinib IV dose followed by lorlatinib oral dose, each with at least a 10-day washout between successive lorlatinib doses. Blood samples for pharmacokinetics were collected for up to 144 hours (h) after dosing. Validated liquid chromatographic-tandem mass spectrometry was used to determine plasma concentrations of lorlatinib and its benzoic acid metabolite PF-06895751. RESULTS: In total, 11 participants were enrolled (mean age 37.6 years, all male). The adjusted geometric mean (90% confidence interval) for the absolute oral bioavailability was 80.78% (75.73-86.16%). Using non-compartmental analysis, the estimated arithmetic mean elimination plasma half-life of lorlatinib was 25.5 and 27.0 h after the oral and IV doses, respectively. No deaths, serious adverse events (AEs), or severe AEs were reported, and most treatment-emergent AEs were mild in severity, with two events of transaminase increase of moderate severity. All treatment-emergent AEs were resolved by the end of the study. CONCLUSION: Both oral and IV lorlatinib were well-tolerated in healthy participants and oral lorlatinib is highly bioavailable after oral administration.

Differential Inhibition of Equilibrative Nucleoside Transporter 1 (ENT1) Activity by Tyrosine Kinase Inhibitors.

BACKGROUND AND OBJECTIVES: Equilibrative nucleoside transporter (ENT) 1 is a widely-expressed drug transporter, handling nucleoside analogues as well as endogenous nucleosides. ENT1 has been postulated to be inhibited by some marketed tyrosine kinase inhibitors (TKIs). To obtain insights into this point, the interactions of 24 TKIs with ENT1 activity have been analyzed. METHODS: Inhibition of ENT1 activity was investigated in vitro through quantifying the decrease of [3H]-uridine uptake caused by TKIs in HAP1 ENT2-knockout cells, exhibiting selective ENT1 expression. TKI effects towards ENT1-mediated transport were additionally characterized in terms of their in vivo relevance and of their relationship to TKI molecular descriptors. Putative transport of the TKI lorlatinib by ENT1/ENT2 was analyzed by LC-MS/MS. RESULTS: Of 24 TKIs, 12 of them, each used at 10 µM, were found to behave as moderate or strong inhibitors of ENT1, i.e., they decreased ENT1 activity by at least 35%. This inhibition was concentration-dependent for at least the strongest ones (IC50 less than 10 µM) and was correlated with some molecular descriptors, especially with atom-type E-state indices. Lorlatinib was notably a potent in vitro inhibitor of ENT1/ENT2 (IC50 values around 1.0-2.5 µM) and was predicted to inhibit these nucleoside transporters at relevant clinical concentrations, without, however, being a substrate for them. CONCLUSION: Our data unambiguously add ENT1 to the list of drug transporters inhibited by TKIs, especially by lorlatinib. This point likely merits attention in terms of possible drug-drug interactions, notably for nucleoside analogues, whose ENT1-mediated uptake into their target cells may be hampered by co-administrated TKIs such as lorlatinib.

Real-world efficacy and safety of lorlatinib in treating advanced ALK-positive non-small cell lung cancer patients.

Anaplastic lymphoma kinase (ALK) translocation is a rare driver mutation in lung cancer. This study was aimed to report on the efficacy of lorlatinib in real-world practice and to evaluate the impact of prior ALK inhibitor treatments. We retrospectively evaluated patients with ALK-positive non-small cell lung cancer (NSCLC) treated with lorlatinib regarding its efficacy, the impact of prior ALK inhibitor treatments and the adverse events, in particular dyslipidemia. A total of 22 ALK-positive patients were analyzed. All patients had received at least one second-generation ALK inhibitor(s), while 12 patients had a history of crizotinib treatment. For lorlatinib, the objective response rate was 35.7%, and disease control rate was 64.3%. Their progression-free survival (PFS) was 6.2 months. With prior therapies, patients receiving only second-generation ALK inhibitor(s) treatment showed PFS longer than those with both crizotinib and second-generation ALK inhibitor(s) treatments (15.2 vs. 6.2 months). Moreover, patients who showed benefits from prior ALK inhibitor(s) also had a PFS longer than those who did not (6.5 vs. 3.5 months). Regarding adverse events, 94.7% of patients had dyslipidemia and 21.1% of them were in grade 3 or 4. None of these patients discontinued the treatment due to dyslipidemia. No acute complication occurred with dyslipidemia. The real-world efficacy of lorlatinib and adverse events were similar to those reported in clinical trials. Interestingly, the history and responses of prior ALK inhibitor treatments may influence the efficacy of subsequent lorlatinib treatment.

Population pharmacokinetic model with time-varying clearance for lorlatinib using pooled data from patients with non-small cell lung cancer and healthy participants.

Lorlatinib, a selective inhibitor of anaplastic lymphoma kinase (ALK) and c-ROS oncogene 1 (ROS1) tyrosine kinase, is indicated for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC) following progression on crizotinib and at least one other ALK inhibitor, or alectinib/ceritinib as the first ALK inhibitor therapy for metastatic disease. The population pharmacokinetics (PopPK) of lorlatinib was conducted by nonlinear mixed effects modeling of data from 330 patients with ALK-positive or ROS1-positive NSCLC and 95 healthy participants from six phase I studies in healthy volunteers; demographic, metabolizer phenotype, and patient prognostic factors were evaluated as covariates. Lorlatinib plasma PK was well-characterized by a two-compartment model with sequential zero-order and first-order absorption and a time-varying induction of clearance. Single dose clearance was estimated to be 9.04 L/h. Assuming that the metabolic auto-induction of lorlatinib reaches saturation in ~ 5 half-lives, clearance was estimated to approach a maximum of 14.5 L/h at steady-state after a period of ~ 7.25 days. The volume of distribution of the central compartment was estimated to be 121 L and the first-order absorption rate constant was estimated to be 3.1 h-1 . Baseline albumin and lorlatinib total daily dose were significant covariates on lorlatinib clearance. Use of proton pump inhibitors was found to be a significant covariate on the lorlatinib absorption rate constant. These factors were assessed to have no clinically meaningful impact on lorlatinib plasma exposure, and no dose adjustments are considered necessary based on the examined covariates.

Targeting eIF4F translation initiation complex with SBI-756 sensitises B lymphoma cells to venetoclax.

BACKGROUND: The BCL2 inhibitor venetoclax has shown efficacy in several hematologic malignancies, with the greatest response rates in indolent blood cancers such as chronic lymphocytic leukaemia. There is a lower response rate to venetoclax monotherapy in diffuse large B-cell lymphoma (DLBCL). METHODS: We tested inhibitors of cap-dependent mRNA translation for the ability to sensitise DLBCL and mantle cell lymphoma (MCL) cells to apoptosis by venetoclax. We compared the mTOR kinase inhibitor (TOR-KI) MLN0128 with SBI-756, a compound targeting eukaryotic translation initiation factor 4G1 (eIF4G1), a scaffolding protein in the eIF4F complex. RESULTS: Treatment of DLBCL and MCL cells with SBI-756 synergised with venetoclax to induce apoptosis in vitro, and enhanced venetoclax efficacy in vivo. SBI-756 prevented eIF4E-eIF4G1 association and cap-dependent translation without affecting mTOR substrate phosphorylation. In TOR-KI-resistant DLBCL cells lacking eIF4E binding protein-1, SBI-756 still sensitised to venetoclax. SBI-756 selectively reduced translation of mRNAs encoding ribosomal proteins and translation factors, leading to a reduction in protein synthesis rates in sensitive cells. When normal lymphocytes were treated with SBI-756, only B cells had reduced viability, and this correlated with reduced protein synthesis. CONCLUSIONS: Our data highlight a novel combination for treatment of aggressive lymphomas, and establishes its efficacy and selectivity using preclinical models.

Inflammatory Myofibroblastic Tumor of the Bladder With FN1-ALK Gene Fusion: Different Response to ALK Inhibition.

Inflammatory myofibroblastic tumors are rare tumors with an ALK (anaplastic lymphoma kinase) gene rearrangement in up to 65% of all cases. In our patient, the tumor was not primary resectable due to its extension. Under neoadjuvant treatment with the first generation ALK inhibitor crizotinib no tumor response was seen, but the following therapy with the next generation ALK inhibitor lorlatinib led to a rapid and deep response, enabling a complete tumor resection by partial cystectomy. Our case indicates that ALK positive inflammatory myofibroblastic tumors which do not respond to ALK inhibition with crizotinib can be successfully treated with newer agents.

Discovery of steroidal lactam conjugates of POPAM-NH2 with potent anticancer activity.

Aim: Steroidal prodrugs of nitrogen mustards such as estramustine and prednimustine have proven effective anticancer agents in clinical use since the 1970s. In this work, we aimed to develop steroidal prodrugs of the novel nitrogen mustard POPAM-NH2. POPAM-NH2 is a melphalan analogue that was coupled with three different steroidal lactams. Methodology: The new conjugates were preclinically tested for anticancer activity against nine human and one rodent cancer experimental models, in vitro and in vivo. Results & conclusion: All the steroidal alkylators showed high antitumor activity, in vitro and in vivo, in the experimental systems tested. Moreover, these hybrid compounds showed by far superior anticancer activity compared with the alkylating agents, melphalan and POPAM-NH2.

Isomethoxyneihumicin, a new cytotoxic agent produced by marine Nocardiopsis alba KM6-1.

A new cytotoxic agent designated isomethoxyneihumicin (1 and 2), a mixture of lactam-lactim tautomers, was isolated along with methoxyneihumicin (3) from the culture broth of the marine Nocardiopsis alba KM6-1. The structures of 1 and 2 were elucidated in spectroscopic analyses (1D and 2D NMR data, and ROESY correlations). Isomethoxyneihumicin (15.0 µM) and 3 (15.0 µM) arrested the cell cycle of Jurkat cells at the G2/M phase (66 and 67%) in 12 h. Isomethoxyneihumicin and 3 exhibited cytotoxicity against Jurkat cells with IC50 values of 6.98 and 30.5 µM in 20 h, respectively. These results strongly suggest that isomethoxyneihumicin and 3 exhibit cytotoxicity against Jurkat cells by inhibiting the cell cycle at the G2/M phase.

Pharmacokinetics of a three-way drug interaction between danoprevir, ritonavir and the organic anion transporting polypeptide (OATP) inhibitor ciclosporin.

BACKGROUND: Danoprevir (RG7227) is a potent macrocyclic inhibitor of the hepatitis C virus NS3/4A protease, which is currently in development in combination with low-dose ritonavir for the treatment of chronic hepatitis C infection. Danoprevir is a substrate of cytochrome P450 3A4, and the organic anion transporting polypeptides (OATP) 1B1 and 1B3. OBJECTIVE: The objective of this study was to evaluate the effect of a potent OATP inhibitor, ciclosporin, on danoprevir pharmacokinetics, when administered as danoprevir/ritonavir. The effect of danoprevir/ritonavir on ciclosporin pharmacokinetics was also investigated. METHODS: This was a single-dose, randomized, open-label, two-sequence, three-period, crossover study in healthy volunteers. In the first period, subjects were randomized to receive either a single oral dose of danoprevir 100 mg in combination with ritonavir 100 mg or a single oral dose of ciclosporin 100 mg. After a 14-day washout, patients were crossed over to receive the opposite treatment. In period 3, all subjects received the combination of danoprevir/ritonavir and ciclosporin following a 14-day washout from period 2. Blood samples were collected serially with each dose for pharmacokinetic assessment. Pharmacokinetic parameters were estimated using non-compartmental analysis. Geometric mean ratios (GMRs) and 90 % confidence intervals (CIs) were used to compare pharmacokinetic parameters [maximum concentration (C max), area under the concentration-time curve from time zero to infinity (AUC∞), and concentration 12 h post-dose (C 12h)] of danoprevir/ritonavir and ciclosporin when administered alone or in combination. Measures of safety and tolerability were also evaluated. RESULTS: A total of 18 subjects were enrolled, and 17 completed the study. The C max, AUC∞, and C 12h GMRs (90 % CI) when danoprevir/ritonavir and ciclosporin were co-administered versus danoprevir/ritonavir or ciclosporin alone were 7.22 (5.42-9.62), 13.6 (11.2-16.6), and 22.5 (17.4-29.3), respectively, for danoprevir, 1.97 (1.72-2.27), 2.23 (2.07-2.42), and 2.50 (2.22-2.81), respectively, for ritonavir, and 1.42 (1.29-1.57), 3.65 (3.27-4.08), and 6.15 (5.32-7.11), respectively, for ciclosporin. All treatments were well tolerated, with no laboratory abnormalities, and no clinically significant changes in vital signs, electrocardiograms, or physical examinations observed. CONCLUSIONS: A significant drug-drug interaction was observed between ciclosporin and danoprevir/ritonavir, leading to substantial increases in exposure to danoprevir and a lesser impact on exposure to ritonavir. Therefore, co-administration of danoprevir/ritonavir with potent OATP inhibitors should be undertaken with appropriate precautions.

A multicenter phase II study of the cryptophycin analog LY355703 in patients with platinum-resistant ovarian cancer.

LY355703 is a synthetic product structurally related to the cryptophycin family isolated from the blue-green algae, which exerts a potent destabilization of microtubules during mitosis. This study was performed to determine the activity of LY355703 in patients with platinum-resistant advanced ovarian cancer and to characterize its toxicity profile. Twenty-six patients were enrolled in this study. Resistant disease was defined as a platinum-free interval of <6 months from primary treatment or rechallenge. LY355703 (1.5 mg/m(2)) was administered intravenously on days 1 and 8, every 3 weeks, infused over 2 h. From 24 patients evaluable for response, three partial responses (12.5%) and seven disease stabilizations were registered (29.2%), for an overall clinical benefit of 41.7%. Fourteen patients (58.3%) experienced a progression of the disease during treatment. Among the 25 patients evaluable for toxicity, two episodes of grade 3 anemia (8%); one, grade 3 thrombocytopenia (4%); one, grade 4 elevation of creatinine (4%); and one, grade 3 hyperbilirubinemia (4%) were reported. LY355703 has a modest activity in patients with platinum-resistant advanced ovarian cancer. Nevertheless, the considerable rate of disease stabilization in the absence of serious adverse events in this poor-prognosis study population suggests that this novel cryptophycin may deserve further investigation in this setting.

Attenuation of chronic thermotolerance by KNK437, a benzylidene lactam compound, enhances thermal radiosensitization in mild temperature hyperthermia combined with low dose-rate irradiation.

PURPOSE: We investigated whether the attenuation of chronic thermotolerance by KNK437, a heat shock protein inhibitor, can modify the effect of thermal radiosensitization in mild temperature hyperthermia (MTH) combined with low dose-rate irradiation (LDRI). MATERIALS AND METHODS: The human lung adenocarcinoma cell line A549 was simultaneously exposed to LDRI with MTH at 41 degrees C and KNK437 at a dose of 100 microM. Cell survival was estimated by a clonogenic assay. Cell cycle change during treatment was analyzed by flow cytometry. Expression levels of the heat shock proteins hsp72, hsp27 and heat shock factor 1 (HSF-1) were measured by Western blotting. RESULTS: KNK437 inhibited the expression of inducible hsp72 and hsp27, but produced no change in the mobility shift of HSF-1. The cytotoxicity of LDRI was enhanced by MTH. The survival curve for LDRI + MTH revealed no development of chronic thermotolerance up to 48 h. Simultaneous LDRI and KNK437 treatment also resulted in enhanced cell killing. The radiosensitizing effect of KNK437 was enhanced by simultaneous exposure of the cells to MTH. Flow cytometry analysis of cell cycle progression demonstrated marked G2 arrest and mild G1 arrest with LDRI alone, but mild G1 arrest with MTH alone, and mild G2-M, S-phase accumulation with KNK437 alone. The marked G2 arrest caused by LDRI was partially suppressed by the addition of MTH, and was also suppressed by KNK437 treatment. CONCLUSIONS: Exposure of A549 cells to KNK437 caused inhibition of hsp72 and hsp27 expression. The addition of KNK437 increased not only thermosensitivity to MTH, but also radiosensitivity to LDRI. KNK437 also enhanced the MTH-induced radiosensitization under these experimental conditions.

Phase I and pharmacological studies of the cryptophycin analogue LY355703 administered on a single intermittent or weekly schedule.

LY355703 is a synthetic derivative of the marine cryptophycins, cytotoxic agents which induce mitotic arrest by binding at the microtubule vinca binding domain. Promising preclinical features of LY355703 were the 40-400 greater potency than paclitaxel or vinca alkaloids, the broad spectrum of antitumor activity in xenografts and the antitumour activity in multidrug resistant (MDR)-expressing murine tumours. Aims of this study were to define the maximum tolerated dose (MTD) and the dose recommended for Phase II, the pattern of toxicity, the pharmacokinetic profile and to document hints of antitumour activity of LY355703 given as 2-h infusion on day 1 every 3 weeks (Study 1) or, later on, on days 1, 8 and 15 every 4 weeks (Study 2). The latter weekly regimen was selected because of the acute dose-related toxicity reported in Study 1. The dose was escalated using a modified Continual Reassessment Method. Pharmacokinetic studies were performed on day 1 of cycle 1 in both studies; LY355703 plasma concentrations were assessed by liquid chromatography with tandem mass spectrometry. A total of 35 adult patients with solid tumours entered Study 1; the dose was escalated from 0.1 to 1.92 mg/m(2); at this dose 2 of 5 patients presented grade 3 neuropathy and myalgias; 1.48 mg/m(2) was then recommended for Phase II study. A total of 8 patients were treated in Study 2 at 1 mg/m(2); cumulative long-lasting neuroconstipation and neurosensory toxicity precluded the completion of the cycle in 9 out of 15 cycles; the clinical development of the weekly regimen was then discontinued. Other toxicities included cardiac dysrhythmia and mild alopecia. Pharmacokinetics of LY355703 appeared to be linear over the dose range studied. The administration of LY355703 on a 3-week schedule is associated with an acute dose-dependent peripheral neuropathy and myalgia of high interpatient variability for which possible risk factors and pharmacokinetic correlates could not be identified.

Phase I trial of the cryptophycin analogue LY355703 administered as an intravenous infusion on a day 1 and 8 schedule every 21 days.

The cryptophycin analogue LY355703 is a potent inhibitor of microtubule polymerization that displays in vitro and in vivo activity in cell lines and tumor xenografts displaying the multidrug-resistant phenotype. In a Phase I trial, 25 patients received LY355703 as a 2-h i.v. infusion on day 1 and day 8 repeated every 3 weeks. Doses were escalated from 0.1 to 2.22 mg/m2 using a modified continual reassessment method. Neurological toxicity was found to be dose-limiting at 1.84 and 2.22 mg/m2. Among four patients treated at these doses, two had grade 4 constipation/ileus, one with severe myalgias, and one had grade 3 motor neuropathy. These findings were reversible. The 1.5 mg/m2 dose level was well tolerated. An amended twice-weekly schedule was pursued in 11 patients in an attempt to improve dose intensity and avoid dose-limiting neurotoxicity. Doses of >0.75 mg/m2 on a day 1, 4, 8, and 11 schedule every 21 days were not tolerated as a result of nausea/constipation, suggesting that LY335703 toxicity is not schedule dependent and is related to cumulative dose. LY355703 plasma concentrations measured by liquid chromatography with tandem mass spectrometry were evaluated using a population pharmacokinetic model. LY355703 was eliminated rapidly with a short terminal half-life that ranged from 0.8 to 3.9 h. Interpatient variability with respect to plasma clearance and volume of distribution, including covariates, was moderate at 32% and 39%, respectively. Maximum plasma concentration and area under the plasma concentration-time curve were linear over the dose range studied. A patient with non-small cell lung cancer previously treated with taxanes experienced a partial response lasting 4 months, and five patients had stable disease lasting > or =3 months. LY355703 at a dose of 1.5 mg/m2 is recommended for Phase II evaluation on a days 1 and 8 schedule. Twice-weekly dosing did not allow improvement in dose intensity or tolerability.

Antitumor activity of cryptophycins: effect of infusion time and combination studies.

INTRODUCTION/PURPOSE: Cryptophycins are a family of antitubulin antitumor agents. A synthetic cryptophycin derivative (LY355703, CRYPTO 52) is in early clinical evaluation. The effect of infusion time on the antitumor activity of four cryptophycins was assessed in rats bearing the 13762 mammary carcinoma and combination treatment regimens were assessed in nude mice bearing human tumor xenografts. METHODS: The cryptophycins were prepared in 2% PEG300/8% cremophor/90% normal saline and delivered by jugular vein catheter on days 7, 9 and 11 post tumor implant to 13762 tumor-bearing rats. The cryptophycins prepared in the same formulation were administered by intravenous bolus injection on an alternate day schedule for five doses to human tumor xenograft bearing nude mice. RESULTS: An infusion time of 2 h in the rats increased the tumor growth delay produced by CRYPTO 52 and CRYPTO 55, while increasing the infusion time to 6 h continued to increase the tumor growth delay for CRYPTO 292 and CRYPTO 296. Administering CRYPTO 292 at a higher dose two times was more effective than administering it at a lower dose three times. The tumor growth delays produced by the cryptophycins in the rat 13762 mammary carcinoma were greater than those with cisplatin, doxorubicin, 5-fluorouracil and 5 x 3 Gray and comparable with cyclophosphamide and gemcitabine. Combination studies were carried out in human tumor xenografts including the MX-1 breast carcinoma, the Calu-6 non-small cell lung carcinoma, the H82 small cell lung carcinoma and the SW-2 small cell lung carcinoma. CRYPTO 52 and CRYPTO 55 combined with doxorubicin, paclitaxel and 5-fluorouracil to form highly effective regimens against the human MX-1 breast carcinoma. CRYPTO 52 and CRYPTO 55 were also highly effective against the three lung carcinoma xenografts when combined with the antitumor platinum complexes, cisplatin, carboplatin or oxaliplatin. CONCLUSIONS: Cryptophycins represent a promising new class of antitumor agents that may be optimally administered by intravenous infusion and in combination with doxorubicin, paclitaxel and 5-fluorouracil.

Cryptophycin 52 and cryptophycin 55 in sequential and simultaneous combination treatment regimens in human tumor xenografts.

The antitumor activity of cryptophycin 52 (C52) and cryptophycin 55 (C55) in sequential and simultaneous combination treatment regimens in human tumor xenografts models was explored. The antitumor activity of C52 and C55 was compared alone and in sequential combination with gemcitabine or paclitaxel in four lung cancer models, H460 and Calu-6 NSCLC and SW2 and H82 small cell lung carcinoma. The combination of C52 followed by gemcitabine was additive in three tumors and greater-than-additive in the fourth. The combination of C55 followed by gemcitabine was additive in three tumors and less-than-additive in the fourth. The combination of C52 followed by paclitaxel was greater-than-additive in one tumor, additive in one tumor and less-than-additive in two tumors. The combination of C55 followed by paclitaxel was greater-than-additive in two tumors and less-than-additive in two tumors. The simultaneous combination of C52 or C55 with fractionated radiation therapy was assessed in the H460 NSCLC tumor. Both cryptophycins produced a tumor response that was additive along with radiation therapy. The HCT116 colon carcinoma was used to compare the antitumor activity of simultaneous or sequential combination of 5-fluorouracil or irinotecan with C52. C52 produced greater-than-additive tumor response when administered either simultaneously with or sequentially with 5-fluorouracil or iriniotecan. Finally, when administered to animals bearing intraperitoneal OVCAR-3 ovarian carcinoma, C52, docetaxel and paclitaxel resulted in mean survival times of 123, 80 and 85 days compared with 72 days in the untreated controls. In combination with carboplatin, C52, docetaxel and paclitaxel resulted in mean survival times of 140, 105 and 135 days. Cryptophycins have the potential to be useful chemotherapeutic agents in a wide variety of clinical combinations regimens.

Comparaçäo entre a levofloxacina oral e a associaçäo de amoxicilina e clavulanato de potássio no tratamento da sinusite bacteriana aguda em adultos / A comparison of oral levofloxacin and amoxicillin clavulanate for the treatment of acute bacterial sinusitis in adults

Os autores apresentam um estudo multicêntrico, aberto, randomizado para comparar a eficácia e tolerabilidade da Levofloxacina oral à associação de Amoxicilina e Clavulanato de potássio no tratamento de sinusite bacteriana aguda em adultos. A Levofloxacina foi administrada na dose de 500 mg 1 vez ao dia, enquanto a associação Amoxicilina (500mg)/Clavulanato de potássio (125 mg) foi administrada 3 vezes ao dia, ambos tratamentos com duração de 14 dias. Foram avaliados os sintomas dor facial, rinorréia purulenta e obstrução nasal e também os sinais hiperemia, edema, secreção purulenta e dor a palpação dos seios paranasais. Os pacientes foram avaliados na admissão, com 3 a 6 dias de tratamento, 2 a 5 dias pós terapia e com 28 a 32 dias após o término da terapia. Foram classificados de acordo com a eficácia do tratamento em curados, melhorados, com falha terapêutica ou incapazes de serem avaliados. Foram também submetidos a questionários para verificação da aceitação da medicação. Ao fim do estudo, os autores classificaram a eficácia e a tolerabilidade como boas em ambos os grupos de medicamentos, não havendo diferença estatisticamente significante entre os mesmos. Concluindo, a Levofloxacina oral mostrou-se tão eficaz e com boa tolerabilidade quanto a associação Amoxicilina/Clavulanato de potássio para o tratamento da sinusite bacteriana aguda em adultos.