The safety of cefuroxime and gentamicin in patients with reduced renal function

Summary

The glomerular and tubular function of 7 patients with a spectrum of renal impairment was measured before, during and after 4-days' treatment with cefuroxime and gentamicin. Neither the mean plasma urea nor creatinine concentrations of the group increased after combined treatment, nor was the excretion of cefuroxime slowed. The ability to acidify and to concentrate the urine did not change. In only 1 patient did plasma creatinine increase and GFR fall. This patient had an unexpectedly high plasma gentamicin concentration and was taking frusemide. However, an eighth patient with acute renal failure caused by bacteraemic shock rapidly recovered renal function while being treated with cefuroxime and gentamicin for 15 days after large doses of frusemide intravenously. This limited study suggests that the useful combination of cefuroxime and gentamicin need not be denied to patients with reduced renal function, but emphasizes that the plasma gentamicin concentration must always be monitored.     

Once daily administration of a fluphenazine/nortriptyline preparation in the treatment of mixed anxiety/depressive states

Summary

A study of 223 patients diagnosed as suffering from mixed anxiety/depressive states was carried out in general practice to compare the effectiveness of treatment with a once-daily tablet preparation containing 1.5 mg fluphenazine plus 30 mg nortriptyline, taken either at night or in the morning, with the same total daily dose taken as 1 tablet t.d.s. Patients were randomly assigned to 4-week's treatment with one of the three drug schemes, and patients' self-ratings as well as physicians' ratings were used to assess symptoms. Both rating assessments showed that there were highly significant improvements in each of the three treatment groups over the 4-week period. Although there were no clinically important differences between improvements in the night-time dose and t.d.s. groups, there was a higher incidence of drowsiness and tablet defaulting among patients taking the single morning dose.     

A systematic review of adherence,treatment satisfaction and costs,in fixed-dose combination regimens in type 2 diabetes

Abstract

Objective:

Oral antidiabetics have comparable safety and efficacy when used as fixed-dose combination therapies (FDCT) or loose-pill combination therapies (LPCT) for patients with T2DM. To evaluate alternative outcomes to safety and efficacy with FDCT, a systematic review of literature was conducted.     

Broadening the clinical use of platinum drug–based chemotherapy with new analogues

The three platinum-containing drugs that have been thus far approved by the FDA – cisplatin, carboplatin and oxaliplatin – have had a significant effect in the treatment of patients with some malignancies such as testicular, ovarian and colorectal cancer. However, much more remains to be achieved to widen the therapeutic use of this important class of drug, either via further analogue development or by judicious use of combining the existing drugs with new molecularly targeted agents. Two analogues arising from an academic (Institute of Cancer Research)/pharmaceutical (Johnson Matthey/AnorMed) collaboration – satraplatin (JM-216) and picoplatin (JM-/AMD-473) – have recently shown promising clinical activity; satraplatin (an orally available drug) in hormone-refractory prostate cancer and picoplatin in small-cell lung cancer. There have also been advances in delivery vehicles for platinum drugs (e.g., the diaminocyclohexane [DACH]-based AP-5346 and aroplatin/liposomal cis-bis-neodecanoato-trans-(R,R)-1,2-diaminocyclohexane platinum (II) [L-NDDP] are in early clinical development). Platinum-based drugs have also been successfully combined with molecularly targeted drugs (e.g., the recent approval of the vascular endothelial growth factor monoclonal antibody bevacizumab with carboplatin and paclitaxel in patients with NSCLC).     

Interactions of herbal extract combinations against free radical scavenging activity

Herbal medicines are often combinations of herbal extracts that are assumed to have additive or synergistic effects. This investigation compared the effect of individual herbal extracts with combinations of extracts on antioxidant activity by 1,1-diphenyl picryl hydrazyl (DPPH) method and showed the additive or synergistic effects by studying interactions between herbal extracts in combination. Curcuma longa Linn. (Zingiberaceae), Bacopa monneira Linn. Penn. (Scrophulariaceae), Zingiber officinale Rosc. (Zingiberaceae) and Emblica officinalis Gaertn. (Euphorbiaceae) were collected and used to prepare the extracts. Effects of the extracts on DPPH scavenging activity were estimated quantitatively by a UV-spectrophotometeric method. Combinations of two herbal extracts of the four active extracts and their interactions were tested by the DPPH method. Each extract significantly scavenges the free radical activity in a dose-dependent manner. The active extracts of Curcuma longa, Bacopa monneira, Zingiber officinale and Emblica officinalis were tested as two-extract combinations. Curcuma longa and Bacopa monneiera, when combined, showed additive effect with a trend towards synergistic effect, whereas Curcuma longa and Emblica officinalis together were additive. The four extracts together were significantly (p?≤?0.01) more effective than the two-by-two combinations and the individual extracts alone. The less predictable nature of the two-way combinations suggests a need for careful characterization of the effects of each individual herb based on their intended use.     

Drug-Drug Interaction Studies on First-Line Anti-tuberculosis Drugs

The purpose of this study was to carry out drug-drug compatibility studies on pure first line anti-tuberculosis drugs, viz., rifampicin (R), isoniazid (H), pyrazinamide (Z), and ethambutol hydrochloride (E). Various possible binary, ternary, and quaternary combinations of the four drugs were subjected to accelerated stability test conditions of 40°C and 75% relative humidity (RH) for 3 months. For comparison, parallel studies were also conducted on single drugs. Changes were looked for in the samples drawn after 15, 30, 60, and 90 days of storage. Analyses for R, H, and Z were carried out using a validated HPLC method. The E was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), as it does not absorb in ultraviolet (UV). All single pure drugs were relatively stable and showed only 3%–5% degradation under accelerated conditions for 3 months. However, significant interactions were observed in case of the drug mixtures. In particular, ternary and quaternary drug combinations containing R and H along with Z and/or E were very unstable, showing 90%–95% and 70%–75% loss of R and H, respectively. In all these cases, isonicotinyl hydrazone (HYD) of 3-formylrifamycin and H was found to be the major degradation product. In case of RE and RZE mixtures, where H was absent, 3-formylrifamycin was instead the key degradation product. Another unidentified peak was observed in the mixture containing RZE. Apart from these chemical changes, considerable physical changes were also observed in pure E and the mixtures containing E, viz., RE, ZE, RHE, RZE, and RHZE. In addition, significant physical changes associated with noteworthy loss of H and E were also observed in mixtures containing HE and HZE. The present study thus amply shows that the four primary anti-tuberculosis drugs, when present together, interact with each other in a multiple and complex manner.     

Is weight-based IV dosing of trastuzumab preferable to SC fixed-dose in some patients? A systematic scoping review

Trastuzumab, a key treatment for HER2-positive breast cancer, is available in weight-based IV and fixed-dose (600 mg) SC formulations. While the Phase 3 HannaH trial indicated non-inferiority of the SC formulation, there is some concern that the target plasma concentration may not be reached in overweight/obese patients whereas low-body-weight patients may be at risk of toxicity.This scoping review evaluated whether overweight/obese patients are at risk of below-target exposure with fixed-dose SC trastuzumab, whether low-body-weight patients are at risk of increased toxicity, especially cardiotoxicity, and whether IV and SC trastuzumab are equivalent in terms of treatment-emergent adverse events (TEAEs) (e.g. infections). Thirty-seven publications that met the eligibility criteria were included.Body weight is not an important determinant of exposure to trastuzumab at steady state (i.e. pre-dose cycle 8); however, real-world evidence suggests that the target concentration (20 μg/mL) may not be reached with the first SC dose in overweight/obese patients. There is no evidence that low-body-weight patients are at increased risk of cardiotoxicity with SC trastuzumab, although this may be confounded by the higher rate of cardiovascular comorbidities in overweight patients. In Phase 3 trials, SC trastuzumab was associated with higher rates of ISRs, ADAs and SAEs, the latter often requiring hospitalization and occurring during adjuvant treatment when patients are not burdened by chemotherapy.The route of administration of trastuzumab (IV vs SC) in different treatment settings should be discussed with the patient, taking into account the risks and benefits associated with each route.     

Microtubule-targeting agents in the treatment of non-small cell lung cancer: insights on new combination strategies and investigational compounds

Introduction: The management of non-small cell lung cancer (NSCLC) has been substantially improved in the last few years; it has been revolutionized by a patient-tailored approach, especially in the oncogene addicted disease, and by novel combinations containing immune checkpoint inhibitors. However, chemotherapy still represents a mainstay that persists over the decades with limited novelties. Tubulin inhibitors belong to different sub-classes of drugs that share the capability to interfere with mitosis by a direct action on the microtubule system. Among them, taxanes and vinca alkaloids still have a prominent role in clinical practice.

Areas covered: This review summarizes the mechanisms of action, current role and future directions of microtubule targeting agents; we focus on investigational agents in phase I and II clinical trials.

Expert opinion: Chemotherapy maintains a pivotal role in the treatment of NSCLC. New generation agents that have the potential to overcome the mechanisms of resistance to the available drugs may provide new therapeutic opportunities. Predictive biomarkers derived from combination strategies and phase III studies are necessary going forward.