What are therapeutic alternatives for sodium chloride 4 mEq/mL 200 mL VIAL INTRAVENOUS?

Comment by InpharmD Researcher

One of the front lines of the immune defence is the gut mucosa, where immunoglobulin- (IgA) is continuously produced to react with commensal bacteria and dietary antigens. It is generally accepted that, after antigenic stimulation in the Peyer's patches, IgA+ lymphoblasts (B220+IgA+) migrate through the lymph and blood circulation, and eventually home to the lamina propria of the intestine. Mice that lack activation-induced cytidine deaminase (AID) are defective in class switch recombination (CSR) and somatic hypermutation. CSR changes the immunoglobulin heavy chain constant region (CH) gene being expressed from Cmu to other CH genes, resulting in a switch of the immunoglobulin isotype from IgM to IgG, IgE or IgA. AID-/- mice also secrete large amounts of immunoglobulin-mu (IgM) into faeces, and accumulate B220-IgM+ plasma cells as well as B220+IgM+ cells in the gut.

  

The presence of DN alphabeta T cells with similar functional features in the normal PEC was confirmed by the short term stimulation in vitro. The present results along with other recent reports strongly suggested that, like the mainstream alphabeta T cells, the NK1+ DN alphabeta T cell population consisted of functionally heterogeneous subsets.

Background

Secretory IgA plays a crucial role in the host immune response as a first line of defense. A recent demonstration of in situ IgA class switching in intestinal lamina propria provided an opportunity to reconsider the model for the homing of IgA-committed B cells characterized by distinctive trafficking patterns to effector sites. Those effector sites depend on the organized mucosa-associated lymphoid tissues as their site of induction. In this report we show the preferential presence of IgM(+)B220(+) and IgA(+)B220(+) cells belonging to pre- and post-IgA isotype class-switched cells in the organized mucosa-associated lymphoid tissues, such as nasopharynx-associated lymphoid tissues, isolated lymphoid follicles, and Peyer's patches, and the defect of those populations in the diffuse effector tissues, such as the nasal passage and intestinal lamina propria. Consistent with these findings, the expressions of a series of IgA isotype class switch recombination-related molecules, including activation-induced cytidine deaminase, Ialpha-C micro circle transcripts, and Ialpha-C micro circle transcripts, were selectively detected in these organized mucosa-associated lymphoid structures, but not in the diffuse mucosal effector sites.

Deletion of IL-5R alpha-chain (IL-5R alpha-/-) selectively influenced the mucosal IgA responses in vivo. While levels of IgA in mucosal secretions were more reduced in IL-5R alpha-/- mice than in wild-type mice, the levels of IgA in serum were not changed. The frequency of IgA-producing cells was reduced in mucosal effector sites (e.g., intestinal lamina propria and nasal passage), but not in inductive sites such as Payer's patches and nasal-associated lymphoreticular tissues in IL-5R alpha-/- mice. IgA-committed (surface IgA+; sIgA+) B-1 cells mainly resided in mucosal effector tissues, while conventional sIgA+ B (B-2) cells formed in mucosal inductive sites of wild-type mice. In contrast, in the effector tissue of IL-5R alpha-/- mice, sIgA+ B-1 cells, but not sIgA+ B-2 cells in the inductive site, were significantly reduced. IL-5R alpha was more expressed on sIgA+ B-1 cells than was IL-6R, while both IL-5R alpha and IL-6R were expressed on sIgA+ B-2 cells in wild-type mice. sIgA+ B-1 cells produced high levels of IgA with rIL-5 rather than of rIL-6 in vitro.

Single cells were obtained from LGs of C57BL/6 mice by the enzyme dissociation method using collagenase type IV. Samples underwent flow cytometric analysis to characterize the unique subsets of T and B cells. To test the effectiveness of ocular vaccination, mice were immunized ocularly or nasally with cholera toxin (CT; 10 microg/mouse) suspended in phosphate-buffered saline. Antigen-specific immune responses were determined by isotype and CT-specific enzyme-linked immunosorbent assay (ELISA) and enzyme-linked immunospot (ELISPOT) assay. Immunologic characterization of IgA-committed B-1 and B-2 cells, and unique subsets of T cells isolated from the murine lacrimal gland (LG), the primary exocrine tissue for the ocular surface, which is considered to be a part of the mucosal immune system.

When mononuclear cells (MC) isolated from LG samples were examined by flow cytometry, approximately 28% of cells were characterized as B220+ B cells. Because surface IgA+ (sIgA+) B cells develop from B-1 and B-2 lineages, it was important to examine which subset of B cells gives rise to LG sIgA+ B cells. Examination of the MC isolated from LG samples showed that approximately 4% of cells were sIgA+ B cells. Furthermore, nearly all these sIgA+ B cells (97.5%) belonged to the B-1 lineage, especially the B-1a cell line (B220low, CD5+). Of the isolated CD3+ T cells, 75% were alpha(beta) and 25% were gamma(delta)T-cell receptor positive. The proportion of NK1.1+ alpha(beta) T cells was higher (3%) in LG samples than in submandibular gland samples (0.5%). Ocular immunization with CT-induced antigen-specific mucosal (e.g., found in tear-wash and saliva samples) and systemic (e.g., serum) immune responses. The magnitude of antigen-specific antibody responses was comparable to those induced by nasal immunization.

References:

[1] Nikawa T, Ikemoto M, Kano M, Tokuoka K, Hirasaka K, Uehara S, Takatsu K, Rokutan K, Kishi K. Biochem Biophys Res Commun. 2001 Jul 13;285(2):546-9. doi: 10.1006/bbrc.2001.5138. [2] Vicari AP, Mocci S, Openshaw P, O'Garra A, Zlotnik A. Eur J Immunol. 1996 Jul;26(7):1424-9. doi: 10.1002/eji.1830260704. [3] Hiroi T, Yanagita M, Iijima H, Iwatani K, Yoshida T, Takatsu K, Kiyono H. J Immunol. 1999 Jan 15;162(2):821-8. [4] Nakamura E, Kubota H, Sato M, Sugie T, Yoshida O, Minato N. J Immunol. 1997 Jun 1;158(11):5338-48.
Relevant Prescribing Information

Non-MHC-restricted rejection mechanisms against the murine MHC-negative F9 embryonal carcinoma cells were analyzed. Strains of C57BL/6 (B6) background were resistant to the tumors irrespective of H-2 haplotypes, while others, including BALB/c background, were susceptible. This resistance was suggested to be mediated primarily by the host thymus-dependent alphabeta T cells, since both athymic B6 nude and normal B6 mice depleted with alphabeta T cells showed susceptible phenotype. The difference of the nature of alphabeta T cells infiltrating in H-2-identical B6- and BALB.B-derived tumors was then comparatively analyzed. It was revealed that unique T cells with NK1+ CD4- CD8- (double negative (DN)) alphabeta TCR+ phenotype were accumulated significantly in B6, but few in BALB.B mice. The population freshly isolated from the F9 tumor tissues preferentially expressed potent IL-4 mRNA, and was suggested to be mostly responsible for the endogenous IL-4 production. Indeed, the injection of either anti-NK1.1 or anti-IL-4-neutralizing Ab into the normal B6 rendered them significantly susceptible to the tumor cells. These results strongly suggested that NK1+ DN alphabeta T cells were responsible primarily for the rejection mechanisms against F9 tumors. Histologically, F9 tumors in B6 mice were characterized by abundant macrophage infiltration and massive tumor necrosis, neither of which was observed in those in BALB.B nor B6 mice preinjected with anti-IL-4 Ab, indicating that both histologic features in the resistant strain were dependent on the endogenous IL-4. Present results provide one of the first instances in which a recently emerging minor T cell subpopulation, thymus-dependent NK1+ DN alphabeta T cells, plays an essential role in anti-tumor responses in vivo.

References:

[5] Sugie T, Kubota H, Sato M, Nakamura E, Imamura M, Minato N. J Immunol. 1996 Nov 1;157(9):3925-35.
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

What are therapeutic alternatives for sodium chloride 4 mEq/mL 200 mL VIAL INTRAVENOUS?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Tables 1-2 for your response.

The In Vitro Chrondrotoxicity of Single-Dose Local Anesthetics

Design

Controlled laboratory study

Objective

To evaluate where administration of single doses of 1% lidocaine, 0.25% bupivacaine, and 0.5% ropivacaine resulted in decreased chondrocyte viability or cartilage matrix degradation in vitro

Methods

Human nontransduced, unmodified chondrocytes were obtained via a commercially available normal human chondrocyte line.

Grossly normal human en bloc cartilage samples were obtained from patients undergoing total knee arthroplasty. Only the peripheral rim of intact cartilage was used for evaluation. Eight total samples, each measuring 5 mm in diameter and 2 mm in length, were cultured at 37ºC in humidified air containing 5% carbon dioxide during all experiments.

Three anesthetics were tested: 1% lidocaine, 0.25% bupivacaine, and 0.5% ropivacaine. The dosage of each anesthetic was based on the dose equivalent of 10 mL, which is an accepted clinical dose. Dose adjustments were necessary to account for the scale difference of in vitro versus in vivo environments and could either be made according to absolute cell count or surface area measurements.

Results

Chondrocytes treated for 3 hours with 1% lidocaine exhibited significantly higher cell death than those in control media 7.9% vs 2.9%; p<0.001)

Chondrocytes treated for 6 hours with 0.25% bupivacaine exhibited no difference in cell death compared with those in control media
(2.7& vs 2.8%; p=0.856)

Similarly, cells treated for 12 hours in 0.50% ropivacaine showed no difference in cell death compared with the control group
(2.9% vs 2.4%; p= .084)

Study Author Conclusions

The results of this in vitro study indicate that a single-dose administration of 1% lidocaine resulted in a significant decrease in chondrocyte viability when compared with control cultures.

InpharmD Researcher Critique

Study weaknesses include in vitro administration in a controlled laboratory study (less applicable than in vivo) and small tissue sample population. Further studies in vivo or in human subjects are necessary to truly evaluate intraarticular effects as applied in clinical practice.
Supplemental IV glutathione for cisplatin-related toxicities

Citation

 Design Objective Patients Interventions Main results
Schmidinger et al., 20001 Randomized clinical pilot-trial To compare application of glutathione to intensive hydration in patients undergoing chemotherapy with a regimen including cisplatin

N= 20

Patients undergoing treatment for advanced non-small cell lung cancer (n= 6) or head- and neck cancer (n= 14)

 All patients received 80 mg/m2 cisplatin plus etoposide or 5-fluorouracil every 4 weeks. Patients were randomized to receive either 5 g of glutathione immediately before application of cisplatin followed by 2,000 mL of normal saline (n= 11) or 2,000 mL electrolyte infusion before and 2,000 mL of normal saline with forced diuresis after cisplatin (n= 9).

Intensity of hematologic toxicity was significantly less pronounced in patients treated with glutathione than in the control group (hemoglobin: 10.7 vs 9.5 g/dL respectively, p= 0.039; white blood cell count 3.3 vs 2.2 x 103/microliter respectively, p= 0.004; platelets 167 vs 95 x 103/microliter respectively, p= 0.02).

No difference was observed for non-hematologic toxicity. 

No significant difference was reported for response and overall survival between the two groups.
Smyth et al., 19972 Randomized, multicenter, parallel-group trial

To determine whether glutathione would enhance the feasibility of giving six cycles of cisplatin at 100 mg/m2 without dose reduction due to toxicity

N= 151

Patients with ovarian cancer (stage I-IV)

 Patients were randomized to receive 3 g/m2 glutathione diluted in 200 mL normal saline and infused over 20 minutes immediately before cisplatin 100 mg/m2 or 200 mL normal saline infused over 20 minutes immediately before cisplatin 100 mg/m2.

Of patients receiving glutathione, 58% received 6 courses of cisplatin vs. 39% for those receiving placebo (p= 0.04).

A significant difference was reported between groups for reduction in creatinine clearance for GSH treated patients vs placebo (74% vs. 62%; p= 0.006).

Quality of life scores were significantly improved for patients taking glutathione. 
Parnis et al., 19953 Randomized, double-blind, placebo-controlled study To assess the efficacy of glutathione as an adjunct to escalating doses of cisplatin in ovarian cancer patients 

N= 36

Patients with ovarian cancer

Patients were randomized to 3 groups, each with 12 cisplatin-treated patients (6 glutathione and 6 placebo). Cisplatin was given at a dose of 40 mg/m2 over 2 hours. In Group 1, this treatment was for 2 successive days, Group 2 for 3 days and Group 3 for 4 days, repeated every 4 weeks. Patients in the glutathione group received 1.5 m/m2 as a fixed dose over 15 minutes prior to each cisplatin treatment. 

No significant differences were noted between groups for clinical assessments, laboratory tests, and neurological and audiological exams.

Ototoxicity was noted in both groups, although less was suggested in glutathione patients. Still, the authors concluded glutathione to be ineffective for protection against cisplatin toxicity, possibly due to glutathione's short half-life. 
Cascinu et al., 19954 Randomized double-blind placebo-controlled trial To assess the efficacy of glutathione in the prevention of cisplatin-induced neurotoxicity

N= 50

Patients with advanced gastric cancer receiving weekly cisplatin-based regimen

 Patients were randomized to receive glutathione at a dose of 1.5 g/m2 in 100 mL of normal saline solution over 15 minutes immediately before cisplatin administration and glutathione at a dose of 600 mg by intramuscular injection on days 2 to 5 or normal saline solution. 

At week 9, no patients showed clinically evident neuropathy in glutathione group vs. 16 showing neuropathy in placebo group. After week 15, 4 of 24 assessable patients in the glutathione arm suffered from neurotoxicity versus 16 of 18 in the placebo arm (p= 0.0001). 

Glutathione also reduced hemotransfusion requirements (32 vs. 62) and treatment delay (55 vs. 94 weeks) compared to placebo. 

The response rate was 76% (20% complete response) in the glutathione group and 52% (12% complete response) in the placebo arm. 
Locatelli et al., 19935 Phase II prospective study  To assess the protective action of glutathione against cisplatin nephrotoxicity

N= 20

Patients with advanced ovarian carcinoma

 Patients received 45 mg/m2 IV cisplatin on day 1-2 plus cyclophosphamide 900 mg/m2 on day 2 plus glutathione 2,500 mg IV in 100 mL normal saline (over 15 minutes) before cisplatin every 21-28 days. Glutathione was found to have no negative interference on cisplatin activity. A complete response rate of 55% (11/20) was observed, with a median survival of 26.5 months. Five patients were alive and disease-free at 35 months. 
Di et al., 19936 Prospective cohort study  To investigate the efficacy and toxicity of glutathione as chemoprotection with a high-dose cisplatin regimen 

N= 79

Patients with advanced ovarian cancer, bulky or extensive residual disease after primary laparotomy or with bulky inoperable tumor masses

 All patients received up to five courses of high-dose cisplatin (40 mg/m2 daily in normal saline, for four days) plus glutathione (2,500 mg as a short-term infusion before cisplatin), together with cyclophosphamide (600 mg/m2 as an IV bolus on day 4). Additionally,  standard IV hydration consisting of a total of 2000 mL of fluids without diuretics was given.

Forty-five patients (57%) achieved complete clinical responses and 20 (25%) had partial remissions for an overall response rate of 82%. At median follow-up time of 44 months, the median survival was 40 months.

Nausea/vomiting was the most severe acute toxicity. Nephrotoxicity was minimal with a transient increase (to < 2 mg/dL) in serum creatinine in only 6 patients (8%). Peripheral neurotoxicity and ototoxicity were the most significant long-term toxicities.

Glutathione was considered to be efficacious and tolerable to allow increased cisplatin dose intensity.
Bogliun et al., 19927 Prospective, randomized study

To evaluate the safety and efficacy in terms of oncological response and the effects on the peripheral and central sensory pathways of the administration of cisplatin according to a non-conventional schedule as monochemotherapy or associated with the putative neuroprotective drug glutathione.

N= 33

Patients with relapsing ovarian cancer

 Patients were randomized either to monochemotherapy with cisplatin or to a combination of cisplatin (50 mg/m2 x 9 courses) and glutathione (2.5 g over 15 minutes immediately prior to cisplatin.  Treatment was well tolerated. Overall (complete plus partial) tumor response ratio after chemotherapy was 60% in monotherapy group and 75% in glutathione group. No significant effect on the sensory pathway was observed with glutathione.