Rat Paw-Lick/Muscle Irritation Model for Evaluating Parenteral Formulations for Pain-on-Injection and Muscle Damage

Rat Paw-Lick/Muscle Irritation Model for Evaluating ParenteralFormulations for Pain-on-Injection and Muscle Damage. CHELLMAN,G. J., FAUROT, G. F., LOLLINI, L. O., AND MCCULLOUGH, T. E.(1990). Fundam. Appl. Toxicol. 15, 697–709. A two-phaseassay was developed in the rat to evaluate parenteral formulationsintended for intramuscular administration for the inductionof both acute pain-on-injection and delayed pain/discomfortat the injection site (secondary to muscle damage). Phase 1of the assay assessed pain-on-injection using a modified versionof the previously published rat paw-lick assay. Adult male CDrats (10/group) were given subplantar (footpad) injections of0.1 ml and then observed for 15 min for paw-lick responses.To increase assay sensitivity, responses more subtle than pawlicks (ie., paw lifts) were scored, and injection-site clinicalsigns were recorded 6, 24, and 48 hr after injection. Phase2 of the assay assessed myotoxic potential, using the same ratsafter a 1-week recovery period. The rats were injected intramuscularlyin the anterior thigh with 0.2 ml, bled from the orbital sinusat 2, 6, and 24 hr for analysis of serum creatine kinase (CK),and then necropsied at 24 hr to prepare tissue sections of theinjection site for microscopic examination. A series of cephalosporin-typeantibiotics produced pain-on-injection and muscle damage consistentwith reported clinical experience (cefazolin < cephalothin< cefoxitin). Several nonantibiotic parenteral formulations(diazepam, digoxin, phenytoin, and lidocaine) tested in thepaw-lick/muscle irritation model also produced responses thatcorrelated with the clinic, i.e., virtually no acute pain butmoderate to marked muscle damage. The results indicate thatthe two-phase rat paw-lick/muscle irritation model is effectivein evaluating parenteral formulations for clinical acceptability,and that both phases of the assay are necessary to optimizepredictability of the assay for human clinical experience.     

Organ-Specific Hematopoietic Changes Induced by a Recombinant Human Interferon-{alpha} in Mice

Organ-Specific Hematopoietic Changes Induced by a RecombinantHuman Interferon- in Mice. ROSENTHAL, G. J., STRANAHAN, R. P.,ILL, THOMPSON, M., BLAIR, P., GERMOLEC, D. R., COMMENT, C. E.,SCHWAB, K., AND LUSTER, M. I. (1990). Fundam. Appl. Toxicol.14, 666–675. Interferon-a (IFN-) is a naturally occurringcytokine that mediates numerous biological activities and hasdemonstrated therapeutic potential in a variety of malignancies.Encouraging activity against HIV-1 replication has also beenobserved with IFN- in the treatment of AIDS, although hematotoxicityhas been a frequently observed side effect. In addition, invitro studies have suggested that IFN- may function as a down-regulatorof myelopoiesis. A recombinant hybrid of subtypes of human IFN-,rHuIFN-A/D, has antiviral activity in mu-rine cells in vitroand In vivo. This study examines the effect of acute and subchronicexposure to rHuIFN-A/D on hemopoietic and immune parametersin C57B1/6 mice. IFN-a was administered ip at 0, 1000, 10,000,and 100,000 units/day for either 1 or 10 consecutive days. Manyof the known effects of IFN- in humans such as anemia, leukopenia,and thrombocytopenia were observed in mice following subchronicexposure, with the latter two effects also manifested followingacute exposure. Further analysis showed that this leukopeniawas not selective. Both splenic and bone marrow cells were examinedfollowing 10 days of dosing with the high dose of IFN-. Lymphocyteswere reduced in both compartments, while granulocytes were increasedin both compartments. Bone marrow cells programmed to differentiateinto granulocytes (CFU-G) were suppressed, while macrophageprogenitors (CFU-M) were stimulated. Erythroid cells decreasedin the marrow but increased in the spleen, suggesting that themicroenvironmerit may play a significant role in the effectof IFN-. The proliferative capacity of both B and T spleniclymphocytes was significantly suppressed in a dose-related fashionfollowing multiple exposure to IFN-a. Clinically, IFN-a is mostoften given in multiple doses and the present data suggest thatsuch a regimen is toxic to both erythroid and myeloid cells,as well as being immunotoxic to splenic B and T lymphocytes.     

A comparison of vincristine and doxorubicin infusional chemotherapy with methylprednisolone (VAMP) with the addition of weekly cyclophosphamide (C-VAMP) as induction treatment followed by autografting in previously untreated myeloma

In a sequential nonrandomized study, 204 consecutive unselected patients aged < 70 years received induction chemotherapy with infusional vincristine and adriamycin with oral methyl prednisolone (VAMP; n =75) or with additional cyclophosphamide, C-VAMP ( n =129). 38/129 C-VAMP patients also received verapamil during induction as part of a controlled trial with the aim to overcome drug resistance. A median of five courses (range 1–11) of chemotherapy were required before maximal response was attained and this was similar in both groups. An over-all response rate of 71% was noted at the end of induction. The complete remission (CR) rate with C-VAMP was 24%, which was significantly higher ( P =0.04) than the CR rate with VAMP alone (8%). The addition of verapamil did not alter the response rate of C-VAMP. Compliance to VAMP was overall 83% and not affected by the addition of cyclophosphamide. The proportion of patients going on to receive high-dose chemotherapy and an autograft was the same for VAMP and C-VAMP treated patients (71%). The median overall survival (OS) and progression-free survival (PFS) for the whole group were 4.4 years and 2.0 years and no difference in outcome was observed between the different treatment groups. Therefore the addition of weekly cyclophosphamide to VAMP induction therapy has significantly improved the response rates of previously untreated myeloma patients. C-VAMP was not more toxic and did not compromise the chances of receiving an autograft. Verapamil was without influence on any parameters in this study.     

A longitudinal study of New Zealand children's experience with alcohol

A longitudinal study assessed the use of alcohol and related measures among New Zealand children aged 9, 11, 13 and 15 years. The proportion of children who were abstainers was at a similar level to the adult population by age 15 years. Those remaining abstainers were more likely to have infrequently drinking parents and to have been warned of the bad effects of alcohol by their parents. In terms of amount consumed and frequency of drinking, there was an increase with age and a marked increase between the ages of 13 and 15 years. Frequency of drinking was positively associated with the frequency of drinking by the mother and father. Girls drank less than boys until the age of 15 years, when they drank slightly more and a difference in terms of socio-economic status (SES) emerged at age 15 years with tower SES groups drinking more.