FDA fast-tracking of pet population control drugs.

Theriogenologists have been studying estrus prevention and termination of pregnancy in dogs for at least 2 decades. However, drugs approved for estrus suppression are few. No dog or cat abortifacients or male dog and cat sterilants have been approved. Marketed drugs with alternate indications that have antiestrus and antihormonal activity might be good candidates for study after obtaining an INAD from FDA. With the support of the original drug sponsor or manufacturer and appropriate safety and effectiveness studies, these products may be studied for additional label claims. New (not previously approved) drugs additionally need detailed information regarding the synthesis and manufacturing controls. Drugs offering substantial benefit over existing therapeutics may be eligible for expedited review. Prior to starting any studies in this area, clinical investigators and sponsors should communicate with FDA, an INAD must be granted, and the protocol submitted for evaluation. Approvability is evaluated after establishment of safety and effectiveness in clinical field trials.

Pharmacology and toxicology of novel drug delivery systems. Regulatory issues.

The lure of optimising the effect of the drug on the body (pharmacodynamics) and the body on the drug (pharmacokinetics) has produced an alternative group of products designed to achieve specialised delivery and/or disposition of drugs. A toxic drug may be used in more effective concentrations by targeting the drug to its site of action and decreasing additional systemic toxicity. Four possible regulatory situations for delivery system and drug have been identified, and generalisations regarding the non-clinical studies needed for the initiation of clinical trials and New Drug Application (NDA) have been described. Problems associated with the identification of appropriate controls have been included, and the importance of basing the choice upon a scientifically rational evaluation of the pharmacodynamic and pharmacokinetic study results emphasised, along with the significance of conducting the non-clinical evaluation using the final formulation.

Nonclinical pharmacologic and toxicologic considerations for evaluating biologic products.

Prior to a Phase 1 clinical study, products are studied preclinically to establish evidence of pharmacologic activity, gain an understanding of the mechanism of action, evaluate the potential human risk, and establish a clinical study dose range. Although it is possible to follow this generic itinerary for the development of biologic products, it is difficult to develop generic protocols that will suffice for addressing these preclinical concerns for every biological product. Peptide hormones, cytokines, growth factors, vaccines, allergenics, plasma proteins, enzymes, toxins, monoclonal antibodies, and other heterologous antisera are unique in their physiological interactions, and therefore the toxicologic concerns and suggested studies are tailored to the uniqueness of the compound. This paper represents an attempt to share the thought processes that have been used at the Food and Drug Administration (FDA) to address the nonclinical pharmacology and toxicology study concerns. This presentation of considerations is based on an analysis of what has been done in recent years as a basis for initiating Phase 1 studies (first administration of drugs to humans) and progressing to Phase 2/3 studies (evaluation of optimal dose, effectiveness, and safety in humans), while I was Assistant Director (Pharmacology/Toxicology) of the Office of Biologics and since, as Assistant Director (Pharmacology/Toxicology) of the Office of Drug Evaluation II and a consultant to the Center for Biologics Evaluation and Research.

[Initial evaluation of aluminum concentrations in patients with nephropathy and undergoing hemodialysis at the Miguel Pérez Carreño Hospital and the University Hospital of Caracas (Venezuela)]. / Evaluación inicial de las concentraciones de aluminio en pacientes con nefropatía y sometidos a hemodiálisis en los Hospitales Miguel Pérez Carreño y Universitario de Caracas (Venezuela).

The present work reports the concentrations of aluminum in whole blood and dialysis solutions of 27 patients with chronic renal failure and under hemodialysis treatment at Miguel Pérez Carreño and University Hospitals, both from Caracas city. Aluminum levels of the water used to prepare the dialysates were also monitored and the metal mobilization during dialysis studied. Patients' mean blood aluminum concentrations (ca. 34 micrograms AI/L) were lower than those of renal individuals from Maracaibo (ca. 58 micrograms AI/L), situation related to the low metal contents of the dialysate water (ca. 14 micrograms AI/L). In addition, Caracas drinking water showed up very high aluminum concentrations, above 475 micrograms/L. There was a relationship between the renal patients' blood aluminum concentrations and (1) the metal contents of the dialysis solutions and (2) the ingestion of aluminum hydroxide-based antacids. Aluminum transfer incorporation processes toward the patients' blood were observed in both dialysis units. This was due to the favorable concentration gradients (blood aluminum concentration/dialysate aluminum concentration) established at the start of every hemodialysis treatment.

Preclinical and pharmacology and toxicology of hematopoietic growth factors.

Initial evaluation of the safety of biological products, whether manufactured by biotechnology or not, is dictated by the extent of knowledge of the biological effects in vitro, in animals, and in man at the proposed dose and duration of administration. The quantity of useful information that will be gained from an animal study is considered for each product on a case-by-case basis. This requires consideration of the availability of a relevant species. Relevance is determined by presence and relative affinity and distribution of receptors for the biological product, relative potency in induction of biological activity related to the putative mechanism of action and pharmacokinetic considerations. The impurities and immunogenic potential of the product are also considered in designing the preclinical studies. After evaluating all these factors, the residual lack of knowledge is FDA's basis for recommending specific preclinical testing. The considerations inherent in the preclinical evaluation of factors acting primarily on hematopoietic cells, erythropoietin (EPO), interleukins (IL's) and colony stimulating factors (CSF) (1) will be discussed using case examples.

Comparison of hepatic drug metabolizing enzyme activities in several agricultural species.

1. Several pathways of drug metabolizing enzyme activity were measured in hepatic fractions of cattle, sheep, goats, chickens, turkeys, ducks, rabbits and rats. The pathways examined included the O-demethylation of p-nitrophenol, microsomal ester hydrolysis of procaine and glucuronidation of p-nitrophenol, and the cytosolic acetylation of sulfamethazine and sulfation of 2-naphthol. 2. For most enzymatic pathways measured, goats were more similar to sheep (wether) than to cattle (steers). The exception was UDP-glucuronyltransferase activity, which was significantly higher for the goat than for any other species studied. 3. Within the avian subset, the chicken and turkey were usually the most similar species. 4. The activities of arylsulfotransferase isozymes III and IV were particularly low for the duck compared to the chicken and turkey. 5. N-acetyltransferase activity was very high for rabbits and very low for sheep and goats.

Intracysternal crystalline cytoplasmic inclusions in a cardiac myxoma.

Electron microscopy of an atrial myxoma removed at surgery from a 56-year-old woman revealed unusual intracysternal inclusions in the cytoplasm of tumor cells. These structures appeared in the rough endoplasmic reticulum and consisted of multilaminar arrays of crystalline plates of regular periodicity, about 10 nm apart. Although crystalline and other intracysternal inclusions may occur in different pathologic disorders, their occurrence in an atrial myxoma is a hitherto unreported observation.

Propranolol can inhibit the development of hypertension in SHR.

The ability of propranolol, a beta-adrenergic blocking agent, to decrease blood pressure and inhibit the development of hypertension was assessed in spontaneously hypertensive rats (SHR). Oral propranolol was administered via drinking water to SHR and age matched normotensive control (WKY) groups beginning at conception, birth, three, six, or nine weeks of age. Controls for all groups were given tap water. Propranolol treatment was withdrawn from all groups at twelve weeks of age. A comparison of developmental parameters such as water consumption, weight gain and survival showed no differences between SHR and WKY or between SHR with propranolol vs WKY with propranolol. Systolic blood pressures and heart rates were monitored non-invasively from seven to sixteen weeks of age. There was a variable reduction in SHR blood pressures during propranolol treatments starting at 6 weeks of age or earlier, but when propranolol treatment was withdrawn, SHR blood pressures increased as did SHR without propranolol treatment. In SHR offspring who were exposed to propranolol through fetal and neonatal development and whose sires and dams were pretreated with propranolol, the development of high blood pressure was inhibited. Blood pressures indicated that this group did not develop hypertension for up to four weeks after propranolol was withdrawn even though heart rate returned to normal. Based upon these findings, a critical period during SHR development was defined during which development of hypertension can be inhibited by propranolol.

Heterogeneous response patterns of aortae to norepinephrine.

Concentration-contractile response curves for the thoracic (TA) and abdominal (AbA) aortae from spontaneously hypertensive (SHR) and normotensive control (WKY) rats were determined using adrenergic agonists. The concentrations of epinephrine (E) and norepinephrine (NE) necessary to produce a maximum response in the WKY TA were 7.07 x 10(-7) M and 1.68 x 10(-6) M, respectively. At greater concentrations TA responded with progressive relaxation. When similarly tested, SHR TA responded with significantly less relaxation. The concentrations of E and NE necessary to produce a maximum response in the WKY AbA were greater than 1.0 x 10(-5) M. No significant relaxation occurred at greater concentrations. The relaxation responses of the SHR AbA were no different than their normotensive controls. When propranolol was used the results suggested that relaxation is mediated by the beta-adrenoreceptor. The use of the beta 2-agonist, salbutamol, confirms the hypothesis that relaxation occurring in response to high concentrations of NE and E is partly a beta 2-adrenoeceptor phenomenon, and that this beta 2-adrenergic response decreases with early hypertension in TA. The different response patterns produced may partially account for the diversity of results regarding vascular sensitivity to vasoactive agents in the literature.

Serum enzyme abnormalities in swine associated with systemic infection and fever.

Yucatán miniswine with systemic infections (C. pyogenes and S. marcescens) and accompanying elevated body temperature, also have increased serum creatine kinase (CK), lactate dehydrogenase (LD) and gamma-globulin (GG) levels. The CK and LD levels increase with fever due to infection and decrease as antibiotics are administered and the body temperature is lowered. The GG levels remain elevated. Body temperature due to infection should be taken into account when utilizing CK and LD to assess skeletal muscle, cerebrovascular and myocardial damage.

Studies on the biological disposition of diethylstilbestrol in rats and humans.

Studies were conducted to elucidate the processes involved in the biological disposition of diethylstilbestrol (DES). The apparent biological half-life of [14C] DES decreased with increasing age in immature rats. The half-life of DES in adult rats (14 min) was reached between the 15th and 25th day after birth. Comparison of the intestinal absorption of [14C] DES and [14C]DES monoglucuronide showed the unconjugated drug to be absorbed much more rapidly. Hydrolysis of the conjugate took place in the lower intestine, and this permitted the drug to undergo enterohepatic cycling.