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The results of studies on tedisamil dihydrochloride in the solid state demonstrate that the compound occurs in three polymorphic forms. The three modifications have been characterized by thermomicroscopy, differential scanning calorimetry (DSC), vibrational spectroscopy, solid-state nuclear magnetic resonance (NMR), and X-ray powder diffractometry (XRPD). The thermodynamic relationships are illustrated in a semischematic energy/temperature diagram that gives information about the relative stability and physical properties of the three modifications between 0 K and the melting temperatures. The three modifications are enantiotropically related. Modification II, the material obtained during manufacturing, is the thermodynamically stable crystal form at 20 degrees C. The thermodynamic transition point of mod II with I (instant melting point: 248-250 degrees C) is between 100 and approximately 140 degrees C (DeltaH(t,II/I) = 4.4+/-0.8 kJ/mol (95% CI)). A phase transition of mod II (probably into mod III) was detected thermomicroscopically at about -180 degrees C. The thermodynamic transition point of mod III with I was determined to be at -9 to -6 degrees C. Because mods I and III are thermodynamically and kinetically unstable at ambient conditions, these crystal forms are of analytical interest.

Three modifications of D-mannitol were produced and investigated: mod. I (mp 166.5 degrees C, heat of fusion 53.5 kJ mol(-1)), mod. II (mp 166 degrees C, heat of fusion 52.1 kJ mol(-1)), and mod. III (mp incongruent 150-158 degrees C, heat of transition, III to I 0.2 kJ mol(-1)). The measured densities are 1.490 +/- 0.000 g cm(-3) [95% confidence interval (CI)] for mod. I, 1.468 +/- 0.002 g cm(-3) (95% CI) for mod. II, and 1.499 +/- 0.004 g cm(-3) (95% CI) for mod. III. It was possible to relate the different modifications given in the literature to one of the three pure crystal forms or to mixtures of two or all three modifications. The thermodynamic relationship among the crystal forms is represented in a semi-schematic energy/temperature diagram. From these data we can conclude that mod. III is thermodynamically stable at absolute zero. It is enantiotropically related to mod. I and mod. II. FTIR and Raman spectra, differential scanning calorimetry curves, and X-ray powder patterns of these crystal forms are depicted for doubtless assignment in the future. The water uptake of the three modifications at 92% relative humidity and 25 degrees C is less than 1%. The differences of the heat capacities and the heats of solution between mod. II and III are not significant, whereas mod. I shows small significant differences compared with the other modifications. In addition, compaction studies of these crystal forms were performed by means of an instrumented hydraulic press. The results show that mod. III should have the best tableting behavior under these conditions., (Copyright 2000 Wiley-Liss, Inc.)

The thermodynamic terms enantiotropy and monotropy are demonstrated by means of solid-state analytical results of polymorphous flurbiprofen (FBP). Vibrational spectra, differential scanning calorimetry (DSC), and thermomicroscopy investigations as well as X-ray powder patterns for three modifications of FBP are described. The melting points are mod. I 113-114 degreesC (enthalpy of fusion 27.9 +/- 0.2 kJ mol-1) for modification I (mod. I), 92 degreesC for mod. II, and 87 degreesC for mod. III. The true densities of mod. I (1.279 +/- 0.001 g cm-3) and mod. II (1.231 +/- 0.002 g cm-3) were measured at 25 degreesC. Modification I (commercial product) is the thermodynamically stable crystal form from absolute zero to its melting point. Modification II was crystallized on a gram scale from a warm saturated solution of FBP in n-heptane and rapid cooling of the solution to -18 degreesC. Modification I is monotropically related to mod. II and mod. III, due to application of the density rule and the entropy-of-fusion rule. The thermodynamic relationships between the three modifications are demonstrated by a semischematic energy/temperature diagram. Theoretical vapor pressure/temperature diagrams and energy/temperature diagrams are compared and briefly discussed.

Misonidazole is a hypoxic cell radiosensitizer that induces a peripheral neuropathy in humans after exceeding a schedule-dependent cumulative threshold dose. Clinical studies of misonidazole have been conducted using oral administration, whereas most other radiosensitizers have been administered intravenously. Since route of exposure can potentially influence the toxicity of xenobiotics, the objective of this study was to assess the neurotoxicity of misonidazole in rats following intravenous dosing using a battery of routine clinical, neurofunctional, biochemical, and histopathologic screening methods. Male Sprague-Dawley rats were administered intravenous doses of misonidazole at 0 (vehicle control), 100, 200, 300, or 400 mg kg-1 once per day, 5 days per week, for 2 weeks. Animals were evaluated for neurofunctional and pathological changes following termination of treatment (Days 15-17) and at the end of a 4 week observation period (Days 43-45). During the dosing phase, hypoactivity, salivation, rhinorrhea, chromodacryorrhea, rough pelage and ataxia were observed at 400 mg kg-1, and body weight gain of the 300 and 400 mg kg-1 groups was significantly decreased relative to the vehicle controls by 24% and 49%, respectively. Corresponding reductions in food consumption were 8% and 23%, respectively. Although most 400 mg kg-1 animals appeared normal on Day 15 prior to the neurofunctional evaluations, rotorod testing precipitated a number of clinical signs including: ataxia, impaired righting reflex, excessive rearing, tremors, vocalization, circling, head jerking, excessive sniffing and hyperactivity. All of these animals recovered and appeared normal from Day 17 through study termination. There were no treatment-related effects on motor activity, acoustic startle response, rotorod performance, forelimb group strength, toe and tail pinch reflexes, tibial nerve beta-glucuronidase activity or tail nerve conduction velocity. Although hindlimb grip strength of the 400 mg kg-1 group was significantly decreased by 17% relative to the vehicle controls on Day 15, this finding appeared related to the reduced food consumption and body weight gain in these animals. No microscopic changes were detected in peripheral nerves. Necrosis and proliferation of fibrillary astrocytes (gliosis) were seen in the cerebellum and medulla of the 400 mg kg-1 animals on Day 16. Gliosis in these same brain regions was observed in the 300 and 400 mg kg-1 groups on Day 44. The results show that intravenous administration of misonidazole to rats causes dose-limiting central nervous system toxicity without effects on peripheral nervous tissue. The lack of peripheral neurotoxicity was most likely due to a combination of several interrelated factors including route of administration, duration and intensity of the dosing regimen, and total cumulative dose.

In recent years, concern about possible female reproductive and developmental toxicity due to environmental contaminants, such as PCBs, has been growing. Because this area of toxicology had not been emphasized prior to this time, there are many gaps in current knowledge about female developmental and reproductive toxicology and only a limited number of validated tests to assay effects of toxicants on various parts of the reproductive and developmental cycle. This article reviews the current state of knowledge on this topic and also explores a variety of techniques for assessing female reproductive and developmental toxicity. These include an assay of the state of intercellular communication among the embryo, fetus and placenta; protocols for assessing toxicity in early pregnancy; and techniques for evaluating the role of glutathione in protecting the conceptus from xenobiotics.

Male Sprague-Dawley rats were trained to press a lever on a fixed ratio-40 (FR-40) schedule for food reinforcement. Doses ranging from 0.5 to 16 mg/kg of the mixed narcotic agonist-antagonist cyclazocine (30-min pretreatment) resulted in a dose-dependent decrease in the number of reinforcements obtained and a reciprocal increase in "pausing" (IRT's greater than 10 sec). A 5-min pretreatment with 4 mg/kg of the narcotic antagonist naloxone attenuated the cyclazocine disruption. The 5-HT antagonist metergoline (1 mg/kg; 180-min pretreatment) also blocked cyclazocine effects to approximately the same degree as did naloxone. However, the shift of the dose response pattern of cyclazocine was not parallel for either antagonist. A greater degree of attenuation of the cyclazocine effects was observed when naloxone (4 mg/kg) and metergoline (0.1 mg/kg) were given together, indicating that cyclazocine disruption may be antagonized by either a narcotic antagonist or a 5-HT antagonist, and that these antagonists may operate synergistically. Thus, the behavioral effects of cyclazocine may relate to both opioid and serotonergic components.

Administration of the indolealkylamine hallucinogen d-lysergic acid diethylamide (LSD), the phenethylamine hallucinogen 2,5-dimethoxy-4-methylamphetamine (DOM) and the putative 5-hydroxytryptamine (5-HT) agonist quipazine all produced a dose-dependent decrease in fixed ratio (FR-40) response rates and a concomitant increase in the number of 10-second pause intervals. Although naloxone (4.0 mg/kg) had no effect on FR-40 responding per se, the pause-producing effects of LSD and, to a lesser extent, DOM were potentiated by pretreatment with naloxone. The action of quipazine on reinforcers was unaffected by combination with naloxone, while the effect on pause intervals was slightly attenuated by naloxone pretreatment. These data and previous studies suggest that the pause-producing effects of indolealkylamine and phenethylamine hallucinogens reflect their activation of a selective portion of brain 5-HT receptors. The potentiation of these effects by naloxone may relate to a modulation of central 5-HT systems by endogenous opioid mechanisms tending to restore an imbalance in various 5-HT pathways caused by the hallucinogenic 5-HT agonists. The more generalized disruptive effects of quipazine on brain 5-HT systems may be less susceptible to the endogenous opioid modulation or may actually combine with it to induce a greater disruption.

The mixed narcotic agonist-antagonist cyclazocine and the 5-HT agonist quipazine disrupt food-rewarded fixed ratio-40 (FR-40) operant behavior in rats as a dose-dependent decrease in the number of reinforcers obtained and a reciprocal increase in the number of 10-second intervals between responding ("pausing"). This disruption has been shown to result in part from interaction with 5-HT neuronal systems, and may be a consequence of: (1) disruption of cognitive processes, (2) motivational impairment, or (3) motor deficits. To identify which of these components is (are) involved in the disruption of operant responding, female Sprague-Dawley rats were tested for food consumption, spontaneous locomotor activity, or rotarod performance following intraperitoneal injection of cyclazocine, quipazine, or both. Cyclazocine decreased food consumption at doses larger than those required to disrupt operant behavior, while quipazine decreased consumption at doses disruptive to operant responding. Little effect was exerted by either drug on spontaneous locomotor activity, while rotarod performance was disrupted only by very large doses of either drug relative to effects of FR-40 behavior. These data indicate that neither drug appears to disrupt operant behavior by causing gross motor deficits. Thus, cyclazocine may disrupt operant responding by impairing cognition, while quipazine may act through food satiation mechanisms.