Ziprasidone-associated mania: a case series and review of the mechanism.

Atypical antipsychotics are now commonly used in the treatment of bipolar disorder, as they have been shown to have effects on mania as well as psychosis. Shortly after the introduction of atypical antipsychotics, several cases of associated hypomania and mania were reported. Ziprasidone is an atypical antipsychotic recently approved by the Food and Drug Administration for the treatment of psychosis. Although ziprasidone has also been shown to be effective in treating mania, it may be associated with the induction of mania or hypomania. We report four cases of mania associated with initiation of ziprasidone, which, to our knowledge, are the first reported for this drug in bipolar patients. As ziprasidone has substantial serotonergic and noradrenergic action, we hypothesize, it may more likely induce mania than other atypical antipsychotics. We advocate future studies to evaluate ziprasidone's efficacy in treating bipolar disorder and caution clinicians that induction of mania or hypomania may be possible with this agent.

Severe oligohydramnios with intact membranes: an indication for diagnostic amnioinfusion.

OBJECTIVE: To quantify the improvement in ultrasonographic fetal imaging following diagnostic amnioinfusion for the indication of unexplained midtrimester oligohydramnios. METHODS: Patients referred for unexplained midtrimester oligohydramnios were retrospectively reviewed. Videotapes of those undergoing diagnostic antenatal amnioinfusion were analyzed for quality of visualization of routinely imaged structures before and after the infusion procedure. RESULTS: The overall rate of adequate visualization of fetal structures improved from 50.98 to 76.79% (p < 0.0001). In fetuses having preinfusion-identified obstructive uropathy, there was improvement in identification of associated anomalies from 11.8 to 31.3%. CONCLUSIONS: Several authors have suggested that diagnostic amnioinfusion can facilitate fetal imaging and increase diagnostic precision in the setting of unexplained severe oligohydramnios. We have quantified the improvement in the rate of optimal visualization of fetal structures which likely translates, in experienced hands, into this observed improved diagnostic precision. Of particular importance is the improvement in appreciation of associated anomalies in cases of obstructive uropathy in which such findings may determine whether or not invasive fetal therapy is indicated.

Cyclobutane quisqualic acid analogues as selective mGluR5a metabotropic glutamic acid receptor ligands.

The conformationally constrained cyclobutane analogues of quisqualic acid (Z)- and (E)-1-amino-3-[2'-(3',5'-dioxo-1',2', 4'-oxadiazolidinyl)]cyclobutane-1-carboxylic acid, compounds 2 and 3, respectively, were synthesized. Both 2 and 3 stimulated phosphoinositide (PI) hydrolysis in the hippocampus with EC50 values of 18 +/- 6 and 53 +/- 19 microM, respectively. Neither analogue stimulated PI hydrolysis in the cerebellum. The effects of 2 and 3 were also examined in BHK cells which expressed either mGluR1a or mGluR5a receptors. Compounds 2 and 3 stimulated PI hydrolysis in cells expressing mGluR5a but not in those cells expressing mGluR1a. The EC50 value for 2 was 11 +/- 4 microM, while that for 3 was 49 +/- 25 microM. Both 2 and 3 did not show any significant effect on cells expressing the mGluR2 and mGluR4a receptors. In addition, neither compound blocked [3H]glutamic acid uptake into synaptosomal membranes, and neither compound was able to produce the QUIS effect as does quisqualic acid. This pharmacological profile indicates that 2 and 3 are selective ligands for the mGluR5a metabotropic glutamic acid receptor.

Selective reduction for multifetal pregnancy. Early opinions revisited.

Multifetal pregnancy reduction has emerged as a staple of infertility therapy. With increasing utilization of aggressive infertility therapies, thousands of couples have been able to achieve pregnancies who otherwise would not have, but an increasing number and proportion of patients have multifetal pregnancies. Multifetal pregnancy reduction (MFPR) has been shown to be a safe and effective treatment for reducing the number of pregnancies, thereby reducing both perinatal morbidity and mortality in resultant pregnancies. The world experience suggests that the risks of MFPR are directly related to the starting number of fetuses but that in the majority of instances, healthy children can be achieved.

Effects of quisqualic acid analogs on metabotropic glutamate receptors coupled to phosphoinositide hydrolysis in rat hippocampus.

L-Glutamic acid (L-Glu) and L-aspartic acid (L-Asp) activate several receptor subtypes, including metabotropic Glu receptors coupled to phosphoinositide (PI) hydrolysis. Quisqualic acid (Quis) is the most potent agonist of these receptors. There is evidence that activation of these receptors may cause a long lasting sensitization of neurons to depolarization, a phenomenon called the Quis effect. The purpose of the current studies was to use Quis analogs and the recently identified metabotropic receptor antagonist, (+)-alpha-methyl-4-carboxy-phenylglycine((+)-MCPG), to define the structural properties required for interaction with the metabotropic receptors coupled to PI hydrolysis and to determine if the Quis effect is mediated by these receptors. The effects of Quis analogs on PI hydrolysis were studied in the absence or presence of the metabotropic receptor-specific agonist 1SR,3RS-1-amino-1,3-cyclopentanedicarboxylic acid (1SR,3RS-ACPD) in neonatal rat hippocampus. Some of the compounds that induce the Quis effect also stimulate PI hydrolysis, including Quis itself and 9 (homoquisqualic acid). Not all of the Quis analogs that stimulate PI hydrolysis, however, induce the Quis effect, including 7A (EC50 = 750 +/- 150 microM) and (RS)-4-bromohomoibotenic acid (BrHI) (EC50 = 130 +/- 40 microM). Although (+)-MCPG blocked PI hydrolysis stimulated by Quis (IC50 = 370 +/- 70 microM), it had no effect on the induction of the Quis effect. Other Quis analogs did not stimulate PI hydrolysis but rather blocked the effects of 1SR,3RS-ACPD. The IC50 values were 240 +/- 70 microM for 2, 250 +/- 90 microM for 3, and 640 +/- 200 microM for 4. Data for inhibition by 2 and 3 were consistent with non-competitive mechanisms of action. These studies provide new information about the structural features of Quis required for interaction with metabotropic receptors coupled to PI hydrolysis and provide evidence that the Quis effect is not mediated by (+)-MCPG sensitive subtypes of these receptors.

The effects of L-glutamate and trans-(+-)-1-amino-1,3-cyclopentanedicarboxylate on phosphoinositide hydrolysis can be pharmacologically differentiated.

The excitatory amino acid analogues L-glutamate (L-Glu), L-aspartate (L-Asp), D-Asp, and trans-(+-)-1-amino-1,3-cyclopentanedicarboxylate (trans-ACPD) stimulate the hydrolysis of phosphoinositides (PI). In the present studies, the effects of noncompetitive and competitive inhibitors on PI hydrolysis stimulated by excitatory amino acid analogues were examined. When agonist and inhibitor were added simultaneously to hippocampal tissue, the noncompetitive inhibitor L-2-amino-3-phosphonopropionate (L-AP3) did not block the effects of L-Glu, L-Asp, or D-Asp at concentrations that block the effects of trans-ACPD by more than 80%. When tissue was preincubated with L-AP3, the effects of L-Glu, L-Asp, or D-Asp were blocked (IC50 values between 65 and 210 microM). Unlike L-AP3, L-aspartate-beta-hydroxamate (L-A beta HA) inhibited PI hydrolysis stimulated by trans-ACPD, L-Glu, L-Asp, or D-Asp when agonist and inhibitor were added simultaneously in hippocampus; its effects were not time-dependent. In cerebellum, both L-AP3 and L-A beta HA had agonist activity. Inhibition by the recently identified competitive inhibitor (+)-alpha-methyl-4-carboxyphenylglycine [(+)-MCPG] of PI hydrolysis was also examined. (+)-MCPG blocked PI hydrolysis stimulated by trans-ACPD, L-Asp, or D-Asp in both hippocampus and cerebellum (IC50 values between 220 and 1,700 microM). The effects of (+)-MCPG were consistent with a competitive mechanism of action. (+)-MCPG (up to 3 mM) blocked PI hydrolysis stimulated by L-Glu by less than 25% in both hippocampus and cerebellum.

Multiple subtypes of excitatory amino acid receptors coupled to the hydrolysis of phosphoinositides in rat brain.

The excitatory amino acid (EAA) analogues quisqualate, ibotenate, and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylate (trans-ACPD) activate the metabotropic EAA receptors that are coupled to the hydrolysis of phosphoinositides (PI). Previous studies of hippocampal cross sections demonstrated that PI hydrolysis stimulated by these agonists can be inhibited by either L-aspartate-beta-hydroxamate (L-A beta HA) or DL-2-amino-3-phosphonopropionate (DL-AP3). The goal of the present studies was to determine if all metabotropic EAA receptors are sensitive to L-A beta HA and DL-AP3. Two approaches were used. In the first, using cerebellar cross sections, the effects of these agonists and inhibitors were examined. The EC50 values (the concentrations required to evoke half-maximal stimulation) of quisqualate, ibotenate, and trans-ACPD in cerebellum were similar to the EC50 values that we observed previously in hippocampus, but neither L-A beta HA nor DL-AP3 blocked PI hydrolysis. The EC50 values were 0.65 +/- 0.17 microM for quisqualate, 12.8 +/- 2.5 microM for ibotenate, and 18.1 +/- 3.1 microM for trans-ACPD. All data were best fit to theoretical curves that had Hill slopes of 1. In the second approach, another EAA analogue, D-aspartate, was identified as an agonist that stimulates PI hydrolysis. The EC50 for PI hydrolysis stimulated by D-aspartate was 470 +/- 90 microM in hippocampus. Neither L-A beta HA nor DL-AP3 blocked PI hydrolysis stimulated by D-aspartate in hippocampus.(ABSTRACT TRUNCATED AT 250 WORDS)

Multiple mechanisms for inhibition of excitatory amino acid receptors coupled to phosphoinositide hydrolysis.

Excitatory amino acid (EAA) analogues activate receptors that are coupled to the increased hydrolysis of phosphoinositides (PIs). In these studies, hippocampal slices were prepared from neonatal rats (6-11 days old) to characterize the effects of EAA analogues on these receptors. The concentrations of ibotenate and trans-(+/-)-1-amino-1,3-cyclopentanedicarboxylate (trans-ACPD) required to evoke half-maximal stimulation (EC50 values) were 28 and 51 microM, respectively. Although the data for stimulation of PI hydrolysis by ibotenate and trans-ACPD were best fit to theoretical curves that had Hill slopes of 1, data for stimulation of PI hydrolysis by quisqualate were best fit to two sites. The EC50 values were 0.43 and 44 microM. The high-affinity sites were 70% of the total. A number of EAA analogues were tested for inhibition of PI metabolism. One of these, L-aspartate-beta-hydroxamate (L-A beta HA), was identified as a novel inhibitor of this response. L-A beta HA was equipotent as an inhibitor of PI metabolism stimulated by ibotenate, quisqualate, and trans-ACPD. The data for this inhibition were best fit to two sites. Between 32 and 48% of the total sites had high affinity with IC50 values in the range of 1.2-6.3 microM. The low-affinity sites had IC50 values between 610 and 2,700 microM. DL-2-Amino-3-phosphonopropionate (DL-AP3) was also equipotent as an inhibitor of PI hydrolysis stimulated by ibotenate, quisqualate, and trans-ACPD (IC50 values were 480-850 microM). In contrast to the data for L-A beta HA, the data for DL-AP3 were best fit to a single site. Both of these inhibitors reduced the maximal response caused by the agonists, consistent with noncompetitive mechanisms of action. Several experiments were designed to examine potential mechanisms for these noncompetitive effects. These studies suggest that either L-A beta HA and DL-AP3 bind to a site on the receptor and irreversibly block activation of the receptor, or that these inhibitors act via a distinct site that specifically regulates EAA receptors coupled to PI hydrolysis.

The embolization of bone wax from sternotomy incisions.

We discuss our study on the effects of discontinuation of the usage of bone wax as a hemostatic agent in sternotomy incisions. In 1976, we abandoned use of bone wax because it was suspected of causing several cases of Mycobacterium fortuitum sternal osteomyelitis. In a retrospective study involving 400 patients, we found that this step did not increase postoperative bleeding as measured by drainage from the chest tube and by the need to return patients to the operating room because of bleeding. It also was observed that there was an appreciable simultaneous drop in pulmonary complications. To test our theory that the wax pressed into the bone marrow can embolize to the lung, radioactively tagged bone wax was pressed into the cut sternum in animal models, and a search was made for radioactive deposits in the peripheral lung tissue. Shortly after the application of the wax, there was evidence of large radioactive deposits in the lungs. It is probable that this embolization occurs also under clinical conditions and may play a role in pulmonary complications following open-heart operations.

Multiple lymphoid polyposis and familial polyposis of the colon: a genetic relationship.

A case of multiple lymphoid polyposis of the colon and terminal ileum occurring in a family of familial polyposis is presented. Only one other such case has been reported. Other cases where an association between the conditions was mentioned are reviewed. There is a genetic factor in the etiology of the condition, and a definite link with familial polyposis of the colon is found to exist. Differentiation of the conditions on clinical grounds could be very difficult.

Leiomyosarcoma of the rectum: report of a case.

A case report of a leiomyosarcoma of the rectum recurrent after six years is presented. The diagnostic criteria for determining malignancy are reviewed. The diagnosis of a benign lesion must be supported by the absence of mitoses; mitotic figures are considered proof of malignancy. Abdominoperineal resection is the procedure of choice for leiomyosarcoma of the rectum.