Ubrogepant to treat migraine.

Migraine is the primary headache disorder affecting a significant population worldwide. Ubrogepant is an orally bioavailable calcitonin gene-related peptide (CGRP) receptor antagonist (gepant) approved by the U.S. Food and Drug Administration (FDA) for the acute treatment of migraine headaches with or without aura in adults. Ubrogepant is the first oral CGRP receptor antagonist approved for the acute treatment of migraine. CGRP is an important key mediator of migraine pain; CGRP levels have been shown to be significantly higher during a migraine attack. Two pivotal phase III clinical trials (ACHIEVE I and ACHIEVE II) demonstrated effectiveness and safety of ubrogepant in acute migraine attacks. Ubrogepant can be administered as 50- and 100-mg tablets, with a maximum dose of 200 mg within 48 h. Besides minimizing pain, the drug is equally effective in alleviating migraine-associated symptoms such as nausea, photophobia and sound sensitivity. Unlike other gepants, ubrogepant is free from hepatotoxicity at the therapeutic doses. In certain cases (1 in 5), a full relief of pain was achieved with a single dose of the drug. The molecule is not effective as a preventive migraine therapy. The present review discusses the background, preclinical and clinical pharmacology, indication and safety of ubrogepant for the treatment of migraine attacks.

Cenobamate for the treatment of focal epilepsy.

Focal-onset or partial seizures are localized to a specific brain area or areas of the cerebral hemisphere. Cenobamate (CNB, Xcopri, YKP-3089; SK Life Science) is a recent U.S. Food and Drug Administration (FDA)-approved drug for the treatment of focal-onset seizures in the adult population. CNB has demonstrated broad-spectrum efficacy in alternative preclinical models of epilepsy. The molecule exerts an antiseizure effect due to its dual mechanism of action: besides inhibiting the voltage-gated persistent component of the sodium currents, CNB is additionally an allosteric GABA(A) channel modulator in a non-benzodiazepine fashion. The superior clinical effect of this molecule over placebo in reducing seizure frequency may be observed after 2 weeks following a starting oral dose of 50 mg/day. The drug can be titrated up to a maximum daily maintenance dose of 400 mg/day. CNB has mild to moderate side effects. During initial development, a critical drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome was noticed in 3 patients. However, the DRESS effect was not observed in the large C021 safety study involving 1,347 patients, suggesting a maximum potential risk of no more than 0.3%. The present monograph describes the background, preclinical and clinical pharmacology, indication and safety of CNB for the treatment of partial/focal seizures.

Sports interest mediating exercise and compulsive internet use among undergraduates.

With the massive growth in Internet technologies, people have become wary of excessive Internet usage, known as compulsive Internet usage or Internet addiction. This study looks into how exercise is related to compulsive Internet usage. Previous research showed varying results regarding the relationship between sports habit and Internet usage; this project clarifies the relationship by investigating mediating variables in terms of interest in different aspects of sports, such as physical education, mastering sport skills, sports participation, and watching sports. Two survey studies were conducted. The participants were 232 male and 107 female Taiwanese undergraduate students in the first survey, totaling 339 students. The second survey had 233 males, 98 female students, and 2 who did not disclose their gender, with a final total of 333. The results reveal that interest in physical education (IPE) mediates sports habit and compulsive Internet usage. As long as the student had a habit of doing sports that increased IPE, this would in turn decrease compulsive Internet use. The importance of igniting students' IPE is discussed.

Vortioxetine for the treatment of major depression.

Vortioxetine (Lu-AA-21004; 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine hydrobromide) is a novel orally active molecule that is being investigated by Lundbeck and Takeda for the treatment of major depression and generalized anxiety disorders. Vortioxetine has a unique "multi-modal" mechanism of action. It inhibits the activity of serotonin transporters and is an agonist of serotonin 5-HT1A receptor, partial agonist of 5-HT1B and antagonist of 5-HT3A, 5-HT7 and 5-HT1D receptors. Vortioxetine has been effective in various animal models of depression and anxiety and clinical studies have shown the antidepressant and antianxiety properties of vortioxetine in a dose range of 5-20 mg/day. Vortioxetine reverses cognitive decline in patients with depression making it a unique molecule. The molecule lacks any serious side effects and drug-drug interactions. However, dose adjustments are required if vortioxetine is co-administered with rifampicin or bupropion. The molecule is under review by various regulatory agencies around the world for the treatment of major depression.

Pulmonary embolism in cancer patients.

AIMS AND OBJECTIVES: Pulmonary embolism (PE) is rare in the Indian population and is under-reported in patients with malignancy. We studied the clinical profile and outcome of patients with PE and cancer in the Indian population. MATERIALS AND METHODS: Data of cancer patients with PE, admitted in a tertiary cancer centre, was analyzed. The prevalence of PE was calculated as the number of patients with PE per 10,000 hospital admissions. The demographic data, details of cancer, co-morbidities, details of PE, and treatment given for PE and their outcomes were recorded and analyzed. RESULTS: There were 56,425 hospital admissions in the study period. The prevalence of PE was 6.4 per 10,000 hospital admissions .Thirty-six cancer patients were diagnosed to have PE. In females, gynecological malignancies (36.84%) and in males gastrointestinal, head and neck cancers, and hematological malignancies were the most common sites (17.7% each). PE was associated with DVT in 41.7%. Dyspnea was the most common presenting symptom. Five patients (13.88%) were asymptomatic and were incidentally detected to have PE . The most common echocardiographic finding was right ventricular dysfunction (55.55%). Mortality among the treated patients was 22% (7 / 31) and in untreated patients it was 80% (4 / 5). The factors that had an impact on a three-month survival were, the presence of massive PE (P = 0.019) and the presence of RV dysfunction at presentation (P = 0.005). CONCLUSION: The prevalence of PE and mortality due to PE is high in cancer patients. Risk stratification for venous thromboembolism (VTE) should be done in all cancer patients and thromboprophylaxis should be optimally used.

An overview of curcumin in neurological disorders.

Curcumin, the principal curcuminoid found in spice turmeric, has recently been studied for its active role in the treatment of various central nervous system disorders. Curcumin demonstrates neuroprotective action in Alzheimer's disease, tardive dyskinesia, major depression, epilepsy, and other related neurodegenerative and neuropsychiatric disorders. The mechanism of its neuroprotective action is not completely understood. However, it has been hypothesized to act majorly through its anti-inflammatory and antioxidant properties. Also, it is a potent inhibitor of reactive astrocyte expression and thus prevents cell death. Curcumin also modulates various neurotransmitter levels in the brain. The present review attempts to discuss some of the potential protective role of curcumin in animal models of major depression, tardive dyskinesia and diabetic neuropathy. These studies call for well planned clinical studies on curcumin for its potential use in neurological disorders.

Effect of various antiepileptic drugs in a pentylenetetrazol-induced seizure model in mice.

The present study was undertaken to compare the anticonvulsant effect of various antiepileptic drugs on the intravenous pentylenetetrazol (PTZ)-induced seizure threshold in mice. Minimal doses of PTZ needed to induce different phases (myoclonic jerks, generalized clonus and tonic extensor) of convulsions were recorded as an index of seizure threshold. Furthermore, TID50 (the dose of an anticonvulsant drug required to increase the PTZ seizure threshold for tonic extensor by 50%) was calculated for all drugs, and from these values the potency ratio was determined. Pentobarbital (10-40 mg/kg i.p.), phenobarbital (5-20 mg/kg i.p.), phenytoin (20-40 mg/kg i.p.), carbamazepine (5-20 mg/kg i.p.), diazepam (0.5-2 mg/kg i.p.), chlordiazepoxide (1-4 mg/kg i.p.), triazolam (0.02-0.08 mg/kg i.p.), clonazepam (0.03125-0.25 mg/kg i.p.), GABA (25-100 mg/kg i.p.), ethanol (1000-4000 mg/kg of 10% v/v p.o.), ashwagandha (50-200 mg/kg p.o.), tiagabine (20 and 40 mg/kg i.p.), gabapentin (50-200 mg/kg i.p.), pregabalin (10-40 mg/kg i.p.), progesterone (20-80 mg/kg s.c.), adenosine (25-200 mg/kg i.p.) and rofecoxib (1-4 mg/kg i.p.) exhibited dose-dependent anticonvulsant effects. The TID50 of triazolam was found to be the lowest among all the drugs tested, indicating higher potency. The relative potency of standard drugs to increase the PTZ seizure threshold for tonic extensor was found to be: triazolam > clonazepam > diazepam > rofecoxib > chlordiazepoxide > phenobarbital > carbamazepine > pentobarbital > pregabalin > phenytoin > progesterone > tiagabine > GABA > adenosine > gabapentin > ashwagandha > ethanol. The results of the present study indicate that the intravenous PTZ seizure threshold may be useful for assessing the anticonvulsant effect of drugs effective against different stages of convulsions.

Gamma probe radioguided parathyroid forearm surgery in recurrent hyperparathyroidism.

A case is described of a successful radioguided forearm graft parathyroidectomy. This is the first report of both pre-operative diagnostic and successful intra-operative localisation during a single procedure, of autologous transplanted parathyroid tissue.

Rofecoxib potentiates the anticonvulsant effect of topiramate.

The present study examines the effect of rofecoxib in combination with topiramate (a newer antiepileptic) against PTZ (80 mg/kg, i. p.)-induced chemoconvulsions in mice. Pretreatment with rofecoxib (1.0 and 5.0 mg/kg., i. p.) or topiramate (50 and 100 mg/kg., i. p.) dose dependently protected the animals against PTZ-induced convulsions. However, the lower dose of neither rofecoxib (0.5 mg/kg., i. p.) nor topiramate (25 mg/kg., i. p.) modified the latency of any of the phase of PTZ-induced convulsions. When a subeffective doses of rofecoxib (0.5 mg/kg, i. p.) was coadministered with a subprotective dose of topiramate (25 mg/kg, i. p.), there was no increase in onset latency of myoclonic jerks but an increase in the latency for clonus and extensor phase were observed. Rofecoxib may be used as an adjunct therapy with topiramate in the treatment of epilepsy.

Involvement of sigma (sigma1) receptors in modulating the anti-depressant effect of neurosteroids (dehydroepiandrosterone or pregnenolone) in mouse tail-suspension test.

The present study investigated the effects of neurosteroids dehydroepiandrosterone sulfate (DHEAS) or pregnenolone sulfate (PS) on the tail-suspension test (TST) of depression in mice, and also the possible involvement of sigma (sigma) receptors. Immobility time in the TST was measured for a total period of 6 min. DHEAS (10 and 40 mg/kg, s.c.) or PS (40 mg/kg, s.c.) significantly reduced the immobility period without accompanying changes in the locomotor activity in mice. The effect on behavioural despair by DHEAS (10 and 40 mg/kg, s.c.) and PS (40 mg/kg, s.c.) was blocked by BD 1047 (1 mg/kg, s.c.), a novel sigma1-receptor antagonist, progesterone (10 mg/kg, s.c.), a sigma-receptor antagonistic neurosteroid or rimcazole (5 mg/kg, s.c.), another sigma1-receptor antagonistic property, respectively. The treatments and their combination did not alter the motor activity in mice. These data suggested a role for the central sigma receptors particularly sigma-1 (sigma1) receptors in the anti-depressant-like effects of neurosteroids.

Ascorbic Acid inhibits development of tolerance and dependence to opiates in mice: possible glutamatergic or dopaminergic modulation.

In a recent study, it has been demonstrated that ascorbic acid possessed antidopaminergic activity and modulate the glutamatergic neurotransmission in mice. With this background, the present study was undertaken to study the effect of ascorbic acid on the development of tolerance and dependence to opiate and its mechanism of action. Male Swiss mice weighing 20-25 g were used in the present study. Mice were made physically dependent on opioid by the chronic administration of morphine (10 mg/kg, twice a day, for 9 days) intraperitoneally. Ascorbic acid, haloperidol (dopamine antagonist) or MK 801 (NMDA receptor antagonist) was administered daily for 9 d before challenging the animals with morphine. The development of tolerance was assessed by noting the tail-flick latency on day 1, 3, 9 and 10. On the 10(th) day after the measurement of tail-flick latency, animals were challenged with naloxone (2 mg/kg., i.p.) and incidence of escape jumps were recorded by placing the animals in 45 cm high plexiglass container. Ascorbic acid (400-1600 mg/kg) dose dependently inhibited development of tolerance and dependence to morphine as noted from tail-flick latency. When given along with MK 801 (0.01 mg/kg., i.p) or haloperidol (0.1 mg/kg i.p.), ascorbic acid (800 mg/kg., i.p.) potentiated the response of MK 801 or haloperidol. In conclusion, it is hypothesized that inhibition of development of tolerance and dependence to morphine by ascorbic acid appears to have two components, namely dopaminergic and glutamatergic.

Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor potentiates the anticonvulsant activity of tiagabine against pentylenetetrazol-induced convulsions in mice.

Numerous studies have implicated prostaglandins as potential modulators in seizure activity. The objective of the present study was to elucidate the effect of rofecoxib (selective COX-2 inhibitor) alone or in combination with newer antiepileptic drug tiagabine (gamma-amino acid reuptake inhibitor) against pentylenetetrazol (PTZ) (80 mg/kg, i.p.)-induced chemoconvulsions in mice. Rofecoxib or tiagabine was administered 45 min prior to the PTZ challenge. In combination study, rofecoxib was administered 10 min before tiagabine and after 35 min the animals were challenged with convulsive dose of PTZ. Mean onset time of jerks, clonus and extensor phases following PTZ challenge was noted. Pretreatment with rofecoxib (1-5.0 mg/kg, i.p.) or tiagabine (1-10 mg/kg, i.p.) dose dependently protected the animals against PTZ-induced convulsions. The mean onset time of jerks, clonus and extensor phase were increased. A subeffective dose of rofecoxib (0.5 mg/kg, i.p.) potentiated the effect of subprotective dose of tiagabine (0.5 mg/kg, i.p.). The results of the present study suggested that the protective effect of rofecoxib, a COX-2 inhibitor against PTZ-induced convulsions may be possibly through the GABAergic modulation. Rofecoxib may have a place as adjuvant therapy with standard antiepileptic drugs such as tiagabine in the treatment of epilepsy.

Novel variations in the signal peptide region of transforming growth factor beta1 gene in patients with hepatitis: a brief report from India.

Genotypic status of the signal peptide region of transforming growth factor beta1 (TGF-beta1) showed a significant difference in C/C-genotype frequency at +29 position (codon 10) between a range of viral hepatitis patients and controls (P = 0.009, OR = 3.15, CI = 1.29-7.678), contributed by those who were infected with hepatitis B virus (HBV) alone or HBV + hepatitis delta virus (HDV) (P = 0.003, OR = 5.0, CI = 1.78-13.97).

Minimal access surgery for hydatid cyst disease: laparoscopic, thoracoscopic, and retroperitoneoscopic approach.

Surgery has remained the mainstay for the treatment of hydatid cyst. The rapid development of laparoscopic techniques has encouraged surgeons to replicate principles of conventional hydatid surgery using a minimally invasive approach. Several reports have confirmed the feasibility of laparoscopic hepatic hydatid surgery. We report the use of a laparoscopic approach for cysts located in the liver, lung, and retroperitoneum. Fifteen patients with hydatid cysts, including one patient with a recurrent cyst, of various organs, including the liver, lung, and retroperitoneum, were operated on laparoscopically. Sixteen hydatid cysts were drained in a total of 15 patients. The mean operative time was 84 +/- 6 minutes (60-125 minutes). The mean duration of the hospital stay was 2.3 days (1-6 days). The mean cyst diameter was 9.2 cm (6.4-13.5 cm). No conversions to open surgery were required. One complication, a trocar-induced bowel perforation, occurred, and there was no mortality. During 3 to 44 months (mean, 27 months) of follow-up, no recurrences developed. Minimal access surgery is a safe, effective, and viable option for the management of selected patients with hydatid cysts in various locations, such as the liver, lung, and retroperitoneum.

General anaesthesia for exodontia in children: experience of a dental teaching hospital in relation to changes in national guidance.

OBJECTIVES: To examine, in relation to changes in national guidance, trends in the provision of general anaesthesia for exodontia in children. DESIGN: Retrospective analysis of hospital records. SETTING: University Dental Hospital, Cardiff, UK. METHODS: Data were drawn from records of services provided in each of four index months during 1989, 1991, 1997 and 1999 (the years immediately preceding/following the Poswillo Report of 1990 and the General Dental Council's revised guidance of 1998). RESULTS: In the first year after publication of the Poswillo report, there was a 19.6% increase in use of 'chair case' general anaesthesia over the four index months. Subsequently, upon the emergence of additional providers, patient flow in 1997 had fallen to 65.8% of that seen at baseline. Following the General Dental Council's revised guidance of 1998, there was a further reduction in the provision of 'chair case' general anaesthesia (to 40.8% of that seen at baseline). CONCLUSIONS: In this unit, throughput of children receiving general anaesthesia for exodontia has fluctuated in periods marked by changing national guidance. However, it is not possible to attribute such fluctuations in patient flow solely to this factor.

A successful PPMC (physician practice management company) acquisition strategy: vision, focus and discipline.

Acquisitions have become increasingly necessary for managed care organizations to create product value and operating synergies. Physician practice management companies (PPMCs) that have successfully acquired and consolidated group practices and IPAs have a clear vision of their mission, focus on their target markets, and adhere to a disciplined methodology of financial evaluation, negotiation, and transition. Growing a PPMC entails risks, but expectations are for continued expansion of these organizations. The vision-focus-discipline method can help buyers adhere to a successful strategy during the acquisition process.

Basal cell carcinoma on the scalp of an Indian patient.

BACKGROUND: Basal cell carcinoma (BCC) is the most common malignancy in whites, but it rarely occurs in dark persons. OBJECTIVE: To report a BCC on the hairy scalp of an Asian Indian female with no obvious risk factors except previous scalp trauma. METHODS: We review the English literature concerning BCC in Indians, and compare this with data for North American blacks and whites; and reports of BCC arising in areas of prior trauma. RESULTS/CONCLUSION: Skin cancer accounts for 1-2% of malignancies in blacks and Indians, compared with one-third of neoplasms in whites. BCC comprises 75% of skin cancers in whites, but squamous cell carcinoma represents 60-65% of skin cancers in blacks and Indians. Although most BCCs occur in sun-exposed areas in whites, blacks, and Indians, a significant percentage also develop in photoprotected areas. Trauma may be a significant risk factor for BCC, either with actinic damage or alone, as in our case.

Treatment of perioperative low cardiac output syndrome.

New approaches to the treatment of perioperative low cardiac output are considered. In particular, use of the phosphodiesterase III inhibitors and their cardiovascular actions are reviewed and contrasted with those of conventional inotropic agents. The increasing recognition of right-sided dysfunction is highlighted, and appropriate therapeutic strategies are considered. The increasing role of pulmonary-specific vasodilators such as inhaled nitric oxide is emphasized. Strategies to preserve right heart perfusion while producing pulmonary vasodilatation are discussed.