Siriporn Tiamkao

Analgesic, antipyretic, anti-inflammatory and toxic effects of andrographolide derivatives in experimental animals

Andrographolide (1) and 14-deoxy-11,12-didehydroandrographolide (2) are active constituents of Andrographis paniculata (Burm. f.), family Acanthaceae. A. paniculata extracts are reported to have antiviral, antipyretic, immunostimulant and anticancer activities. In this study, 1 and its 14-acetyl- (4) and 3,19-isopropylidenyl- (3) derivatives, as well as 2 and its 3,19-dipalmitoyl-derivative (5), were intraperitoneally tested for their analgesic, antipyretic, anti-inflammatory and acute toxicity effects in animal models. Analgesic effects were tested in mice using hot plate and writhing tests to distinguish the central and peripheral effects, respectively. The results showed that, at 4 mg/kg, all tested substances have significant analgesic effects, and the highest potency was seen with 3, 4 and 5. Increasing the dose of 3 and 5 to 8 mg/kg did not increase the analgesic effect. In the writhing test, 3 and 5, but not 1, showed significant results. In a baker’s yeast-induced fever model, 3 and 5 significantly reduced rats’ rectal temperature (p < 0.05). In a carrageenan-induced inflammation model, 1, 3 and 5 significantly reduced rats’ paw volume. Doses of 3 and 5 up to 100 mg/kg did not show any serious toxic effects. From this study, 3 and 5 are the most interesting derivatives, showing much greater potency than their parent compounds. These could be further developed as analgesic, antipyretic and anti-inflammatory agents, without any serious toxicity.

Seizures in nonketotic hyperglycaemia

Dear Sir, The association between focal seizures and hyperglycaemia was first reported in 19651. The disorder is characterized by hyperglycaemia, no ketoacidosis, full consciousness (or minimal depression of sensorium) and focal seizures. We report 21 patients, who presented with seizures and nonketotic hyperglycaemia (NKH). This is a large case series. The aim of this report is to study clinical and laboratory characteristics of seizures in NKH. A retrospective study was done in a teaching hospital. Inclusion criteria were (1) hyperglycaemia (plasma glucose more than 11.11 mmol/l), (2) seizures, and (3) seizure stopping after control of the hyperglycaemia. Patients with seizures explained by causes other than hyperglycaemia were excluded from the study. Of the 21 patients, 9 were men (43%) and 12 were women (57%) who developed seizures and NKH (23 events). One patient had three events. Six patients had a previous history of diabetes mellitus (DM). Fifteen patients had no previous history of DM. They presented with seizures and NKH, and were diagnosed with DM in the index admission. Of the 21 patients, 3 were DM type 1 (14.3%) and 18 were DM type 2 (85.7%). The average duration of seizures before admission was 5 days (range 1–14 days). The average duration of seizures in each episode was 3 minutes (range 1–5 minutes). Total of 22 events (95.65%) were partial seizures, and 1 event was an unclassified tonic-clonic seizure. Among the 22 partial onset seizures, 14 were epilepsia partialis continua, 6 became secondarily generalized tonic-clonic seizures, and 2 were complex partial seizures (CPS). In all 20 events of partial seizures without CPS, seizures started in one extremity or the face: 14 started in an upper extremity, 5 in the face, and 1 in a lower extremity. Partial seizures started slightly more often on the left side (12 cases) than the right side (8 cases). At the time of the seizure, the average plasma glucose value was 32.61 mmol/l (range 16.11–61.33 mmol/l). The average calculated serum osmolarity was 302 mOsm/l (range 288–323 mOsm/l). When the seizures stopped, the average plasma glucose value was 11.3 mmol/l (range 4.11–21.67 mmol/l). Neurologic manifestations, particularly seizures, may provide the first clinical clue to the presence of NKH. Focal motor seizures are the most common type2. However, seizures in NKH are still not fully appreciated by physician and patient. Our patients took an average of 5 days before they got the correct diagnosis and treatment. Knowledge of this condition may shorten the time to diagnosis and decrease the discomfort of patients. Every patient who presents with seizures especially focal seizures should have an immediate determination of plasma glucose levels. Seizures in NKH happen equally in both sexes. In 15 of the 21 patients (71.4%), seizures were the earliest manifestation of DM and led to discovery of DM in these patients. Most of patients had type 2 DM. Although 3 of the 21 patients had type 1 DM, none of them had ketoacidosis during the seizure. This finding may be explained by the fact that ketosis has an anticonvulsant action, due to intracellular acidosis increasing glutamic acid and decarboxylase activity leading to increased levels of GABA3. Epilepsia partialis continua was the most common type (60.87%) of seizure in our series, as previously reported2. Interestingly, we found 2 (8.7%) of our patients presented with CPS. Our finding confirmed previous reports of CPS induced by hyperglycaemia4. The mechanism of seizures in NKH is still debated. The possible mechanisms are hyperglycaemia or hyperosmolarity, a low level of gamma aminobutyric acid (GABA), and focal ischaemia. Each mechanism, considered alone, is unsatisfactory. Mean plasma glucose value in our report was 32.61 (16.11–61.33 mmol/l), and osmolarity ranged from normal to a moderate value (288–323 mOsm/l). Almost all of our seizures in NKH patients have plasma osmolarity less than the classical diagnostic level (320 mOsm/l) of NKH. In addition, mean plasma glucose ranged from normal to hyperglycaemia (4.11–21.67 mmol/l) when seizures stopped. So, the explanation of hyperglycaemia or hyperosmolarity alone is unsatisfactory. In addition, the Krebs cycle in NKH is inhibited, GABA metabolism is increased and the levels may be decreased, thus lowering the threshold for seizure activtiy3, 5.

Biphasic effects of Morus alba leaves green tea extract on mice in chronic forced swimming model

In this study, the effects of an aqueous extract of Morus alba leaves green tea (ME) on mouse behaviors (depression, anxiety, climbing activity and thermal response), muscle coordination and muscle strength were studied. Male IRC mice received a single intraperitoneal injection of either the ME, desipramine or diazepam. Thirty minutes after injection, the mice were tested in all experimental models. A significant antidepressant‐like effect could be detected in the animals receiving either 100 or 200 mg/kg ME. The effect of 200 mg/kg ME in decreasing the immobility time was comparable to 10 mg/kg desipramine. With higher dose (1000 mg/kg), a significant increase in immobility time could be observed. In the elevated plus maze, no increase in time in the open arm could be observed in mice treated with ME at either 100 or 200 mg/kg. However, high doses of ME (500 or 1000 mg/kg) decreased both time in the open arm and the number of entries in the maze. No change in thermal response could be seen in mice treated with ME at doses up to 500 mg/kg, however, at 1000 mg/kg, the response time to heat was increased significantly. The ME at either 500 or 1000 mg/kg also decreased muscle coordination, strength and climbing activity significantly when compared with the control. This study suggests that ME possesses an antidepressant‐ without an anxiolytic‐like effect, however, at high doses, the extract might show the sedative effect and alter other functions such as muscle strength, animal activity in the maze and pain response. Copyright

Synthesis and evaluation of N1-substituted-3-propyl-1,4-benzodiazepine-2-ones as cholecystokinin (CCK2) receptor ligands

A novel synthetic approach towards N1‐alkylated 3‐propyl‐1,4‐benzodiazepineswas developed in five synthetic steps from 2‐amino‐4‐chlorobenzophenone, in which the N‐oxide 4 served as a key intermediate. The structure‐activity relationship optimization of this 3‐propyl‐1,4‐benzodiazepine template was carried out on the N1‐position by selective alkylation reactions and resulted in a ligand with an improved affinity on the cholecystokinin (CCK2) receptor. The N‐allyl‐3‐propyl‐benzodiazepine 6d displayed an affinity towards the CCK2 (CCK‐B) receptor of 170 nM in a radiolabelled receptor‐binding assay. The anxiolytic activity of this allyl‐3‐propyl‐1,4‐benzodiazepine 6d was subsequently determined in in‐vivo psychotropic assays. This novel lig and had ED50 values of 4.7 and 5.2 mg kg−1 in the black and white box test and the x‐maze, respectively, and no significant sedation/muscle relaxation was observed.

Therapeutic drug monitoring in epilepsy clinic: a multi-disciplinary approach.

Epilepsy is a common public health problem and needs multi-disciplinary treatment. Therapeutic drug monitoring (TDM) is one of step of the multi-disciplinary treatment in epilepsy at Epilepsy clinic, Khon Kaen University (Thailand). The TDM service has been established since 2008. Here, we aimed to study the roles of TDM order and epilepsy control. This is a prospective descriptive study in which data collection was done from January 1 to December 31, 2010, the period when pharmacists took part in assessing the appropriateness in measurement and interpretation of TDM in order to provide suggestions for physicians. The 112 patients under study had an average age of 38.21±15.36 years; 254 samples were collected for therapeutic drug monitoring; phenytoin was submitted mostly for drug monitoring at 46.46%; 44.49% of submissions for drug level monitoring were made owing to a suspected sub-therapeutic level. Associations were found between reasons of sending samples for drug level monitoring and the measured drug levels, i.e., 66.67% of drug levels found was so low that they were undetectable in sample for patients’ compliance investigation and 38.94% of the drug levels were found to be sub-therapeutic as for the case where submission of samples was done because of suspected sub-therapeutic level, 40% of the cases were found to be in toxicity range in the cases with suspected over-therapeutic levels and monitoring levels, 58.25% were found to be within the therapeutic range. Pharmacists used the interpreted results in patients’ care by recommending physicians to monitor therapeutic drug closely, to adjust the dosage of drugs, and to recommend checking patients’ compliance in their use of drugs at 56.5, 38.9, and 4.3%, respectively. Physicians’ responses were found to be absolute follow, partial follow and not follow at 77.95, 11.03, and 7.48%, respectively. In conclusion, associations were found between reasons of TDM order and measured drug level. Therapeutic drug monitoring services at the Epilepsy Clinic was useful in supporting clinical information queries. Pharmacists could make use of interpreted drug level information by recommending physicians to monitor drug levels and adjust individual dosage regimen accordingly. It should be noted that physicians accepted pharmacists’ recommendation, denoting multi-disciplinary care team that would lead to greater efficiency.

Age Predicts Functional Outcome in Acute Stroke Patients with rt-PA Treatment

The standard treatment for acute ischemic stroke is thrombolytic therapy. There is limited data on prognostic factors of acute stroke with thrombolytic therapy particularly in Asian population. Acute ischemic stroke patients who were treated with thrombolytic therapy at Srinagarind Hospital between May 2008 and July 2010 were included. Factors associated with Barthel index more than 80 were studied by multiple logistic regression analysis. There were 75 patients included in the study. The mean NIHSS scores before treatment and at 3 months were 9.16 ± 4.82 and 3.83 ± 4.00, respectively, and median Barthel index at 3 months was 86. Only significant predictor for having Barthel index more than 80 points at 3 months was age (adjusted odds ratio 0.929, 95% confidence interval 0.874, 0.988). Four patients developed intracranial hemorrhage after the treatment (5%), and two died (2.6%). In conclusion, age predicts Barthel index in acute stroke patients with rt-PA treatment.

Predictive risk factors of seizure-related injury in persons with epilepsy

OBJECTIVE The clinical risk factors for seizure-related injuries (SRI) in adult persons with epilepsy (PWE) were studied and analyzed to develop a predictive model. METHODS We enrolled 300 consecutive cases from three epilepsy clinics in Northeast, Thailand. Subjects were eligible if reported to have at least one seizure attack during the past 12 months. Face-to-face questionnaire was used to evaluate SRI, baseline characteristics and other seizure-related variables. RESULTS There were 247 and 91 PWE who met a criterion and had SRI, respectively. By multivariate logistic regression method, GTC seizure type, having history of seizure attacks at least 12 times/year, and daytime seizure were significant risk factors of having SRI with odds ratio of 2.376, 2.460, and 3.562, respectively. We developed the predictive model for having SRI in PWE and it gave 90.3% sensitivity and 46.7% specificity on the occurrence of SRI. The estimated probability of SRI can be found online at http://sribykku.webs.com/. CONCLUSIONS The significant predictive factors for SRI in PWE were the occurrence of GTCs, seizures at least 12 times/year or daytime seizures. Clinicians or PWE can easily evaluate the risk of having SRI in individuals by the online predictive model.

Adjunctive enteral phenobarbital for adult status epilepticus: a brief report

Background Status epilepticus (SE) is a neurological emergency condition. Intravenous phenobarbital (PB) is recommended for refractory SE treatment. However, intravenous PB is unavailable in Thailand. Enteral PB has been shown to be effective in SE children. Methods In adult SE patients, the efficacy of enteral PB as an adjunctive therapy has been reported. This is a case series of adult SE patients who were treated with enteral PB at Khon Kaen University Hospital, Thailand. The clinical features and clinical outcomes are reported. Results There were six patients; five patients had convulsive SE, and one patient had nonconvulsive SE. All patients received PB enterally, at dosages of 900 mg initially and repeated doses of 900 mg as needed. This was gradually reduced to a maintenance dosage of 180 mg/day. Three out of six patients were completely controlled, whereas the other three patients were partially controlled. Three out of six patients were seizure-free after the initial loading dose of PB. No adverse effects were found in this study. Conclusion In adult patients, enteral PB may be effective as an add-on for refractory SE therapy.

Bioequivalence study of two meloxicam tablet formulations after single-dose administration in healthy Thai male volunteers.

OBJECTIVES To compare the bioavailability of two meloxicam tablet formulations (MEL-OD, Zydus Cadila Healthcare Limited, India, as a test formulation and Mobic, Boehringer Ingelheim International GmbH, Germany, as a reference formulation) in healthy Thai male volunteers under fasting condition. MATERIALS AND METHODS A randomized, 2-treatment, 2-period, 2-sequence, single dose, crossover with a washout period of 2 weeks, was conducted in 26 healthy Thai male volunteers. Blood samples were collected 0, 1, 2, 3, 3.5, 4, 4.5, 5, 5.5, 6, 7, 8, 10, 12, 24, 36, 48, 72 and 96 h post dose. Plasma concentrations of meloxicam were determined using a validated HPLC method. The pharmacokinetic parameters of meloxicam were determined using a non-compartmental model. RESULTS The mean Cmax was 1,027.32 +/- 251.91 and 1,151.89 +/- 282.58 ng/ml while the mean AUC0-t was 34,024.31 +/- 11,811.68 and 35,137.66 +/- 11,970.47 ng x h/ml for the test and reference formulation, respectively. In addition, the mean AUC0-infinity for test formulation was 37,241.44 +/- 14,888.85 ng x h/ml and for the reference formulation was 39,541.04 +/- 16,624.64 ng x h/ml. The median tmax for the test and reference formulation was 4.50 (range 2.00 - 12.00) and 4.50 (range 3.00 - 10.00), respectively. The geometric means (90% confidence intervals) of the ratio for the log-transformed pharmacokinetic parameters, Cmax, AUC0-t and AUC0-inf were 0.8919 (82.58 - 96.32%), 0.9697 (89.46 - 105.10%) and 0.9525 (87.68 - 103.47%), respectively. CONCLUSIONS It can be concluded that two meloxicam tablet formulations are bioequivalent both in term of rate and extent of absorption after single-dose administration under fasting condition.

Patient adherence to generic gabapentin: A pragmatic study

Generic medication is cheaper than the original brand. Patient adherence to generic gabapentin has never been studied. The study was a retrospective longitudinal study. All consecutive adult patients of ages >15 years who received gabapentin treatment at Srinagarind Hospital were included. The study period was from August 2011 to March 2013. Initially, all patients received generic gabapentin (Siam Pharmaceutical, Thailand). Physicians could switch to original gabapentin (Neurontin®, Pfizer, USA) if the patients did not improve after generic gabapentin treatment. The rate of original gabapentin switch treatment was calculated. Clinical features of all patients who required original gabapentin were also reviewed. The generic gabapentin was prescribed for 5195 patients during the study period. Of those, 310 patients (6.0%) required switch therapy to original gabapentin. The most common indication of gabapentin in the patients who had the need to switch therapy was neuropathic pain in 266 patients (85.8%). Spondylosis was the most common diagnosis in 229 patients (73.8%) The average generic gabapentin use before original gabapentin therapy was 107 days (SD 94). The reason to switch therapy to original gabapentin was recorded in 22 patients (7.1%) due to ineffective treatment. In conclusion, generic gabapentin therapy is effective as a pain controller in neuropathic pain with adherence rate of 94.0%. Generic gabapentin therapy may reduce cost and budget from the original gabapentin.